WO2012007332A1 - Dispositif et procédé destinés à réduire le risque d'occlusion et de resténose après l'implantation d'une endoprothèse - Google Patents

Dispositif et procédé destinés à réduire le risque d'occlusion et de resténose après l'implantation d'une endoprothèse Download PDF

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Publication number
WO2012007332A1
WO2012007332A1 PCT/EP2011/061397 EP2011061397W WO2012007332A1 WO 2012007332 A1 WO2012007332 A1 WO 2012007332A1 EP 2011061397 W EP2011061397 W EP 2011061397W WO 2012007332 A1 WO2012007332 A1 WO 2012007332A1
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WO
WIPO (PCT)
Prior art keywords
stent
current
voltage
operable
electrode
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PCT/EP2011/061397
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English (en)
Inventor
Simon P. Hoerstrup
Gregor Zünd
Michael Gabi
Alexandre Larmagnac
Janos VÖRÖS
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Universität Zürich
ETH Zürich
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Publication of WO2012007332A1 publication Critical patent/WO2012007332A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/007—Heating or cooling appliances for medical or therapeutic treatment of the human body characterised by electric heating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/205—Applying electric currents by contact electrodes continuous direct currents for promoting a biological process
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
    • A61B2017/22001—Angioplasty, e.g. PCTA
    • A61B2017/22002—Angioplasty, e.g. PCTA preventing restenosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A61F2007/126—Devices for heating or cooling internal body cavities for invasive application, e.g. for introducing into blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/372—Arrangements in connection with the implantation of stimulators
    • A61N1/378—Electrical supply
    • A61N1/3787—Electrical supply from an external energy source
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals

Definitions

  • the present invention relates to a medical device for the permanent or temporal support of the wall of a blood vessel and to a related method of reducing the risk of occlusion, stenosis and/or restenosis after implantation of such a device.
  • a stent is an artificial tubular structure, usually having a mesh-like configuration, that may be inserted into a blood vessel to support the wall of the blood vessel and/or prevent occlusion and restenosis.
  • Stents are often implanted after the widening of an obstructed blood vessel by one of a variety of different methods, e.g. by balloon angioplasty. Stents may also be used in other medical contexts in the vasculature, e.g., to support an aneurysm in an artery.
  • Occlusion is the narrowing or blockage of a blood vessel through thrombus formation.
  • Stenosis is the occurrence of a narrowing of the blood vessel, leading to restricted blood flow.
  • Restenosis is the reoccurrence of stenosis after treatment to clear a narrowing or blockage of the blood vessel.
  • Restenosis after implantation of a stent may be separated into two stages. In a first stage, thrombosis may occur. Administration of Ilb/IIIa inhibitors immediately after surgery greatly reduces this risk.
  • a medical device for the permanent or temporal support of the wall of a blood vessel comprising:
  • an implantable tubular stent having at least one electrically conducting portion; and a power source operable to supply a voltage and/or current to the electrically conducting portion after implantation of the stent into a blood vessel of a living human or animal body (in the following also called the "patient body") effective to prevent or reduce a risk of occlusion, stenosis or restenosis of said blood vessel.
  • a power source operable to supply a voltage and/or current to the electrically conducting portion after implantation of the stent into a blood vessel of a living human or animal body (in the following also called the "patient body") effective to prevent or reduce a risk of occlusion, stenosis or restenosis of said blood vessel.
  • the inventors have shown that cell growth and cell adhesion on vascular implants such as stents can be reduced in vivo by supplying an electrical voltage or current to the stent, which is expected to reduce the risk of occlusion, stenosis and restenosis.
  • the voltage and/or current may be supplied locally to the stent only, e.g. for eluting drugs or heating the stent, as described in more detail below.
  • the voltage/current causes a small current flow through surrounding material of the patient body, e.g., for electrochemically changing the environment of the stent.
  • the term "environmental body material” is to be understood broadly as encompassing any material of the patient body in the vicinity of the implanted stent. The material may be in direct contact with the stent or may be separated from the stent by other body material. Body materials include but are not limited to muscle tissue, mucosa, fat tissue, blood and other body fluids etc.
  • the surface current density is between 100 nA/mm 2 and 2 ⁇ 00 nA/mm 2 . More preferably, the surface current density is between 200 nA/mm 2 and 000 nA/mm 2 . If the current density is too low, its effect might not be sufficient to reduce cell growth or cell adhesion to a degree required to be effective in preventing occlusion, stenosis or restenosis. On the other hand, if the current density is too high, increased electrophoretic and electrolytic/electrochemical effects might lead to undesired side effects.
  • the power source is preferably operable to actively control the voltage and/or current that is supplied to the stent so as to ensure that the current density stays in the desired range.
  • Power sources providing a well-defined current with a predetermined magnitude are well known in the field of electronics and are then usually called current sources. However, in simple embodiments, it may be sufficient to supply the voltage and/or current without actively controlling its magnitude, e.g., by simply maintaining a predetermined voltage between two electrodes of which at least one is connected to the stent.
  • the power source may be wholly or partially integrated with the stent (i.e., the stent and at least parts of the power source may together form a single implantable unit), or it may be disposed remote from the stent, being connected to the stent by surgical wires or supplying energy to the stent in other ways, as further detailed below.
  • the voltage and/or current may be supplied in a pulsed manner.
  • the intervals during which the current is switched off do not exceed 60 seconds, more preferably 30 seconds, in particular 10 seconds.
  • the pulsed voltage and/or current is preferably supplied periodically, with a period in the range of a few hundred milliseconds to about a minute.
  • the period of the pulsed current is preferably between 0.2 seconds and 60 seconds, more preferably between 1 second and 30 seconds.
  • the voltage and/or current may be applied with alternating polarity (i.e., as an AC current, in particular as a low-frequency AC current with a frequency below 1 kHz), it is preferred to supply the current with a single polarity only.
  • the stent acts as the anode for the current, with a counter electrode acting as the cathode.
  • the stent acts as the cathode, or that different portions of the stent act as the cathode and anode, respectively.
  • the power source may comprise an implantable battery.
  • the battery may be disposed in a separate housing or, preferably, in a common housing with the rest of the power source.
  • the power source including the battery, and the stent may form a single, self-supported implantable unit.
  • the battery may be disposable or rechargeable. If the battery is rechargeable, the power source may comprise means for supplying recharging energy to the battery, as detailed below.
  • energy may be supplied to the stent transcutaneously from outside the patient body, either permanently during operation of the device, as in the case where no additional implanted energy source or energy storage means are available, or intermittently, as in the case when a rechargeable battery or other implanted, rechargeable energy storage means such as a large capacitance is present.
  • the power source will generally comprise an energy transmitter to be placed outside the human or animal body, the energy transmitter being operable to transmit energy from outside the body to a location inside the body in a contact-less fashion, and an implantable energy receiver operable to receive energy from the energy transmitter in a contact-less fashion when implanted in the body.
  • Various means for transmitting energy from outside a body to inside a body in a contact-less fashion are known, e.g., from the technical field of cardiac pacemakers or implantable medicament pumps.
  • the most widely employed principle in such applications is inductive, i.e., an inductive coupling between the energy transmitter and the energy receiver is established, much like in a (core-less) transformer.
  • the energy transmitter is in such cases operable to generate an (alternating) electromagnetic field
  • the energy receiver is operable to receive the electromagnetic field generated by the energy transmitter and to convert said electromagnetic field into an electrical current, as known in the art.
  • Alternative means for energy transmission might include the transmission of light, of X-rays, of heat or of mechanical vibrations, including ultrasound vibrations.
  • the stent As the stent is generally implanted in the inside of a blood vessel, an additional problem arises of how to supply energy from the outside of the blood vessel to its inside, through the wall of the blood vessel.
  • surgical wires extending through the vessel wall may be used.
  • this might lead to complications, as this will imply a permanent perforation of the vessel wall. It is therefore desirable to transmit energy from a location outside the blood vessel to the stent inside the blood vessel in a contact-less fashion. In first preferred embodiments, this is achieved by inductive coupling.
  • the stent may be inductively coupled to an inductor outside of the blood vessel, e.g. to a solenoid coil placed around the blood vessel or to a coil outside the patient body, to generate a magnetic field at the location of the stent that induces a voltage in an inductor associated with the stent.
  • the power source then comprises a first inductor adapted to be placed outside the blood vessel (inside or outside the patient body; if inside the patient body, the first inductor may be implantable at the outside of a blood vessel) and operable to generate a substantial magnetic field acting on the stent, and a voltage generator operable to supply said first inductor with a time-dependent first voltage.
  • the stent then comprises a second inductor (which may be represented by the stent itself) which, after implantation of the stent inside the blood vessel and, as the case may be, of the first inductor outside of the blood vessel, is inductively coupled with said first inductor through the vessel wall.
  • a second voltage may be induced in the second inductor via a time-dependent magnetic field generated by a time-dependent current in the first inductor caused by the first voltage.
  • the (generally time-dependent) voltage induced in the stent-associated second inductor may cause a current in the stent and possibly in the surrounding body material in a variety of different ways.
  • the stent has a first and a second electrode connected to the second inductor, and, after implantation of the stent, the first and second electrode are electrically connected with environmental body material in a manner that the second voltage causes a current to flow through the body material.
  • the first and second electrode act as anode and cathode, respectively, i.e., no separate, remote counter electrode is required.
  • the voltage may first be rectified by a suitable rectifier (a diode in the simplest case), and the rectified voltage may be supplied to the electrodes.
  • a control circuit for controlling the magnitude of the resulting current may further be associated with the stent.
  • the present invention also provides a stent which is particularly adapted for this kind of operation.
  • Such an implantable tubular stent will have at least two electrodes connectable to environmental body material, the electrodes acting as the terminals of an inductor operable to receive a time-dependent magnetic field so as to induce a voltage between said electrodes.
  • the stent will generally define a stent axis by its long (tube) axis.
  • the inductor then preferably defines a substantially helicoidal current path around said stent axis.
  • the second inductor may have a first and a second terminal which are connected directly or indirectly, without the involvement of any environmental body material, to form a closed circuit with the second inductor.
  • the terminals may be electrically connected by a connection having a low ohmic resistance (e.g., the terminals may essentially be shorted).
  • the terminals may be electrically insulated from the environmental body material.
  • the voltage generator may then be operable to supply the time-dependent first voltage in a manner to induce a closed- loop current in the closed circuit.
  • the stent comprises a drug releasable from the stent by the application of such a current, e.g., by having a drug-eluting coating whose elution rate may be controlled by current.
  • the drug may be released electrophoretically or by electrochemical means, or by a (possibly local) heating of a portion of the stent due to the current.
  • the power source may comprise:
  • a first electrode placed in the vicinity of said stent to form a capacitance with the stent
  • a voltage generator operable to supply said first electrode and said second electrode with a time-dependent first voltage so as to cause a capacitive current between the first electrode and the stent and an ionic current between the stent and the second electrode.
  • the first electrode is preferably electrically insulated from the stent and from the surrounding body material. It may partially or fully surround the stent.
  • the second electrode may be placed remote from the first electrode and from the stent, in electrical connection with the surrounding body material. Likewise, the stent is required in this case to have an electrical connection with the surrounding body material.
  • the power source may comprise an implantable electrical generator operable to transform mechanical energy into electrical energy.
  • the electrical generator may then be operable to transform mechanical energy associated with blood flow, with arterial palpation or with general other body movements into electrical energy.
  • the stent being in contact with blood, the stent could also be powered by bio- electrochemical means, e.g. via enzymatic reactions such as oxidation of glucose by glucose oxidase molecules.
  • the stent may contain a drug, the release of the drug being controllable by a voltage and/or current applied to the stent.
  • the stent may comprise a drug-releasing coating, and the device may then be operable to control release of a drug from the coating by means of said voltage and/or current.
  • the stent may be fully or at least partially resorbable, and the device may then be operable to control a rate of resorption by means of the current.
  • the electrically conductive portions of the stent are preferably electrochemically inert under the conditions employed. They may be made of any of the following:
  • a metal or a semiconductor in particular, Au, Ag, Ir, Ni, Cr, Co, Pt, C, Cu, Al, Ti, In, Sn, Si and any combination of thereof, in bulk form or in the form of a porous matrix; an electrically conductive polymer, in particular, poly(acetylene)s, poly(pyrrole), poly(thiophene), polyanilines, polythiophene, poly(p-phenylene sulfide), poly(p-phenylene vinylene)s, polyindole, polypyrene, polycarbazole, polyazulene, polyazepine, poly(fluorene), or polynaphthalene;
  • an electrically conductive polymer in particular, poly(acetylene)s, poly(pyrrole), poly(thiophene), polyanilines, polythiophene, poly(p-phenylene sulfide), poly(p-phenylene vinylene)s, polyindole, polypyrene, poly
  • the associated method of reducing a risk of occlusion, stenosis or restenosis of a blood vessel of a human or animal body comprises:
  • the stent may be implanted, e.g., in a coronary artery, in a cerebral blood vessel or in a peripheral blood vessel.
  • Fig. 1 is a sketch illustrating a stent implanted in a blood vessel, to which current is supplied inductively;
  • Fig. 2 is a sketch illustrating a stent in which a current is driven inductively
  • Fig. 3 is a sketch illustrating a stent implanted in a blood vessel, to which a capacitive current is supplied;
  • Fig. 4 is a sketch illustrated how the stent can be supplied with energy transcutaneously in a contact-less manner
  • Fig. 5 is a sketch illustrating an alternative embodiment of supplying the stent with energy in a contact-less manner
  • Fig. 6 illustrates the pulse generator and electrode design of an implant for in-vitro and in-vivo testing
  • A schematics of the electrode and its cross section through the active Pt* electrode; the Pt film on the lower side is not connected to the pulse generator and serves as control
  • B photograph of the working electrode connected to the Teflon-coated connected to the pulse generator
  • C photograph of the whole implant consisting of the pulse generator (electric circuit and battery), two active electrodes, and one counter electrode in comparison with a 0.05 CHF Swiss coin
  • D schematics of the in vitro experimental setup using the two active electrodes, one counter electrode and the pulse generator submerged in cell culture medium;
  • Fig. 7 is a diagram illustrating the percentage of dead cells versus time on an active Pt* surface and on a passive Si0 2 surface.
  • FIG. 1 illustrates a first embodiment of the present invention.
  • a stent 3 is implanted inside a blood vessel 1, e.g., of the coronary, cerebral or peripheral vasculature.
  • An inductor 2 e.g., in the form of a solenoid coil wound around the vessel, is placed in the vicinity of the stent 3 outside the blood vessel 1.
  • An AC voltage or, more generally, a time- dependent voltage is supplied to the inductor 2 from an implanted or extracorporeal voltage generator 6 through wires 4 and 5.
  • the time-dependent voltage causes a time- dependent current to flow through the inductor 2.
  • This current causes a time-varying magnetic field B that permeates the stent, as illustrated in Fig. 2.
  • the time-varying magnetic field causes a time-dependent voltage to be induced in the conducting portions of the stent.
  • the stent may act as an inductor comprising a single, meandering but generally helical conducting path, as illustrated in Fig. 2.
  • the stent will thus act as a second solenoid coil.
  • the induced time-dependent voltage will be available at the terminals of this conducting path.
  • no such open-loop conducting path will generally exist.
  • This voltage may be used in a variety of ways to generate currents.
  • the conducting path is short-circuited. Current flow is then restricted to the stent in a closed current loop, and no current will flow in the environmental body material.
  • This current flow may be used to release a drug in a controlled manner if the stent comprises a drug- eluting coating or if drugs are otherwise embedded in the stent. This can be done by the current causing electrochemical reactions in the stent for releasing the drug. The induced current will also cause some ohmic heating of the conducting path. If strong enough, this local heating may likewise be employed to release a drug from the stent.
  • the induced voltage may be used to cause a current i through the tissue and blood in the immediate surroundings of the stent.
  • the current may be rectified by a diode or a bridge rectifier, if desired, and its magnitude may be electronically controlled by a control circuit (not shown).
  • FIG. 3 illustrates a second embodiment.
  • the blood vessel 1 containing the stent 3 is surrounded by a cylindrical electrode 7.
  • This electrode is electrically insulated from the blood vessel and from the surrounding body tissue.
  • a counter electrode 8 is placed in some surrounding body tissue to be in electrical contact with this tissue.
  • An AC voltage or, more generally, a time-dependent voltage is applied by generator 6 to the electrode 7 and to the counter electrode 8. This causes a capacitive current to flow between the electrode 7 and the stent 3, and an ionic current to flow between the stent 3 and the counter electrode 8. In other words, an ionic pathway is formed between the stent 3 and the counter electrode 8.
  • the current generated by the generator 6 will be transmitted capacitively from the electrode 7 to the stent 3 and electrochemically from the stent 3 to the counter electrode 8 through the environmental body material.
  • This arrangement is particularly suited to cause currents between the stent and environmental body material such as blood and tissue.
  • Figures 4 and 5 illustrate two possibilities of how the stent may be supplied with energy in a contact-less fashion.
  • a patient 13 has been implanted with a stent (not shown).
  • An internal power supply 14 is implanted in the body.
  • the power supply acts as a power source for the stent, either directly through surgical wires, or indirectly, e.g. through inductive or capacitive means as described above in conjunction with Figs. 1-3.
  • a primary coil 12 is wound around the body of the patient.
  • the primary coil 12 is connected to an external power supply 10 by a cable 11.
  • the external power supply supplies a time- dependent electric current to coil 12, which causes a time-dependent magnetic field acting at the location of the internal power supply.
  • a secondary voltage is induced in a pickup coil (not shown) of the internal power supply .
  • This secondary voltage is used either to directly power the stent, or to recharge a storage capacitor or battery in the secondary power supply.
  • the internal power supply may also be omitted entirely, and the time-dependent magnetic field may act to directly induce a secondary voltage in the stent itself, as described above in conjunction with Figs. 1 and 2.
  • FIG. 5 An alternative embodiment is shown in Fig. 5. Like parts are denoted with the same reference signs as in Fig. 4. Instead of a primary coil wound around the body, the primary coil 12' in this embodiment is a flat coil placed on the skin of the patient. While the direction of the magnetic field generated by this primary coil is different than in the embodiment of Fig. 4, the principle of operation is the same.
  • rat aortic derived cells RAOC
  • the pulsed currents (370 nA/mm 2 ) caused apoptosis within 24 h as shown by the positive staining for cleaved caspase-3 and classically apoptotic morphology.
  • the pulse generator was implanted subcutaneously in the rat model.
  • the electrode/tissue interface histology revealed no difference between an active platinum surface and a neighboring control surface.
  • a large difference between electrodes that were functional during the entire experiment and non-active electrodes was found.
  • These non-active electrodes showed an increase in impedance at higher frequencies 21 days post-implantation, whereas working electrodes retained their impedance value for the entire experiment.
  • the electrodes were fabricated on microscopy glass slides coated with platinum and an insulating Si0 2 film. Briefly, the glass slides were consecutively cleaned in pure acetone, isopropanol, ethanol, water, blow dried with N 2 and then coated with a 10 nm layer of Ti as an adhesion promoter followed by a 40 nm layer of Pt in an electron beam evaporator (Pfeiffer Classic 500, Wetzler, Germany). One coated slide was then cut into 7 x 2 mm pieces to be used as counter electrodes.
  • the other coated slide was partly protected with Kapton® tape (Distrelec, Switzerland), so that the following physical vapor deposition (PVD) Si0 2 coating formed an electrically insulating, 3 mm wide and 100 nm thick Si0 2 strip after removal of the tape.
  • the slide was cut with a diamond saw into individual electrodes.
  • Biocompatible Teflon®-coated stainless steel wires AS632; Cooner Wire, Chatsworth, CA
  • the connection was then coated with EPOTEK-320M (Epoxy Technology, Billerica MA, USA) and cured at 60 °C for 6 h to ensure full biocompatibility and electrical insulation of the connection.
  • An electric pulse generator was built with prospect for implantation by using a low power stable multivibrator HEF4047BT from Philips (Distrelec, Switzerland) powered by a 3 V, 25 mAh coin cell lithium ion battery (Energizer CR1216, France).
  • Ohmic resistor (10 ⁇ ) and capacitor (220 nF) were used to set the period of the current pulses. This way the pulse generator delivers two differently pulsed DC square wave signals at different ports (2.5 s current, 2.5 s pause - referred to hereafter as electrode 1; 5 s current, 5 s pause - electrode 2).
  • the electrically active Pt coated working electrode surface is labeled hereafter as Pt*.
  • the third electrode served as the counter electrode to close the circuit.
  • RAOC were proliferated under standard incubator conditions (37°C, 5% C0 2 ) in endothelial basal medium (EBMTM-2; Cambrex, Walkersville, MD) containing growth factors and supplement: vascular endothelial growth factor (VEGF), human fibroblasts growth factor (hFGF), human recombinant long-insulin- like growth factor- 1 (R-3-IGF-1), human epidermal growth factor (hEGF), gentamycin and amphotericin (GA-1000), hydrocortisone, heparin, ascorbic acid, and 2% fetal bovine serum (FBS).
  • EBMTM-2 endothelial basal medium
  • VEGF vascular endothelial growth factor
  • hFGF human fibroblasts growth factor
  • R-3-IGF-1 human recombinant long-insulin- like growth factor- 1
  • hEGF human epidermal growth factor
  • GA-1000 gentamycin and amphotericin
  • the electrodes were again sterilized with 70% ethanol and irradiated for 30 minutes with UV light.
  • the cells were detached using 0.25%> trypsin/EDTA solution (PAN Biotech GmbH, Aidenbach, Germany) and seeded directly onto the implant lying in a Petri dish (Fig. 5 D).
  • the systems were then incubated for 1, 6, 12 and 24 h at 37 °C and 5% C0 2 .
  • the number of dead cells on the electrodes was visualized by propidium iodide staining (Molecular Probes Inc., Eugene, OR).
  • Hoechst 33342 (Molecular Probes) was used to count the total number of cells as it stains the condensed chromatin of all cells irrespective of membrane integrity.
  • a control experiment was performed over 24 h with the same method as above, however without the application of current (data not shown).
  • the type of cell death and the cell adhesion contact size was investigated with immunochemical staining: after exposing the RAOCs to electric current for 24 h, the electrodes were washed in phosphate buffered saline (PBS, pH 7.4 ) solution, then blocked with 0.1 M glycine in PBS for 5 min and permeated for 10 min in PBS containing 0.2% Triton X-100.
  • PBS phosphate buffered saline
  • Fluorescence-labeled secondary antibodies - Cy3 anti-mouse or Cy2 anti-rabbit IgG were diluted in 1% bovine serum albumin (BSA) containing Tris-buffered saline (TBS; 20 mM Tris base, 155 mM NaCl, 2mM ethylene glycol tetra acetic acid, 2 mM magnesium chloride) and incubated for 1 h at room temperature. All samples were counter stained with DAPI (Sigma, Switzerland) for nuclear localization. Actin filaments were visualized by Alexa488 and Alexa546 labeled phalloidin (Molecular Probes, Invitrogen, Switzerland).
  • a single implant consisting of the pulse generator and three electrodes was implanted in each of 20 Sprague-Dawley rats obtained from Harlan Laboratories (Horst, Netherlands). All procedures were performed in a laminar flow cabinet under sterile conditions using sterile equipment and standard surgical techniques. Anesthesia was induced by 2.5-5% isofluorane inhalation with 1 L/min oxygen in an enclosed induction box. Once the rat was sufficiently anesthetized, it was laid in a prone position. Sterile ophthalmic ointment was applied to the eyes of all animals. A custom-made mask was applied to supply continuous oxygen (1 L/min) and isofluorane (2.5-5%) as necessary to maintain adequate anesthesia throughout the procedure.
  • the level of anesthesia was monitored by observing breathing rate, heart rate and color of mucous membranes.
  • the dorsal implantation area was prepared for surgery by shaving off all fur from the nape of the neck to the mid back, and the skin disinfected with Kodan® (Schulke & Mayr, Switzerland). A dorsal, midline, transcutaneous incision was then made to allow implantation of the electrodes.
  • the three electrodes were placed approximately 5 mm apart in distended pockets in the fascial plane created by blunt dissection and individually secured with a single stay suture 6/0.
  • the counter electrode in each system was implanted between the two working anodes, and the pulse generator was placed a minimum of 5 cm away from the electrodes.
  • the spectra were measured with an amplitude of 50 mV between 0.2 Hz - 1 MHz.
  • the pulse generator was therefore taken out of the anaesthetized rat, the wires were cut and dismantled, while the electrodes remained in their position under the skin.
  • the free ends of the cables were then connected to the potentiostat with Kleps clamps.
  • the impedance was measured between the active Pt* electrode and counter electrode. After a lethal dose of carbon dioxide inhalation the rats were decapitated to keep the electrodes in their position in the tissue.
  • the implant's operational capability was then tested ex situ with a voltmeter and implants with no signal where categorized as "non working".
  • Impedance measurement control experiments were performed in culture medium and in a freshly sacrificed mouse. After removing the coat, two incisions were made in the hind limb muscles and the electrodes were placed in the pockets to measure the resistance of muscle tissue. Filling the incisions with culture medium simulated the liquid gap between electrode and tissue. The impedance was also measured across fascia
  • the rat heads with the implanted electrodes were put in 4% formaldehyde for fixation at 4 °C.
  • the solution was exchanged daily during one week.
  • the skull was separated from the neck with the electrodes to minimize the tissue amount for embedding.
  • the neck was then rinsed with H 2 0 3 x for 30 min.
  • the tissue was dehydrated in a watery solution with increasing ethanol content 50% 90min, 70% 24h, 80% 24h, 90% 12h, 96% 12h, 100% 96h, then the sample was stored in Xylene for 4 days.
  • the tissue was embedded in PMMA (Polymethylmethacrylate) by placing the sample into a small Tupperware® container and filled with the PMMA precursor mixture 89.5% methyl methacrylate MMA (Fluka Chemie, Switzerland), 10% dibutyl phthalate DBP (Merck, Germany) and 0.5% di(4-tert-butylcyclohexyl) peroxydicarbonate Perkadox 16 (Dr. Grogg Chemie, Switzerland).
  • PMMA Polymethylmethacrylate
  • the block was then cut into 0.6 mm slices with a saw microtome Leica SP1600 (Leica Microsystems) and glued on acrylic glass carrier for polished on a Planopol V (Struers, Denmark) with decreasing grain size.
  • the polished slice was then 4 min etched in 0.7% formic acid and blow dried before staining for 20 min in 1% toluidine blue solution.
  • the implant and the electrodes were placed in a Petri dish before adding the RAOC suspension.
  • the RAOCs displayed an increase in cell death with time (Fig. 7).
  • the cell mortality was higher on electrode 2 (5 s current, 5 s pause) for the first hour.
  • cell death was 96 ⁇ 3% on electrode 1 (2.5 s current, 2.5 s pause) and 96 ⁇ 5.0% on electrode 2.
  • cells grown on the Si0 2 control on the same electrode had a mortality of 3-8% throughout the experimental time.
  • the cell death was highly localized to the active Pt* surface, with a well defined boundary limited to the active Pt* electrode surface.
  • Type of cell death The presence of apoptotic cell death was determined by staining with anti-cleaved caspase 3 antibody which detects the large fragment (17/19kDa) of activated caspase-3; a determinant protease of apoptosis.
  • the cells on the Si0 2 control surface showed minimal cleaved caspase-3 activity, while 95 ⁇ 4 % of RAOCs on the active Pt* surface, were stained positive for this apoptotic marker.
  • the electrode impedance was measured in vivo from seven electrodes that remained functional for the entire experimental time and from 17 electrodes of implants that stopped working during the experiment.
  • the impedance spectrum of all electrodes was measured with an amplitude of 50 mV between 0.2 Hz and 1 MHz.
  • the impedance value remains on a more or less constant level during the entire experiment, whereas the non working implants showed an increase in impedance at the selected frequencies.
  • caspase- 3 As the anti-cleaved caspase- 3 antibody does not recognize full length caspase-3 or other cleaved caspases, its detection indicates apoptosis only via the caspase-3 pathway. As a result, although caspase-3 is considered the hallmark key executioners of apoptosis, the presence of other apoptotic pathways cannot be excluded.
  • cells were exposed to pulsed currents throughout the experiment, i.e. including some time preceding cell attachment, in order to simulate the conditions during in vivo implantation of clinically used electrodes. Although the generated electrochemical products diffuses into the culture medium, the space between cells and electrode becomes a small gap of around 100 nm, when a cell attaches to the electrode surface.
  • the products are accumulated within this gap and might reach toxic concentration levels depending on the current applied, adhesion size and the diffusion coefficient of the toxic products.
  • the cells in suspension have a round shape. Cells must therefore attach to the electrode before a significantly large area of their membrane gets exposed to the "dangerous zone" causing cell death. This is a possible explanation of why we observed cell death after increased time in comparison to other studies that exposed cells to electric currents only after they had formed a confluent layer on the electrode.
  • the adhesion size was optically determined by vinculin (focal contacts) staining. Vinculin represents a key element in the transmembrane linkage of the extracellular matrix to the cytoplasmic microfilament system and is associated with a large number of cytoskeletal and focal adhesion proteins. These multi-protein complexes are further associated with cell adhesion signaling molecules important to rendering cells susceptible or resistant to apoptosis.
  • HOCl hypochloric acid
  • the initial inflammatory tissue response increased the amount of exudate around the implants and kept impedance low for all electrodes for the first 15 days. After 21 days, the histology samples no longer showed a liquid gap between the electrode surface and the tissue.
  • the impedance of the non working electrodes showed the expected increase due to the diminished fluid gap and the presence of densely packed cells on the platinum electrode surface.
  • the impedance was decreased by -40% adding culture media to the electrode interface.
  • the electrodes with applied pulsed current showed no increase in impedance at 1 kHz and 0.5 MHz even though histological data did not reveal any changes comparing the tissue surrounding the active electrode surface Pt* with the platinum control surface Pt and the Si0 2 control surface.
  • Apoptosis In vitro, small pulsed currents induce apoptosis within 24 h in almost all cells attached to the electrode surface. Apoptosis is induced either directly by toxic concentrations of electrochemically generated products in the gap between the cell and the surface or indirectly by inhibiting cell adhesion, which induces then apoptosis.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Radiology & Medical Imaging (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Transplantation (AREA)
  • Physics & Mathematics (AREA)
  • Thermal Sciences (AREA)
  • Prostheses (AREA)

Abstract

La présente invention concerne un dispositif médical destiné au support permanent ou provisoire de la paroi d'un vaisseau sanguin. Le dispositif comprend une endoprothèse tubulaire implantable (3) dotée d'au moins une partie électroconductrice, et une source d'alimentation (2, 4, 5, 6) utilisable pour fournir une tension ou un courant à la partie électroconductrice après implantation de l'endoprothèse à l'intérieur d'un vaisseau sanguin dans un corps humain ou d'animal. De cette manière, on peut réduire le risque d'occlusion, de sténose ou de resténose du vaisseau sanguin. Dans des modes de réalisation préférés, une petite densité de courant de surface dans la plage allant de 10 à 10 000 nA/mm2 est générée à l'intérieur de la matière corporelle entourant les endoprothèses. L'invention concerne également des moyens de fournir de l'énergie à l'endoprothèse à la fois de manière transcutanée et via une paroi du vaisseau sanguin.
PCT/EP2011/061397 2010-07-16 2011-07-06 Dispositif et procédé destinés à réduire le risque d'occlusion et de resténose après l'implantation d'une endoprothèse WO2012007332A1 (fr)

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KR20200107007A (ko) * 2019-03-05 2020-09-16 (주)시지바이오 약물 방출 스텐트 및 이의 제조 방법
WO2020188559A1 (fr) 2019-03-18 2020-09-24 Rambam Medtech Ltd. Charge alternative pour inhiber la sorption sur des surfaces exposées à des substances biologiques
CN115414163A (zh) * 2022-11-04 2022-12-02 清华大学 血管支架、人体血管局部变形与血管局部动力学监测系统

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Publication number Priority date Publication date Assignee Title
KR20200107007A (ko) * 2019-03-05 2020-09-16 (주)시지바이오 약물 방출 스텐트 및 이의 제조 방법
KR102207960B1 (ko) * 2019-03-05 2021-01-27 (주)시지바이오 약물 방출 스텐트 및 이의 제조 방법
WO2020188559A1 (fr) 2019-03-18 2020-09-24 Rambam Medtech Ltd. Charge alternative pour inhiber la sorption sur des surfaces exposées à des substances biologiques
CN115414163A (zh) * 2022-11-04 2022-12-02 清华大学 血管支架、人体血管局部变形与血管局部动力学监测系统
CN115414163B (zh) * 2022-11-04 2023-02-28 清华大学 血管支架、人体血管局部变形与血管局部动力学监测系统

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