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    • 专利摘要:
    SHIFT-RESISTANT MICROELECTRODE, MICROELECTROD BEAM AND MICROELECTROD MATRIX. A medical microelectrode has an anterior end, a posterior end and a density at 20 ° C of 0.80 to 1.15. The electrode comprises any one of: an electrically conductive tubular guide comprising or consisting of a metal and / or an electrically conductive polymer, the guide having an outer face and a sealed lumen; an electrically conductive wire guide comprising or consisting of a metal and / or an electrically conductive polymer, the guide having a surface and a floating element of a density less than 1.0 attached to the surface.
    公开号:BR112013004428B1
    申请号:R112013004428-4
    申请日:2011-08-25
    公开日:2021-03-02
    发明作者:Jens Schouenburg；Gustav Lind；Christopher Hirst；Lars-Ake Clementz
    申请人:Neuronano Ab；
    IPC主号:
    专利说明:

    Description: FIELD OF THE INVENTION
    The invention relates to a medical microelectrode, a bundle of microelectrodes and an array of microelectrodes and / or bundles of microelectrodes. The microelectrode, bundle of microelectrodes and array of microelectrodes or bundles of microelectrodes of the invention are intended for insertion into soft tissue, such as the brain, spinal cord, endocrine organs, muscles and connective tissue. The medical microelectrode, bundle of microelectrodes and the array of microelectrodes and / or bundles of microelectrodes are designed to resist displacement in the tissue. BACKGROUND OF THE INVENTION
    Microelectrodes that can be implanted for a long time in the central nervous system (CNS) have a wide field of application. In principle, all brain nuclei can be registered to or stimulated by such electrodes and have their functions monitored. Of particular importance is the use of a multi-channel design in the stimulation of brain nuclei. In such a design, groups of electrodes or even individual electrodes can be treated separately. This allows the user to select those electrodes whose stimulation produces a therapeutic effect that is improved compared to non-selective stimulation. Stimulation of the brain or spinal cord may be of particular value in situations when the nuclei of the brain are degenerated or impaired. In certain situations, it would also be useful to be able to combine controlled electrical stimulation and localized gene transfer. A multichannel design can also allow the user to effectively measure the effects on various neurons and other cells after administering drugs in a systemic or local manner or gene transfer. Of particular interest is the ability to simultaneously measure the effects of multiple drug candidates on neuronal function. The monitoring of brain activity through implanted electrodes can also be useful if it is used to control the release of the drug locally or systemically or other therapeutic methods, such as electrical stimulation of brain nuclei. Multiple channel electrodes can also be used for specific and limited tissue injury sites after abnormal impulse activity has been detected by the records obtained through the electrodes.
    To record and stimulate brain structures, various forms of implantable electrodes have been developed (US 6,253,110 Bl, US 5,957,958, US 4,573,481, US 7,146,221 B2, US 5,741,319, US 4,920,979, US 5,215,008, US 5,031,621, US 6,993,392 B2, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062, US 6,032,062 4,852,573, US 3,995,560, US 7,041, 492, US 6,421,566 Bl, US 4,379,462, US 5,417,719, US 3,822,708, US 5,501,703, US 7,099,718 Bl, US 3,724,467; US 2007/0197892 Al).
    For the function of an electrode implant it is important to have a fixed spatial relationship between the registration / stimulation sites on the implant and the measured entities. The body, and thus the tissue, exhibit considerable movement during daily life. The movements are caused, for example, by breathing, heartbeat, bowel movement and skeletal movements such as turning the head in relation to the body. The movements can also be caused by external forces in the body. Relative movements between the tissue and the electrodes can cause changes in the registered biological signals, such as electrical or chemical signals, as transmitting substances. For example, an action potential corresponds to a voltage change of the order of 100 mV over the neuronal membrane. This change in potential quickly disappears with the distance from the cell. Consequently, the movements of the electrode in relation to a measured cell can result in a considerable variation in the amplitude of the measured action potential. Likewise, when the electrodes are used for electrical stimulation, a change in the location of the electrode in relation to the tissue can result in a displacement of the stimulated neurons. It is, therefore, very important that the sites on the medical electrode where the records or stimulation are made on the tissue can follow the movements of the tissue in which it is incorporated as faithfully as possible. In addition to impairing the recorded signal or the effectiveness of stimulation, the movements between the implants and the tissue can cause tissue damage that, in turn, can trigger a tissue reaction and loss of function of the implant. Mechanical stability between the electrode and the tissue is particularly important for intracellular recordings because movements of the electrode in relation to the cell can easily damage the membrane and cause leakage of extracellular fluid into the cell and vice versa. Currently, there are no known electrode implants designed or suitable for intracellular recording simultaneously on many neurons over time such as days, weeks or months in freely moving animals or humans.
    Ultrathin electrodes that are flexible and thus overcome problems related to movements between the tissue and the electrode are known in the art (WO 2007/040442). By incorporating such electrodes into a hard dissolvable matrix, it is possible to implant them in the soft tissues, without any additional help like a syringe. Such ultrathin electrodes must be made of a material that is not degraded by the fabric or easily oxidized, causing high electrical resistance and, thus, reducing the signal: noise ratio. Examples of suitable conductors are noble metals, such as gold and platinum. Commonly, an alloy of platinum and iridium is used as an implant material used for stimulation.
    To achieve physically stable contact with cells in the nervous system, it is also important that the electrode is anchored in the tissue close to the stimulated or measured tissue. Electrodes with electrically conductive wires and electrode plates equipped with holes through which the tissue can grow and thus firmly attach to the electrode are known in the art (WO 2007/040442; WO 2008/091197; WO 2009/075625). However, implants can cause chronic inflammation and even infections and may have to be removed. In the situation when the electrode is removed from tissue anchoring devices known in the art, such as wires or, in particular, holes in the electrode body allowing the tissue growing inward to cause major damage to the tissue. It is, therefore, desirable to solve the problem of how to anchor a medical electrode in the soft tissue, so that the medical electrode is physically stabilized in the tissue and can still be removed from the tissue with reduced tissue damage. OBJECTS OF THE INVENTION
    It is an object of the invention to provide a microelectrode that is stabilized against displacement within the tissue in which it was implanted.
    It is another object of the invention to provide a bundle of microelectrodes comprising such electrodes.
    It is another object of the invention to provide a microelectrode array and a microelectrode beam array comprising such electrodes.
    Other objects of the invention will become apparent from the following summary of the invention, from a variety of preferred embodiments of the invention illustrated in a drawing and from the appended claims. SUMMARY OF THE INVENTION
    The present invention is based on the perception that, in order to optimally resist displacement within the soft tissue to which it has been implanted, a microelectrode must approach the specific weight of the tissue. By such an approximation, the electrode is "floating" in the tissue and can be called a floating microelectrode. The floating property of the electrode makes it follow the displacement of the surrounding tissue when the tissue is accelerated or delayed. The stabilization according to the invention, therefore, is a counter displacement within a fabric, as opposed to stabilization against the removal of the fabric by means of mechanical anchoring, such as wires, nails and the like. It is, of course, possible to supply the electrode of the invention additionally with such means against tissue removal. The stabilization according to the invention is particularly useful for electrodes implanted in delicate non-fibrous soft tissue, such as tissues of the brain, spinal canal and bone marrow.
    The microelectrode of the invention is intended to record electrical signals from tissue, particularly nervous tissue, but can also be used for electrical tissue stimulation.
    Thus, according to the present invention, a medical microelectrode resistant to inertia displacement in soft tissue is disclosed.
    The electrode comprises an electrically conductive tubular lead that comprises or consists of a metal and / or an electrically conductive polymer. The tubular lead has an outer face and an inner face. The outer face of the tubiform lead may be porous, but not in a way that allows aqueous body fluid to penetrate the lumen. In this way, the pores do not penetrate the outer face or are sealed to a desired depth, for example, by applying a polymer coating to the inner luminal surface of the lead pipe. Tubiform lead has a front or distal end, a posterior or proximal end, and a sealed lumen placed between the anterior end and the posterior end. The lumen of the lead tubiform is empty or comprises one or more empty sections and one or more sections partially or completely filled with filler. The density at 20 ° C of the filler is preferably 0.8 or less, in particular 0.6 or less. Advantageously, the filler comprises or consists of a porous material, in particular a porous material with closed pores. It is preferable for the filler to consist of or comprise a polymer, particularly a polymer with closed pores. The polymer is preferably flexible, particularly resiliently flexible.
    Alternatively, the electrode comprises or consists of a wire conductor. The wire conductor can be porous or non-porous. In the mode in which the conductor is a conductor in wires, the insulation of the conductor may be of a porous polymeric material which comprises the closed pores, that is, pores that do not absorb body liquid. Alternatively, in a thin non-porous insulating layer over the wire conductor, a porous polymeric material comprising sealed pores is disposed. The volume of the porous insulating material is selected in order to compensate for the high density of the conductor in metallic wires.
    The electrode density at a temperature of 20 ° C is preferably from 0.80 to 1.15, more preferably from 0.90 to 1.07, even more preferably from 0.95 to 1.03, most preferably 0.99 ± 0.02. Optionally, a part of the outer face of the electrode is electrically isolated. Guides of an elliptical or cylindrical cross section are preferred, however guides of another type of cross section, such as triangular, square or hexagonal, are not excluded from the invention. In this application, an oblong guide is one with a length / diameter ratio of 5 or more, particularly 10 or more, more preferably 20 or more. A preferred guide diameter is 1 to 200 μm. The guide is preferably made of a metal selected from gold, silver, platinum and copper or an alloy comprising one or more of these metals. Alternatively, the guide is an electrically conductive carbon modification, such as carbon nanotubes or an electrically conductive polymer. The guide may also comprise a combination of such materials.
    According to a preferred aspect of the invention, the electrode is totally or partially incorporated in a dissolvable or degradable matrix in a body liquid.
    According to another preferred aspect of the invention, the electrode comprises an electronic amplification medium and / or a microprocessor medium, with the proviso that the combination of electrode and electronic amplification medium / microprocessor medium has a density at 20 ° C of 0, 80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03 and even more than 0.99 ± 0.02. It is preferable that the electronic amplification medium / microprocessor medium is placed at or near the rear end of the electrode.
    Alternatively, an electronic amplification medium and / or microprocessor separate from the electrode implanted in the tissue is provided. The electrical communication between the electrode and the electronic amplification medium / processor medium placed at a distance from the electrode is carried out by an insulated electrical conductor such as by an ultrathin insulated wire mounted on or near the rear end of the electrode, on the one hand, and on the electronic amplification medium / processor, on the other hand; a preferred wire thickness is 50 μm or less. It is preferable that the conductor is of approximately the same density as that of the electrode, that is, of a density of about 1, in particular, from 0.9 to 1.1. The density of the wire-type electrical conductor can be controlled by supplying it with a floating element of a density <1 such as, for example, an insulating coating of spongy polymer. It is also preferable that the electronic amplification medium / processor separated from the electrode has a density approximately equal to that of the electrode, that is, a density of about 1, particularly from 0.9 to 1.1. The electrode amplification medium / electrode processor can be powered, for example, by a power source, such as a battery implanted in the tissue or external to it; an electrical connection between the power source and the electrode amplification medium / electrode processor being provided by an electrical conductor of the aforementioned type made floating, by providing it with a floating element.
    Microprocessor means separated from the electrode are preferably arranged in the soft tissues of said person or animal, but they can also be placed externally of said person or animal. The amplification / microprocessor medium may comprise an electrical power source, such as a battery, or be connected to an external source by an electrical guide. The amplification / microprocessor means may also comprise a means for transmitting and / or receiving radiation to / from a control unit disposed externally of the patient or animal. The electrode of the invention is capable of carrying out electrical communication with the microprocessor medium disposed at a distance from it in the tissue of the person or animal, or externally to it. The microprocessor medium can comprise an electrical power source, such as a LiH cell. The microprocessor may also comprise a means for transmitting and / or receiving radiation to / from a control unit disposed externally of said patient or animal.
    According to another preferred aspect of the invention, the electrode may comprise an anchoring means placed at or near its front end, preferably integrated with the electrode guide. Since the electrode of the invention is not easily displaced by a sudden displacement of the tissue in which it is embedded, the need to anchor it in the tissue is less pronounced than with traditional microelectrodes of a density substantially greater than 1. A surface of rough electrode or a rough part of it, such as a rough electrode tip, may be sufficient for anchoring.
    According to a further preferred aspect, the electrode may be of an electrically porous conductive material, or comprise such a material. Electrically porous conductive materials are sintered metal powders, particularly titanium, aluminum and their alloys. Other electrically porous conductive materials comprise or consist of carbon nanotubes and / or fullerenes and / or thin graphite sheets up to graphite monolayers. The pores of such materials opening on the electrode surface can be sealed, for example, by electrically insulating materials such as polyurethane or polyimide coatings or, in non-electrically isolated portion / portions of the electrode, by electrically conductive materials such as electrolytically deposited layers of gold or other noble metals.
    Alternatively, the electrode may comprise an electrically non-conductive porous material. Preferred electrically non-conductive porous materials include porous organic polymers, such as porous polyurethane and porous ceramic materials, such as sintered alumina, in which an electrically conductive layer comprising or consisting of a metal or metal alloy has been deposited, for example, by ion spraying.
    The pores of the electrically conductive or non-conductive porous material of the electrode of the invention can be opened or closed. If opened, they are protected against the ingress of aqueous body fluids by sealing, for example, with non-conductive lacquers or thin metal layers deposited thereon by ion spraying or other suitable techniques. In order to supply the entire electrode with the preferred density of the invention at 20 ° C from 0.80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03 and even from 0.99 ± 0.02, the porosity of the electrically conductive or non-conductive porous material of the electrode is dimensioned so as to fully compensate for at least substantially partially the> 1 density of the mass electrode material. To achieve the preferred density, the porous electrode materials of the invention can be advantageously combined with electrodes with a sealed lumen and / or comprising a floating element attached to their surface.
    According to the present invention, there is also disclosed an electrode array comprising two or more electrodes of the invention. The electrode bundle comprises a non-permanent packaging means, preferably in the form of a material soluble or degradable in a body liquid in which the two or more electrodes are placed in a substantially parallel configuration. Consequently, an electrode of the invention can be comprised of such an electrode bundle. It is preferable that the electrode beam has a density at 20 ° C of 0.80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03 and even from 0.99 ± 0.02.
    According to another preferred aspect of the invention, an electrode guide is disclosed which comprises multiple electrically conductive layers interspersed with non-conductive layers of low density polymeric material; such guides can be manufactured by electrospinning, for example, gold nanowires spun in parallel with or around low density polymeric fibers. The fusion of the guide ends by means of laser radiation or any other suitable heat source establishes the electrical contact between the electrically conductive layers to make them constituents of a single electrode guide. The electrode of the invention may, moreover, comprise useful features known from the state of the art microelectrodes.
    According to the present invention, an electrode matrix is also disclosed which comprises two or more electrodes and / or electrode bundles of the invention. According to an advantageous aspect of the invention, the electrode matrix is partially or completely enveloped in a material soluble or degradable in a body liquid. It is preferable that the electrode matrix has a density at 20 ° C of 0.80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03 and even from 0.99 ± 0.02. Consequently, an electrode of the invention can be comprised of such an electrode matrix.
    The incorporation of the electrode of the invention in a material destined to be dissolved or degraded through the implantation of the electrode allows thin and flexible microelectrodes, and bundles and hues comprising them, to be inserted into the tissue without putting its integrity at risk. The material of incorporation of the electrode is disregarded when considering the determination of the density of the electrode of the invention.
    According to another important aspect, the invention teaches that, in addition to the whole electrode being designed so that its density approaches that of the soft tissue, that is, about 1.0, it is important to design the electrode in order to distribute the high density elements and the low density elements over the entire electrode, in the most uniform way possible. Most commonly, the electrode of the invention will be oblong; in an oblong electrode configuration, it is therefore advantageous to compensate for density deviations along the electrode. This type of compensation avoids the preferential orientation of the electrode portions in the tissue by the effect of gravity, such as, for example, an inventive electrode having a relatively high density front end section pointing downwards in a flowing state in the tissue and a section of relatively low density pointing upwards in the same state, or vice versa. High density elements comprise metallic electrode guides, microsignal amplifiers or other electronic device connected to the electrode guide at its rear end, etc; low density elements comprise buoyancy elements arranged in the electrode guide or voids in the electrode guide. It is also of great importance the proper selection of materials, particularly metallic materials, including compounds comprising metals for electrode guides. Thus, it is preferable that the electrode of the invention has a balanced density. By "balanced density" it is understood that it is not only the high density portions of the electrode balanced by low density potions in order to obtain an electrode of desired density as a whole, but that the density balance is located in portions of the electrode that need balance. A measure of equilibrium for an electrode of the invention is the distance between its center of gravity (Cg) and the center of gravity (Cg-) of an electrode of identical shape with uniform density. In a balanced electrode of the invention with an anterior and posterior extremity spaced by a distance L, the distance I between said centers of gravity Cg, Cg- is less than 25% of the distance L, preferably less than 15%, more preferably less than 10%.
    According to the present invention, there is also disclosed an electrode array and an electrode array comprising one or more electrodes of the invention. An electrode array comprises two or more electrodes of the invention packaged by a packaging means that can be permanent or temporary. "Permanent" and "temporary" refer to a state of the electrode beam after implantation. A permanent packaging means is one designed to preserve the integrity of the beam during the period of use of the electrode in the tissue, whereas a temporary packaging means is one designed to preserve such integrity during the insertion of the beam into the tissue, but not during period of use of the electrode in the tissue. A permanent packaging means comprises, for example, a belt or sleeve confining two or more electrodes of the invention arranged in parallel near its anterior ends, the belt or sleeve of which is not easily dissolved or degraded by a body liquid. A temporary packaging means comprises, for example, a glue that connects at least the front portions of the electrodes thus placed close to their front ends, the glue being soluble in a body liquid. For easy implantation, the electrode bundle and the electrode matrix of the invention can be partially or totally surrounded by a soluble or degradable material in a body liquid. This type of delimitation can also fulfill the function of the packaging means of the temporary electrode of the invention. A partial delimitation at least surrounds the anterior portions of the electrode beam electrodes or the electrode beam matrix.
    The invention will now be described in more detail with reference to a variety of preferred embodiments illustrated in a drawing. Figures 1 to 11 of the drawing are not to scale, but are only intended to clearly illustrate the main features of the invention. BRIEF DESCRIPTION OF THE DRAWINGS
    Figure 1 shows a first embodiment of the electrode of the invention in an axial section (A-A);
    Figures 1 to 8 show variations of the modality of Figure 1, in the same view;
    Figure 9 shows a second embodiment of the electrode of the invention in an axial section (B-B);
    Figure 10 shows a variation of the embodiment of Figure 9, in the same view;
    Figure 11 shows the electrode of Figure 10 inserted in the body of the soluble matrix;
    Figures 12a to 12f show examples of electrode guides of the invention in the radial section. DESCRIPTION OF PREFERENTIAL MODALITIES
    A first embodiment of the medical microelectrode 1 illustrated in Figure 1 comprises an electrically conductive silver-conductor guide 2 bonded with 20% copper. At its front end 3, the guide 2 is closed and has a sharp tip 11. At its rear end 4, the lumen 5 of the guide 2 is sealed by a polyethylene plug 6 placed in the lumen 5 at the rear end 4. A wire of thin insulated metal (not shown) 9 is conductively bonded by solder 10 to the outer surface of the guide 2 at the rear end 4 thereof. Wire 9 connects electrode 1 to an electrode control unit (not shown) comprising the microprocessor medium.
    In a first variation 101 of the microelectrode of Figure 1 illustrated in Figure 2, a polyethylene plug 106 is placed in the lumen 105 at a distance from the rear end 104 of the pointed guide 102 111 of an aluminum alloy, in order to divide the lumen 105 in a ratio of about 2: 1 on a sealed portion, extending from buffer 104 towards the front end 103 and an open portion extending from buffer 104 towards the rear end 104. The open portion of lumen 105 is filled with compacted glucose powder 107. By inserting the electrode 101 into the soft tissue, the aqueous body liquid comes into contact with the powder 107 and slowly dissolves it. Filling the open potion of lumen 105 with a material soluble in an aqueous liquid prevents an air-filled pouch from remaining in the open portion of lumen 105.
    In a second variation 201 of the microelectrode of Figure 1 illustrated in Figure 3, the entire lumen of the pointed electrode guide 202 211 of a gold / silver alloy extending from the closed front end 203 to the open rear end 204 is filled with foam of polyurethane 208 with closed pores.
    The third variation 301 of the microelectrode in Figure 1 illustrated in Figure 4 differs from the variation in Figure 3 in that only one potion from the rear end 304 of the lumen 305 is filled with polyurethane foam 308. The front end portion of the lumen 305 is in this way it is sealed and remains empty. Again, the electrode guide 302 is pointed 311 at its front end 303 and opened at its rear end 304.
    The fourth variation of microelectrode 401 illustrated in Figure 4 differs from the microelectrode of Figure 1 by the front end 403 of the guide 402 having a blunt end 411. At the rear end 404, the lumen 405 is closed by a polyethylene plug 406. A thin insulating wire ( not shown) 409 welded (in 410) on the outer surface of guide 402 provides electrical communication between electrode 401 and an electrode control unit (not shown).
    The fifth variation 501 of the microelectrode of Figure 1 shown in Figure 6 differs from the microelectrode of Figure 2 in that its tip 511 is provided with anchoring means in the form of wires 512 to fix the electrode, once inserted in the soft tissue, preventing it from being accidentally removed. The reference numbers, 502, 503, 504, 506 and 507 identify elements corresponding to those listed 202, 203, 204, 206 and 207, in Figure 2.
    The sixth variation 601 of the microelectrode of Figure 1 illustrated in Figure 7 comprises a tubular platinum alloy guide 602 closed at its anterior end 603 by a pointed tip 611 and opened at its rear end 604. The lumen is filled with polymeric foam. At its rear end, the guide 602 is provided with a signal amplifier 613 from which an ultrathin insulating wire 609 extends. Wire 609 provided the electrical connection of the signal amplifier 613 to an electrode control unit (not shown). Except for its pointed front end tip 603, the guide 602 and the signal amplifier 613 are encapsulated by an electrically insulating lacquer 615.
    The seventh variation 701 of the microelectrode of Figure 1 illustrated in Figure 8 comprises a tubular guide 702 that is rotationally symmetrical, with the exception of its pointed tip 711 of the anterior end 603. The lumen 702 is partially filled with polymeric foam, a first section of foam 708 extending from the rear end 704 of the guide 702 towards the front end 703 and a second section of foam 708 ', extending from the front end 703 towards the rear end 704 so as to delimit an empty central section 705 of the lumen of the guide.
    A second embodiment 801 of the medical microelectrode of the invention illustrated in Figure 9 comprises a solid titanium electrode guide 802 with an anterior end 803 and a posterior end 804, the anterior end 803 being provided with a pointed tip 811. Except for the fact that , at its tip 811, the guide 802 is bounded by a floating layer 814 of the polymeric foam with closed pores, which touches the guide 802 and adheres firmly to it. The floating layer 814 is substantially shaped like a mandrel in the guide 802. At the rear end of the guide 802, an electrode signal amplifier 813 is placed, which is sealed by a thin layer 815 of lacquer. Amplifier 813 is in electrical communication with an electrode control unit (not shown) via an 809 insulated ultrafine metal wire.
    A variation 901 of the second embodiment of the medical microelectrode of the invention is illustrated in Figure 10. The floating layer comprises two spaced sections 914, 914 ', the first section 914 placed close to the front end 903 and the second section 914' placed close to the rear end 904 of the tungsten electrode guide 902. The guide surface 902 extends between sections 914, 914 'and is insulated by a lacquer 915. Thus, only rotationally asymmetric points 911 are not insulated. At its rear end, electrode 901 has an electrically insulated ultra-thin wire 909 welded to it, which provides electrical communication with an electrode control unit (not shown) placed at a distance from electrode 901 inside or outside the body.
    Figure 11 shows the electrode of Figure 10 embedded in a body of a carbohydrate matrix 920 through which the small electrode 901 can be inserted into the soft tissue without compromising its physical integrity. After insertion, the matrix body 902 is dissolved by the aqueous body liquid in order to establish physical contact between the electrode and the tissue. The matrix body 920 is rotationally symmetrical and thus arranged around the electrode 901 to make its axis of rotation coincide with that of the electrode 901. At its front end, the matrix body 920 has a pointed tip 921. Sizing of the electrodes of the invention
    The radial sizing of the electrodes of the invention so as to have their 1.0 density approaches is illustrated below in a variety of examples. The outer diameter of the electrodes is defined as 100 μm. The radial dimensions of the thicker or thinner electrodes are obtained by multiplying the thickness of the electrode layers by the desired size factor. In the Examples, the axial length of the electrode tip is considered to be insignificant in relation to the total length of the electrode guide. EXAMPLE 1
    Tubiform silver guide, Figure 12a; dAg = 10.4. Internal diameter (lumen): 95 μm Density (calculated): 1.01. EXAMPLE 2
    Tubiform gold guide, Figure 12b; dAu = 19.3. Inner diameter (lumen): 97.3 μm. Density (calculated): 1.03. EXAMPLE 3
    Tubiform bilayer guide, Figure 12c. Gold outer layer, dAu = 19.3, titanium inner layer, dT ±, = 4.5. Inner diameter (lumen): 92 μm; titanium layer thickness: 19; gold layer thickness: 1 μm. Density (calculated): 0.986. EXAMPLE 4
    Tubiform bilayer guide, Figure 12d. Gold outer layer, dAu = 19.3, titanium inner layer, dT ±, = 4.5. Inner diameter (lumen): 92 μm; titanium layer thickness: 7.5 μm; gold layer thickness: 0.5 μm. Lumen filled with polyurethane foam, dpuF = 0.20. Density (calculated): 0.963. EXAMPLE 5
    Gold wire guide covered with polyurethane foam with closed pores, Figure 12e. dAu = 19.3 dPUF = 0.24. Gold wire diameter: 40 μm. Density (calculated): 1.00. EXAMPLE 6
    Tubiform titanium guide covered with polyurethane foam with closed pores, Figure 12f. dTi = 4.5; dPUF = 0.20. External diameter of the titanium guide: 70 μm; internal diameter (lumen): 53 μm. Density (calculated): 1.04. EXAMPLE 7
    Porous nickel guide manufactured by the electrodeposition method of US 7,393,446 B2 using polystyrene beads about 60 μm in diameter. Guide outside diameter: 500 μm. A guide with a density of about 1.1 was produced as one of a series of guides produced varying the duration of the electrodeposition. After the formation of the cellular metal structure with open pores, the polystyrene matrix is removed by immersion with acetone. The cylindrical porous nickel guide is completely washed with acetone, dried and then galvanized with gold to a plating thickness of about 10 μ, in order to keep the pores open. The guide is thoroughly washed with water, then with acetone, and dried. One end of the guide is carefully heated with an acetylene burner in order to reduce it to form a blunt tip. The other end of the guide is connected by welding to a thin insulated copper wire. Except for the shrunk tip portion, the electrode guide is immersed in a polyurethane solution (Tecoflex® solution grade SG-85A, The Lubrizol Corporation, Cleveland, OH) in THE (20%, w / w)) to close the pores and isolate the main part of the electrode guide. Other dip coating materials, such as Thoralon®, for use in the invention, comprise polyetherurethanourea containing soft segments, made of polytetramethylene oxide, and hard segments made of 4,4'-diphenylmethane diisocyanate and ethylenediamine (BPS-215, Thoratec Corporation, Pleasanton, CA). Manufacture of the electrodes of the invention
    The tube electrodes of the invention can be manufactured from the corresponding metal microtubes. Noble metal microtubes can be obtained, for example, by electrolytic coating of a less noble metal, such as aluminum or iron, with noble metals, such as silver, gold, platinum, etc. but also copper, followed by the dissolution of the less noble metal by a strong non-oxidizing acid such as hydrochloric acid. The front ends of the microtubes can be closed by heating a short portion of the crude tube to just below its melting point, then pulling their ends in opposite directions at this temperature, followed by raising the temperature to the melting point so that a finely pulled out portion breaks. The tube is then pulled away and microtubes with two points, either pointed or rounded, depending on the material and working conditions, are obtained, which can be cut to a desired length. Alternatively, a microtube can be closed at its end by welding, optionally after flattening the end portion before welding. The rear end of the closed microtube at its rear end can be sealed, for example, by a slightly conical polyethylene or polypropylene plug that is forced at the open end to a desired distance. Filling the lumen of a microtube with polymeric foam is accomplished by injecting a solution or suspension of prepolymer in a highly volatile solvent, such as propane or butane, followed by gentle heating of the filled microtube. Particulate solid fillers can be poured into the lumen and compacted there by a piston of suitable diameter, if necessary.
    Electrically conductive polymers suitable for use in the invention include polyethylenedioxythiophene, polyaniline, polyacetylene and polypyrrole.
    Wired electrodes can be covered with polymeric foam, for example, by placing them in a closed compartment that comprises a container filled with a solution or suspension of prepolymer from the above mentioned, immersing them in the solution or suspension, removing them from the solution or suspension, closing the container, allowing the entry of air, particularly moist air into the compartment, storing the electrodes thus covered in a humid atmosphere until the polymer is fully cured. The thickness of the polymer layer with closed pores in the wire can be controlled by controlling the viscosity of the prepolymer solution or suspension and / or the temperature of the solution or suspension in the container and / or the type of solvent.
    Ultra-thin insulation layers can be obtained by applying electrically insulating lacquers to the desired part of the electrode. Alternatively or in addition, parylene C insulation coatings can, for example, be used.
    The electrodes of the invention comprising porous metal structures can be manufactured, for example, by the methods described in US 7,393,446 B2.
    The electrodes of the invention can be packaged or stacked in substantially the same manner as described in WO 2007/040442 Al. The electrodes of the invention can also be incorporated into matrices such as those described in WO 2008/091197 Al. Suitable procedures for incorporating the electrodes of the invention and the electrode bundles and electrode bundle arrangements of the invention in rigid matrix bodies soluble in body fluids are disclosed in WO 2009/075625 A1. Methods of incorporating the microelectrodes of the invention in a soluble matrix
    A method for incorporating the microelectrode of the invention comprises providing a fixation means, fixing the electrode and, optionally, additional elements to be incorporated, such as optical fibers, contractile elements, etc., in the fixation means in a desired configuration, applying a sheath covering the electrode thus fixed and accessories, except for in the proximal coupling section of the same, apply a solution or suspension of a first matrix material on the electrode in order to cover the portions of the electrode intended to be incorporated, allow the solvent / dispersant of the solution or matrix suspension, respectively, evaporate or harden, remove the sheath and release the electrode from the fixation medium. To incorporate the electrode into two matrix materials to form the corresponding matrix compartments, each comprising a portion of the electrode, a suitable portion of the electrode fixed by a fixing means as described above is coated with a solution or suspension of the first matrix material matrix, the solvent / dispersant from which it is subsequently evaporated, followed by coating the remaining portion of the electrode to be coated with a solution or suspension of the second matrix material, subsequently evaporating the solvent / dispersant from the second matrix material and releasing the electrode of the fixing means. In the method, the electrode is preferably placed in a sheath of smooth material with low humidification capacity, such as a polyfluorinated hydrocarbon polymer or silicone rubber, and attached to it. To facilitate evaporation of the solvent, the sheath material is advantageously porous, particularly microporous. After application and drying of the matrix material (s), the electrode is removed from the sheath. If desired, a drug or combination of drugs can be incorporated into the matrix.
    An alternative method of incorporating an electrode of the invention into two matrix materials forming separate matrix compartments comprises incorporating the entire electrode into a first matrix material, dissolving a portion of the first matrix material, preferably a distal portion extending from from the distal end, covering the now unincorporated distal portion of the electrode with a second matrix material, for example, using a sheath applied over the unincorporated distal portion, filling the sheath with a solution or suspension of the second matrix material, evaporating the solvent in order to dry / harden the second matrix material and removing the sheath. The electrode of the invention can be coated using a single coating technique or a combination of coating techniques, such as dip coating, spray coating, melting processes including extrusion, compression molding and injection molding, or a combination of different techniques.
    In a representative example of a step-by-step procedure, the electrode is first coated by immersion with a resorbable polymer or mixture of polymers, particularly collagen, gelatin, polyvinyl alcohol and starch, dissolved in a suitable solvent. Other polymers can also be used. The thickness of the polymeric layer is controlled in a manner known to a person skilled in the art. The coating is then subjected to a drying step. The dip coating and drying steps can be done once or can be repeated, depending on the required thickness of the final coating. In the next step, the polymer is loaded with the drug. The electrode is submerged in a solution containing the drug. The solvent used must be one in which the polymer swells and in which the drug dissolves. After an appropriate contact time, such as less than a second to 5 minutes or more, the electrode is removed from the solution and the matrix is dried by evaporation of the solvent, possibly under reduced pressure.
    In a one-pot procedure, the electrode is submerged in a polymer solution and the drug of choice in an ideal concentration for a desired coating thickness and, optionally, a desired drug loading. The electrode is then removed from the solution and the solvent is evaporated, possibly under reduced pressure.
    Alternatively, the coating is generated by spray coating, in which a polymer solution optionally containing a drug or a combination of drugs in a suitable solvent is sprayed onto the electrode body. The thickness of the coating can be controlled by the number of spraying and drying (evaporation) cycles and the amount of polymer and drug in the solution.
    Also included by the invention are hydrogel coatings of partially hydrolyzed water-soluble polymers, such as polyvinyl alcohol, polyacrylic acid and polyacrylic acid derivatives, for example, poly (N-isopropylacrylamide). An increase in temperature causes these hydrogels to contract, thereby expelling a drug or a combination of drugs incorporated in the coating. Alternatively, the temperature sensitive hydrogel is an interpenetrating network of (poly) acrylamide and (poly) acrylic acid, and the increase in temperature causes the hydrogel to swell, thus allowing the drug to diffuse out of the gel. . It is also understood by the invention the use of a polymer or mixtures of polymers for the electrically driven release, such as polyvinyl alcohol / chitosan.
    Electrode bundles, electrode arrays and electrode bundles of the invention can be incorporated into a matrix in substantially the same manner as described above for individual electrodes. Uses
    The invention also relates to the use of electrode embedded in a matrix, the electrode beam embedded in a matrix or the matrix of electrode bundles embedded in a matrix for long-term nerve stimulation, records of multiple channels of neuronal electrical activity and levels of transmitting substance through measurements of redox reactions and tissue damage for scientific, medical and veterinary purposes.
    According to a preferred aspect of the invention, the microelectrode, the microelectrode bundle and the microelectrode array or the microelectrode bundles of the invention are used in a patient or animal to: record signals from the remaining neurons after damage to the brain or spine; stimulate neurons to compensate for lost functions; provide pain relief by stimulating analgesic brainstem centers; provide relief or decrease in tremor and other motor symptoms in Parkinson's disease; alleviation or decrease of choreic movements and other involuntary movements by stimulation in the basal ganglia or associated nuclei; memory enhancement by stimulation of cholinergic and / or monoaminergic nuclei in the case of Alzheimer's disease or other degenerative diseases; control of mood, aggression, anxiety, phobia, affection, sexual overactivity, impotence, eating disorders by stimulation of limbic centers or other brain areas; proportion of rehabilitation after stroke or damage to the brain and / or spinal cord by stimulation of the remaining connections in the cerebral cortex or descending motor pathways; proportion of restoring control of spinal functions such as emptying the bladder and emptying the intestine after spinal cord injury by stimulation of the relevant parts of the spinal cord; proportion of spasticity control by stimulation of the supraspinous descending inhibitory centers or adequate cerebellar areas; proportion of the restoration of somatosensory, auditory, visual and olfactory senses by stimulation of the relevant nuclei in the spinal cord and brain.
    According to another preferred aspect of the invention, the microelectrode, the microelectrode bundle and the microelectrode array or the microelectrode bundles of the invention are used in a patient or animal for monitoring and stimulation, particularly to: monitor epileptic attacks by implanted electrodes in the epileptic focus coupled to a system to administer antiepileptic drugs or electrical pulses; compensate for a lost connection in the motor system by recording central motor commands, followed by stimulation of the executing parts of the motor system distal to the injuries; records of blood glucose levels to control hormone release.
    According to a further preferred aspect of the invention, the microelectrode, the microelectrode array and the microelectrode array or the microelectrode array of the invention are used in a patient or animal to damage the tissue locally, particularly the abnormally active tumor or nerve tissue or epileptogenic by the passage of current of sufficient magnitude through said electrode, electrode bundle or array of electrode bundles.
    In biomedical research, the use of the microelectrode, the microelectrode bundle and the microelectrode array or microelectrode bundles of the invention can be used to study the normal and pathological functions of the brain and spinal cord, particularly over a long period of time. time.
    In a patient with a neuroprosthetic device, the microelectrode, the microelectrode bundle and the microelectrode array or the microelectrode bundles of the invention can be used to form an interface between a nerve and said device.
    In a patient or an animal, the microelectrode, the microelectrode array and the microelectrode array or the microelectrode array of the invention can be used to control the function of an endocrine or exocrine organ, such as by controlling hormonal secretion.
    In a patient or an animal, the microelectrode, the microelectrode array and the microelectrode array or the microelectrode array of the invention can be used to control the function of one or more skeletal or heart muscle.
    权利要求:
    Claims (29)
    [0001]
    1. Medical microelectrode for implantation in soft tissue of a person or animal resistant to displacement in the tissue by inertia, the electrode having an anterior end, a posterior end and a density at 20 ° C of 0.80 to 1.15, particularly of 0.90 to 1.07, more particularly from 0.95 to 1.03, CHARACTERIZED by the fact that it comprises any of: an electrically conductive tubular guide comprising a metal and / or an electrically conductive polymer, the guide having an outer face and a sealed lumen; an electrically conductive wire guide comprising an electrically conductive metal and / or polymer, the guide having a surface and a floating element of a density less than 1.0 attached to the surface; wherein a portion of the outer surface or the surface, respectively, is electrically isolated.
    [0002]
    2. Microelectrode, according to claim 1, CHARACTERIZED by the fact that the density is 0.99 ± 0.02.
    [0003]
    3. Microelectrode, according to claim 1, CHARACTERIZED by the fact that the lumen is empty.
    [0004]
    4. Microelectrode, according to claim 1, CHARACTERIZED by the fact that the lumen comprises one or more sections filled with filling and, optionally, one or more empty sections.
    [0005]
    5. Microelectrode according to claim 4, CHARACTERIZED by the fact that the density of the filler is 0.8 or less, particularly 0.6 or less.
    [0006]
    6. Microelectrode, according to claim 4, CHARACTERIZED by the fact that the filler comprises a porous material.
    [0007]
    7. Microelectrode, according to claim 4, CHARACTERIZED by the fact that the filler comprises a polymer.
    [0008]
    8. Microelectrode according to claim 7, CHARACTERIZED by the fact that the polymer is flexible, particularly resiliently flexible.
    [0009]
    9. Microelectrode, according to claim 7, CHARACTERIZED by the fact that the polymer comprises closed pores.
    [0010]
    10. Microelectrode, according to claim 9, CHARACTERIZED by the fact that the density at 20 ° C of the polymer is less than 0.8, preferably less than 0.6.
    [0011]
    11. Microelectrode, according to claim 1, CHARACTERIZED by the fact that the floating element comprises a polymer consisting of closed pores.
    [0012]
    12. Microelectrode, according to claim 11, CHARACTERIZED by the fact that the density at 20 ° C of the polymer is less than 0.8, preferably less than 0.6.
    [0013]
    13. Microelectrode according to claim 11, CHARACTERIZED by the fact that the polymer is flexible, particularly resiliently flexible.
    [0014]
    14. Microelectrode, according to claim 1, CHARACTERIZED by the fact that it is totally or partially incorporated in a soluble or degradable matrix in a body liquid.
    [0015]
    15. Microelectrode, according to claim 1, CHARACTERIZED by the fact that it comprises an electronic amplification medium and / or a microprocessor medium, with the proviso that the combination of the electrode and the electronic amplification medium / processor has a density at 20 ° C from 0.80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03.
    [0016]
    16. Microelectrode, according to claim 15, CHARACTERIZED by the fact that the density is 0.99 ± 0.02.
    [0017]
    17. Microelectrode, according to claim 15, CHARACTERIZED by the fact that the electronic amplification medium / processor is placed at or near the rear end.
    [0018]
    18. Microelectrode, according to claim 1, CHARACTERIZED by the fact that it is fixed at or near its posterior end to an ultrathin insulated wire for electrical communication with an electronic amplification / processor medium at a distance from it.
    [0019]
    19. Microelectrode, according to claim 18, CHARACTERIZED by the fact that the ultrathin insulated wire is integral with the electrode wire.
    [0020]
    20. Microelectrode, according to claim 15, CHARACTERIZED by the fact that the electronic amplification medium / processor is placed in the soft tissue of said person or animal.
    [0021]
    21. Microelectrode, according to claim 15, CHARACTERIZED by the fact that the electronic amplification medium / microprocessor comprises a source of electrical energy.
    [0022]
    22. Microelectrode, according to claim 15, CHARACTERIZED by the fact that said means of electronic amplification / microprocessor comprises a transmitter and / or receiver that transmits and / or receives radiation to / from a control unit disposed externally to said patient or animal.
    [0023]
    23. Microelectrode, according to claim 1, CHARACTERIZED by the fact that it comprises anchoring means placed at or near its anterior end.
    [0024]
    24. Microelectrode, according to claim 1, CHARACTERIZED by the fact that it additionally comprises a sealed porous material.
    [0025]
    25. Electrode bundle, CHARACTERIZED by the fact that it comprises two or more microelectrodes as defined in claim 1.
    [0026]
    26. Electrode bundle according to claim 25, CHARACTERIZED by the fact that it is surrounded totally or partially in a material soluble or degradable in a body liquid.
    [0027]
    27. Electrode array, CHARACTERIZED by the fact that it comprises two or more microelectrodes as defined in claim 1.
    [0028]
    28. Electrode array, according to claim 27, CHARACTERIZED by the fact that it is totally or partially surrounded by a soluble or degradable material in a body liquid.
    [0029]
    29. Electrode array, CHARACTERIZED by the fact that it comprises two or more electrode bundles as defined in claim 25.
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    PL2612691T3|2015-04-30|
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    法律状态:
    2017-11-28| B25G| Requested change of headquarter approved|Owner name: NEURONANO AB (SE) |
    2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-12-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-12-22| B09A| Decision: intention to grant|
    2021-03-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 25/08/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    SE1000862-1|2010-08-25|
    SE1000862|2010-08-25|
    PCT/EP2011/064641|WO2012025596A2|2010-08-25|2011-08-25|Displacement resistant microelectrode, microelectrode bundle and microelectrode array|
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