WO2018232145A1 - Appareil et méthode de régénération neurale - Google Patents

Appareil et méthode de régénération neurale Download PDF

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Publication number
WO2018232145A1
WO2018232145A1 PCT/US2018/037585 US2018037585W WO2018232145A1 WO 2018232145 A1 WO2018232145 A1 WO 2018232145A1 US 2018037585 W US2018037585 W US 2018037585W WO 2018232145 A1 WO2018232145 A1 WO 2018232145A1
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Prior art keywords
neural
electrodes
site
electric current
external device
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PCT/US2018/037585
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English (en)
Inventor
Li Yao
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Wichita State University
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Publication of WO2018232145A1 publication Critical patent/WO2018232145A1/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
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0551—Spinal or peripheral nerve electrodes
    • A61N1/0556—Cuff electrodes
    • 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
    • A61N1/326—Applying electric currents by contact electrodes alternating or intermittent currents for promoting growth of cells, e.g. bone cells
    • 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
    • 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
    • A61N1/36103—Neuro-rehabilitation; Repair or reorganisation of neural tissue, e.g. after stroke
    • 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
    • A61N1/372—Arrangements in connection with the implantation of stimulators
    • A61N1/37211—Means for communicating with stimulators
    • A61N1/37235—Aspects of the external programmer

Definitions

  • the present invention relates generally to an apparatus and method for promoting axonal growth and neural cell migration to promote, accomplish, and/or enhance neural regeneration in damaged nerves, spinal cord, neural cells, or nervous tissues.
  • Spinal cord and nerve injuries can be debilitating, often causing permanent changes in strength, sensation, and other body functions below the site of injury. Muscle weakness, loss of muscle function, sensation, or autonomic functions in parts of the body below the injury are also seen. The prognosis for patients experiencing spinal cord and nerve injuries varies depending on the severity of the injury. In some cases, complete paralysis can occur, while other patients experience muscle atrophy, pressure sores, infections, and respiratory problems. Spinal cord and nerve injuries can also include traumatic injury, Central Cord Syndrome, Anterior Cord Syndrome, Brown-Sequard Syndrome, Posterior Cord Syndrome, Conus medullaris, and cauda equine syndromes. Most of these injuries result in lasting or permanent damage to the nervous system and some incurable impairment.
  • neural conduits are used to repair nerve defects or spinal cord lesion, or cover compressed spinal cord tissue.
  • Conduits act like a bridge that connects two damaged nerve endings together or repair a spinal cord lesion, providing a channel and scaffold to guide and facilitate axon growth and neural cell migration.
  • the axon regrow along the conduit can establish new neural connection and restore function. Restoration of function in the peripheral nervous system is possible, but there are a number of factors surrounding the repair of the central nervous system to make it much more challenging. Attempts have also been made in the art to treat nervous system damage using electric fields (EFs) to promote axonal growth of damaged neurons and neural cell migration, although the use of EFs to accomplish this growth is not very well understood.
  • EFs electric fields
  • the current technology lacks the ability to provide effective stimulation in order to promote axonal growth. Further, in order to accomplish a greater level of treatment and therapy for spinal cord and nerve injuries, suitable devices and methods for attracting neural cells to the damaged area along with axonal growth are needed.
  • the present disclosure solves the problems inherent in previous EF technologies and provides an apparatus and methods for promoting axonal growth and neural cell migration in patients with an injured spinal cord, nerve, or other neural tissue.
  • the apparatus/system for promoting neural regeneration generally comprises a neural conduit comprising an elongated hollow body configured for implantation at a site of neural tissue damage for guiding axon regeneration and neural cell migration in order to establish new functional connection across the lesion; a pair of electrodes configured for application to a site of neural tissue damage in a patient, and optionally for application to the neural conduit; and a power source configured to provide electric current to the pair of electrodes, wherein the pair of electrodes generate a unidirectional electric field at the site of neural tissue damage.
  • the site of neural tissue damage can include transected (fully cut) ends of a neural, or compressed, torn, or otherwise damaged, but not fully transected neural tissue.
  • the apparatus is capable of providing a controlled voltage to a specific area, where such voltage, including the direction, strength, and frequency of flow of the current and generated electric field, is able to be controlled.
  • Methods of providing therapy and promoting neural regeneration are also described for patients with a spinal cord or neural injury.
  • the steps generally include the applying the system to a patient experiencing a spinal cord or neural injury. This involves implanting the neural conduit at the site of neural tissue damage in the patient for guiding and promoting axon regeneration and neural cell migration in the patient, followed by applying the pair of electrodes at the site of neural tissue damage; and applying an electric current to the site of neural tissue damage via the electrodes, thereby generating a unidirectional electric field at the site of neural tissue damage.
  • the therapy regimen will vary depending on several factors, including, but not limited to, the type of injury, the species of patient, the size of the patient, the patient's overall response to therapy, the voltage and current administered, the amount of time the voltage is administered, the number of breaks, the length of time of the break, the recovery of the patient after administration of the voltage, as well as other factors.
  • Figure (Fig.) 1 is a block diagram of a system according to embodiments of the invention for promoting axonal growth and neural cell migration using an applied electric field 50;
  • Fig. 2 is a diagram of the components of the controller 210;
  • Fig. 3 is a diagram of the components of the external device 220, including a power source
  • Fig. 4 is a flow diagram of the process for inducing the unidirectional electric field using the system of the invention to promote repair of a damaged nerve 10 or other neural tissue;
  • Fig. 5 illustrations use of the system, including a neural conduit 110 along with the electrodes 250 to promote axonal growth and neural cell migration;
  • Fig. 6 is a flow diagram of the process of generating a directional electric field at the damaged location to achieve neural regeneration.
  • the system for promoting neural regeneration comprises an electrical stimulation apparatus and a neural conduit 110.
  • the electrical stimulation apparatus comprises a controller 210, an external device 220, a power source 230, and a pair of electrodes 250 (aka electrode array) configured to be applied to a patient so as to transmit electrical stimulation to the applied area.
  • the controller 210 comprises any suitable device that permits a user to control the external device and thereby control the pair of electrodes 250.
  • the controller 210 may rely on mechanical, pneumatic, or electronic techniques.
  • existing devices with or without extensive hardware or software modifications, may serve as the controller 210 in the present invention, include various computing devices that include a non-transitory computer readable medium (memory) 214 for storing the data, a processor 212 to execute machine-readable instructions for controlling the external device, a transceiver 216 for transmitting and receiving information to/from the external device, and a display interface 218 for the data to be visualized by the user, as illustrated in Fig. 2.
  • the display 218 may also allow a user to view and monitor functions of any other components included in the system.
  • the display interface 218 may be a touchscreen display and/or may further be accommodated with a keyboard, mouse, etc.
  • a non-limiting list of exemplary controllers includes a general purpose computer, laptop, smartphone, tablet, other smart devices, hospital or clinic health station, and any other device that can perform the necessary functions of the components included within the controller 210 for the purposes of this disclosure. It will be appreciated that the controller 210 will also include a power supply 230 for powering the controller 210, which may include a battery, rechargeable capacitor, Faraday generator, power outlet, and combinations thereof. In one aspect, the controller 210 is a separate and independent unit from the external device 220, which allows a user to wirelessly control the external device 220, potentially even remotely control the external device 220.
  • the processor 212 can include a computer or microprocessor that may be used in combination with a non-transitory computer readable medium 214 to convey operation commands to the external device 220.
  • the processor 212 executes the programs stored in the non-transitory computer readable medium 214.
  • the non- transitory computer readable medium can include a memory component, but may also involve working memory of the processor 212.
  • the medium 214 stores predetermined settings allowing a user to administer a pre-defined voltage for a specified amount of time that is to be distributed by the external device 220 to the pair of electrodes 250.
  • the settings may be directed by a software-based program, including automated programs; however, the settings and parameters may also be input manually into the controller 210 for transmission to the external device 220.
  • the controller 210 may further be configured to receive inputs from a user related to one or more patient parameters, including name, age, health status, etc., and store those on the memory. This information may be correlated via the processor to the selected parameters for the duration and voltage of the electrical stimulation to be applied by the pair of electrodes.
  • the non-transitory computer readable medium 214 in combination with the processor 212 can perform at least one of the following functions, including measuring, monitoring, gathering, or storing of data pertaining to the controller functions, and the combination of functions thereof.
  • the controller 210 can include the suitable hardware, software, and/or firmware for sending and communicating data.
  • the controller' s transceiver 216 comprises a transmitter and a receiver allowing communication functions.
  • the controller 210 is in remote communication with the external device 220.
  • the controller 210 is in wireless communication with the external device 220, and includes wireless communication interface and protocols.
  • Such forms of wireless communication can include one of, but not limited to, Bluetooth, Wi-Fi, cellular, RFID, NFC, or WLAN and any other form of data or information transfer across a wireless medium.
  • the controller 210 may contain a transceiver 216 configured to transmit a wireless power supply to the external device 220.
  • the power supply may rely on power transmission technology that uses time varying electric, magnetic, or electromagnetic fields.
  • the transmission of energy from a transceiver 216 located on the controller to a transceiver 226 located on the external device 220 via an oscillating magnetic field may also be used.
  • the external device 220 is configured receive operating commands from the controller 210 in order to deliver a specified voltage to the pair of electrodes 250 which have been attached to the patient.
  • the external device 220 can deliver the controlled voltage to the pair of electrodes 250 through either a wired connection 228 from the external device 220 to the pair of electrodes 250, or a wireless connection.
  • the external device 220 generally comprises electronic circuitry configured to transmit electric current to the pair of electrodes 250 according to instructions from the controller 210.
  • the external device 220 comprises a processor 222 and a non-transitory computer readable medium 224 (memory) that stores the programs to be executed by the processor 222.
  • the processor 222 can include a computer or microprocessor for executing the programs stored in the non-transitory computer readable medium 224 located adjacent to the processor 222.
  • the non-transitory computer readable medium can include a memory component, but may also involve working memory of the processor 222.
  • the medium 224 preferably stores a command program to administer a particular voltage for a specified amount of time to the pair of electrodes 250, which is defined by the controller 210.
  • the settings may be directed by a software- based program, including automated programs; however, the settings and parameters may also be input manually into the controller 210 for transmission to the external device 222.
  • the non-transitory computer readable medium 224 in combination with the processor 222 can perform at least one of the following processing functions, including measuring, monitoring, gathering, or storing of data pertaining to the external device functions, and the combination of functions thereof.
  • Exemplary external devices 220 comprise a processor board, which may or may not be enclosed within a suitable housing (not shown).
  • Exemplary processor boards include Bluetooth Low Energy (BLE) development boards with built-in USB and battery charging inputs (e.g., Adafruit Feather, Adafruit Industries LLC).
  • An exemplary device includes the Adafruit Feather nRF52 Bluefruit processor board.
  • the external device 220 is portable and independent of the controller 210. In one or more embodiments, the external device 220 remains external to the patient's body and is not implanted therein. In one or more embodiments, the external device 220 remains in proximate location to the patient's body, and in particular proximate to the location of treatment 10 (e.g., location of nerve damage/injury). It will be appreciated that the maximum distance between the patient's body and the external device 220 may be dictated by the length of the wires connected to the pair of electrodes 250. In one or more embodiments, if the external device 220 is in wireless communication with the pair of electrodes 250, then the external device 220 may be remote from the patient, even in another room, etc.
  • the external device 220 is an implantable device located on or internal and proximal to the body at or near the location of neural damage/injury 10.
  • the term “nerve” may be used herein and in the figures to encompass nerves, as well as other neural tissues, such as spinal cord, brain neurons, and the like.
  • the external device 220 can include the suitable hardware, software, and/or firmware for communicating with the controller 220 and the pair of electrodes 250.
  • external device 220 further comprises a transceiver 226 that comprises a transmitter and a receiver allowing communication functions. As noted above, communication between the controller 210 and the external device 220 can be wired or wireless.
  • the external device 220 further includes a power source 230 (aka voltage source), which can be derived from any source of power configured to provide electric current of sufficient voltage to allow the pair of electrodes 250 to function.
  • the power source 230 is connected to the external device 220 through one or more wires, which then transmits the electric current to the pair of electrodes 250 at the desired voltage.
  • Exemplary wired power sources include batteries (single-use, disposable, rechargeable, solar, alkaline, lithium ion, etc.) or rechargeable capacitators.
  • the power source 230 provides wireless power to the pair of electrodes 250.
  • the wireless power source may rely on power transmission technology that uses time varying electric, magnetic, or electromagnetic fields.
  • the transmission of energy from a first transceiver to a second transceiver via an oscillating magnetic field may also be used, where the first transceiver is housed in the external device 220 and the second transceiver is housed with the pair of electrodes 250.
  • the external 220 device further includes a power supply 229 for powering the device itself.
  • the power supply 229 can be the same source of power as the power source 230 used to generate the electric current for the electrodes, as discussed above.
  • the external 220 device could also share its power supply with the controller 210, or be powered (e.g., via USB) by the controller 210.
  • the transceiver 226 includes an antenna configured to receive a wireless power signal emitted by the transceiver 216 located on the controller 210 and configured to provide power to one or more functions of the external device 220.
  • the wireless power signal may rely on power transmission technology that uses time varying electric, magnetic, or electromagnetic fields.
  • the transmission of energy from a first transceiver to a second transceiver via an oscillating magnetic field may also be used, wherein the first transceiver is located in the controller 210 and the second transceiver is housed in the external device 220.
  • the external device 220 can alternatively be powered by a separate and distinct power supply 229 (not shown) from either the controller 210 or the power source 230, including solar power and the like.
  • the external device 220 may be configured to carry out additional functions, such as measuring, monitoring, or transmitting feedback of the external device 220 functions to the controller 210, and combinations thereof.
  • additional functionality can be achieved by adding other sensors or devices to the external device 220; however, this is not a required step.
  • considerations for other sensors and devices may be limited by the capacity of the power supply to provide adequate power to components included within the circuitry of the external device 220 to function properly.
  • Additional sensors or devices that would be of interest for the present disclosure can include, but are not limited to, those that are capable of monitoring heart rate, temperature, or blood oxygen levels.
  • the pair of electrodes 250 is preferably a configuration of two opposing electrodes for administering and measuring an electric current or voltage to the damaged neural tissue, as described in Fig. 4.
  • the pair of electrodes 250 may operate in a bidirectional fashion, but preferably provides a stimulating pattern of electric current in a single direction.
  • the stimulating pattern can include continuous direct current (DC) stimulation, pulsed, or alternative current (AC) stimulation.
  • DC direct current
  • AC alternative current
  • the pair of electrodes 250 may be selected from, but not limited to, a Schlumberger array, a Wenner alpha array, a Wenner beta array, a Wenner gamma array, a pole-pole array, a dipole-dipole array, a pole-dipole array, or an equatorial dipole-dipole array.
  • the pair of electrodes 250 preferably comprises at least one anode 252, at least one cathode 254, and more preferably consists of a single anode 252 and a single cathode 254. In a preferred embodiment, the arrangement of the electrode array consists of one anode 252 and one cathode 254.
  • a single anode 252 and single cathode 254 be used to generate a single electric field with a strong directional (and linear) bias opposite to the direction of the current (electron) flow.
  • the current at any given time preferably flows in a single direction (i.e., is unidirectional) when applied, to thereby promote cell growth and regeneration in a direction that is generally parallel to the linear neuronal path (and corresponds to the direction of the induced electric field). This is in contrast to an electric field generated by an array of four or more electrodes where the current and field flow in multiple different directions.
  • the system with its unidirectional electric field can be used to promote neural repair and regeneration along a descending pathway (i.e., from the cranial to caudal/distal direction, aka head-to-toe) or along the opposite ascending pathway (i.e., from the distal to cranial direction), depending upon the relative position of the anodal or cathodal electrode.
  • a descending pathway i.e., from the cranial to caudal/distal direction, aka head-to-toe
  • the opposite ascending pathway i.e., from the distal to cranial direction
  • the pair of electrodes 250 are preferably configured to be attached to a damaged nerve and/or implanted neural conduit. Accordingly, it will be appreciated that the pair of electrodes 250 may have respective sizes depending upon the species of the patient, of about 0.5 mm to about 2 cm, preferably from about 1 mm to about 1 cm, more preferably from about 2 mm to about 0.5 cm, to permit them sutured in place at the location of damage on the neural tissue (e.g., nerve, spinal cord, or neuron).
  • the neural tissue e.g., nerve, spinal cord, or neuron
  • the system for neural regeneration further includes a neural conduit 1 10 for repairing the damaged neural tissue section.
  • the neural conduit 110 is preferably sized to fit the lesion, cover the damaged or compression area, or in some cases even bridge a gap between two damaged neural tissue segments 10 of a patient's spinal cord, nerve, or other neural tissue, that sustained an injury /lesion.
  • the neural conduit 110 is configured to substantially encircle at least two damaged nerve segments and any gap there between (if present). Therefore, the circumference and length of the neural conduit 1 10 will vary depending on the size of the patient, species of the patient, area of injury, and extent of injury.
  • the neural conduit 1 10 could even be 3D printed to precisely fit the damaged site' s shape or the shape of the compression to bridge the damaged hemisection of the neural tissue.
  • the neural conduit 110 is preferably made from natural materials, natural polymers, synthetic polymers, or semi-synthetic polymers.
  • the natural materials are preferably selected from collagen, fibrin, fibronectin, laminin, hyaluronic acid, other types of naturally-produced materials, synthesized proteins, and peptides.
  • the polymers are preferably selected from, but not limited to, Matrigel, hyaluronic acid, chitin, chitosan, silk, guar gum, gum karaya, agar, treated agar, fenugreek seed mucilage, soy polysaccharide, gellan gum, mango peel pectin, lepidium sativum mucilage, plantago ovata seed mucilage, aegle marmelos gum (AMG), locust bean gum, ficus indica fruit mucilage, mangifera indica gum (MIG), hibiscus rosa sinesis mucilage and treated agar, dehydrated banana powder (DBP), collagen, fibrin, fibronectin, laminin, polysilozane, polyphosphazene, low-density polyethylene (LDPE), high-density polyethylene (HDPE), plastic, polypropylene (PP), polyvinyl chloride (PVC),
  • the neural conduit 110 preferably includes an attachment means for securing the neural conduit to the damaged nerve or spinal cord 10 of the patient.
  • Such attachment means may be a perforation down the length of the neural conduit so that it may be wrapped around the area where the neural cell or nervous tissue has been injured.
  • One non-limiting example of a neural conduit can be found in U. S. Patent No. 8,926,886, incorporated herein by reference.
  • the neural conduit 110 preferably has one or more materials filling an inside space 1 12.
  • the inside space 1 12 of the neural conduit can include at least one channel travelling the length of the conduit.
  • the neural conduit 110 includes more than one channel travelling the length of the conduit.
  • the neural conduit 1 10 is filled with hydrogel 120, aligned nanofibers, and combinations thereof.
  • hydrogel 120 refers to a solid jelly-like material where the liquid component is water.
  • the hydrogel 120 is preferably a network of polymer chains that are hydrophilic, where water is the dispersion medium.
  • the hydrogel 120 is preferably highly biodegradable, biocompatible and possess a degree of flexibility very similar to natural neural tissue.
  • the hydrogel 120 preferably comprises at least one component selected from, but not limited to, chitin, chitosan, guar gum, gum karaya, agar, treated agar, fenugreek seed mucilage, soy polysaccharide, gellan gum, mango peel pectin, lepidium sativum mucilage, plantago ovata seed mucilage, aegle marmelos gum (AMG), locust bean gum, ficus indica fruit mucilage, mangifera indica gum (MIG), hibiscus rosa sinesis mucilage and treated agar, dehydrated banana powder (DBP), collagen, fibrin, fibronectin, laminin, hyaluronic acid, polysilozane, polyphosphazene, low-density polyethylene (LDPE), high- density polyethylene (HDPE), plastic, polypropylene (PP), polyvinyl chloride (PVC), polyst
  • the apparatus is capable of providing a voltage to the damaged nerve 20 in a range of from about 0.01 millivolt (mV/mm) to 1 volt (V/mm), where ranges and values such as O. lmV/mm to 750 mV/mm, 1 mV/mm to 500 mV/mm, 5 mV/mm to 350 mV/mm, 10 mV/mm to 200 mV/mm, 5 mV/mm to 100 mV/mm, 5 mV/mm to 50 mV/mm, 1 mV/mm to 50 mV/mm, 1 mV/mm to 20 mV/mm, 20 mV/mm to 50 mV/mm, 20 mV/mm to 75mV/mm, 50 mV/mm to 75mV/mm, 50 mV/mm to 300 mV/mm, 350 mV/mm to 750 mV/mm, 500 mV/mm to IV, 500 mV/mm to 800 mV, 500
  • the apparatus is capable of providing a current to a damaged nerve in a range of about 0.01 microampere (uA) to 10 milliampere (mA), where all ranges and values in-between are envisioned.
  • the apparatus has the ability to provide any given voltage 20 to a damaged neural tissue for any specified period of time, where the applied voltage can be of continuous direct (DC), pulsed DC, or alternating (AC) currents.
  • the therapeutic approach may involve intermittent (i.e., "on"/" off') application of DC, pulsed, or AC current over a defined period of time at specific intervals.
  • a constant (continuous) application of (continuous) DC, pulsed DC, or AC current over a defined period of time is also envisioned.
  • the apparatus may provide a specific voltage for at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least one week, at least two week, at least three weeks, or at least one month, or at least three months; however, these values are not meant to be limiting.
  • Ranges of the time that the apparatus may apply a specific voltage include, but are not limited to, 1 to 5 minutes, 1 to 10 minutes, 1 to 30 minutes, 1 minute to 1 hour, 30 minutes to 1 hour, 1 to 2 hours, 1 to 4 hours, 1 to 6 hours, 1 to 8 hours, 1 to 12 hours, 1 to 24 hours, 2 to 4 hours, 2 to 6 hours, 12 to 24 hours, 3 to 6 hours, 2 to 4 hours, 2 to 12 hours, 8 to 24 hours, 12 hours to 2 days, 1 day to 5 days, 1 day to 2 days, and all values in-between.
  • the controller 210 is connected to a power supply, where the power supply powers the controller 210.
  • the controller 210 emits a power signal to be received by a transceiver 226 located on the external device 220.
  • the transceiver 226 provides power to the adjacently located functional components of the external device 220, including, but not limited to, the transceiver 226 and electrodes 250.
  • the power sent to the transceiver 226 allows the processor to operate.
  • the transceiver 226 is preferably in active communication with the controller 210 and has the ability to send/receive information and to execute the functions defined by the controller 210 to the electrodes 250.
  • the external device 220 is preferably capable of monitoring the adjacently-located electrode 250 functions and sub- functions of applied electrical stimulation.
  • the processor located on the external device 220 preferably distributes the power source, in the form of electric stimulation, to the pair of electrodes 250 in at least one on the following ways, including: delivering continuous direct current (DC), pulsed DC, or delivering alternative current (AC), reversing the current polarity, providing a bidirectional electric current, or any combination thereof.
  • DC direct current
  • AC alternative current
  • reversing the current polarity providing a bidirectional electric current, or any combination thereof.
  • the pair of electrodes 250 preferably delivers the electric stimulation, transmitted via the external device 220, to the damaged neural tissue area in order to induce an electric field at a specific location and/or in a region of the biological tissue that contains the damaged spinal cord or nerve.
  • the pair of electrodes 250 preferably consists of one anode 252 and one cathode 254.
  • the methods of promoting neural regeneration in peripheral and/or central nervous systems generally comprise connecting a first portion of the neural conduit to one end, either rostral or caudal stump, of the damaged spinal cord or nerve.
  • the neural conduit is generally implanted at a "site of nerve tissue damage," which refers to the damaged segment itself, as well as (relatively) undamaged adjacent segments or stumps on either side of the damaged segment (or gap).
  • the damaged segment may be compression, lesion, tear, or the like, or may include a completely transected nerve.
  • a second portion of the neural conduit is attached to the opposite end or stump of the damaged spinal cord or nerve segment.
  • the neural conduit can be secured in place using any suitable biocompatible technique, including suturing. Such attachment means may be a perforation down the length of the neural conduit so that it may be wrapped around the area where the neural cell or nervous tissue has been injured, and sutured into place if desired.
  • the anodal electrode 352 of the apparatus is applied to the rostral stump 12 of the injured neural tissue (i.e., upstream of the injured or damaged portion). In one or more embodiments the anodal electrode 352 is inserted into or attached to the nerve tissue. In one or more embodiments, the anodal electrode 352 is applied to the neural tissue without being inserted therein. In either embodiments, the anodal electrode 352 may be sutured or otherwise secured into place.
  • the cathodal electrode 354 is also applied to the neural conduit 1 10 which bridges the defect or fits in the lesion of the injured neural tissue (extending from the rostral end 312 to the caudal end 314).
  • the cathodal electrode 354 may be applied to the caudal stump 14 of the injured neural tissue (i.e., downstream of the injured or damaged portion, not shown). In one or more embodiments, the cathodal electrode 354 may be inserted into or attached to the neural conduit 1 10 or neural tissue. In one or more embodiments, the cathodal electrode 354 is applied to the neural conduit 1 10 or neural tissue without being inserted therein. In either embodiments, the cathodal electrode 354 may be sutured or otherwise secured into place.
  • the controller 210 sends a signal to the external device 220 to transmit the electric current to the applied pair of electrodes 250.
  • the induced electric field promotes axonal growth or neural cell migration in a defined (single, and generally linera) direction towards either the anode 252 or cathode 254, depending on the type of neural cells, with many neural cells having a preference for migrating toward the cathode 254 electrode, although glial cells have a tendency to migrate toward the anode (i.e., generally opposite the electric field).
  • the induced electric field promotes the migration of neurons, neural progenitor/stem cells, and glial cells from other areas in the body to the site of the lesion/injury.
  • the induced electric field further promotes the differentiation of endogenous or transplanted precursor / stem cells into neural cells.
  • Stem cells such as induced pluripotent stem cells, embryonic stem cells, neural stem cells and mesenchymal stem cells, can be encapsulated in the neural conduits and then be implanted into the damaged neural tissue.
  • the applied electric stimulation to the damaged neural tissue and neural conduits, resulting in an induced electric field with a unidirectional bias can promote the differentiation of the stem cells into neural cells.
  • the disclosure provides a method for administering therapy to a patient with a spinal cord or nerve injury.
  • the steps of the method generally include generating an electric current in the patient at the site of spinal cord or nerve injury or damage, specifically by inducing a unidirectional electric current to generate an opposing electric field and promote cell migration or axon growth along the damaged section via an implanted neural conduit.
  • the method preferably further includes a treatment regimen based on several factors, including, but not limited to: the type of injury, location of injury, species of patient, size of patient, amount of voltage used, amount of time voltage applied, general patient response to treatment, as well as a combination of those factors.
  • the treatment regimen may be any combination of voltage for any amount of time, where different voltages for different amounts of time may be applied in a single treatment regimen. Further, any number of breaks may be inserted between time frames where voltage is being applied.
  • a treatment regimen for a human or animal may include lOmV/mm for 4 hours/day repeated for 5 days, break for 2 days, then 50 mV/mm is applied for 1 hour/ day for 3 days, wherein the current applied can be of continuous DC, pulsed, or AC.
  • the type of nerve injury may be any damage to neural cells or nervous tissue within the body of the patient.
  • the nerve injury can occur in central nervous system (CNS) or the peripheral nervous system (PNS).
  • CNS central nervous system
  • PNS peripheral nervous system
  • Injuries of the CNS may occur anywhere in the CNS, such as, but not limited to the spinal cord or brain.
  • Injuries of the PNS may occur anywhere in the PNS, such as body extremities, but not limited to, face, arms, hands, legs, feet, or phalanges.
  • the nerve injury is preferably selected from, but not limited to spinal cord injury, nerve injury, neuropraxia, axonotmesis, and neurotmesis.
  • the method disclosed herein preferably results in growth of the axon of the neural cell or nervous tissues already near the site of injury, as well as migration of neuronal cells from other areas of the neural tissue to the site of injury.
  • the method of the present disclosure results in at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% further axonal growth than previous methods of treatment using EFs.
  • the method results in at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% more neural cells migrating to the site of injury from other areas of the body to help re-establish functional neural circuit within or near the site of injury.
  • the method may further comprise transplant of neural cell, stem cell, or nervous tissues to the site of injury in combination with therapy, however, this step is not a required step of the disclosed method.
  • the patient for purposes of this disclosure may be any human or animal having a neural injury.
  • Non-limiting examples include, human and non-human mammals, such as dogs, cats, equine, bovine, or porcine subjects, goats, rodents (e.g., rats, rabbits, mice), elephants, monkeys, gorillas, zebras, camels, lions, tigers, bears, and the like.
  • rodents e.g., rats, rabbits, mice
  • elephants, monkeys, gorillas, zebras camels, lions, tigers, bears, and the like.
  • the phrase "and/or," when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed.
  • the composition can contain or exclude A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination.
  • the present description also uses numerical ranges to quantify certain parameters relating to various embodiments of the invention. It should be understood that when numerical ranges are provided, such ranges are to be construed as providing literal support for claim limitations that only recite the lower value of the range as well as claim limitations that only recite the upper value of the range. For example, a disclosed numerical range of about 10 to about 100 provides literal support for a claim reciting "greater than about 10" (with no upper bounds) and a claim reciting "less than about 100" (with no lower bounds).

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  • Radiology & Medical Imaging (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rehabilitation Therapy (AREA)
  • Cell Biology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Electrotherapy Devices (AREA)

Abstract

L'invention concerne un système, comprenant un appareil et une méthode de régénération neurale dans des cellules neurales ou un tissu neural endommagés. Le système stimule la croissance axonale et la migration de cellules neurales vers le site de lésion, par application d'une stimulation électrique unidirectionnelle au niveau du site d'endommagement de tissu neural en vue de favoriser la migration cellulaire à travers le site endommagé, qui est facilitée par un conduit neural implanté qui recouvre des zones de tissu neural et/ou qui comble tout espace entre des segments de tissu neural endommagés.
PCT/US2018/037585 2017-06-14 2018-06-14 Appareil et méthode de régénération neurale WO2018232145A1 (fr)

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CN112237685A (zh) * 2019-07-17 2021-01-19 中国医学科学院基础医学研究所 外周神经电刺激器
WO2023288218A1 (fr) * 2021-07-14 2023-01-19 Tulavi Therapeutics, Inc. Procédés et dispositifs de régénération nerveuse
US11890393B2 (en) 2018-07-02 2024-02-06 Tulavi Therapeutics, Inc. Methods and devices for in situ formed nerve cap
US11918595B2 (en) 2016-02-09 2024-03-05 Tulavi Therapeutics, Inc. Methods, agents, and devices for local neuromodulation of autonomic nerves

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CN112237685B (zh) * 2019-07-17 2023-09-19 中国医学科学院基础医学研究所 外周神经电刺激器
WO2023288218A1 (fr) * 2021-07-14 2023-01-19 Tulavi Therapeutics, Inc. Procédés et dispositifs de régénération nerveuse

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