US20100023071A1 - Systems and devices for neural stimulation and controlled drug delivery - Google Patents

Systems and devices for neural stimulation and controlled drug delivery Download PDF

Info

Publication number
US20100023071A1
US20100023071A1 US12/572,899 US57289909A US2010023071A1 US 20100023071 A1 US20100023071 A1 US 20100023071A1 US 57289909 A US57289909 A US 57289909A US 2010023071 A1 US2010023071 A1 US 2010023071A1
Authority
US
United States
Prior art keywords
drug
drug delivery
system
stimulation
patient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/572,899
Inventor
Barry M. Yomtov
Stephen J. Herman
John T. Santini, Jr.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MicroCHIPS Inc
Original Assignee
MicroCHIPS Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US41601002P priority Critical
Priority to US10/679,763 priority patent/US7599737B2/en
Application filed by MicroCHIPS Inc filed Critical MicroCHIPS Inc
Priority to US12/572,899 priority patent/US20100023071A1/en
Publication of US20100023071A1 publication Critical patent/US20100023071A1/en
Application status is Abandoned legal-status Critical

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/20Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36071Pain
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/08Arrangements or circuits for monitoring, protecting, controlling or indicating

Abstract

Medical devices and methods are provided for electrical stimulation of neural tissue and controlled drug delivery to a patient. The device includes an implantable drug delivery module which comprises a plurality of reservoirs, a release system comprising at least one drug contained in each of the reservoirs, and control means for selectively releasing a pharmaceutically effective amount of drug from each reservoir; a neural electrical stimulator which comprises a signal generator connected to at least one stimulation electrode for operable engagement with a neural tissue of the patient; and at least one microcontroller for controlling operational interaction of the drug delivery module and the neural electrical stimulator. The microcontroller may control the signal generator and the control means of the drug delivery module. The device may further include a sensor operable to deliver a signal to the microcontroller, for example to indicate when to deliver electrical stimulation, drug, or both.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This is a continuation of U.S. application Ser. No. 10/679,763, filed Oct. 6, 2003, which claims the benefit of U.S. Provisional Application No. 60/416,010, filed Oct. 4, 2002. The applications are incorporated herein by reference in their entirety.
  • BACKGROUND OF THE INVENTION
  • This invention is generally in the field of methods and devices for the delivery of electrical signals to neural tissues in a medical patient in combination with the delivery of one or more drugs to the patient.
  • Electrical signals from implanted pulse generators have been applied to neural tissues for the control of chronic pain or movement disorders. For example, the delivery of electrical stimulation to the nervous system using an implanted electrode has been found effective in the relief of chest pain, such as angina pectoris, that often accompanies myocardial ischemia. U.S. Pat. No. 5,058,584 to Bourgeois, for example, discloses a system and method for treating chest pain using electrical stimulation within the epidural space of the spinal cord. U.S. Pat. No. 6,058,331 to King discloses a system and method for treating ischemia by automatically adjusting electrical stimulation to the spinal cord, peripheral nerve, or neural tissue ganglia based on a sensed patient condition. U.S. Pat. No. 5,199,428 to Obel et al. discloses a system for stimulating the epidural space with continuous and/or phasic electrical pulses using an implanted pulse generator upon the detection of myocardial ischemia to decrease cardiac workload, and thus reduce cell death associated with the ischemic event. As another example, U.S. Pat. No. 5,824,021 to discloses a system and method for providing spinal cord stimulation to relieve angina, and for notifying the patient that an ischemic event is occurring.
  • Other publications disclose therapeutic strategies and devices for the delivery of drug by catheters in combination with the use of electrical stimulation. See, e.g., U.S. Patent Application No. 2002/0013612 A1, U.S. Patent Application No. 2002/0055761 A1, and U.S. Patent Application No. 2002/0107553 A1, all of which are incorporated herein by reference.
  • When applied to control pain, implanted neural stimulators use electrical pulses to block the transmission of pain-related signals through neural tissue. In many cases, however, the neural stimulation is not completely effective in controlling the pain. It would be desirable to provide methods and devices for enhancing the control of chronic pain. When applied to control movement, the implanted neural stimulators use electrical pulses to block the transmission of cortical signals associated with the onset of certain types of seizures or for the control of continuous involuntary movement disorders. It would be desirable to provide methods and devices for enhancing the control of movement disorders. It would also be desirable to provide new devices and methods for the controlled delivery of electrical stimulation in combination with drug delivery for a variety of therapeutic applications.
  • SUMMARY OF THE INVENTION
  • Medical devices and methods are provided for electrical stimulation of neural tissue and controlled drug delivery to a patient in need thereof.
  • In one aspect, the medical device includes an implantable drug delivery module which comprises a plurality of reservoirs, a release system contained in each of the reservoirs, wherein the release system comprises at least one drug, and a control means for selectively releasing a pharmaceutically effective amount of the drug from each of the reservoirs; a neural electrical stimulator which comprises a signal generator connected to at least one stimulation electrode for operable engagement with a neural tissue of a patient; and at least one microcontroller for controlling operational interaction of the drug delivery module and the neural electrical stimulator. In one embodiment, the microcontroller controls both the signal generator and the control means of the drug delivery module. In one embodiment, the device further includes one or more sensors operable to deliver a signal to the microcontroller. For example, the sensors can control release of the drug from the drug delivery module and control generation of an electrical current from the neural stimulator to neural tissue. The device can further include a power source, for example, to operate the microcontroller, neural electrical stimulator, drug delivery module, or sensor if included.
  • In one embodiment, the stimulation electrode is on an outer surface of a hermetically sealed encasement containing the drug delivery module and microcontroller. In another embodiment, the stimulation electrode extends a distance from a hermetically sealed encasement containing the drug delivery module and microcontroller. For example, a flexible catheter can connect the stimulation electrode to the encasement.
  • In one embodiment, the device further includes telemetry components in operable communication with the microcontroller. This could be used, for example, to allow one to reprogram the medical device during use (e.g., to adjust the drug dose and/or the neural stimulation operational parameters), or to communicate sensor readings or device functions (e.g., battery status) to the patient.
  • In one embodiment, the neural electrical stimulator is provided as a module separate from the drug delivery module. In one embodiment, the neural electrical stimulator module is implantable. In one embodiment, the drug delivery module is controlled by a telemetry or hard-wired signal from the stimulator module. In one embodiment, the device comprises two microcontrollers, one of which controls the stimulator module and the other which controls the drug delivery module.
  • In one embodiment, the drug delivery module comprises a microchip drug delivery device. In one embodiment, the control means for selectively releasing a pharmaceutically effective amount of the drug comprises a reservoir cap positioned over each reservoir and a means for actively disintegrating the reservoir cap. For example, the reservoir cap can comprise an electrically conductive material and the means for actively disintegrating the reservoir cap can comprise an input lead and an output lead each connected to the reservoir cap and a power source for delivering an effective amount of electrical current through the reservoir cap, via the input lead and output lead, to heat and rupture the reservoir cap to release the drug.
  • In another aspect, a method is provided for treating a patient comprising delivery of an electrical signal and at least one drug to the patient. In one embodiment, the method includes implanting into the patient the implantable drug delivery module of the medical device described above; bringing the stimulator electrode of the medical device into operable engagement with a neural tissue of the patient; activating the signal generator to deliver electrical stimulation from the stimulator electrode to the neural tissue of the patient; and releasing the drug from the reservoir into the patient. In one embodiment, the method further includes implanting the neural electrical stimulator into the patient. In various embodiments, the electrical stimulation is delivered intermittently or continuously.
  • In one embodiment, the drug and the electrical neural stimulation are delivered simultaneously. In another embodiment, release of the drug is alternated with delivery of the electrical stimulation. In various embodiments,
  • the drug is delivered intermittently or continuously. In one embodiment, the drug is released before the electrical neural stimulation and is effective to reduce the stimulation threshold of the neural tissue.
  • In exemplary applications, the devices and methods are adapted for treating chronic pain, for treating a movement disorder, for treating incontinence, for treating obesity, or for controlling seizures in the patient. In various embodiments, the drug comprises an analgesic, an anti-anxiety agent, an anti-incontinence agent, a skeletal muscle relaxant, an anti-convulsant, or an anti-parkinson agent.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a schematic drawing of the components in one embodiment of the medical device described herein.
  • FIG. 2 is a plan view of one embodiment of a medical device comprising an implantable drug delivery module with a remote neural stimulation electrode.
  • FIG. 3 is a plan view of one embodiment of a medical device comprising an implantable drug delivery module operably linked to a stimulation module by a hardwired communication link.
  • FIG. 4 is a plan view of one embodiment of a medical device comprising an implantable drug delivery module operably linked to a stimulation module by a wireless communication link.
  • FIG. 5 is a perspective view of one embodiment of an implantable medical device that includes a catheter having drug-containing reservoirs at the distal end portion.
  • FIG. 6A is a plan view of one embodiment of the distal end portion of a catheter having an array of drug-containing reservoirs covered by reservoir caps that can be activated/opened using electrothermal ablation as described herein.
  • FIG. 6B is a cross-sectional view of the device shown in FIG. 6A, taken along line B/B, and FIG. 6C is a cross-section view of the device, taken along line C/C.
  • DETAILED DESCRIPTION OF THE INVENTION
  • A medical device is provided for use in neural stimulation and the controlled delivery of one or more therapeutic or prophylactic drugs. The devices are useful for treating patients suffering from diseases and disorders that may be better treated or managed with a combination of electrical stimulation and drug therapy. For example, the drug may augment the stimulation therapy, it may negate a side effect of the stimulation therapy, or it may reduce the stimulation threshold in the treatment.
  • In one embodiment, the devices are used in the control of chronic pain. The devices advantageously can provide a more effective treatment with the combination than with either alone, for example, by alternating electrical stimulation and drug delivery in order to prevent a potential tolerance build-up to either therapeutic approach if used alone. This could extend the useful longevity of an implanted electrical stimulation device.
  • In another embodiment, the devices are used in the treatment of movement disorders, by blocking the transmission of cortical signals associated with the onset of certain types of seizures or for the control of continuous involuntary movement disorders. For example, this embodiment could be used in the treatment of epilepsy, Parkinson's disease, or spasticity. Advantageously, these devices could deliver a drug that reduces the stimulation threshold, thereby enabling a reduction in power requirements. This also could extend the device longevity, or could permit a smaller implant size than might otherwise be required (e.g., enabling the use of a smaller battery).
  • In still other embodiments, the therapeutic devices could be used in the treatment or control of incontinence, or mood and/or anxiety disorders.
  • As used herein, the terms “comprise,” “comprising,” “include,” and “including” are intended to be open, non-limiting terms, unless the contrary is expressly indicated.
  • I. Device Components and Materials
  • In one embodiment, the medical device includes (i) an implantable drug delivery module which comprises a plurality of reservoirs, a release system contained in each of the reservoirs, wherein the release system comprises at least one drug, and a control means for selectively releasing a pharmaceutically effective amount of the drug from each of the reservoirs; (ii) a neural electrical stimulator which comprises a signal generator connected to at least one stimulation electrode for operable engagement with a neural tissue of a patient; and (iii) at least one microcontroller for controlling operational interaction of the drug delivery module and the neural electrical stimulator, such as for controlling the signal generator and the control means of the drug delivery module. The device may further include a sensor operable to deliver a signal to the microcontroller, for example to indicate when to deliver electrical stimulation, drug, or both. One embodiment of the medical device is illustrated schematically in FIG. 1.
  • In one embodiment, the entire medical device is implanted into the body of the patient at a single location, such that the electrodes are mounted onto a surface of the packaged medical device.
  • In another embodiment, the drug delivery device is implanted at a first location and the electrodes extend to neural tissue at another location, such as with a catheter, which would be particularly useful to place the stimulation electrode in the epidural space of the spinal cord. One example is illustrated in FIG. 2. It shows implantable medical device 10 which includes drug delivery module 12 provided in titanium case 18. The drug delivery module 12 includes an exposed array of reservoir caps 24 which cover drug-containing reservoirs. The medical device 10 further includes a plastic header 20 connected to the titanium case 18. An electrical lead extends through hermetic feed through 22 in the header 20, into stimulation catheter 16, and connects to stimulation electrode 14.
  • In yet another embodiment, the drug delivery module is “free-standing” from the neural stimulator portion (i.e., the stimulator module) of the medical device. For example, the drug delivery module could be implanted and controlled by a telemetry or hard-wired signal from the stimulator module, as illustrated in FIG. 3 and FIG. 4. In such embodiments, there may be two microcontrollers: one for the stimulator module and one for the drug delivery module. In one embodiment, the two modules could “hand off” operation to each another at specified timed intervals, or upon patient activated events. For example, the medical device could further include a physiological sensor capable of detecting onset of a seizure (e.g. epilepsy), where the stimulation module delivers electrical stimulation to prevent or reduce the occurrence of seizures and the drug delivery module activates release of a drug if a seizure is detected. Alternatively, the operation of the two modules could occur simultaneously or in an overlapping manner. The stimulator module could be implanted and used in combination with a drug delivery module for pain control or motion control. When both modules are implanted separately, they can be replaced independently at the required intervals, e.g., the drug delivery module when the drugs have been expended and the stimulator when the battery fails.
  • A. The Electrical Stimulation Means
  • The stimulation module includes a signal generator connected to at least one stimulation electrode suitable for operable engagement with a neural tissue of a patient. The stimulation electrode is connected to a power source, such as a battery/pulse generator, which provides the energy/signal source for the stimulation. The stimulation is between a stimulation electrode (i.e., a cathode) and a return electrode (i.e., an anode), which could be either the case (i.e., packaging) of the medical device or a secondary remote electrode. The electrode may be either monopolar, bipolar, or multipolar.
  • The electrodes may come in a variety of forms or structures, depending on the particular application. Preferably, the electrode is a known type suitable for implantation within a patient, preferably for an extended period of time. The implantable electrode may be positioned at a location within a patient by any of a variety of conventional mechanisms (including mechanical or chemical means, and possibly relying on gravity and/or frictional forces). In one embodiment, conventional implantable electrodes may be surgically inserted into the spinal region adjacent the T1-T12 and C1-C8 vertebrae, and may be located near or even immediately adjacent the T1-T12 and C1-C8 nerve bundles for spinal cord stimulation.
  • Preferably, the stimulating electrical signal is operated at a voltage between about 0.1 μV and about 20 V, more preferably between about 1 V to about 15 V. For microstimulation, it is preferable to stimulate within the range of 0.1 μV and about 1 V. Generally, the electric signal source is operated at a frequency range between about 2 Hz and about 2500 Hz, preferably between about 2 Hz and about 200 Hz. The pulse width of the oscillating electrical signal can be between about 10 μs and about 1,000 μs, preferably between about 50 μs and about 500 μs.
  • The electrodes may be placed subcutaneously to stimulate underlying muscles, overlying cutaneous nerves, or passing somatic nerves. For example, peripheral nerve stimulation leads are available from Medtronic, Inc. (e.g., lead Model 3987, On Point™, which includes contacts and a polyester mesh skirt for fixation to subcutaneous tissue or muscle fascia; lead Model 3587A or Model 3998, which have an insulative paddle enlargement; or lead Model 3487A or Model 3888, which do not have an insulative paddle enlargement). In both surface mounted and implanted electrodes, electrical signals supplied by a microcontroller to the electrodes electrically stimulate nervous tissue in the spinal canal.
  • Implantable electrodes may be placed adjacent to nerves such as the median, peroneal, ulnar, and ansalenticularis nerves. Similarly, implantable electrodes may be placed near the vagus nerves, carotid sinus, and all other cranial nerves to provide stimulation. Finally, implantable electrodes may be placed epicardially or transvenously near the cardiac ganglia or plexi and employed in this manner. Some examples of commercially available electrode stimulator devices that could be adapted for use with the drug delivery devices described herein include the VNS (Vagus Nerve Stimulator) using a cuff type electrode made by Cyberonics, Inc. (Houston, Tex.), as well as certain electrodes/stimulators made by Medtronics, Inc. (Minneapolis, Minn.), which includes deep brain catheter leads/electrodes for use in some movement disorders/tremors.
  • In one embodiment, as described above, the stimulating electrode may be remote from the titanium case enclosure, as shown in FIG. 2.
  • B. The Controlled Drug Delivery Module
  • The drug delivery device includes a substrate having a plurality of reservoirs, which contain the drug molecules for delivery. In one embodiment, the drug delivery module comprises a microchip drug delivery device. The substrate, reservoirs, reservoir caps, control circuitry, and power source are described at least in part herein and/or in U.S. Pat. No. 5,797,898, U.S. Pat. No. 6,123,861, U.S. Pat. No. 6,551,838, U.S. Pat. No. 6,491,666, and U.S. Pat. No. 6,527,762, as well as U.S. Patent Application Publications No. 2002/0138067, No. 2002/0072784, No. 2002/0151776, and No. 2002/0107470. In one embodiment, control of reservoir cap opening includes electro-thermal ablation techniques, as described in U.S. patent application Ser. No. 10/641,507, filed Aug. 15, 2003, published as U.S. Patent Publication No. 2004/0121486, which is incorporated herein by reference.
  • The Substrate and Reservoirs
  • The substrate is the structural body (e.g., part of a device) in which the reservoirs are formed, e.g., it contains the etched, machined, or molded reservoirs. A reservoir is a well, a container. MEMS methods, micromolding, and micromachining techniques known in the art can be used to fabricate the substrate/reservoirs from a variety of materials. See, for example, U.S. Pat. No. 6,123,861 and U.S. Patent Application Publication No. 2002/0107470. Examples of suitable substrate materials include metals, ceramics, semiconductors, and degradable and non-degradable polymers. The substrate, or portions thereof, may be coated, encapsulated, or otherwise contained in a biocompatible material. Examples of coating materials include poly(ethylene glycol), polytetrafluoroethylene-like materials, inert ceramics, titanium, diamond-like carbon, and the like. In one embodiment, the substrate is formed of silicon.
  • The substrate can be flexible or rigid. In one embodiment, the substrate serves as the support for a drug delivery microchip.
  • The substrate can have a variety of shapes, or shaped surfaces. It can, for example, have a release side (i.e., an area having reservoir caps) that is planar or curved. The substrate may, for example, be in a shape selected from disks, cylinders, or spheres. In one embodiment, the release side can be shaped to conform to a curved tissue surface or into a body lumen. In another embodiment, the back side (distal the release side) is shaped to conform to an attachment surface.
  • The substrate may consist of only one material, or may be a composite or multi-laminate material, that is, composed of several layers of the same or different substrate materials that are bonded together.
  • Preferably, the substrate is hermetic, that is impermeable (at least during the time of use of the reservoir device) to the molecules to be delivered and to surrounding gases or fluids (e.g., water, blood, electrolytes or other solutions).
  • In another embodiment, the substrate is made of a strong material that degrades or dissolves over a defined period of time into biocompatible components. Examples of biocompatible polymers include poly(lactic acid)s, poly(glycolic acid)s, and poly(lactic-co-glycolic acid)s, as well as degradable poly(anhydride-co-imides).
  • The substrate thickness can vary. For example, the thickness of a device may vary from approximately 10 μm to several millimeters (e.g., 500 μm). Total substrate thickness and reservoir volume can be increased by bonding or attaching wafers or layers of substrate materials together. The device thickness may affect the volume of each reservoir and/or may affect the maximum number of reservoirs that can be incorporated onto a substrate. The size and number of substrates and reservoirs can be selected to accommodate the quantity and volume of drug formulation needed for a particular application, although other constraints such as manufacturing limitations or total device size limitations (e.g., for implantation into a patient) also may come into play. For example, devices for in vivo applications desirably would be small enough to be implanted using minimally invasive procedures.
  • The substrate includes at least two and preferably tens or hundreds of reservoirs. For example, one reservoir could be provided for each daily dose of drug required, for example, over a 3-, 8-, or 12-month course of treatment. The substrate could include, for example, 300 to 400 reservoirs.
  • In one embodiment, the reservoir has a volume equal to or less than 500 μL (e.g., less than 250 μL, less than 100 μL, less than 50 μL, less than 25 μL, less than 10 μL, etc.) and greater than about 1 nL (e.g., greater than 5 nL, greater than 10 nL, greater than about 25 nL, greater than about 50 nL, greater than about 1 μL, etc.).
  • Drug and Release System
  • The drug delivery device includes a single drug or a combination of two or more drugs for release. The drug can comprise small molecules, large (i.e., macro-) molecules, or a combination thereof, having a bioactive effect. In one embodiment, the large molecule drug is a protein or a peptide. In various embodiments, the drug can be selected from amino acids, nucleic acids, oligonucleotides, polysaccharides, and synthetic organic molecules. In one embodiment, the drug is selected from nucleosides, nucleotides, and analogs and conjugates thereof. Representative examples of drugs include analgesics, anesthetics, anti-angiogenic molecules, antibiotics, antibodies, antineoplastic agents, antioxidants, antiviral agents, chemotherapeutic agents, gene delivery vectors, immunomodulators, ion channel regulators, metabolites, sugars, psychotropic agents, vaccines, vitamins.
  • In one embodiment, the drug is used in the control of chronic pain. For example, the drug could be an analgesic, such as aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine, oxycodone, codeine, dihydrocodeine bitartrate, pentazocine, hydrocodone bitartrate, levorphanol, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, fentanyl, or meprobamate.
  • In other embodiments, the drug is used in the treatment of movement disorders, seizures, or for the control of continuous involuntary movement disorders (epilepsy, Parkinson's disease, or spasticity). Examples of anti-parkinson agents include anticholinergics, dopaminergic agents, and ethosuximides. Examples of skeletal muscle relaxants include baclofen, tizanidine, and dantrolen. Examples of anticonvulsants include barbiturates, hydrantoins, succinimides, oxazolidindiones, and benzodiazepines.
  • In another embodiment, the drug is used in the treatment or control of incontinence. Examples of drugs possibly useful in the treatment or control of incontinence include oxybutynin, tolterodine, lamotrigine and valproate.
  • In yet another embodiment, the drug is used in the treatment of mood and/or anxiety disorders. Examples of antianxiety agents include lorazepam, buspirone, prazepam, chlordiazepoxide, oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, and dantrolene.
  • In various embodiments, the drug molecules for release can be PEGylated, a technique known in the art to extend the in vivo lifetime of a bioactive molecule, for example by attaching the bioactive molecule to PEG or another oligomeric or polymeric stabilizing agent.
  • The drug can be provided as part of a “release system,” as taught in U.S. Pat. No. 5,797,898, the degradation, dissolution, or diffusion properties of which can provide a method for controlling the release rate of the molecules. The release system may include one or more pharmaceutical excipients. Suitable pharmaceutically acceptable excipients include most carriers approved for parenteral administration, including various aqueous solutions. Other excipients may be used to maintain the drug in suspensions as an aid to reservoir filling, stability, or release. Depending on the properties of the drug, such excipients may be aqueous or non-aqueous, hydrophobic or hydrophilic, polar or non-polar, protic or aprotic. See. e.g., U.S. Pat. No. 6,264,990 to Knepp et al. The release system optionally includes stabilizers, antioxidants, antimicrobials, preservatives, buffering agents, surfactants, and other additives useful for storing and releasing molecules from the reservoirs in vivo.
  • Reservoir Caps
  • As used herein, the term “reservoir cap” includes a membrane or other structure suitable for separating the contents of a reservoir from the environment outside of the reservoir. It generally is self-supporting across the reservoir opening, although caps having additional structures to provide mechanical support to the cap can be fabricated. Selectively removing the reservoir cap or making it permeable will then “expose” the contents of the reservoir to the environment (or selected components thereof) surrounding the reservoir. In preferred embodiments, the reservoir cap is selectively disintegrated. As used herein, the term “disintegrate” is used broadly to include without limitation degrading, dissolving, rupturing, fracturing or some other form of mechanical failure, as well as a loss of structural integrity due to a chemical reaction (e.g., electrochemical degradation) or phase change (e.g., melting) in response to a change in temperature, unless a specific one of these mechanisms is indicated. In one specific embodiment, the “disintegration” is by an electrochemical activation technique, such as described in U.S. Pat. No. 5,797,898. In another specific embodiment, the “disintegration” is by an electro-thermal ablation technique, such as described in U.S. Patent Application Publication No. 2004/0121486.
  • In active release devices, the reservoir cap generally includes any material that can be disintegrated or permeabilized in response to an applied stimulus, e.g., electric field or current, magnetic field, change in pH, or by thermal, chemical, electrochemical, or mechanical means.
  • In one embodiment, the reservoir cap is a thin metal film and is impermeable to the surrounding environment (e.g., body fluids). In one variation, a particular electric potential is applied to the metal reservoir cap, which is then oxidized and disintegrated by an electrochemical reaction, to release the drug from the reservoir. Examples of suitable reservoir cap materials include gold, silver, copper, and zinc. In another variation, the reservoir cap is heated (e.g., using a resistive heater) to cause the reservoir cap to melt and be displaced from the reservoir to open it. This latter variation could be used, for example, with reservoir caps formed of a metal or a non-metal material, e.g., a polymer. In yet another variation, the reservoir cap is formed of a polymer or other material that undergoes a temperature-dependent change in permeability such that upon heating to a pre-selected temperature, the reservoir is rendered permeable to the drug and bodily fluids to permit the drug to be released from the reservoir through the reservoir cap.
  • In still another embodiment, the reservoir cap is formed of a conductive material, such as a metal film, through which an electrical current can be passed to electrothermally ablate it, as described in U.S. Patent Application Publication No. 2004/0121486. Representative examples of suitable reservoir cap materials include gold, copper, aluminum, silver, platinum, titanium, palladium, various alloys (e.g., Au/Si, Au/Ge, Pt—Ir, Ni—Ti, Pt—Si, SS 304, SS 316), and silicon doped with an impurity to increase electrical conductivity, as known in the art. In one embodiment, the reservoir cap is in the form of a thin metal film. In one embodiment, the reservoir cap is part of a multiple layer structure, for example, the reservoir cap can be made of multiple metal layers, such as a multi-layer/laminate structure of platinum/titanium/platinum. The reservoir cap is operably (i.e. electrically) connected to an electrical input lead and to an electrical output lead, to facilitate flow of an electrical current through the reservoir cap. When an effective amount of an electrical current is applied through the leads and reservoir cap, the temperature of the reservoir cap is locally increased due to resistive heating, and the heat generated within the reservoir cap increases the temperature sufficiently to cause the reservoir cap to be electrothermally ablated (i.e., ruptured).
  • In passive release devices, the reservoir cap is formed from a material or mixture of materials that degrade, dissolve, or disintegrate over time, or that do not degrade, dissolve, or disintegrate, but are permeable or become permeable to molecules or energy. Representative examples of reservoir cap materials include polymeric materials, and non-polymeric materials such as porous forms of metals, semiconductors, and ceramics. Passive semiconductor reservoir cap materials include nanoporous or microporous silicon membranes.
  • Characteristics can be different for each reservoir cap to provide different times of release of drug formulation. For example, any combination of polymer, degree of crosslinking, or polymer thickness can be modified to obtain a specific release time or rate.
  • Any combination of passive and/or active release reservoir cap can be present in a single drug delivery module. For example, the reservoir cap can be removed by electrothermal ablation to expose a passive release system that only begins its passive release after the reservoir cap has been actively removed. Alternatively, a given device can include both passive and active release reservoirs.
  • Means for Controlling Drug Release
  • The drug delivery device includes a control means to control the time at which the drug is released from the device, and into the patient's body.
  • In one embodiment, the means for controllably releasing the drug provides selective actuation of each reservoir, which is done under the control of a microprocessor. Preferably, such means includes an input source, a microprocessor, a timer, a demultiplexer (or multiplexer), and a power source. As used herein, the term “demultiplexer” also refers to multiplexers. The power source provides energy to activate the selected reservoir, i.e., trigger release of drug from the particular reservoir desired for a given dose. The microprocessor can be programmed to initiate the disintegration or permeabilization of the reservoir cap in response at a pre-selected time or in response to one or more of signals or measured parameters, including receipt of a signal from another device (for example by remote control or wireless methods) or detection of a particular condition using a sensor such as a biosensor.
  • The medical device can also be activated or powered using wireless means, for example, as described in U.S. 20020072784 A1 to Sheppard et al. The telemetry means shown in FIG. 1 can be employed in this manner, as well as to communicate instructions for or power the electrical stimulation.
  • In one embodiment, the medical device includes a substrate having a two-dimensional array of reservoirs arranged therein, a release system comprising drug contained in the reservoirs, anode reservoir caps covering each of the reservoirs, cathodes positioned on the substrate near the anodes, and means for actively controlling disintegration of the reservoir caps. The energy drives a reaction between selected anodes and cathodes. Upon application of a small potential between the electrodes, electrons pass from the anode to the cathode through the external circuit causing the anode material (reservoir cap) to oxidize and dissolve into the surrounding fluids, exposing the release system containing the drug for delivery to the surrounding fluids, e.g., in vivo. For example, the microprocessor can direct power to specific electrode pairs through a demultiplexer as directed by an EPROM, remote control, or biosensor.
  • In another embodiment, the activation energy initiates a thermally driven rupturing or permeabilization process, for example, as described in PCT WO 01/12157. For example, the means for controlling release can actively disintegrate or permeabilize a reservoir cap using a resistive heater. The resistive heater can cause the reservoir cap to undergo a phase change or fracture, for example, as a result of thermal expansion of the reservoir cap or release system, thereby rupturing the reservoir cap and releasing the drug from the selected reservoir. The application of electric current to the resistive heater can be delivered and controlled using components as described above for use in the electrochemical disintegration embodiment. For example, a microprocessor can direct current to select reservoirs at desired intervals.
  • In yet another embodiment, control means controls electro-thermal ablation of the reservoir cap. For example, the drug delivery device could include a reservoir cap formed of an electrically conductive material, which prevents the reservoir contents from passing out from the device; an electrical input lead connected to the reservoir cap; an electrical output lead connected to the reservoir cap; and a control means to deliver an effective amount of electrical current through the reservoir cap, via the input lead and output lead, to heat and rupture the reservoir cap to release the drug. In one embodiment, the reservoir cap and conductive leads are formed of the same material, where the temperature of the reservoir cap increases locally under applied current because the reservoir cap is suspended in a medium that is less thermally conductive than the substrate. Alternatively, the reservoir cap and conductive leads are formed of the same material, and the reservoir cap has a smaller cross-sectional area in the direction of electric current flow, where the increase in current density through the reservoir cap causes an increase in localized heating. The reservoir cap alternatively can be formed of a material that is different from the material forming the leads, wherein the material forming the reservoir cap has a different electrical resistivity, thermal diffusivity, thermal conductivity, and/or a lower melting temperature than the material forming the leads. Various combinations of these embodiments can be employed as described in U.S. patent application Ser. No. 10/641,507, filed Aug. 15, 2003.
  • In one embodiment, the drug delivery device utilizes an accelerated release mechanism. In one embodiment, a positive displacement feature can be included to facilitate release of the drug from the reservoirs. For example, the device may include an osmotic engine or water-swellable component, which can be used to drive a drug formulation from the reservoirs. For example, such a feature can provide very fast release of drug the efficacy of which is dependent on a fast pharmacokinetic pulsatile profile. As used herein, the term “accelerated release” refers to an increase in the transport rate of drug out of the reservoir relative to the transport rate of the drug solely by diffusion down its own chemical gradient. The terms also refer to expelling reservoir contents that would not otherwise egress from an open reservoir, i.e., where no or negligible diffusion could occur.
  • C. Microcontroller and Other Components
  • As used herein, the term “microcontroller” is used to refer to microprocessors, state machines, digital logic, or a combination thereof, which is operable to control (i) the drug delivery module, (ii) the neural electrical stimulator, (iii) the interaction of the drug delivery module and the neural electrical stimulator module, or (iv) a combination thereof.
  • For example, the microcontroller means controls the signal generator for the delivery of electrical stimulation to neural tissue and the control means of the drug delivery device. In one embodiment, the device includes control circuitry comprising a microprocessor, a timer, a demultiplexer, and an input source (for example, a memory source, a signal receiver, or a biosensor), telemetry communication circuit, and a power source. The timer and demultiplexer circuitry can be designed and incorporated directly onto the surface of the drug delivery device substrate during electrode fabrication, or may be incorporated in a separate integrated circuit. The criteria for selection of a microprocessor are small size, low power requirement, and the ability to translate the output from memory sources, communication signals, signal receivers, or biosensors into an address for the direction of power through the demultiplexer to a specific drug reservoir and/or the generation of an electrical signal for neural tissue stimulation (see, e.g., Ji, et al., IEEE J. Solid-State Circuits 27:433-43 (1992)). Selection of a source of input to the microprocessor such as memory sources, signal receivers, or biosensors depends on the medical device's particular application and whether device operation is preprogrammed, controlled by remote means, or controlled by feedback from its environment (i.e., biofeedback).
  • A microprocessor is used in conjunction with a source of memory (such as an erasable programmable read only memory (EPROM), an on-board flash memory, and/or an external EEPROM), a timer, a demultiplexer, and a power source such as a battery (e.g., a lithium battery). A programmed sequence of events including the time a reservoir is to be opened and the location or address of the reservoir can be stored into the memory source by the user. When the time for exposure or release has been reached as indicated by the timer, the microprocessor sends a signal corresponding to the address (location) of a particular reservoir to the demultiplexer. The demultiplexer routes an input, such as an electric potential or current, to the reservoir addressed by the microprocessor.
  • Sensors
  • In an optional embodiment, the medical device includes a sensor or sensing component. For example, the sensor or sensing component can be located in a reservoir or can be attached to the device substrate. The sensor can operably communicate with the device, e.g., through a microprocessor, to control or modify the drug release variables, including dosage amount and frequency, time of release, effective rate of release, selection of drug or drug combination, and the like. The “sensing component” includes a component utilized in measuring or analyzing the presence, absence, or change in a chemical or ionic species, energy, or one or more physical properties (e.g., pH, pressure). Types of sensors include biosensors, chemical sensors, physical sensors, or optical sensors. Further examples of such sensors and sensor components are described in PCT WO 01/64344. The sensor or sensing component detects (or not) the species or property at the site of in vivo implantation (e.g., in a bodily fluid or tissue), and further may relay a signal to the microprocessor used for controlling release from the medical device, as detailed below and herein. Such a signal could provide feedback on and/or finely control the release of drug and electrical stimulation. In one possible embodiment, the sensor could be used to sense an upcoming neural event, such as an epileptic seizure.
  • There are several different options for receiving and analyzing data obtained with devices located in the medical device. For example, the medical device may be controlled by local microprocessors or remote control. Biosensor information may provide input to the controller to determine the time and type of activation automatically, with human intervention, or a combination thereof. In one embodiment, the medical device includes a biosensor that can detect an oncoming of a biological event, and the device can initiate or alter the drug therapy or stimulation therapy or both provided by the medical device such that the effects of the biological event are limited or prevented.
  • Typically, the operation of the medical device will be controlled by an on-board (i.e., within the package) microprocessor. After analysis and processing, the output signal can be stored in a writeable computer memory chip, and/or can be sent (e.g., wirelessly) to a remote location away from the microchip. Power can be supplied locally by a battery or remotely by wireless transmission.
  • In one embodiment, the medical device includes one or more biosensors (which may be sealed in reservoirs until needed for use) that are capable of detecting and/or measuring signals within the body of a patient. As used herein, the term “biosensor” includes sensing devices that transduce the chemical potential of an analyte of interest into an electrical signal (e.g., an ion selective field effect transistor or ISFET), as well as electrodes that measure electrical signals directly or indirectly (e.g., by converting a mechanical or thermal energy into an electrical signal). For example, the biosensor may measure intrinsic electrical signals (electrocardiogram (ECG), electroencephalogram (EEG), evoked response, or other neural signals), pressure, temperature, pH, or loads on tissue structures at various in vivo locations. The electrical signal from the biosensor can then be measured, for example by a microprocessor/controller, which then can transmit the information to a remote controller, another local controller, or both. For example, the system can be used to relay or record information on the patient's vital signs or the implant environment, such as drug concentration.
  • Packaging
  • The medical devices described herein will typically be packaged into a hermetically sealed package, e.g., in a titanium encasement, which essentially exposes only the reservoir caps and stimulation electrodes. These microelectronic device packages are typically made of an insulating or dielectric material such as aluminum oxide or silicon nitride. Low cost packages can also be made of ceramics, plastics, or reinforced epoxies. The package serves to allow all components of the device to be placed in close proximity and to facilitate the interconnection of components to power sources and to each other, while protecting the electronics from the environment.
  • In one embodiment, the device comprises an outer layer comprising a single layer or a multi-layer/laminate structure that includes combinations of silicon oxide (SiOx), silicon nitride (SiNx) or silicon carbide (SiCx). In one embodiment, photoresist is patterned on top of the dielectric to protect it from etching except on the reservoir caps covering each reservoir. The dielectric material can be etched by physical or chemical etching techniques. The purpose of this film is to protect the reservoir caps and leads from corrosion, degradation, delamination, or dissolution in all areas where they do not have to be exposed to the surrounding environment, to shield electrically active components from the in vivo environment, and to enhance the biostability of the device materials.
  • Methods of Making the Devices
  • The devices and modules described herein can be made using techniques known in the art and/or described herein. Certain methods are described in U.S. Pat. No. 5,797,898; U.S. Pat. No. 6,123,861; U.S. Patent Application Publication No. 2002/0107470; and U.S. Patent Application Publication No. 2002/0151776, which are hereby incorporated by reference in their entirety. One skilled in the art can fabricate, or obtain the components and assemble them into, the medical devices described herein. The assembly of a complete medical device may involve a number of packaging steps which can include (1) attachment of electrical leads to a microchip drug delivery device, (2) filling of the reservoirs with a release system comprising drug, (3) sealing the reservoirs, (4) integration with electronic components and power sources and electrodes, and (5) placing the drug delivery module and associated components within a single enclosure or “package.”
  • Operation and Use of the Devices
  • A number of treatment regiments utilizing electrical stimulation and drug therapy can be employed for a vast array of physiological disorders or pathological conditions associated with the sympathetic and parasympathetic nervous system. Physiological disorders that may be treated include hyperhydrosis, complex regional pain syndrome and other pain syndromes such as headaches, cluster headaches, abnormal cardiac sympathetic output, cardiac contractility, excessive blushing condition, hypertension, renal disease, heart failure, angina, hypertension, and intestinal motility disorders, dry eye or mouth disorders, sexual dysfunction, asthma, liver disorders, pancreas disorders, and heart disorders, pulmonary disorders, gastrointestinal disorders, and billatory disorders. The number of disorders to be treated is limited only by the number, variety, and placement of electrodes (or combinations of multiple electrodes) along the sympathetic nervous system. In one embodiment, complications can be largely minimized, or possibly eliminated, by the use of chronic or intermittent electrical stimulation and/or sensing aberrant neuronal signaling continuous or intermittent drug infusion. The reasons are many, and include the possibility of changing which contacts of a multipolar lead are stimulated to minimize stimulating a portion of the ganglion. Adjusting parameters, such as frequency, pulse amplitude, and/or pulse width, of the electronic stimulation should also minimize adverse consequences and increase beneficiary effects.
  • In many instances, the preferred effect is to stimulate or reversibly block nervous tissue. Use of the term “block” or “blockade” in this application means disruption, modulation, and inhibition of nerve impulse transmission. Abnormal regulation can result in an excitation of the pathways or a loss of inhibition of the pathways, with the net result being an increased perception or response. Therapeutic measures can be directed towards either blocking the transmission of signals or stimulating inhibitory feedback. Electrical stimulation permits such stimulation of the target neural structures and, equally importantly, prevents the total destruction of the nervous system. Additionally, electrical stimulation parameters can be adjusted so that benefits are maximized and side effects are minimized.
  • In one embodiment of an active-release embodiment, the medical device can be controlled by a pre-programmed microprocessor to open one or a portion of the reservoirs intermittently (that is, a different one or more reservoirs after predetermined time intervals) to effect release intermittently, e.g., in a pulsatile manner. In other variations, the microprocessor (and thus release) is controlled by a sensor, e.g., a biosensor, or by remote control. The microprocessor also coordinates and controls delivery of the electrical signals to the electrodes connected to the neural tissue to be stimulated.
  • Further details on methods of using microchip devices for controlled release of drug are described in U.S. Pat. No. 5,797,898 and U.S. Pat. No. 6,123,861; and PCT WO 02/30401, WO 02/30264, WO 01/91902, WO 01/64344, WO 01/41736, WO 01/35928, and WO 01/12157.
  • In one embodiment, the drug delivery module is for subcutaneous drug delivery, to release drugs into the subcutaneous region which then diffuse into regional tissue or into body fluid-containing structures, including, for example, the cardiovascular system, the lymphatic system, the respiratory system, the digestive system, the central nervous system (cerebral spinal fluid), the genitourinary system, or the eyes. With the device, a drug can be administered to treat one or more of these tissues or structures or fluids within the structures, or can be transported through these tissues or structures to distal treatment locations or to cellular binding sites.
  • In another embodiment, the drug delivery module provides direct communication between the source of the drug (e.g., a reservoir) and the particular fluid-containing structure of interest, so that when drug is released, it enters the fluid without contacting the subcutaneous region. This could be useful, for example, for administrating a drug that if released in the subcutaneous space would cause inflammation, irritation, other tissue injury/dysfunction, or would diffuse too slowly into a fluid-containing structure to achieve an effective concentration in the fluid (e.g., because of clearance mechanisms). For example, the device could directly release a therapeutic agent into one or more body cavities or tissue lumens, including an intrathecal space, an intracranial space, an abdominal/peritoneal space, a thoracic space, an intrapericardial space, a renal space, or a hepatic space. For example, the substrate could have a shape that is compatible with the fluid-containing structure, such as tubular to reside within a blood vessel (e.g., intravascular), rounded and buoyant to float in the bladder, or curved to conform to the eye. The control circuitry and power needed to activate the reservoir caps can be located in a control module outside or inside of the fluid-containing structure. If the control module is located external to the fluid-containing structure, electrical conductors can be used to connect to the reservoir caps.
  • In one embodiment, a drug delivery module includes a catheter which can be inserted into the tissue lumen or structure of interest and which has one or more drug-containing reservoirs fabricated therein, for example at a distal portion of the catheter. FIG. 5 illustrates one embodiment of a medical device 50 which includes a catheter 52 which can be inserted into the tissue lumen or structure of interest and which has one or more drug-containing reservoirs 54 fabricated therein, for example at a distal portion 53 of the catheter. The body of the catheter serves as the substrate in which the reservoirs are fabricated, for example using soft lithography or other techniques known in the art. For example, tens or hundreds of micro-reservoirs could be arrayed around the catheter body at the distal tip portion. The reservoirs are hermetically sealed by conductive reservoir caps, which are electrically connected to a power source and can be disintegrated by electrothermal ablation as described herein. Advantageously, the power source and control hardware 56 can be located at a proximal end of the catheter 55, so they need not fit into or be located at the delivery site. The electrical traces could be built into the catheter body or supported on an inner or outer surface of the catheter body. FIGS. 6A-C illustrates a catheter tip portion 60 which has reservoirs 62 is substrate/catheter body 64, wherein the reservoirs contain therapeutic agent 65 and are covered by conductive reservoir caps 66, each of which are connected to input and output electrical leads 68 and 69, respectively. See U.S. Patent Application No. 2002/0111601, which disclosed another embodiment of a catheter type implantable medical device, one that utilizes a different reservoir opening technology than the electrothermal ablation system described herein. Optionally, the catheter can have an internal fluid passageway extending between a proximal end portion and a distal end portion. The fluid passageway can be in communication with an infusion pump and a reservoir (e.g., a refillable reservoir containing a therapeutic fluid), so that the device can deliver a therapeutic fluid through the passageway to the delivery site. In one embodiment, the pump is placed abdominally in a subcutaneous pocket, and the catheter is inserted into the intrathecal space of the spine, tunneled under the skin and connected to the pump. Such an embodiment could be used, for example, in the management of chronic pain or for spasticity therapy. The microarray of drug-containing reservoirs can be provided (i) on or in the body of the catheter, (ii) in a substrate device that is located at the proximal end of the catheter and releases drug into an infusion fluid pumped across the microarray openings to form a fluid/drug mixture that is pumped through the fluid passageway of the catheter, or (iii) in a combination of these. In one embodiment, the distal tip portion of the catheter includes one or more biological sensors to detect patient conditions that indicate the desirability or need for drug release. The sensors could extend from or be on the surface of the tip portion of the catheter body or could be located within one or more reservoirs. In one version, the device could include one catheter having a sensor on the distal end portion for implantation at a first site in vivo, and a second catheter having drug-containing reservoirs on the distal end portion for implantation at a second site in vivo.
  • Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.

Claims (19)

1. A system for electrical stimulation of neural tissue in a patient and controlled drug delivery to the patient, comprising:
a drug delivery module suitable for implantation in the patient at a first site, the module comprising
a plurality of reservoirs containing at least one drug, each reservoir having at least one opening for release of the drug,
electrically conductive reservoir caps closing off the openings of the reservoirs, and
a power source and control circuitry for disintegrating the reservoir caps;
a stimulator module suitable for implantation in the patient at a second site, the stimulator comprising
an electrical signal generator, and
at least one stimulation electrode for operable engagement with a neural tissue of the patient, wherein the stimulation electrode is operably connected to the electrical signal generator; and
at least one microcontroller for controlling the drug delivery module and the stimulator module.
2. The system of claim 1, wherein the stimulation electrode comprises a peripheral nerve stimulation lead.
3. The system of claim 1, wherein the stimulation electrode comprises a deep brain catheter lead/electrode for treating movement disorders or tremors.
4. The system of claim 1, wherein a drug delivery device is configured for subcutaneous implantation.
5. The system of claim 1, wherein the drug delivery module comprises a flexible catheter which comprises the drug-containing reservoirs.
6. The system of claim 1, wherein the at least one microcontroller controls both the signal generator and the disintegration of the reservoir caps.
7. The system of claim 1, wherein the at least one microcontroller controls the drug delivery module by a telemetry signal.
8. The system of claim 1, wherein the at least one microcontroller controls the drug delivery module by a hard-wired signal.
9. The system of claim 1, wherein the at least one microcontroller is located in the drug delivery module.
10. The system of claim 1, wherein the at least one microcontroller is located in the stimulation module.
11. The system of claim 1, comprising two microcontrollers, one of which controls the stimulator module and the other which controls the drug delivery module.
12. The system of claim 11, wherein the first and second microcontroller are operably connected to each other.
13. The system of claim 1, wherein the drug delivery module comprises a pump for subcutaneous implantation and a catheter having a proximal end in fluid connection to the pump and a distal end for insertion into an intrathecal space, the drug-containing reservoirs being provided in the catheter in a configuration to release the drug into an infusion fluid pumped through the catheter.
14. The system of claim 13, wherein the power source and control circuitry are housed with the pump at a proximal end of the catheter and electrical traces are built into the catheter and operably connected to the reservoir caps covering reservoir openings at the distal end of the catheter.
15. The system of claim 1, wherein each of the reservoir caps is connected to an electrical input lead and to an electrical output lead.
16. A method for treating a patient, comprising:
implanting a drug delivery module in the patient, the drug delivery module being configured to provide controlled release of a drug to a first site in the patient;
implanting a neural stimulation module in the patient, the neural stimulation module being configures to stimulate a neural tissue at a second site in the patient; and
controlling with at least one microcontroller the controlled release of the drug and the stimulation of the neural tissue.
17. The method of claim 16, wherein the drug delivery module comprises a plurality of discrete reservoirs containing the drug, and a plurality of reservoir caps closing off openings in the reservoirs, and wherein release of the drug from the drug delivery module comprising disintegrating the reservoir caps.
18. The method of claim 16, wherein the stimulator module comprises an electrical signal generator and an electrical lead extending through a stimulation catheter and connecting to a stimulation electrode.
19. The method of claim 18, wherein the second site is selected from cutaneous nerves, somatic nerves, peripheral nerves, median nerves, peroneal nerves, ulnar nerves, ansalenticularis nerves, vagus nerves, carotid sinus, and the brain.
US12/572,899 2002-10-04 2009-10-02 Systems and devices for neural stimulation and controlled drug delivery Abandoned US20100023071A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US41601002P true 2002-10-04 2002-10-04
US10/679,763 US7599737B2 (en) 2002-10-04 2003-10-06 Medical device for neural stimulation and controlled drug delivery
US12/572,899 US20100023071A1 (en) 2002-10-04 2009-10-02 Systems and devices for neural stimulation and controlled drug delivery

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12/572,899 US20100023071A1 (en) 2002-10-04 2009-10-02 Systems and devices for neural stimulation and controlled drug delivery

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/679,763 Continuation US7599737B2 (en) 2002-10-04 2003-10-06 Medical device for neural stimulation and controlled drug delivery

Publications (1)

Publication Number Publication Date
US20100023071A1 true US20100023071A1 (en) 2010-01-28

Family

ID=32093798

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/679,763 Active 2024-11-13 US7599737B2 (en) 2002-10-04 2003-10-06 Medical device for neural stimulation and controlled drug delivery
US12/572,899 Abandoned US20100023071A1 (en) 2002-10-04 2009-10-02 Systems and devices for neural stimulation and controlled drug delivery

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/679,763 Active 2024-11-13 US7599737B2 (en) 2002-10-04 2003-10-06 Medical device for neural stimulation and controlled drug delivery

Country Status (4)

Country Link
US (2) US7599737B2 (en)
EP (1) EP1551499A1 (en)
AU (1) AU2003284018A1 (en)
WO (1) WO2004033034A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222649A1 (en) * 2009-03-02 2010-09-02 American Well Systems Remote medical servicing
US20110125078A1 (en) * 2009-11-25 2011-05-26 Medtronic, Inc. Optical stimulation therapy
US20120290025A1 (en) * 2011-05-12 2012-11-15 Medtronic, Inc. Leadless implantable medical device with osmotic pump
US20140122108A1 (en) * 2012-10-25 2014-05-01 Analyte Health, Inc. System and Method for Coordinating Payment for Healthcare Services
US9024394B2 (en) 2013-05-22 2015-05-05 Transient Electronics, Inc. Controlled transformation of non-transient electronics

Families Citing this family (151)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5289001A (en) * 2000-03-02 2001-09-12 Microchips Inc Microfabricated devices for the storage and selective exposure of chemicals and devices
AU2002241834B2 (en) 2001-01-09 2006-11-09 Microchips, Inc. Flexible microchip devices for opthalmic and other applications
US7493172B2 (en) * 2001-01-30 2009-02-17 Boston Scientific Neuromodulation Corp. Methods and systems for stimulating a nerve originating in an upper cervical spine area to treat a medical condition
US20050143789A1 (en) * 2001-01-30 2005-06-30 Whitehurst Todd K. Methods and systems for stimulating a peripheral nerve to treat chronic pain
US20060064140A1 (en) * 2001-01-30 2006-03-23 Whitehurst Todd K Methods and systems for stimulating a trigeminal nerve to treat a psychiatric disorder
US6978174B2 (en) 2002-04-08 2005-12-20 Ardian, Inc. Methods and devices for renal nerve blocking
US20070135875A1 (en) * 2002-04-08 2007-06-14 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US20080213331A1 (en) 2002-04-08 2008-09-04 Ardian, Inc. Methods and devices for renal nerve blocking
US8131371B2 (en) * 2002-04-08 2012-03-06 Ardian, Inc. Methods and apparatus for monopolar renal neuromodulation
US20060206150A1 (en) 2002-04-08 2006-09-14 Ardian, Inc. Methods and apparatus for treating acute myocardial infarction
US8347891B2 (en) 2002-04-08 2013-01-08 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for performing a non-continuous circumferential treatment of a body lumen
US20140018880A1 (en) 2002-04-08 2014-01-16 Medtronic Ardian Luxembourg S.A.R.L. Methods for monopolar renal neuromodulation
US7617005B2 (en) 2002-04-08 2009-11-10 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US9636174B2 (en) 2002-04-08 2017-05-02 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US8145317B2 (en) * 2002-04-08 2012-03-27 Ardian, Inc. Methods for renal neuromodulation
US7162303B2 (en) 2002-04-08 2007-01-09 Ardian, Inc. Renal nerve stimulation method and apparatus for treatment of patients
US20070129761A1 (en) 2002-04-08 2007-06-07 Ardian, Inc. Methods for treating heart arrhythmia
US8150519B2 (en) 2002-04-08 2012-04-03 Ardian, Inc. Methods and apparatus for bilateral renal neuromodulation
US9308044B2 (en) 2002-04-08 2016-04-12 Medtronic Ardian Luxembourg S.A.R.L. Methods for therapeutic renal neuromodulation
US7756583B2 (en) 2002-04-08 2010-07-13 Ardian, Inc. Methods and apparatus for intravascularly-induced neuromodulation
US9308043B2 (en) 2002-04-08 2016-04-12 Medtronic Ardian Luxembourg S.A.R.L. Methods for monopolar renal neuromodulation
US8774922B2 (en) 2002-04-08 2014-07-08 Medtronic Ardian Luxembourg S.A.R.L. Catheter apparatuses having expandable balloons for renal neuromodulation and associated systems and methods
US8774913B2 (en) 2002-04-08 2014-07-08 Medtronic Ardian Luxembourg S.A.R.L. Methods and apparatus for intravasculary-induced neuromodulation
US7853333B2 (en) 2002-04-08 2010-12-14 Ardian, Inc. Methods and apparatus for multi-vessel renal neuromodulation
US8145316B2 (en) 2002-04-08 2012-03-27 Ardian, Inc. Methods and apparatus for renal neuromodulation
US7653438B2 (en) 2002-04-08 2010-01-26 Ardian, Inc. Methods and apparatus for renal neuromodulation
US20040082859A1 (en) 2002-07-01 2004-04-29 Alan Schaer Method and apparatus employing ultrasound energy to treat body sphincters
EP1528940B1 (en) * 2002-08-16 2011-04-13 Microchips, Inc. Controlled release device and method
AU2003278766A1 (en) 2002-09-04 2004-03-29 Microchips, Inc. Method and device for the controlled delivery of parathyroid hormone
AT458534T (en) * 2002-10-04 2010-03-15 Microchips Inc A heart monitoring medical device for controlled drug delivery, as well as and / or cardiac stimulation
US8118722B2 (en) * 2003-03-07 2012-02-21 Neuronetics, Inc. Reducing discomfort caused by electrical stimulation
US7153256B2 (en) * 2003-03-07 2006-12-26 Neuronetics, Inc. Reducing discomfort caused by electrical stimulation
US20040226556A1 (en) 2003-05-13 2004-11-18 Deem Mark E. Apparatus for treating asthma using neurotoxin
US7114312B2 (en) * 2003-07-17 2006-10-03 Microchips, Inc. Low temperature methods for hermetically sealing reservoir devices
US20070036835A1 (en) * 2004-07-19 2007-02-15 Microchips, Inc. Hermetically Sealed Devices for Controlled Release or Exposure of Reservoir Contents
US20050055014A1 (en) * 2003-08-04 2005-03-10 Coppeta Jonathan R. Methods for accelerated release of material from a reservoir device
US20050102006A1 (en) * 2003-09-25 2005-05-12 Whitehurst Todd K. Skull-mounted electrical stimulation system
US7657312B2 (en) 2003-11-03 2010-02-02 Cardiac Pacemakers, Inc. Multi-site ventricular pacing therapy with parasympathetic stimulation
US8095197B2 (en) * 2003-11-03 2012-01-10 Microchips, Inc. Medical device for sensing glucose
WO2005062829A2 (en) * 2003-12-19 2005-07-14 Advanced Bionics Corporation Skull-mounted electrical stimulation system and method for treating patients
US7647114B2 (en) 2003-12-24 2010-01-12 Cardiac Pacemakers, Inc. Baroreflex modulation based on monitored cardiovascular parameter
US8024050B2 (en) 2003-12-24 2011-09-20 Cardiac Pacemakers, Inc. Lead for stimulating the baroreceptors in the pulmonary artery
US7869881B2 (en) 2003-12-24 2011-01-11 Cardiac Pacemakers, Inc. Baroreflex stimulator with integrated pressure sensor
US8126560B2 (en) 2003-12-24 2012-02-28 Cardiac Pacemakers, Inc. Stimulation lead for stimulating the baroreceptors in the pulmonary artery
US7651459B2 (en) * 2004-01-06 2010-01-26 Neuronetics, Inc. Method and apparatus for coil positioning for TMS studies
US8177702B2 (en) * 2004-04-15 2012-05-15 Neuronetics, Inc. Method and apparatus for determining the proximity of a TMS coil to a subject's head
US7601115B2 (en) * 2004-05-24 2009-10-13 Neuronetics, Inc. Seizure therapy method and apparatus
EP1765455A2 (en) * 2004-06-01 2007-03-28 Microchips, Inc. Devices and methods for measuring and enhancing drug or analyte transport to/from medical implant
US7537590B2 (en) * 2004-07-30 2009-05-26 Microchips, Inc. Multi-reservoir device for transdermal drug delivery and sensing
EP1627659A1 (en) * 2004-08-17 2006-02-22 Advanced Neuromodulation Systems, Inc. Electrical stimulation system and method for stimulating nerve tissue in the brain using a stimulation lead having a tip electrode, having at least five electrodes, or both
JP5107041B2 (en) 2004-09-01 2012-12-26 マイクロチップス・インコーポレーテッド For the controlled release or exposure of reservoir contents, the multi-cap reservoir bus device
CA2583911A1 (en) * 2004-10-28 2006-05-11 Microchips, Inc. Orthopedic and dental implant devices providing controlled drug delivery
US7857746B2 (en) * 2004-10-29 2010-12-28 Nueronetics, Inc. System and method to reduce discomfort using nerve stimulation
SG191562A1 (en) 2004-11-04 2013-07-31 Microchips Inc Compression cold welding process for forming vias
US7413846B2 (en) 2004-11-15 2008-08-19 Microchips, Inc. Fabrication methods and structures for micro-reservoir devices
EP1827388A2 (en) * 2004-12-14 2007-09-05 E-Pill Pharma Ltd. Local delivery of drugs or substances using electronic permeability increase
US8088058B2 (en) * 2005-01-20 2012-01-03 Neuronetics, Inc. Articulating arm
US20070060954A1 (en) * 2005-02-25 2007-03-15 Tracy Cameron Method of using spinal cord stimulation to treat neurological disorders or conditions
US20060199159A1 (en) * 2005-03-01 2006-09-07 Neuronetics, Inc. Head phantom for simulating the patient response to magnetic stimulation
US7396326B2 (en) * 2005-05-17 2008-07-08 Neuronetics, Inc. Ferrofluidic cooling and acoustical noise reduction in magnetic stimulators
US8309057B2 (en) * 2005-06-10 2012-11-13 The Invention Science Fund I, Llc Methods for elevating neurotrophic agents
WO2007001624A2 (en) * 2005-06-28 2007-01-04 Microchips, Inc. Medical and dental implant devices for controlled drug delivery
US7824324B2 (en) * 2005-07-27 2010-11-02 Neuronetics, Inc. Magnetic core for medical procedures
US20070073354A1 (en) 2005-09-26 2007-03-29 Knudson Mark B Neural blocking therapy
US7729773B2 (en) * 2005-10-19 2010-06-01 Advanced Neuromodualation Systems, Inc. Neural stimulation and optical monitoring systems and methods
WO2007055726A2 (en) * 2005-11-08 2007-05-18 The Regents Of The University Of California Devices and methods for stimulation of tissue
EP1948301B8 (en) * 2005-11-10 2014-03-12 ElectroCore LLC Electrical stimulation treatment of bronchial constriction
US9037247B2 (en) 2005-11-10 2015-05-19 ElectroCore, LLC Non-invasive treatment of bronchial constriction
US8812112B2 (en) 2005-11-10 2014-08-19 ElectroCore, LLC Electrical treatment of bronchial constriction
US7610103B2 (en) * 2005-12-19 2009-10-27 Boston Scientific Neuromodulation Corporation Electrode arrangement for nerve stimulation and methods of treating disorders
US7620451B2 (en) 2005-12-29 2009-11-17 Ardian, Inc. Methods and apparatus for pulsed electric field neuromodulation via an intra-to-extravascular approach
US8041428B2 (en) 2006-02-10 2011-10-18 Electrocore Llc Electrical stimulation treatment of hypotension
CN101400402A (en) 2006-02-10 2009-04-01 电子核心公司 Electrical stimulation treatment of hypotension
JP2009525806A (en) 2006-02-10 2009-07-16 エレクトロコア、インコーポレイテッド Low blood pressure electrical stimulation therapy
US8027718B2 (en) * 2006-03-07 2011-09-27 Mayo Foundation For Medical Education And Research Regional anesthetic
US8326431B2 (en) * 2006-04-28 2012-12-04 Medtronic, Inc. Implantable medical device for the concurrent treatment of a plurality of neurological disorders and method therefore
CN101438410A (en) * 2006-05-05 2009-05-20 皇家飞利浦电子股份有限公司 Device and method for the controlled release of a predefined quantity of a substance
US9026205B2 (en) 2006-05-25 2015-05-05 Cochlear Limited Stimulating device
US8401654B1 (en) * 2006-06-30 2013-03-19 Boston Scientific Neuromodulation Corporation Methods and systems for treating one or more effects of deafferentation
US20080046080A1 (en) * 2006-07-07 2008-02-21 Interuniversitair Microelektronica Centrum (Imec) Method for forming packaged microelectronic devices and devices thus obtained
WO2008008845A2 (en) * 2006-07-11 2008-01-17 Microchips, Inc. Multi-reservoir pump device for dialysis, biosensing, or delivery of substances
US8170668B2 (en) 2006-07-14 2012-05-01 Cardiac Pacemakers, Inc. Baroreflex sensitivity monitoring and trending for tachyarrhythmia detection and therapy
WO2008017042A1 (en) * 2006-08-03 2008-02-07 Microchips, Inc. Cardiac biosensor devices and methods
EP2120555A1 (en) * 2007-01-31 2009-11-25 Adam Heller Methods and compositions for the treatment of pain
US7813811B2 (en) 2007-02-08 2010-10-12 Neuropace, Inc. Refillable reservoir lead systems
US7844345B2 (en) * 2007-02-08 2010-11-30 Neuropace, Inc. Drug eluting lead systems
US20100284984A1 (en) * 2007-07-30 2010-11-11 University Of Rochester Adenosine and its mimetics. modulators, transport inhibitors, and receptor agonists as a therapeutic tool to replace or improve the efficacy of deep brain stimulation
WO2009059050A2 (en) * 2007-10-30 2009-05-07 The Regents Of The University Of Colorado Tlr modulators and methods for using the same
US20090204173A1 (en) 2007-11-05 2009-08-13 Zi-Ping Fang Multi-Frequency Neural Treatments and Associated Systems and Methods
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
US9884200B2 (en) 2008-03-10 2018-02-06 Neuronetics, Inc. Apparatus for coil positioning for TMS studies
US8216287B2 (en) * 2008-03-31 2012-07-10 Cochlear Limited Tangential force resistant coupling for a prosthetic device
WO2009124233A1 (en) 2008-04-04 2009-10-08 Enteromedics, Inc. Methods and systems for glucose regulation
CN102014779B (en) 2008-05-09 2014-10-22 赫莱拉公司 A system, components and methods for treating bronchial tree
DE102008024447A1 (en) 2008-05-20 2009-11-26 Biotronik Crm Patent Ag Implantable shock electrode line and implantable defibrillation
EP2376011A4 (en) 2009-01-09 2012-08-22 Recor Medical Inc Methods and apparatus for treatment of mitral valve insufficiency
US9700721B2 (en) * 2012-05-14 2017-07-11 Autonomic Technologies, Inc. Stimulation method for treatment of ocular conditions
US8255057B2 (en) 2009-01-29 2012-08-28 Nevro Corporation Systems and methods for producing asynchronous neural responses to treat pain and/or other patient conditions
EP3228350A1 (en) 2009-04-22 2017-10-11 Nevro Corporation Selective high frequency spinal cord modulation for inhibiting pain with reduced side effects, and associated systems and methods
US8414559B2 (en) 2009-05-07 2013-04-09 Rainbow Medical Ltd. Gastroretentive duodenal pill
US8498710B2 (en) 2009-07-28 2013-07-30 Nevro Corporation Linked area parameter adjustment for spinal cord stimulation and associated systems and methods
CA2779135C (en) 2009-10-27 2018-09-04 Innovative Pulmonary Solutions, Inc. Delivery devices with coolable energy emitting assemblies
US8911439B2 (en) 2009-11-11 2014-12-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
AU2010319477A1 (en) 2009-11-11 2012-05-24 Holaira, Inc. Systems, apparatuses, and methods for treating tissue and controlling stenosis
US8965482B2 (en) 2010-09-30 2015-02-24 Nevro Corporation Systems and methods for positioning implanted devices in a patient
US8805519B2 (en) 2010-09-30 2014-08-12 Nevro Corporation Systems and methods for detecting intrathecal penetration
EP2632373B1 (en) 2010-10-25 2018-07-18 Medtronic Ardian Luxembourg S.à.r.l. System for evaluation and feedback of neuromodulation treatment
US9821159B2 (en) 2010-11-16 2017-11-21 The Board Of Trustees Of The Leland Stanford Junior University Stimulation devices and methods
RU2013127313A (en) 2010-11-16 2014-12-27 Те Борд Оф Трастиз Оф Те Лилэнд Стэнфорд Джуниор Юниверсити Systems and methods for treating dry eye
US8649874B2 (en) 2010-11-30 2014-02-11 Nevro Corporation Extended pain relief via high frequency spinal cord modulation, and associated systems and methods
US8424388B2 (en) * 2011-01-28 2013-04-23 Medtronic, Inc. Implantable capacitive pressure sensor apparatus and methods regarding same
EP2741810A4 (en) 2011-08-12 2015-05-20 Micron Devices Llc Microwave field stimulator
US10245436B2 (en) * 2012-07-17 2019-04-02 Stimwave Technologies Incorporated Miniature implantable device and methods
WO2012103519A2 (en) 2011-01-28 2012-08-02 Stimwave Technologies Incorporated Neural stimulator system
CN107789730A (en) 2011-07-29 2018-03-13 米克伦设备有限责任公司 Remote control of power or polarity selection for a neural stimulator
US9220897B2 (en) 2011-04-04 2015-12-29 Micron Devices Llc Implantable lead
JP2014514069A (en) * 2011-04-04 2014-06-19 スティムウェイブ テクノロジーズ インコーポレイテッド Implantable leads
US8663202B2 (en) * 2011-05-20 2014-03-04 Advastim, Inc. Wireless remote neurostimulator
EP2747642A2 (en) * 2011-08-25 2014-07-02 Microchips, Inc. Space-efficient containment devices and method of making same
US9327121B2 (en) 2011-09-08 2016-05-03 Nevro Corporation Selective high frequency spinal cord modulation for inhibiting pain, including cephalic and/or total body pain with reduced side effects, and associated systems and methods
WO2013040549A1 (en) 2011-09-15 2013-03-21 Stimwave Technologies Incorporated Relay module for implant
AU2012318586B2 (en) 2011-10-04 2017-06-08 Nevro Corporation Modeling positions of implanted devices in a patient
JP6441679B2 (en) 2011-12-09 2018-12-19 メタベンション インコーポレイテッド Therapeutic neuromodulation of the liver system
CA2862443C (en) * 2011-12-30 2018-09-11 Kibur Medical, Inc. Implantable devices and methods for the evaluation of active agents
US8676331B2 (en) 2012-04-02 2014-03-18 Nevro Corporation Devices for controlling spinal cord modulation for inhibiting pain, and associated systems and methods, including controllers for automated parameter selection
US8903502B2 (en) 2012-05-21 2014-12-02 Micron Devices Llc Methods and devices for modulating excitable tissue of the exiting spinal nerves
US9833614B1 (en) 2012-06-22 2017-12-05 Nevro Corp. Autonomic nervous system control via high frequency spinal cord modulation, and associated systems and methods
US20140110296A1 (en) 2012-10-19 2014-04-24 Medtronic Ardian Luxembourg S.A.R.L. Packaging for Catheter Treatment Devices and Associated Devices, Systems, and Methods
US9919103B2 (en) 2012-12-21 2018-03-20 Microchips Biotech, Inc. Implantable medical device for minimally-invasive insertion
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
SG11201506675PA (en) 2013-02-28 2015-09-29 Microchips Biotech Inc Implantable medical device for minimally-invasive insertion
US9265956B2 (en) 2013-03-08 2016-02-23 Oculeve, Inc. Devices and methods for treating dry eye in animals
WO2014165124A1 (en) 2013-03-12 2014-10-09 Oculeve, Inc. Implant delivery devices, systems, and methods
WO2014172693A2 (en) 2013-04-19 2014-10-23 Oculeve, Inc. Nasal stimulation devices and methods
KR20160039575A (en) 2013-05-30 2016-04-11 그라함 에이치. 크리시 Topical neurological stimulation
US9895539B1 (en) 2013-06-10 2018-02-20 Nevro Corp. Methods and systems for disease treatment using electrical stimulation
US10019555B2 (en) 2013-10-19 2018-07-10 Cohero Health, Inc. Interactive respiratory device usage tracking system
US10149978B1 (en) 2013-11-07 2018-12-11 Nevro Corp. Spinal cord modulation for inhibiting pain via short pulse width waveforms, and associated systems and methods
MX2016011118A (en) 2014-02-25 2016-12-05 Oculeve Inc Polymer formulations for nasolacrimal stimulation.
US9980766B1 (en) 2014-03-28 2018-05-29 Medtronic Ardian Luxembourg S.A.R.L. Methods and systems for renal neuromodulation
US10194980B1 (en) 2014-03-28 2019-02-05 Medtronic Ardian Luxembourg S.A.R.L. Methods for catheter-based renal neuromodulation
US10194979B1 (en) 2014-03-28 2019-02-05 Medtronic Ardian Luxembourg S.A.R.L. Methods for catheter-based renal neuromodulation
CN106794339A (en) 2014-05-12 2017-05-31 米克伦设备有限责任公司 Remote RF power system with low profile transmitting antenna
US9687652B2 (en) 2014-07-25 2017-06-27 Oculeve, Inc. Stimulation patterns for treating dry eye
US10207108B2 (en) 2014-10-22 2019-02-19 Oculeve, Inc. Implantable nasal stimulator systems and methods
BR112017008267A2 (en) 2014-10-22 2017-12-19 Oculeve Inc devices and methods for treating dry eye
WO2016065211A1 (en) 2014-10-22 2016-04-28 Oculeve, Inc. Contact lens for increasing tear production
US9675812B2 (en) 2015-04-01 2017-06-13 Elwha Llc Implantable heart treatment systems, devices, and methods
US9682245B2 (en) 2015-04-01 2017-06-20 Elwha Llc Implantable heart treatment systems, devices, and methods
US9700664B2 (en) 2015-04-01 2017-07-11 Elwha Llc Implantable heart treatment systems, devices, and methods
US10252048B2 (en) 2016-02-19 2019-04-09 Oculeve, Inc. Nasal stimulation for rhinitis, nasal congestion, and ocular allergies

Citations (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4360019A (en) * 1979-02-28 1982-11-23 Andros Incorporated Implantable infusion device
US4731051A (en) * 1979-04-27 1988-03-15 The Johns Hopkins University Programmable control means for providing safe and controlled medication infusion
US5041107A (en) * 1989-10-06 1991-08-20 Cardiac Pacemakers, Inc. Electrically controllable, non-occluding, body implantable drug delivery system
US5167625A (en) * 1990-10-09 1992-12-01 Sarcos Group Multiple vesicle implantable drug delivery system
US5200051A (en) * 1988-11-14 1993-04-06 I-Stat Corporation Wholly microfabricated biosensors and process for the manufacture and use thereof
US5252294A (en) * 1988-06-01 1993-10-12 Messerschmitt-Bolkow-Blohm Gmbh Micromechanical structure
US5324316A (en) * 1991-12-18 1994-06-28 Alfred E. Mann Foundation For Scientific Research Implantable microstimulator
US5366454A (en) * 1993-03-17 1994-11-22 La Corporation De L'ecole Polytechnique Implantable medication dispensing device
US5368588A (en) * 1993-02-26 1994-11-29 Bettinger; David S. Parenteral fluid medication reservoir pump
US5368704A (en) * 1993-08-06 1994-11-29 Teknekron Corporation Micro-electrochemical valves and method
US5380272A (en) * 1993-01-28 1995-01-10 Scientific Innovations Ltd. Transcutaneous drug delivery applicator
US5493177A (en) * 1990-12-03 1996-02-20 The Regents Of The University Of California Sealed micromachined vacuum and gas filled devices
US5504026A (en) * 1995-04-14 1996-04-02 Analog Devices, Inc. Methods for planarization and encapsulation of micromechanical devices in semiconductor processes
US5524338A (en) * 1991-10-22 1996-06-11 Pi Medical Corporation Method of making implantable microelectrode
US5662689A (en) * 1995-09-08 1997-09-02 Medtronic, Inc. Method and apparatus for alleviating cardioversion shock pain
US5797898A (en) * 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
US5807397A (en) * 1995-01-04 1998-09-15 Plexus, Inc. Implantable stimulator with replenishable, high value capacitive power source and method therefor
US5949187A (en) * 1997-07-29 1999-09-07 Motorola, Inc. Organic electroluminescent device with plural microcavities
US5971931A (en) * 1994-03-29 1999-10-26 Raff; Gilbert Lewis Biologic micromonitoring methods and systems
US5989445A (en) * 1995-06-09 1999-11-23 The Regents Of The University Of Michigan Microchannel system for fluid delivery
US6001090A (en) * 1998-02-09 1999-12-14 Lenhart; Douglas Thermal pharmaceutical delivery system
US6016449A (en) * 1997-10-27 2000-01-18 Neuropace, Inc. System for treatment of neurological disorders
US6051017A (en) * 1996-02-20 2000-04-18 Advanced Bionics Corporation Implantable microstimulator and systems employing the same
US6081736A (en) * 1997-10-20 2000-06-27 Alfred E. Mann Foundation Implantable enzyme-based monitoring systems adapted for long term use
US6114658A (en) * 1996-03-15 2000-09-05 Fraunhofer-Gesellschaft Zur Forderung Der Angewandten Forschung E.V. Device for the encapsulated reception of a material
US6129685A (en) * 1994-02-09 2000-10-10 The University Of Iowa Research Foundation Stereotactic hypothalamic obesity probe
US6161047A (en) * 1998-04-30 2000-12-12 Medtronic Inc. Apparatus and method for expanding a stimulation lead body in situ
US6178349B1 (en) * 1999-04-15 2001-01-23 Medtronic, Inc. Drug delivery neural stimulation device for treatment of cardiovascular disorders
US6243608B1 (en) * 1998-06-12 2001-06-05 Intermedics Inc. Implantable device with optical telemetry
US6289237B1 (en) * 1998-12-22 2001-09-11 University Of Pittsburgh Of The Commonwealth System Of Higher Education Apparatus for energizing a remote station and related method
US6319241B1 (en) * 1998-04-30 2001-11-20 Medtronic, Inc. Techniques for positioning therapy delivery elements within a spinal cord or a brain
US6334859B1 (en) * 1999-07-26 2002-01-01 Zuli Holdings Ltd. Subcutaneous apparatus and subcutaneous method for treating bodily tissues with electricity or medicaments
US6349232B1 (en) * 1997-07-11 2002-02-19 Pets 'n People Ltd. Apparatus and method for dispensing pet care substances
US6384353B1 (en) * 2000-02-01 2002-05-07 Motorola, Inc. Micro-electromechanical system device
US6436853B2 (en) * 1998-12-03 2002-08-20 University Of Michigan Microstructures
US6480730B2 (en) * 1998-10-05 2002-11-12 The Regents Of The University Of California Chemical sensor system
US6491666B1 (en) * 1999-11-17 2002-12-10 Microchips, Inc. Microfabricated devices for the delivery of molecules into a carrier fluid
US20020187260A1 (en) * 2001-05-30 2002-12-12 Sheppard Norman F. Conformal coated microchip reservoir devices
US6527762B1 (en) * 1999-08-18 2003-03-04 Microchips, Inc. Thermally-activated microchip chemical delivery devices
US6551838B2 (en) * 2000-03-02 2003-04-22 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
US6571125B2 (en) * 2001-02-12 2003-05-27 Medtronic, Inc. Drug delivery device
US6587719B1 (en) * 1999-07-01 2003-07-01 Cyberonics, Inc. Treatment of obesity by bilateral vagus nerve stimulation
US6666821B2 (en) * 2001-01-08 2003-12-23 Medtronic, Inc. Sensor system
US6733485B1 (en) * 2001-05-25 2004-05-11 Advanced Bionics Corporation Microstimulator-based electrochemotherapy methods and systems
US6757560B1 (en) * 1999-04-09 2004-06-29 Novosis Pharma Ag Transdermal delivery system (TDS) with electrode network
US6908770B1 (en) * 1998-07-16 2005-06-21 Board Of Regents, The University Of Texas System Fluid based analysis of multiple analytes by a sensor array

Family Cites Families (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5058584A (en) 1990-08-30 1991-10-22 Medtronic, Inc. Method and apparatus for epidural burst stimulation for angina pectoris
US5199428A (en) 1991-03-22 1993-04-06 Medtronic, Inc. Implantable electrical nerve stimulator/pacemaker with ischemia for decreasing cardiac workload
US7611533B2 (en) 1995-06-07 2009-11-03 Cook Incorporated Coated implantable medical device
US5824021A (en) 1996-04-25 1998-10-20 Medtronic Inc. Method and apparatus for providing feedback to spinal cord stimulation for angina
IN184589B (en) 1996-10-16 2000-09-09 Alza Corp A method for preparing a stable protein composition
DE19716683C1 (en) 1997-04-21 1998-06-04 Fraunhofer Ges Forschung Miniature encapsulation device for sensitive materials
US6058331A (en) 1998-04-27 2000-05-02 Medtronic, Inc. Apparatus and method for treating peripheral vascular disease and organ ischemia by electrical stimulation with closed loop feedback control
US6941171B2 (en) 1998-07-06 2005-09-06 Advanced Bionics Corporation Implantable stimulator methods for treatment of incontinence and pain
US6923784B2 (en) 1999-04-30 2005-08-02 Medtronic, Inc. Therapeutic treatment of disorders based on timing information
US7190997B1 (en) * 1999-06-04 2007-03-13 Impulse Dynamics Nv Drug delivery device
US6804558B2 (en) 1999-07-07 2004-10-12 Medtronic, Inc. System and method of communicating between an implantable medical device and a remote computer system or health care provider
US6442434B1 (en) 1999-10-19 2002-08-27 Abiomed, Inc. Methods and apparatus for providing a sufficiently stable power to a load in an energy transfer system
WO2001037926A1 (en) 1999-11-22 2001-05-31 Abiomed, Inc. Apparatus for transferring energy across a boundary
DE60027458T2 (en) 1999-12-10 2007-07-05 Massachusetts Institute Of Technology, Cambridge Microchip drug administration systems and manufacturing processes
AU6512801A (en) 2000-05-30 2001-12-11 Massachusetts Inst Technology Methods and devices for sealing microchip reservoir devices
AU6847301A (en) 2000-06-20 2002-01-02 Advanced Bionics Corp Apparatus for treatment of mood and/or anxiety disorders by electrical brain stimulation and/or drug infusion
WO2002030264A2 (en) 2000-10-10 2002-04-18 Microchips, Inc. Microchip reservoir devices using wireless transmission of power and data
US6773429B2 (en) 2000-10-11 2004-08-10 Microchips, Inc. Microchip reservoir devices and facilitated corrosion of electrodes
WO2002034330A2 (en) 2000-10-26 2002-05-02 Medtronic, Inc. Method and apparatus to minimize the effects of a cardiac insult
US7010345B2 (en) 2000-10-26 2006-03-07 Medtronic, Inc. Method and apparatus to minimize effects of a cardiac insult
JP4177102B2 (en) 2000-10-26 2008-11-05 メドトロニック・インコーポレーテッド Apparatus for improving cardiac function and cardiac efficiency
US6950707B2 (en) * 2000-11-21 2005-09-27 Advanced Bionics Corporation Systems and methods for treatment of obesity and eating disorders by electrical brain stimulation and/or drug infusion
DE10063612C2 (en) 2000-12-20 2002-11-07 Fraunhofer Ges Forschung Microsystem for control of drug release from a drug reservoir and implant Microsystems
AU2002241834B2 (en) 2001-01-09 2006-11-09 Microchips, Inc. Flexible microchip devices for opthalmic and other applications
US6926670B2 (en) 2001-01-22 2005-08-09 Integrated Sensing Systems, Inc. Wireless MEMS capacitive sensor for physiologic parameter measurement
US7181287B2 (en) 2001-02-13 2007-02-20 Second Sight Medical Products, Inc. Implantable drug delivery device
US7338522B2 (en) 2001-02-13 2008-03-04 Second Sight Medical Products, Inc. Implantable retinal electrode array configuration for minimal retinal damage and method of reducing retinal stress
US7097775B2 (en) * 2001-10-26 2006-08-29 Second Sight Medical Products, Inc. Coated microfluidic delivery system
US20020144548A1 (en) 2001-04-06 2002-10-10 Cohn Michael B. High precision accelerometer
EP1395335A1 (en) 2001-05-29 2004-03-10 Medtronic, Inc. Closed-loop neuromodulation for prevention and treatment of cardiac conditions
WO2002099457A1 (en) 2001-05-31 2002-12-12 Massachusetts Inst Technology Microchip devices with improved reservoir opening
DE60202468T2 (en) 2001-06-28 2006-02-16 Microchips, Inc., Bedford A method for hermetically seal microchip reservoir devices
US6970741B1 (en) * 2001-09-18 2005-11-29 Advanced Bionics Corporation Monitoring, preventing, and treating rejection of transplanted organs
AU2003278766A1 (en) * 2002-09-04 2004-03-29 Microchips, Inc. Method and device for the controlled delivery of parathyroid hormone
KR101471731B1 (en) 2003-09-11 2014-12-15 테라노스, 인코포레이티드 Medical device for analyte monitoring and drug delivery

Patent Citations (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4360019A (en) * 1979-02-28 1982-11-23 Andros Incorporated Implantable infusion device
US4731051A (en) * 1979-04-27 1988-03-15 The Johns Hopkins University Programmable control means for providing safe and controlled medication infusion
US5252294A (en) * 1988-06-01 1993-10-12 Messerschmitt-Bolkow-Blohm Gmbh Micromechanical structure
US5200051A (en) * 1988-11-14 1993-04-06 I-Stat Corporation Wholly microfabricated biosensors and process for the manufacture and use thereof
US5041107A (en) * 1989-10-06 1991-08-20 Cardiac Pacemakers, Inc. Electrically controllable, non-occluding, body implantable drug delivery system
US5167625A (en) * 1990-10-09 1992-12-01 Sarcos Group Multiple vesicle implantable drug delivery system
US5493177A (en) * 1990-12-03 1996-02-20 The Regents Of The University Of California Sealed micromachined vacuum and gas filled devices
US5524338A (en) * 1991-10-22 1996-06-11 Pi Medical Corporation Method of making implantable microelectrode
US5324316A (en) * 1991-12-18 1994-06-28 Alfred E. Mann Foundation For Scientific Research Implantable microstimulator
US5380272A (en) * 1993-01-28 1995-01-10 Scientific Innovations Ltd. Transcutaneous drug delivery applicator
US5368588A (en) * 1993-02-26 1994-11-29 Bettinger; David S. Parenteral fluid medication reservoir pump
US5366454A (en) * 1993-03-17 1994-11-22 La Corporation De L'ecole Polytechnique Implantable medication dispensing device
US5368704A (en) * 1993-08-06 1994-11-29 Teknekron Corporation Micro-electrochemical valves and method
US6129685A (en) * 1994-02-09 2000-10-10 The University Of Iowa Research Foundation Stereotactic hypothalamic obesity probe
US5971931A (en) * 1994-03-29 1999-10-26 Raff; Gilbert Lewis Biologic micromonitoring methods and systems
US5807397A (en) * 1995-01-04 1998-09-15 Plexus, Inc. Implantable stimulator with replenishable, high value capacitive power source and method therefor
US5504026A (en) * 1995-04-14 1996-04-02 Analog Devices, Inc. Methods for planarization and encapsulation of micromechanical devices in semiconductor processes
US5989445A (en) * 1995-06-09 1999-11-23 The Regents Of The University Of Michigan Microchannel system for fluid delivery
US5662689A (en) * 1995-09-08 1997-09-02 Medtronic, Inc. Method and apparatus for alleviating cardioversion shock pain
US6051017A (en) * 1996-02-20 2000-04-18 Advanced Bionics Corporation Implantable microstimulator and systems employing the same
US6185455B1 (en) * 1996-02-20 2001-02-06 Advanced Bionics Corporation Method of reducing the incidence of medical complications using implantable microstimulators
US6214032B1 (en) * 1996-02-20 2001-04-10 Advanced Bionics Corporation System for implanting a microstimulator
US6114658A (en) * 1996-03-15 2000-09-05 Fraunhofer-Gesellschaft Zur Forderung Der Angewandten Forschung E.V. Device for the encapsulated reception of a material
US6123861A (en) * 1996-07-02 2000-09-26 Massachusetts Institute Of Technology Fabrication of microchip drug delivery devices
US5797898A (en) * 1996-07-02 1998-08-25 Massachusetts Institute Of Technology Microchip drug delivery devices
US6349232B1 (en) * 1997-07-11 2002-02-19 Pets 'n People Ltd. Apparatus and method for dispensing pet care substances
US5949187A (en) * 1997-07-29 1999-09-07 Motorola, Inc. Organic electroluminescent device with plural microcavities
US6081736A (en) * 1997-10-20 2000-06-27 Alfred E. Mann Foundation Implantable enzyme-based monitoring systems adapted for long term use
US6016449A (en) * 1997-10-27 2000-01-18 Neuropace, Inc. System for treatment of neurological disorders
US6001090A (en) * 1998-02-09 1999-12-14 Lenhart; Douglas Thermal pharmaceutical delivery system
US6319241B1 (en) * 1998-04-30 2001-11-20 Medtronic, Inc. Techniques for positioning therapy delivery elements within a spinal cord or a brain
US6161047A (en) * 1998-04-30 2000-12-12 Medtronic Inc. Apparatus and method for expanding a stimulation lead body in situ
US6243608B1 (en) * 1998-06-12 2001-06-05 Intermedics Inc. Implantable device with optical telemetry
US6908770B1 (en) * 1998-07-16 2005-06-21 Board Of Regents, The University Of Texas System Fluid based analysis of multiple analytes by a sensor array
US6480730B2 (en) * 1998-10-05 2002-11-12 The Regents Of The University Of California Chemical sensor system
US6436853B2 (en) * 1998-12-03 2002-08-20 University Of Michigan Microstructures
US6289237B1 (en) * 1998-12-22 2001-09-11 University Of Pittsburgh Of The Commonwealth System Of Higher Education Apparatus for energizing a remote station and related method
US6757560B1 (en) * 1999-04-09 2004-06-29 Novosis Pharma Ag Transdermal delivery system (TDS) with electrode network
US6178349B1 (en) * 1999-04-15 2001-01-23 Medtronic, Inc. Drug delivery neural stimulation device for treatment of cardiovascular disorders
US6587719B1 (en) * 1999-07-01 2003-07-01 Cyberonics, Inc. Treatment of obesity by bilateral vagus nerve stimulation
US6334859B1 (en) * 1999-07-26 2002-01-01 Zuli Holdings Ltd. Subcutaneous apparatus and subcutaneous method for treating bodily tissues with electricity or medicaments
US6669683B2 (en) * 1999-08-18 2003-12-30 Microchips, Inc. Thermally-activated microchip chemical delivery devices
US6527762B1 (en) * 1999-08-18 2003-03-04 Microchips, Inc. Thermally-activated microchip chemical delivery devices
US6656162B2 (en) * 1999-11-17 2003-12-02 Microchips, Inc. Implantable drug delivery stents
US6491666B1 (en) * 1999-11-17 2002-12-10 Microchips, Inc. Microfabricated devices for the delivery of molecules into a carrier fluid
US6537256B2 (en) * 1999-11-17 2003-03-25 Microchips, Inc. Microfabricated devices for the delivery of molecules into a carrier fluid
US6384353B1 (en) * 2000-02-01 2002-05-07 Motorola, Inc. Micro-electromechanical system device
US6551838B2 (en) * 2000-03-02 2003-04-22 Microchips, Inc. Microfabricated devices for the storage and selective exposure of chemicals and devices
US6666821B2 (en) * 2001-01-08 2003-12-23 Medtronic, Inc. Sensor system
US6571125B2 (en) * 2001-02-12 2003-05-27 Medtronic, Inc. Drug delivery device
US6733485B1 (en) * 2001-05-25 2004-05-11 Advanced Bionics Corporation Microstimulator-based electrochemotherapy methods and systems
US20020187260A1 (en) * 2001-05-30 2002-12-12 Sheppard Norman F. Conformal coated microchip reservoir devices

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222649A1 (en) * 2009-03-02 2010-09-02 American Well Systems Remote medical servicing
US20110125078A1 (en) * 2009-11-25 2011-05-26 Medtronic, Inc. Optical stimulation therapy
US20120290025A1 (en) * 2011-05-12 2012-11-15 Medtronic, Inc. Leadless implantable medical device with osmotic pump
US9592398B2 (en) * 2011-05-12 2017-03-14 Medtronic, Inc. Leadless implantable medical device with osmotic pump
US20140122108A1 (en) * 2012-10-25 2014-05-01 Analyte Health, Inc. System and Method for Coordinating Payment for Healthcare Services
US20140122106A1 (en) * 2012-10-25 2014-05-01 Analyte Health, Inc. System and Method for Coordinating Administration of a Medical Test to a User
US20140122107A1 (en) * 2012-10-25 2014-05-01 Analyte Health, Inc. System and Method for Reporting of Medical Advice
US9024394B2 (en) 2013-05-22 2015-05-05 Transient Electronics, Inc. Controlled transformation of non-transient electronics

Also Published As

Publication number Publication date
US7599737B2 (en) 2009-10-06
AU2003284018A1 (en) 2004-05-04
WO2004033034A1 (en) 2004-04-22
US20040127942A1 (en) 2004-07-01
EP1551499A1 (en) 2005-07-13

Similar Documents

Publication Publication Date Title
Velasco et al. Double‐blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures
Kerrigan et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy
US9409028B2 (en) Implantable microstimulators with programmable multielectrode configuration and uses thereof
US6922590B1 (en) Systems and methods for treatment of diabetes by electrical brain stimulation and/or drug infusion
US7013177B1 (en) Treatment of pain by brain stimulation
US8295946B2 (en) Electrode assembly with fibers for a medical device
US9999532B2 (en) Methods and devices for treating obesity, incontinence, and neurological and physiological disorders
AU2009313879B2 (en) Ingestible therapy activator system and method
US7333857B2 (en) Treatment of pain
US7734342B2 (en) Techniques for positioning therapy delivery elements within a spinal cord or brain
CA2617039C (en) Selective nerve stimulation for the treatment of eating disorders
US7780981B2 (en) Biosynchronous transdermal drug delivery
JP3493197B2 (en) Treatment of migraine due to nerve stimulation
US6597946B2 (en) Electronic card for transdermal drug delivery and analyte extraction
US7761166B2 (en) Electrical stimulation of iliohypogastric nerve to alleviate chronic pelvic pain
US6366814B1 (en) External stimulator for adjunct (add-on) treatment for neurological, neuropsychiatric, and urological disorders
EP1330288B1 (en) Devices for cardiovascular reflex control
US7769461B2 (en) Skull-mounted electrical stimulation system and method for treating patients
US7660631B2 (en) Methods and systems for electrical and/or drug stimulation as a therapy for erectile dysfunction
US6862479B1 (en) Spinal cord stimulation as a therapy for sexual dysfunction
KR100411502B1 (en) Apparatus and method for treating body tissues with electricity or medicaments
ES2550960T3 (en) Neurostimulation system for measuring the activity of a patient
US8560076B2 (en) Devices and methods for electrode implantation
JP5554062B2 (en) Implantable nerve stimulator that regulate cardiovascular function
ES2529704T3 (en) Electrode cable design of implantable electrical stimulation systems and manufacturing methods