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WO1998015317A1 - Electrode a injection de medicament regulable - Google Patents

Electrode a injection de medicament regulable Download PDF

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Publication number
WO1998015317A1
WO1998015317A1 PCT/US1997/015734 US9715734W WO9815317A1 WO 1998015317 A1 WO1998015317 A1 WO 1998015317A1 US 9715734 W US9715734 W US 9715734W WO 9815317 A1 WO9815317 A1 WO 9815317A1
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WO
WIPO (PCT)
Prior art keywords
lead
current
pharmaceutical
drug
charge
Prior art date
Application number
PCT/US1997/015734
Other languages
English (en)
Inventor
David Prutchi
Edward A. Schroeppel
Andre G. Routh
Original Assignee
Sulzer Intermedics 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
Application filed by Sulzer Intermedics Inc. filed Critical Sulzer Intermedics Inc.
Publication of WO1998015317A1 publication Critical patent/WO1998015317A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/056—Transvascular endocardial electrode systems
    • A61N1/0565—Electrode heads
    • A61N1/0568—Electrode heads with drug delivery

Definitions

  • the invention relates to implantable electrodes. More particularly, it relates to implantable cardiac electrodes. It more specifically relates to such electrodes capable of controllably-releasing a drug, such as a steroid, at the site of implantation of the electrode in the target tissue.
  • a drug such as a steroid
  • the controlled release of the drug is achieved using a iontophoretic or ionto inetic process.
  • Stimulation electrodes must overcome the stimulation threshold in order to deliver an effective electrical stimulus to a target tissue in which the electrode is implanted.
  • the stimulation threshold is a measure of the amount of energy required in order for a pulse to initiate and maintain regular, rhythmic cardiac contractions.
  • the stimulation threshold is typically low.
  • the stimulation threshold begins to rise, and may do so for a number of weeks until the physiological environment at the site of insertion of the electrode stabilizes. It is generally believed that the rise in the stimulation threshold results from increased spacing or electrical resistance of the tissue between the electrode and the target tissue, and that such increased spacing and resistance is a result of the inflammatory response and subsequent development of fibrous capsule materials around the electrode tip.
  • a clot forms in about 1-2 days around the tip of the lead where it is affixed to the myocardium.
  • fibrotic activity is seen to occur.
  • a peak in inflammation in the wound occurs about 3-6 days post implantation.
  • This series of wound-clot- inflammation-fibrosis-stabilization can recur if additional trauma at the lead insertion site occurs, such as by movement or shifting of the lead.
  • stimulation threshold-reducing drugs can be diffused into target tissue (e.g., myocardium) in order to cause the reduction of inflammation, thrombosis or fibrosis. For that reason, efforts have been made to devise drug-delivery systems to be used in combination with stimulation of certain tissues, particularly the heart.
  • target tissue e.g., myocardium
  • Drug-eluting stimulation leads have been described previously. See. e.g. , U.S. Patent No. 4,506,680 (Stokes). Such implantable devices rely exclusively on a passive drug-elution mechanism which cannot be controlled by the implanted device. Elution is a process in which an adsorbent is washed out or otherwise removed by means of a solvent. See also; U.S. Patent Nos. 4,577,642 (Stokes), 4,711,251 (Stokes), 4,819,661 (Heil, Jr.), 4,819,662 (Heil, Jr.), 4,953,564 (Berthelsen), and 5 ,496 , 360 (Hoffmann) .
  • molecular sieving materials are used to entrap the drug to be eluted in a cationic framework of aluminosilicates known as zeolites.
  • This process involves first loading drug into cavities of such matrices in which the resident water molecules have been driven out by heating in a vacuum. Once loaded with drug and implanted, such a matrix will be exposed to the water of the tissue and will relinquish the entrapped drug molecules which are less polar than are the water molecules, thereby delivering the drug to the target tissue. See, Stokes, U.S. Patent Nos. 4,577,642, 4,711,251. However, once in contact with a water environment, such electrodes irreversibly deliver the entrapped drug.
  • the passive elution mechanisms of these prior art devices deliver the drug upon implantation without regard for amount or timing.
  • the drug is automatically delivered to the insertion site tissue, no further delivery of drug is possible, and no physiologically-demanded dosage is possible.
  • darts constructed out of biocompatible materials and which are part of an integrated stimulation electrode have been used to deliver a drug to target tissue. See, e.g., U.S. Patent No. 5,531,780 (Vachon).
  • the dart includes a drug carried in a bioabsorbable, polymeric matrix.
  • the embedded drug is slowly delivered to the target tissue by co-dissolution, diffusion, or resorption.
  • the dart drug delivery mechanism is not under control of the stimulation device, being automatically and continuously delivered to the tissue upon fixation of the dart in the myocardium at the time of implant. It is also likely that the fixation of the dart itself will lead to increased inflammation, since active fixation of the dart in the tissue is required. In order to effect release of the dart, mechanical moving parts must be integrated into the stimulation electrode.
  • Iontophoresis is a form of electrophoresis which uses an electrical potential or current in order to drive ionic species, such as ionic pharmaceuticals, toward a target treatment site. Iontophoresis can also include the concept of dragging non-ionic species toward a target site by incorporating the non-ionic drugs in an ionic solution or carrier. When water is the carrier material, electrophoretic movement of non-ionic species in that water to the target tissue is referred to as iontokinesis, or more specifically iontohydrokinesis.
  • AICD automatic implantable cardioverter defibrillator
  • implantable devices and methods of using them capable of delivering substance to a tissue, by iontophoretic processes through the stimulation lead itself, without need for additional conduits.
  • Such devices and methods will preferably possess a reservoir of a deliverable substance that can be electrically and controllably delivered over extended periods of time without complex additional circuitry over that necessary for the stimulation device itself. More preferably, such devices and methods will operate using the existing electrodes and current sources of an implantable device, obviating the need for additional conduits, and will not cause such a drain on the current source as to require a larger current source or a more frequent replacement of the current source.
  • Such devices will preferably not require valving, springs, or other such mechanical devices in order to effect drug-delivery.
  • such devices and methods are needed for cardiac stimulation, where drugs may be provided to the cardiac tissue in order to reduce the threshold needed to pace or to defibrillate the heart. Disclosure of the Invention
  • the present invention provides, for the first time, implantable stimulation devices and methods of using them, capable of delivering a substance to a tissue by an ion-dependent electrophoresis process.
  • the devices and methods of the present invention provide a reservoir containing a substance which can be electrically delivered from the reservoir. These devices and methods operate using the existing electrodes and current sources of an implantable device, without need for an additional conduit or mechanical additions to the electrode, and without causing the modification or frequent exchange of the current source.
  • the devices and methods of the invention are preferably cardiac pacemakers and defibrillators, in which drugs are provided to the cardiac tissue in order to reduce the threshold needed to pace or to defibrillate the heart.
  • the devices and methods of the invention are cardiac pacing electrodes capable of controllably delivering an anti-inflammatory drug.
  • the invention relates to an implantable stimulation lead capable of delivering a negatively-charged substance to a tissue.
  • the lead comprises a cathodic reservoir capable of being loaded with the substance, a cathode electrode, and a source of current.
  • the current source is connected electrically to the cathode electrode, which is in turn electrically connected to the reservoir.
  • the electrical hook-up is done in such a manner as to allow electrophoretic displacement by the current of the charged substance from the reservoir into the tissue in which the lead is implanted.
  • the preferred embodiments of the stimulation lead will utilize a positively-charged matrix or reservoir, it is also possible to utilize a neutrally charged reservoir /matrix, so long as the entrapped drag is reasonably well maintained within the matrix/reservoir and can be electrically driven out of the matrix/reservoir by the repulsive force imparted by the net electrical current.
  • the reservoir matrix may also be coupled with a secondary reservoir in the stimulation lead.
  • the stylet channel may function as the secondary reservoir. In pacing leads, this stylet channel may have a volume of 5 to 20 microliters. In defibrillation leads, the stylet channel which can function as a secondary reservoir will be much larger than 20 microliters.
  • neutral reservoir/matrix will be particularly useful where two or more drugs of varying charge or varying strength of charge are to be delivered.
  • a neutral matrix with a mixture of a positively-charged drug and a negatively-charged drug.
  • the net current can be adjusted to either positive or negative, selectively delivering the drug of choice.
  • the trapping energy the energy which must be overcome by a current of a charge similar to the charge of the drug
  • the selective release of a given drug where the trapping energy of drug A is less than that for drug B, if current is delivered below that energy level needed to dislodge drug A, no drug will be delivered. If the current is delivered above the level needed to dislodge drug A, but less than the level necessary to dislodge drug B, then only drug A will be released. If the current delivered is in excess of the trapping energy of drug B, then both drug A and B will be delivered.
  • the lead is a pacing lead. In other embodiments, the lead is a defibrillation lead.
  • the preferred modes of application relate to cardiac stimulation, similar modes of operation can be devised for muscular or neural stimulation.
  • the substance to be delivered by the leads of the invention will typically be a pharmaceutical.
  • the drug may be selected from drags such as: glucocorticosteroids such as dexamethasone sodium phosphate, and other steroids, including fluoro-trihydroxy-methyl-pregnadiene/dione, and fluoro- methylprednisolone; ions and salts, such as sodium ion, sodium phosphate, the sodium salt of methoxy-methyl-naphthalene acetic acid, the sodium salt of isobutylphenyl-propionic acid.
  • the delivered drag will be a salt of dexamethasone.
  • anti- inflammatory drugs and substances which provide a desired therapeutic effect at the target tissue site of insertion can also be used so long as the substance can be delivered, either separately or in combination with a suitable coating, as an anion into the surrounding tissue. Because the devices of the invention allow for a controlled delivery of such drags, more aggressive (more toxic) drags can be utilized than would be safe where an implantable electrode is fitted with an uncontrolled drag- delivery system.
  • antiarrhythmic and antifibrillation drugs are antiarrhythmic and antifibrillation drugs.
  • antiarrhythmic drug is ibutelide.
  • Other substances which may be delivered to target tissues will be thyroid hormones such as thyroxine, T3, their analogs, derivatives, and combinations thereof, for resuscitation of patients undergoing cardiac arrest. It is also possible to administer with the electrode of the invention, thrombolytic drugs, such as urokinase, streptokinase, and tissue plasminogen activator. It is also possible to deliver anionic gene therapy reagents such as nucleic acids.
  • the lead of the invention is to deliver a neutrally- or positively-charged active ingredient which ingredient will, by itself, not be repulsed by the net negative current flow through the cathodic reservoir, it will be necessary to encapsulate or otherwise cause the neutral or positive substance to present a net negative charge to the current.
  • This may be accomplished in a variety of ways including solubilizing the neutral/cationic molecule in a negatively charged liposome, microcapsule or other covering.
  • the negatively-charged fatty acids are in iontophoretically transported out of the supporting matrix, they will carry the neutral drag with them.
  • weakly-cationic drugs it will be possible to bond them to bivalent anionic transport molecules. For instance, where the transport molecule has a weak acid site, the drag will form a weak salt upon delivery of the complexed transporter and drug to the tissue, and the weak salt will hydrolyze liberating the drug to the tissue.
  • Such an embodiment may find particular usefulness in releasing anti-arrhythmic drugs.
  • the leads of the invention are those in which the net current is provided by truncation of an active discharge from a tank capacitor during a stimulation cycle.
  • typical cardiac stimulation devices allow for an active discharge period following the stimulation pulse in order to bring the net electronic balance to zero.
  • the leads of the invention extract variable amounts of the current from truncating such active discharging cycles and route it to the drag reservoir in order to displace drug therein.
  • the current is a net negative current flowing from the current source into the tissue through a cathode, which causes stimulation of the tissue and prevents corrosion of the electrode tip. For this reason, the preferred manner of operating the stimulation lead of the invention will involve displacement by a negative current.
  • a cardiac pacing or defibrillation lead capable of delivering a pharmaceutical such as an anti-inflammatory steroid to a cardiac tissue.
  • the cathodic reservoir matrix is loaded with the steroid pre-implantation, and is in close electrical connection with an anodic electrode (cathode) and a source of current.
  • the current is provided by truncating the active discharge from a tank capacitor of the pacemaker or AICD during the stimulation cycle allowing electrophoretic displacement of the steroid from the reservoir into the tissue.
  • the invention may also be viewed as a substantially improved device comprising a cathodic reservoir capable of being loaded with a pharmaceutical substance, an anodic electrode, and a source of current, each in electrical connection with the other, where the improvement comprises electrophoretic displacement by the current of the substance from the reservoir into the tissue, and where the current is provided by truncation of an active discharge from a DC DC blocking capacitor during a stimulation cycle.
  • the invention in other regards discloses methods of delivering a charged substance from an implantable stimulation electrode to a tissue.
  • Such methods comprise filling a reservoir with the charged substance, placing an electrode in electrical connection via a body path with the reservoir, delivering a current of the same charge as that of the substance through the electrode and through the reservoir from a current source, thereby displacing the charged substance into the tissue.
  • the invention provides, in certain preferred embodiments, devices and methods by which a drug can be injected in the locality of an implanted cardiac stimulation electrode to lower the pacing or defibrillation threshold at the time of implant or at other times under the control of the implantable cardiac stimulator.
  • a drug can be injected in the locality of an implanted cardiac stimulation electrode to lower the pacing or defibrillation threshold at the time of implant or at other times under the control of the implantable cardiac stimulator.
  • lowering the threshold just prior to shock permits smaller effective shocks, and thus, smaller batteries and capacitors. These smaller components, in turn, reduce the size of the AICD, decreasing trauma to the patient and its associated expenses or, alternatively, provide a mechanism to extend the life of the power supply.
  • the present invention substantially differs from prior art approaches using drug-elution electrodes, yet similarly lowers the thresholds for pacing and/or defibrillation.
  • the present invention in preferred embodiments allows the controlled release of a steroidal substance or other drug to selectively lower defibrillation thresholds prior to defibrillation, thus requiring less drug availability on the lead than with passive, drug-eluting electrodes. Moreover, more aggressive substances can be used, since their release occurs only when required to effectively lower pacing and/or defibrillation thresholds.
  • the active injection device of the invention is one that releases a drug in a controlled manner from an electrode, such as a stimulation electrode of a pacemaker or AICD system.
  • the electrode does not elute a drug to lower the stimulation threshold, but rather forces it out on command from the cardiac stimulation device.
  • the controller of the implantable device causes a DC current flow or non-compensated pulse current flow between a combined iontophoresis/stimulating electrode and some other implanted reference electrode (e.g. , the metallic enclosure of the implantable cardiac stimulation device).
  • a combined iontophoresis/stimulating electrode e.g. , the metallic enclosure of the implantable cardiac stimulation device.
  • This current causes the release of a trapped drug from a reservoir matrix placed in electrical and physical contact with the stimulation electrode.
  • the threshold-reducing drag then diffuses into the target tissue (e.g., myocardium) causing the reduction of inflammation, thrombosis or fibrosis.
  • the output waveform of a cardiac stimulation device can be modified whenever iontophoretic drag delivery is desired.
  • the circuit can be made to deliver balanced or unbalanced stimulation under the control of the onboard microprocessor. Pulses which result in a balanced waveform — one which produces zero net ionic current over the complete stimulation pulse cycle - may stimulate the heart, but will not release the trapped drug. However, a charge imbalance with the correct polarity dominance will result in the active ejection of trapped drug from the reservoir matrix into the myocardium and adjacent tissues.
  • the matrix materials will preferably be physiologically inert and capable of retaining the charged drug to be delivered.
  • Matrix materials which may be used include: polyacetic acid, polyglycolic acid, polyorthoesters, polyesters, polyurethanes, polyamino acids such as polylysine. lactic/glycolic acid copolymers, poly anhydrides and ion exchange resins such as sulfonated polytetrafluorethylene. Additionally, it is possible to construct the matrices from natural proteins or materials which are crosslinked using a crosslinking agent such as l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride.
  • a crosslinking agent such as l-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride.
  • Such natural materials are those such as albumin, collagen, gelatin, keratin, potato starch hydrolyzed for use in electrophoresis, and agar-agar (agarose).
  • Synthetic electrophoretic matrices are also suitable including polyacrylimide, acrylimide/bis-acrylimide mixtures, cellulose acetate, glyoxyl agarose, and SephadexTM (Pharmacia Fine Chemicals, Inc.) suitable for use in isoelectrofocusing. It is also possible to use combinations of such matrices, such as the combination of polyacrylimide and agarose, in order to fabricate the cathodic matrix of the invention.
  • multiple-layered cathodic reservoirs it is possible to fabricate multiple-layered cathodic reservoirs. Such multiple-layered reservoirs will find usefulness in certain embodiments in which there is desire to have additional control over the rate at which the charged substance is electrophoresed from the matrix.
  • a relatively strongly-cationic matrix material may be used to cap a relatively weakly-cationic matrix material.
  • This multiple-layered matrix embodiment may be preferentially utilized where a relatively more toxic, but more efficacious drug is to be initially utilized to lower the immediate post-implantation stimulation threshold, followed by a relatively less toxic, lower effectiveness drug.
  • a second drag delivered at a later time will assist in overcoming tissue non-responsiveness .
  • a multiple-layered matrix approach will find usefulness where drags are to be administered temporally for different therapies.
  • a first drag will be usefully delivered to the target tissue in order to lower the immediately post-implantation stimulation threshold.
  • a multiple-layered matrix it is also possible to sequentially deliver a gradually declining (or increasing, or cyclical) concentration of a drug.
  • the distal most matrix reservoir may contain a first lower dose of a drag, followed by a next most distal matrix with a concentration of drug higher than the first, and so on.
  • stimulation leads of the present invention are under the control of software in the implanted device, it will be possible to program a variety of drag-delivery protocols.
  • an anti- inflammatory agent such as the sodium salt of methoxy-methyl- naphthalene acetic acid is to be used, which substance is not soluble in aqueous media in its acid form
  • the insoluble form of the drug may be incorporated into a suitable matrix, either with or without a coating, and delivered to the target tissue.
  • the charged substances be solubilized while entrapped in the cathodic reservoir, it is possible to impregnate the matrix with highly-concentrated crystalline forms of certain substances such as anti- inflammatory drugs, especially where such drugs are loaded as the salt of an acid or base of the active drug ionic species.
  • an auxiliary reservoir in fluid connection to the cathodic matrix reservoir in order to provide a reserve of additional drug useful in recharging the cathodic matrix as drug is eluted into the target tissue.
  • the auxiliary reservoir is attached to the cathodic matrix which is in turn in contact with the target tissue.
  • the auxiliary reservoir may contain an identical drag as that initially impregnated into the cathodic matrix pre-implantation, or it may contain a drag distinct from that initially loaded in the matrix.
  • this embodiment may be preferentially utilized where a relatively more toxic, but more efficacious drug is to be initially utilized to lower the immediate post-implantation stimulation threshold, followed by a relatively less toxic, lower effectiveness drug.
  • Delivery of the charged substance or delivery of the substance in its charged carrier is carried out iontophoretically.
  • the substance such as a drag or its carrier having a charge of the same polarity as that of the electrode is forced to migrate away from the matrix reservoir.
  • Precise control can be maintained over the dosage of the delivered drag in that the amount delivered to the target tissue is directly proportional to the product of the current flow and time (Faraday's Law of Electrolysis).
  • Control of the delivery of the drug by the devices of the invention is variable. It is possible to merely program the device to deliver its entire load of iontophoretically deliverable drug upon implantation or shortly thereafter. In this mode of operation, the devices of the invention operate like prior art devices, albeit utilizing the novel delivery mechanisms of the invention. More preferably, the devices of the invention are programmed to monitor one or more physiological conditions in order to coincide the timing of the drug delivery to the greatest physiological demand.
  • the physiological criterion monitored by the device is the stimulation threshold of the target tissue
  • drag delivery occurs only when such threshold reaches a predetermined maximum.
  • physiological parameter monitored by the devices of the invention is arrhythmia or fibrillation
  • drug delivery is coincident with detection of such conditions.
  • Fig. 1 depicts the drug-delivering stimulation electrode in electrical connection with the iontophoretic and stimulating circuit.
  • Fig. 2 is a sectional view of the drug-delivering electrode in electrical connection with the iontophoretic circuit which is in turn electrically connected to the current source, wherein in the absence of current flow by virtue of the switched off circuit, no iontophoresis of the matrix-entrapped particles occurs.
  • Fig. 3 is a sectional view of the drug-delivering electrode in electrical connection with the iontophoretic circuit which is in turn electrically connected to the current source, wherein in the initial stages of current flow by virtue of the switched on circuit, iontophoresis of the matrix- entrapped particles into the surrounding tissue is beginning to occur.
  • Fig. 4 is a sectional view of the drug-delivering electrode in electrical connection with the iontophoretic circuit which is in turn electrically connected to the current source, wherein in the later stages of current flow by virtue of the switched on circuit, iontophoresis of the matrix-entrapped particles into the surrounding tissue is complete.
  • Fig. 5 is a diagram of the switching cycles and the resultant waveform of the current over time, wherein by virtue of the closing of switch S3 throughout the active discharge period, the pacing pulse current is balanced and no excess current is delivered to the cathodic drug reservoir.
  • Fig. 6 is a diagram of the switching cycles and the resultant waveform of the current over time, wherein by virtue of the premature opening of switch S3 and closure of switch S4 prior to the end of the normal active discharge period, a portion of the excess current is delivered to the cathodic drug reservoir.
  • Fig. 7 is a diagram of the switching cycles and the resultant waveform of the current over time, wherein by virtue of the failure to close switch S3 at any time and by shunting the DC-blocking capacitor through switch S4, all excess current is delivered to the cathodic drag reservoir.
  • Best Mode for Carrying Out the Invention Turning now to the figures, exemplary devices of the invention are seen. For purposes of example, operation of preferred modes using the devices of the invention are described in a cardiac pacing application. Of course, it will be understood by those of skill in the art that similar examples could be given for use of the devices of the invention for different cardiac stimulation scenarios, particularly for AICD or defibrillation applications.

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Abstract

Cette invention se rapporte à des électrodes implantables (10), et plus particulièrement, à des électrodes cardiaques implantables. Elle se rapporte spécifiquement à de telles électrodes (10) capables de libérer de façon régulable un médicament tel qu'un stéroïde dans les tissus cibles (26) se trouvant à l'emplacement de l'électrode. Cette libération régulée du médicament est obtenue au moyen d'un procédé iontophorétique ou iontocinétique et elle ne nécessite pas de conduits additionnels pour le médicament ni de composants mécaniques additionnels, en plus de ceux que l'on trouve généralement dans de tels câbles d'électrodes de stimulation.
PCT/US1997/015734 1996-10-07 1997-10-07 Electrode a injection de medicament regulable WO1998015317A1 (fr)

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US72771696A 1996-10-07 1996-10-07
US08/727,716 1996-10-07

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US6810286B2 (en) 2000-03-06 2004-10-26 Medtronic, Inc Stimulation for delivery of molecular therapy
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US7729761B2 (en) * 2004-07-14 2010-06-01 Cardiac Pacemakers, Inc. Method and apparatus for controlled gene or protein delivery
US8858983B2 (en) 2009-04-30 2014-10-14 Medtronic, Inc. Antioxidants and antimicrobial accessories including antioxidants
US8911427B2 (en) 2010-12-28 2014-12-16 Medtronic, Inc. Therapeutic agent reservoir delivery system
US8934975B2 (en) 2010-02-01 2015-01-13 Metacure Limited Gastrointestinal electrical therapy
US8958872B2 (en) 1996-01-08 2015-02-17 Impulse Dynamics, N.V. Electrical muscle controller
US8977353B2 (en) 2004-03-10 2015-03-10 Impulse Dynamics Nv Protein activity modification
US9101765B2 (en) 1999-03-05 2015-08-11 Metacure Limited Non-immediate effects of therapy
US9289618B1 (en) 1996-01-08 2016-03-22 Impulse Dynamics Nv Electrical muscle controller
EP2979659A3 (fr) * 2014-08-01 2016-04-06 Covidien LP Procédés d'amélioration des fuites haute fréquence de générateurs électrochirurgicaux
US9364565B2 (en) 2000-03-15 2016-06-14 Orbusneich Medical, Inc. Medical device with coating for capturing genetically-altered cells and methods of using same
US9522217B2 (en) 2000-03-15 2016-12-20 Orbusneich Medical, Inc. Medical device with coating for capturing genetically-altered cells and methods for using same
US9642670B2 (en) 2013-10-29 2017-05-09 Covidien Lp Resonant inverter with a common mode choke
US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US10105172B2 (en) 2013-10-16 2018-10-23 Covidien Lp Radiofrequency amplifier impedance optimization
US10188446B2 (en) 2013-10-16 2019-01-29 Covidien Lp Resonant inverter
WO2021102448A1 (fr) * 2019-11-24 2021-05-27 Presidio Medical, Inc. Systèmes de moteurs de stimulation et de génération d'impulsions
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US11752329B2 (en) 2018-07-01 2023-09-12 Presidio Medical, Inc. Systems and methods for nerve conduction block
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification
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US11918803B2 (en) 2017-04-03 2024-03-05 Presidio Medical, Inc. Systems and methods for direct current nerve conduction block
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