WO2024044515A2 - Systèmes et méthodes de traitement des maladies inflammatoires chroniques de l'intestin par neuromodulation - Google Patents

Systèmes et méthodes de traitement des maladies inflammatoires chroniques de l'intestin par neuromodulation Download PDF

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Publication number
WO2024044515A2
WO2024044515A2 PCT/US2023/072507 US2023072507W WO2024044515A2 WO 2024044515 A2 WO2024044515 A2 WO 2024044515A2 US 2023072507 W US2023072507 W US 2023072507W WO 2024044515 A2 WO2024044515 A2 WO 2024044515A2
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WIPO (PCT)
Prior art keywords
patient
electrical signal
signal
microseconds
inflammation
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PCT/US2023/072507
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English (en)
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WO2024044515A3 (fr
Inventor
John Morriss
David Miller
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Boomerang Medical, Inc.
Medtronic, Inc.
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Application filed by Boomerang Medical, Inc., Medtronic, Inc. filed Critical Boomerang Medical, Inc.
Publication of WO2024044515A2 publication Critical patent/WO2024044515A2/fr
Publication of WO2024044515A3 publication Critical patent/WO2024044515A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36062—Spinal stimulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36053—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation

Definitions

  • the present technology is directed toward electrically modulating nervous tissue to treat a patient condition.
  • IBD Inflammatory Bowel Disease
  • Crohn's disease causes intermittent inflammation of the gastrointestinal tract
  • ulcerative colitis causes continuous inflammation of the colon. Both Crohn's disease and ulcerative colitis cause similar patient symptoms, including patient discomfort (e.g., abdominal pain), abnormal gastrointestinal tract function (e.g., diarrhea), and other complications (e.g., fever, weight loss, etc.).
  • IBD is typically treated using pharmaceutical therapies including anti-inflammatory drugs and immune system suppressors. In extreme cases, patients may even undergo surgery to remove inflamed or damaged portions of the colon or other portions of the digestive tract. However, neither pharmaceuticals nor surgery cure IBD, and symptoms often persist or recur during or after treatment. Moreover, in certain patients, pharmaceuticals and surgery have minimal efficacy and/or induce unwanted side effects. Accordingly, a need exists for improved treatments for IBD.
  • Neurological stimulation systems generally have a signal generator that generates electrical pulses, and one or more signal delivery devices such as leads that deliver the electrical pulses to neurological tissue or muscle tissue.
  • the delivered electrical pulses modulate neural activity to treat an underlying patient condition.
  • neurostimulation has been used to treat various disorders such as pain, movement disorders, cardiac disorders, and various other medical conditions.
  • Sacral neuromodulation is a type of neuromodulation in which electrical stimulation is applied to one or more sacral nerves to treat a patient condition.
  • SNM has been used to treat various urological disorders, including urinary retention, urinatory incontinence, and fecal incontinence.
  • Figure 1A is a partially schematic illustration of an implantable sacral neuromodulation system positioned at a patient's sacral region to deliver electrical signals in accordance with some embodiments of the present technology.
  • Figure 1 B illustrates sacral nerve anatomy of a patient, along with a portion of a signal delivery device of the system of Figure 1 A shown as implanted at a representative location in accordance with some embodiments of the present technology.
  • Figure 2A is a partially schematic illustration of an electrical signal generated in accordance with some embodiments of the present technology.
  • Figure 2B is a partially schematic illustration of another electrical signal generated in accordance with some embodiments of the present technology.
  • Figure 3A is a graph depicting results of an animal study examining the use of sacral nerve stimulation to treat IBD in accordance with embodiments of the present technology.
  • Figure 3B is another graph depicting results of the animal study examining the use of sacral nerve stimulation to treat IBD in accordance with embodiments of the present technology.
  • the present technology is directed to treating Inflammatory Bowel Disease (IBD) using neuromodulation.
  • IBD Inflammatory Bowel Disease
  • many of the embodiments described herein include electrically stimulating one or more sacral nerves of a patient to treat the patient's IBD.
  • the electrical signal can be delivered via an implanted signal delivery device positioned proximate one or more of the patient's sacral nerves.
  • the electrical signal can modulate the activity of the sacral nerve(s) and/or other nerves, which may in turn reduce inflammation in the patient by altering an imbalance between the patient's sympathetic nervous system and parasympathetic nervous system and/or modifying a threshold for an inflammatory response in the gastrointestinal system.
  • it is expected that delivering electrical signals to the patient's sacral nerve in accordance with the present technology may induce fewer side effects and/or provide a more effective treatment than current treatment options for IBD.
  • modulate refer generally to electrical signals that have an inhibitory, excitatory, and/or other effect on a target neural population. Accordingly, a sacral nerve “stimulator” can have an inhibitory effect and/or an excitatory effect on certain neural populations.
  • electrical therapy signal As used herein, the terms "electrical therapy signal,” “electrical signal,” “therapy signal,” “signal,” and other associated terms are used interchangeably and generally refer to an electrical signal that can be characterized by one more parameters, such as frequency, pulse width, and/or amplitude.
  • proximate a target neural population refers to the placement of a signal delivery element such that it can deliver electrical stimulation to the target neural population.
  • the target population includes the third sacral spinal nerve
  • proximate the target neural population includes, but is not limited to, the relative lead positions described and shown in Figure 1 B, as well as other positions not expressly described herein.
  • the modulation may in some instances be directed to other neurological structures and/or target neural populations and/or other neurological tissues throughout the body.
  • some embodiments may include modulating the vagus nerve, the splenic nerve, the splanchnic nerve, and/or other peripheral nerves.
  • Some embodiments can have configurations, components, and/or procedures different than those described herein, and other embodiments may eliminate particular components and/or procedures.
  • a person of ordinary skill in the relevant art, therefore, will understand that the present disclosure may include other embodiments with additional elements, and/or may include other embodiments without several of the features shown and described below with reference to Figures 1 A-3B.
  • FIG. 1A schematically illustrates a sacral neuromodulation system 100 (“the system 100") implanted to stimulate a patient's sacral nerves and configured in accordance with embodiments of the present technology.
  • the system 100 includes a signal generator 1 10 and a signal delivery device 120.
  • the signal generator 110 can be implanted and/or implantable subcutaneously within the patient P.
  • the signal generator 110 is implanted subcutaneously at the lower back/upper buttock area of the patient P (e.g., adjacent but posterior to the iliac crest IC and/or iliac fossa IF).
  • the signal delivery device 120 extends from the signal generator 1 10 and can be implanted within the patient P proximate a target neural population.
  • the target neural population includes one or more of the sacral spinal nerves (e.g., the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve and/or the S4 sacral nerve).
  • the signal delivery device 120 can extend through one of the sacral foramen S1 -S4 (the illustrated embodiment depicts the signal delivery device 120 extending through the sacral foramen S1 ) and adjacent one or more sacral spinal nerves when implanted.
  • the signal delivery device 120 can be implanted proximate the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve, and/or the S4 sacral nerve.
  • the signal delivery device 120 can carry features configured to administer therapy to the target neural population.
  • the signal delivery device 120 can include one or more lead(s) or lead bodies 122 extending from the signal generator 110 toward the target neural population (e.g., toward the S3 sacral nerve).
  • the lead 122 can include or carry one or more electrical contacts or electrodes (e.g., ring electrodes, cuff electrodes, and/or other suitable electrical contacts) that deliver electrical signals to the target neural population.
  • the signal generator 1 10 can generate and transmit signals (e.g., electrical signals) to the signal delivery device 120.
  • the signal delivery device 120 can deliver the electrical signals to the target neural population, e.g., to electrically modulate neurons within the target neural population to induce a therapeutic effect in the patient.
  • Representative electrical signals that can be generated by the signal generator 1 10 and delivered to the patient P via the signal delivery device 120 are described in greater detail below with reference to Figures 2A and 2B.
  • the signal generator 110 can include a machine-readable (e.g., computer- readable) medium containing instructions for generating and transmitting electrical signals. Accordingly, generating electrical signals in accordance with the methods described herein can include executing computer-executable instructions contained by, on, or in computer-readable media located within the signal generator 1 10.
  • the signal generator 110 can also include one or more processors for executing the machine- readable instructions, memory unit(s), batteries (rechargeable and/or non- rechargeable), communication devices (e.g., an antenna), and/or other software or hardware-based components.
  • the signal generator 1 10 can include a single housing for storing some or all of the foregoing components, although in other embodiments some or all of the foregoing components can be stored in separate housings.
  • the signal generator 1 10 can be configured to communicate with one or more external controllers.
  • the signal generator 110 can wirelessly communicate with a physician controller (not shown) that is external to the patient P.
  • a physician or other healthcare provider can use the physician controller to program the signal generator 1 10, e.g., to select parameters for the electrical signal to be generated by the signal generator 110.
  • the signal generator 1 10 can also communicate with a patient controller that is external to the patient P.
  • the patient P can use the patient controller to control various aspects of the therapy provided by the signal generator 1 10.
  • the patient may be able to start and stop electrical stimulation therapy using the patient controller, and/or control certain parameters (e.g., amplitude) of the electrical stimulation using the patient controller.
  • the signal generator 1 10 can transmit data to the physician controller and/or the patient controller for user review.
  • the signal generator 110 may periodically (or on demand) transmit data associated with one or more of electrode impedance, battery power, program settings (e.g., current signal parameters), historical program settings (e.g., historical signal parameters), program/parameter changes, usage data (e.g., stimulation start and stop times), or the like.
  • the physician controller and the patient controller can include a dedicated controller device, or be implemented as an application on a smartphone, tablet, etc.
  • the system 100 can be implanted in the patient P to treat IBD or an associated condition, including Crohn's disease or ulcerative colitis.
  • the system 100 can deliver electrical signals to one or more sacral nerves of the patient to electrically stimulate the one or more sacral nerves.
  • the electrical signal can treat, reduce, and/or ameliorate the IBD.
  • the electrical signal may reduce one or more IBD- related symptoms (e.g., diarrhea, abdominal pain, weight loss, etc.), and/or reduce inflammation causing the one or more symptoms.
  • the system 100 can be configured to provide bilateral sacral nerve stimulation to treat the patient's IBD. Additional details of electrical signals and stimulation regimes for treating IBD are described below with reference to Figures 2A and 2B.
  • the patient P prior to receiving the signal generator 110, the patient P undergoes a trial period during which the patient P receives electrical stimulation to determine whether the patient P responds favorable to stimulation therapy.
  • the patient P may use a temporary, external trial stimulator that generates and transmits electrical signals to the target neural population via the signal delivery device 120 or another implanted signal delivery element. If the patient responds favorably during the trial period, the patient may elect to have the signal generator 1 10 implanted to facilitate chronic stimulation therapy.
  • the trial period can be omitted, and the signal generator 1 10 can be implanted without the patient previously receiving stimulation from a temporary external signal generator.
  • FIG. 1 B is an illustration of a sacral plexus SP of a patient, along with a distal portion of the lead 122 shown as implanted at a representative location.
  • the sacral plexus SP includes four sacral spinal nerves: the first sacral nerve S1 , the second sacral nerve S2, the third sacral nerve S3, and the fourth sacral nerve S4.
  • the lead 122 is shown as extending along (e.g., proximate to) the third sacral nerve S3 such that it can electrically stimulate the third sacral nerve S3.
  • the lead 122 can be positioned proximate other sacral spinal nerves, and/or proximate other nerve fibers of the sacral plexus SP, to electrically stimulate other target tissue.
  • the lead 122 can be positioned proximate other neural structures of the sacral plexus SP.
  • Figure 1 B also shows a plurality of electrodes or electrical contacts 124a-d carried by the lead 122, as described previously. Electrical signals generated by the signal generator 1 10 and transmitted through the lead 122 can be delivered to the target neural population via the electrodes 124a-d. Although shown as having four electrodes, the lead 122 can have more or fewer electrodes, such as one, two, three, four, five, six, seven, eight, or more.
  • test stimulation may be administered to a patient during a procedure to implant the signal delivery device 110. This can be done to ensure adequate placement of the lead 122, e.g., to ensure that the electrical signals delivered via the lead 122 are applied to the target neural population.
  • test stimulation is administered at or above a sensory threshold during an implant procedure such that the patient can give intraoperative feedback about the location of the sensation, and thus the location of the lead 122.
  • test stimulation is administered at or above a motor threshold during the implant procedure, and a motor response to the test stimulation is observed to determine the location of the lead 122. In other embodiments, however, placement of the lead 122 can be confirmed using other techniques (e.g., imaging), such that intraoperative test stimulation is not required.
  • FIG 2A is a partially schematic illustration of a representative electrical signal waveform 200 ("the signal 200") generated in accordance with embodiments of the present technology.
  • the signal 200 can be generated by the system 100 (e.g., by the signal generator 110) described above with respect to Figures 1A and 1 B, or by another sacral neuromodulation system. As described throughout this Detailed Description, the signal 200 can be delivered to a patient's sacral region to treat a patient condition such as IBD.
  • the signal 200 includes repeating pulse periods 201 , with each pulse period 201 having a biphasic pulse 202 followed by an interpulse interval 212.
  • Each pulse 202 includes a first pulse phase 203 having a first polarity followed by a second pulse phase 204 having a second polarity that is opposite the first polarity.
  • the first pulse phase 203 is an anodic pulse phase and the second pulse phase 204 is a cathodic pulse phase, although in other embodiments the anodic pulse phase and the cathodic pulse phase can be reversed, such that the cathodic pulse phase is the first pulse phase and the anodic pulse phase is the second pulse phase.
  • the signal 200 includes monophasic pulses. In such embodiments, the signal 200 includes repeating pulses of the same polarity.
  • the first pulse phase 203 is separated from the second pulse phase 204 by an interphase interval 208.
  • the amplitude of the signal 200 can return to baseline (e.g., zero or about zero), although in other embodiments the amplitude of the signal 200 during the interphase interval 214 can be a non-zero value.
  • the interphase interval 208 is omitted, and the signal 200 transitions directly from the first pulse phase 203 to the second pulse phase 204.
  • the first pulse phase 203 can have a pulse width 206 within a pulse width range of from about 100 microseconds to about 2 milliseconds.
  • the first pulse phase 206 can have a pulse width 206 within a pulse width range of from about 100 microseconds to about 1 .5 milliseconds, or from about 100 microseconds to about 1 millisecond, or from about 100 microseconds to about 800 microseconds, or from about 200 microseconds to about 700 microseconds, or from about 200 microseconds to about 600 microseconds, or from about 300 microseconds to about 700 microseconds, or from about 300 microseconds to about 600 microseconds, or from about 300 microseconds to about 500 microseconds, or from about 400 microseconds to about 600 microseconds, or from about 400 microseconds to about 500 microseconds.
  • the pulse width 206 can be about 100 microseconds, about 150 microseconds, about 200 microseconds, about 250 microseconds, about 300 microseconds, about 350 microseconds, about 400 microseconds, about 450 microseconds, about 500 microseconds, about 550 microseconds, about 600 microseconds, about 650 microseconds, or about 700 microseconds.
  • the foregoing pulse width ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have pulse width values outside the foregoing ranges.
  • the second pulse phase 204 has the same or about the same pulse width as the first pulse phase 203. Accordingly, the second pulse phase 204 can have any of the pulse widths recited above with respect to the first pulse phase 203. In other embodiments, however, the second pulse phase 204 can have a different pulse width than the first pulse phase 203. For example, if the first pulse phase 203 has a pulse width of 400 microseconds or less, the second pulse phase 204 may have a pulse width of 600 microseconds or more. Likewise, if the first pulse phase 203 has a pulse width of 600 microseconds or more, the second pulse phase 204 may have a pulse width of 400 microseconds or less.
  • a total charge delivered during the second pulse phase 204 can be equal or approximately equal in magnitude and opposite in polarity from the total charge delivered during the first pulse phase 203.
  • the second pulse phase 204 is a charge balancing pulse that prevents or at least reduces charge buildup at the electrode used to deliver the signal 200. Accordingly, in embodiments for which the first pulse phase 203 and the second pulse phase 204 have an equal or approximately equal pulse width, the first pulse phase 203 and the second pulse phase 204 can have an equal or approximately equal and opposite amplitude.
  • the first pulse phase 203 and the second pulse phase 204 can have different amplitudes such that the total charge delivered during the first pulse phase 203 and the second pulse phase 204 remains approximately the same.
  • the pulse 202 can be charge imbalanced, such that the first pulse phase 203 and the second pulse phase 204 do not deliver charges of the same magnitude.
  • charge buildup at the electrode may passively dissipate.
  • the interpulse interval 212 is a quiescent period between sequential pulses 202.
  • the signal 200 can return to a baseline amplitude (e.g., zero or about zero) such that little to no charge is administered to the patient.
  • the interpulse interval can be within an interpulse interval range of from about 1 millisecond to about 1 second, such as from about 5 milliseconds to about 500 milliseconds, or from about 50 milliseconds to about 500 milliseconds, or from about 100 milliseconds to about 300 milliseconds.
  • the foregoing interpulse interval ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have interpulse interval values outside the foregoing ranges.
  • the duration of the interpulse interval 212 can be set independently from the duration of the pulses 202. In other embodiments, the duration of the interpulse interval 212 is set based on a selected pulse 202 duration and desired signal frequency.
  • the duration of the pulse period 201 determines the frequency of the signal 200. For example, if the duration of the pulse period 201 is 200 milliseconds, then the frequency of the signal is 5 Hz (i.e., five pulse periods 201 are delivered per second).
  • the signal 200 can have a frequency between about 0.5 Hz and about 50 Hz.
  • the signal 200 can have a frequency within a frequency range of from about 1 Hz to about 40 Hz, or from about 1 Hz to about 30 Hz, or from about 1 Hz to about 25 Hz, or from about 1 Hz to about 20 Hz, or from about 1 Hz to about 15 Hz, or from about 5 Hz to about 15 Hz, or from about 1 Hz to about 12 Hz, or from about 1 Hz to about 10 Hz, or from about 2 Hz to about 8 Hz, or from about 3 Hz to about 7 Hz, or from about 4 Hz to about 6 Hz, or from about 4.5 Hz to about 5.5 Hz, or from about 4.8 Hz to about 5.2 Hz.
  • the signal 200 can have a frequency of about 0.5 Hz, about 1 Hz, about 2 Hz, about 3 Hz, about 4 Hz, about 5 Hz, about 6 Hz, about 7 Hz, or about 8 Hz. In some embodiments, the signal 200 can have a frequency of about 4.2 Hz, about 4.4 Hz, about 4.6 Hz, about 4.8 Hz, about 5.0 Hz, about 5.2 Hz, about 5.4 Hz, about 5.6 Hz, or about 5.8 Hz.
  • the foregoing frequency ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have frequency values outside the foregoing ranges.
  • the pulses 202 can have a current amplitude between about 0.1 mA and about 20 mA.
  • the pulses 202 have a current amplitude within a current amplitude range of from about 0.5 mA to about 15 mA, or from about 1 mA to about 12 mA, or from about 2 mA to about 12 mA, or from about 3 mA to about 10 mA.
  • the pulses 202 can also have a voltage amplitude between about 0.1 V and 15 V.
  • the pulses 202 have a voltage amplitude within a voltage amplitude range of from about 0.1 V to about 10 V, or from about 0.2 V to about 8 V, or from about 0.5 V to about 4 V.
  • the amplitude (e.g., the current amplitude and/or the voltage amplitude) of the signal 200 is set based on an individual patient's sensory threshold and/or motor threshold.
  • the pulses 202 have a peak amplitude that is below the sensory or perception threshold of the patient. In such embodiments, the patient generally cannot actively feel the signal 200 as it is being administered.
  • the pulses 202 may have an amplitude that is 50% of sensory threshold, 60% of sensory threshold, 70% of sensory threshold, 80% of sensory threshold, 90% of sensory threshold, or 95% of sensory threshold.
  • the pulses 202 have an amplitude that is at or above the sensory threshold, such that the patient can perceive the signal 200 being delivered.
  • the pulses 202 have an amplitude that is below the motor threshold of the patient.
  • the signal 200 does not induce clinically discernable movement (e.g., muscle twitching) in the patient while being administered.
  • the pulses 202 may have an amplitude that is 50% of motor threshold, 60% of motor threshold, 70% of motor threshold, 80% of motor threshold, 90% of motor threshold, or 95% of motor threshold.
  • electrical signals generated in accordance with the present technology can have one more ramped parameters.
  • Figure 2B illustrates an electrical signal 250 ("the signal 250") with a ramped amplitude in accordance with some embodiments of the present technology.
  • the signal 250 can be generally similar to the signal 200, and can have any of the parameters and parameter values described above in connection with the signal 200. However, relative to the signal 200, an amplitude of the of the signal 250 can be ramped such that a peak amplitude of the signal 250 changes over time.
  • the signal 250 includes a plurality of pulses 252 (five pulses 252a-252e are shown), with each sequential pulse 252 having a different amplitude than the preceding pulse 252.
  • the amplitude of the signal 250 increases from pulse 252a to pulse 252c, and then decreases from pulse 252c to pulse 252e. This pattern can then be repeated.
  • the signal 250 includes multiple pulses 252 at a common amplitude before being ramped up or down to a different amplitude (e.g., multiple pulses are delivered with an amplitude equal to the pulse 252a before the signal 250 is ramped to delivering pulses with an amplitude equal to the pulse 252b).
  • the signal 250 is ramped only in a single direction (e.g., the amplitude is either increased or decreased, but not both), until a maximum or minimum amplitude is reached.
  • other parameters of the signal 250 can remain constant (e.g., unchanged) as the amplitude of the pulses 252 is ramped.
  • one or more other parameters can be ramped, in addition to the amplitude being ramped.
  • both a pulse width and an amplitude of the pulses 252 is ramped.
  • the pulse width of the pulses 252 may be inversely ramped with the amplitude, such that as the amplitude increases, the pulse width decreases, and vice versa.
  • the pulse width, frequency, or other parameter is ramped instead of the amplitude.
  • the electrical signals described herein are administered during discrete stimulation sessions or periods that have a duration less than 24 hours.
  • the stimulation sessions may have a duration of between about 5 minutes and about 12 hours, such as between about 15 minutes and about 6 hours, or between about 15 minutes and about 4 hours, or between about 15 minutes and about 3 hours, or between about 15 minutes and about 2 hours, or between about 30 minutes and about 3 hours, or between about 30 minutes and about 2 hours, or between about 30 minutes and about 1 .5 hours, or between about 45 minutes and about 1 .5 hours.
  • the stimulation sessions can have a duration of about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours.
  • the patient can receive one or more stimulation sessions per day. For example, in some embodiments the patient receives a single stimulation session per day. In other embodiments, the patient receives multiple (e.g., two, three, four, etc.) discrete stimulation sessions per day. During periods between stimulation sessions, the patient generally does not receive any stimulation, or at least any clinically meaningful stimulation.
  • the foregoing representative stimulation period durations are provided by way of example only — in some embodiments, the electrical signals described herein may be applied during stimulation sessions having different durations. In some embodiments, electrical stimulation is applied for 24 hours per day.
  • the number and/or duration of stimulation sessions can be associated with various patient events or activities.
  • the stimulation sessions may occur while the patient is prandial.
  • the patient may receive one, two, three, or four 30-minute stimulation sessions per day, timed to occur while the patient is eating.
  • the electrical stimulation may be delivered during a single, one to six hour stimulation session per day, timed to (a) precede sleep (b) occur during sleep, or (c) both (a) and (b).
  • the electrical stimulation may be delivered during one or two one-hour stimulation sessions per day, timed to occur before, during, and/or after bowel movements.
  • the electrical stimulation may be delivered during short (e.g., 5-minute) stimulation sessions that occur each hour the patient is awake and/or active.
  • short stimulation sessions e.g., 5-minute
  • the signals can be applied using any of the signal parameters described for the signal 200 with reference to Figure 2A and the signal 250 with reference to Figure 2B.
  • the stimulation sessions can be applied at other times throughout the day, tied to other patient events, and/or according to other intervals beyond those described above.
  • the patient can control when they receive the stimulation session.
  • the patient may have access to a patient controller that can control operation of the signal generator (e.g., the signal generator 110 shown in Figure 1 A) to initiate a stimulation session.
  • a patient controller that can control operation of the signal generator (e.g., the signal generator 110 shown in Figure 1 A) to initiate a stimulation session.
  • Providing the patient with control over the timing of the stimulation sessions may be beneficial because the patient can initiate stimulation during a convenient time and/or when the patient experiences IBD symptoms (or an increase in the severity of IBD symptoms).
  • the patient may select to initiate the stimulation session during the day (e.g., as opposed to at night), while avoiding certain activities (e.g., driving, periods of concentration, etc.), and/or during or after periods or activities that may lead to an increase in symptoms (e.g., during or after consuming food).
  • a signal generator can be programmed to automatically administer the stimulation session during predetermined intervals. For example, the signal generator can be programmed to automatically deliver a stimulation session every day at 1 PM or another selected time. As another example, the signal generator can be programmed to automatically deliver a stimulation session timed with certain patient activities.
  • the signal generator can be programmed to automatically deliver a stimulation session at a time the patient typically eats a meal (e.g., 8AM, 12PM, and/or 6PM). Additionally or alternatively, the signal generator can be programmed to automatically deliver a stimulation session at a time that the patient's symptoms are typically the worst, which can be determined using patient feedback such as questionnaires, symptoms logs, etc. As yet another example, the signal generator can be programmed to automatically deliver a stimulation session based on a time the patient takes other medication (e.g., concurrent with taking medication, a specified duration before taking medication, or a specified duration after taking medication). Programming the signal generator to automatically administer the stimulation session may be advantageous because it eliminates the possibility of a patient forgetting to initiate therapy, and therefore may provide a more consistent therapy.
  • a time the patient typically eats a meal e.g., 8AM, 12PM, and/or 6PM.
  • the signal generator can be programmed to automatically deliver a stimulation session at a time that the patient's symptoms are
  • the electrical signals can be administered intermittently or continuously during the stimulation sessions.
  • the electrical signals can be administered continuously (e.g., without interruption) during the entirety of the stimulation session.
  • the electrical signals can be administered intermittently, such that the signal is only actively delivered during portions of the stimulation sessions.
  • the stimulation session may cycle between "on' 1 times during which the signal is being administered, and "off" times during which the signal is not being administered.
  • the "on" time can be between about 1 second and about 10 minutes
  • the "off" time can be between about 1 second and about 10 minutes.
  • suitable intermittent stimulation schedules include 10 seconds on, 10 seconds off; 10 seconds on, 30 seconds off; 10 seconds on, 60 seconds off; 10 seconds on, 90 seconds off; 30 seconds on, 30 seconds off; 30 seconds on, 60 seconds off; 30 seconds on, 90 seconds off; 1 minute on, 1 minute off; 10 minutes on, 10 minutes off, etc.
  • the on times and off times are provided by way of example only — in some embodiments, the electrical signals described herein may be applied according to different on times and off times.
  • the signal can be administered according to a duty cycle of between about 0.1 % and about 100% during each stimulation session.
  • the term duty cycle refers to the fraction of a single pulse period 201 (which consists of a single pulse 202 and a single interpulse interval 212) in which the pulse 202 is being actively delivered. That is, for a single pulse period, the duty cycle can be expressed as: (pulse width/duration of pulse period) x 100.
  • a pulse period comprises (1 ) a bi-phasic pulse with no interphase interval and with each phase of the pulse having a pulse width of 500 microseconds, followed by (2) an interpulse interval having a duration of 99 milliseconds (e.g., before the following pulse period begins)
  • the duty cycle is 1 % (1 millisecond combined pulse width/100 millisecond pulse period duration, x 100).
  • the term duty cycle is different than the term intermittent, which generally refers to delivering sequential pulse periods in a row for a first duration (e.g., 10 seconds), followed by a quiescent period during which no pulse periods are delivered for a second duration (e.g., for 90 seconds).
  • two or more electrical signals can be delivered concurrently.
  • a first signal is delivered continuously (e.g., for 24 hours per day) as a base signal
  • a second signal is delivered during discrete stimulation sessions (e.g., any of the stimulation sessions described previously).
  • the first signal and the second signal can have any of the signal parameters described for the signal 200 and the signal 250 with reference to Figures 2A and 2B.
  • the first signal may have a first set of signal delivery parameters (e.g., frequency, pulse width, amplitude, duty cycle, etc.), and the second signal may have a second set of signal delivery parameters that at least partially differ from the first set of signal delivery parameters.
  • the first signal may have a frequency of about 1 Hz
  • the second signal may have a frequency of about 5 Hz.
  • the first signal may be applied at a duty cycle of about 1 %
  • the second signal can be applied at a duty cycle of about 50%.
  • the second signal can be programmed to be automatically administered at various time intervals, e.g., to correspond to various patient events or activities as described previously.
  • the second signal can be an "on-demand" signal that the patient can initiate, e.g., in response to an increase in IBD symptoms.
  • the first signal and the second signal are delivered in cycles.
  • the first signal can be administered for a first period of time (e.g., a first stimulation session)
  • the second signal can be administered for a second period of time (e.g., a second stimulation session) after the first period of time.
  • the first period of time may partially overlap with the second period of time, although in other embodiments the first period of time does not overlap with the second period of time.
  • both the first signal and the second signal are generated by the same signal generator (e.g., the signal generator 1 10 described with reference to Figure 1A).
  • the first signal and the second signal can be administered via the same signal delivery device (e.g., the signal delivery device 120 described with reference to Figure 1 A), or via different signal delivery devices.
  • the first signal and the second signal can be delivered by different electrodes of the same signal delivery device (e.g., to enable concurrent delivery of the first signal and the second signal, if desired).
  • the first signal and the second signal may be delivered by the same combination of electrodes.
  • the autonomic nervous system regulates many bodily functions, such as heart rate, digestion, respiratory rate, etc.
  • the autonomic nervous system also has a fundamental role in mediating inflammation.
  • the autonomic nervous system can control release of various immunomodulatory substances (e.g., pro- inflammatory cytokines, anti-inflammatory cytokines, etc.) to mediate inflammation. This is largely controlled by the sympathetic nervous system and the parasympathetic nervous system.
  • the sympathetic nervous system When activated, the sympathetic nervous system may induce release of pro-inflammatory substances (e.g., pro-inflammatory cytokines such as TNF-a, IL-1 , IL-18, etc.), whereas the parasympathetic nervous system may induce release of antiinflammatory substances (e.g., anti-inflammatory cytokines such as IL-4, IL-10, etc.).
  • pro-inflammatory substances e.g., pro-inflammatory cytokines such as TNF-a, IL-1 , IL-18, etc.
  • antiinflammatory substances e.g., anti-inflammatory cytokines such as IL-4, IL-10, etc.
  • the sympathetic and parasympathetic systems may be imbalanced or dysfunctional, which may lead to chronic inflammation.
  • Such patients may have a chronic imbalance between serum levels of pro-inflammatory cytokines and anti-inflammatory cytokines.
  • An example of a chronic condition in which patients may have an imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines includes IBD.
  • the cholinergic anti-inflammatory pathway is a neural mechanism that inhibits pro-inflammatory cytokine release.
  • the CAP when activated, the CAP inhibits synthesis of certain pro-inflammatory molecules (e.g., TNF) in the liver and spleen and reduces the amount of circulating pro-inflammatory molecules.
  • CAP receives inputs from multiple peripheral nerves, including the vagus nerve, the splenic nerve, and the sacral nerve. It has been previously demonstrated that stimulating the vagus nerve activates the CAP, which in turn has been shown to decrease pro- inflammatory cytokine production/release and reduce inflammation.
  • one potential mechanism of action underlying the treatment of IBD with sacral nerve stimulation includes activating the CAP. In some embodiments, this may occur via activation of afferent nerve fibers, which can transmit signals from the sacral nerve toward the brain, which in turn may activate the CAP. In other embodiments, this may occur via direct activation of the CAP, without involvement of the central nervous system. Regardless, activating the CAP may cause T cells within the spleen to release the neurotransmitter acetylcholine, which may bind to a7 nicotinic acetylcholine receptors on macrophages in the spleen.
  • Activating the CAP may also cause direct release of acetylcholine from one or more local nerves (e.g., the splenic nerve, the sacral nerve), bypassing the need for the T-cell intermediary.
  • the reduction in pro-inflammatory cytokines may help restore the imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines observed in many patients with IBD. This in turn may normalize the balance between the sympathetic and parasympathetic nervous systems, leading to reduced inflammation and improvement in IBD-related symptoms.
  • Another potential mechanism of action involves activation of efferent nerve fibers that extend from the sacral nerves toward the gastrointestinal tract (e.g., the colon).
  • activating efferent nerve fibers that innervate the distal bowel may promote the release of acetylcholine from myenteric neurons.
  • the secreted acetylcholine can then bind to receptors (e.g., a7 nicotinic acetylcholine receptors) on macrophages proximate the gastrointestinal tract.
  • receptors e.g., a7 nicotinic acetylcholine receptors
  • the binding of acetylcholine to a7 receptors on the macrophages can reduce the release of pro-inflammatory cytokines and/or block pro-inflammatory cytokines, as described above.
  • the reduction in pro- inflammatory cytokines may reduce inflammation of the gastrointestinal tract, leading to an improvement in IBD-related symptoms.
  • Dextran Sulfate Salt Dextran Sulfate Salt
  • the rats were then divided into a first group (“the test group”) that received sacral nerve stimulation during a second postimplant period, and a second group (“the control group”) that did not receive stimulation during the second post-implant period.
  • the test group stimulation was applied at a frequency of 5.2 Hz, a pulse width of 210 microseconds, and at a voltage amplitude of 80-90% of motor threshold. Stimulation was applied once daily for one hour. During the one hour stimulation session, stimulation was applied continuously. Both groups of rats were scored daily on the Disease Activity Index (DAI) during the first post-implant period and the second post-implant period.
  • DAI Disease Activity Index
  • the DAI included ranking weight loss, stool consistency, and bleeding on a four-point scale (0, 1 , 2, 3), with higher numbers for each category reflecting more severe scores. The score for each rat was then summed to determine the rat's daily summed DAI score (with a maximum daily score of 9).
  • Figure 3A is a graph 300 comparing the average daily DAI summed score for the test group that received daily stimulation during the second post-implant period (line 310) and the control group that did not receive daily stimulating during the second post-implant period (line 320). More specifically, the x-axis measures the number of days post-implant, and the y-axis measures the average summed DAI score. As shown, DAI scores for the test group and the control group increased during the first postimplant period (labeled on the graph 300 as "DSS") as a result of being administered DSS.
  • DSS first postimplant period
  • the rats no longer received DSS and instead either received stimulation (the test group) or sham stimulation (the control group) during the second post-implant period (labeled on the graph 300 as "SNS").
  • DAI scores decreased for both the test group and the control group during the second post-implant stimulation period.
  • the DAI scores for the test group decreased at a faster rate than DAI scores for the control group, indicating that rats receiving the stimulation recovered faster from the DSS induced inflammation.
  • Figure 3B is a graph 350 showing the "area under the curve" ("AUG") for line 310 and line 320 from Figure 3A during both the first stimulation period corresponding to the period labeled as "DSS” in Figure 3A and the second stimulation period corresponding to the period labeled as "SNS” in Figure 3A.
  • a greater AUC indicates a higher average DAI during the relevant period, whereas a lower AUC indicates a lower average DAI during the relative period.
  • the AUC for the test group identified by reference number 360
  • the AUC for the control group identified by reference number 370
  • the AUC for the test group (identified by reference number 365) was notably lower than the AUC for the control group (identified by reference number 375). This further validates that the test group demonstrated a faster reduction in AUC than the control group, reflecting that the sacral nerve stimulation helped lower DAI scores in a rat model of IBD. Without intending to be bound by theory, the animal data reported in Figures 3A and 3B therefore supports that sacral nerve stimulation may be beneficial in treating inflammatory diseases such as IBD.
  • a method of treating a patient with Inflammatory Bowel Disease comprising: generating an electrical signal having a frequency within a frequency range of from about 1 Hz to about 10 Hz, a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and an amplitude that is less than a sensory threshold of the patient; and delivering the electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve of the patient, wherein the electrical signal is delivered continuously for a stimulation session having a duration of between about 15 minutes and about 3 hours, and wherein the electrical signal reduces inflammation in the patient.
  • IBD Inflammatory Bowel Disease
  • the signal delivery device includes a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate the S3 sacral nerve.
  • a method of treating a patient with Inflammatory Bowel Disease comprising: programming a signal generator to deliver an electrical signal to a sacral nerve of the patient, via an implanted signal delivery device, during one or more stimulation sessions having a duration of between about 15 minutes and about 3 hours, wherein the electrical signal has a frequency within a frequency range of from about 1 Hz to about 10 Hz, a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and an amplitude that is less than a sensory threshold of the patient, and wherein the electrical signal reduces inflammation in the patient.
  • IBD Inflammatory Bowel Disease
  • the signal delivery device includes a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate the S3 sacral nerve.
  • a system for treating a patient with Inflammatory Bowel Disease comprising: an implantable signal delivery device postionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to: deliver an electrical signal to a sacral nerve of the patient, via the implanted signal delivery device, during one or more stimulation sessions having a duration of between about 15 minutes and about 3 hours, wherein the electrical signal has a frequency within a frequency range of from about 1 Hz to about 10 Hz, a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and an amplitude that is less than a sensory threshold of the patient, and wherein the electrical signal reduces inflammation in the patient.
  • IBD Inflammatory Bowel Disease
  • the signal delivery device includes a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate the S3 sacral nerve.
  • the electrical signal reduces patient inflammation by reducing secretion of pro-inflammatory cytokines.

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Abstract

La présente invention concerne des systèmes et des méthodes de traitement des maladies inflammatoires chroniques de l'intestin (MICI) par neuromodulation. Par exemple, les MICI peuvent être traitées en délivrant un signal électrique à un ou plusieurs nerfs sacrés d'un patient par l'intermédiaire d'un dispositif de délivrance de signal implanté, positionné à proximité d'un ou de plusieurs des nerfs sacrés du patient. Dans certains modes de réalisation, le signal électrique peut moduler l'activité neuronale chez le patient, ce qui peut à son tour réduire l'inflammation chez le patient en modifiant un déséquilibre entre le système nerveux sympathique et le système nerveux parasympathique du patient, et/ou en modifiant un seuil pour une réponse inflammatoire dans le système gastro-intestinal.
PCT/US2023/072507 2022-08-25 2023-08-18 Systèmes et méthodes de traitement des maladies inflammatoires chroniques de l'intestin par neuromodulation WO2024044515A2 (fr)

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US6885888B2 (en) * 2000-01-20 2005-04-26 The Cleveland Clinic Foundation Electrical stimulation of the sympathetic nerve chain
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