HK1184090B - Displacement resistant microelectrode, microelectrode bundle and microelectrode array - Google Patents

Description

Displacement-resistant microelectrode, microelectrode bundle, and microelectrode array

Technical Field

The present invention relates to medical microelectrodes, to bundles of microelectrodes, and to microelectrodes and/or arrays of bundles of microelectrodes. The microelectrodes, bundles of microelectrodes, and arrays of microelectrodes and/or bundles of microelectrodes of the present invention are intended to be inserted into soft tissue such as the brain, spinal cord, endocrine organs, muscles, and connective tissue. Medical microelectrodes, bundles of microelectrodes, and arrays of microelectrodes and/or bundles of microelectrodes are designed to resist displacement in tissue.

Background

Microelectrodes that can be implanted for long periods in the Central Nervous System (CNS) have a wide range of applications. In principle, all brain nuclear tissues can be recorded or stimulated by such electrodes and their function monitored. Of particular importance is the use of a multichannel design in brain nuclear stimulation. In such designs, groups of electrodes or even individual electrodes may be addressed separately. This allows the user to select those electrodes whose stimulation produces an improved medical effect compared to stimulation without selectivity. Stimulation of the brain or spinal cord is particularly valuable in cases where the brain nuclei are degenerated or damaged. In certain cases, there is also a use for gene transfer that can combine controlled electrical stimulation and localization. The multichannel design may also allow the user to effectively measure the effect on multiple neurons and other cells following systemic or local drug administration or gene transfer. Of particular interest is the simultaneous measurement of the effects of multiple drug candidates on neuronal function. Monitoring brain activity via implanted electrodes is also useful if used to control local or systemic drug delivery or other therapeutic methods such as electrical stimulation of brain nuclei. Multi-channel electrodes may also be used for lesion specific and localized sites in tissue after abnormal pulse activity has been detected by recordings from the electrodes.

Various forms of implantable electrodes have been developed for recording and stimulating brain structures (US 6,253,110b1, US5,957,958, US4,573,481, US7,146,221b2, US5,741,319, US4,920,979, US5,215,008, US5,031,621, US6,993,392b2, US6,032,062, US4,852,573, US3,995,560, US7,041,492, US6,421,566b1, US4,379,462, US5,417,719, US3,822,708, US5,501,703, US7,099,718b1, US3,724,467; US2007/0197892a 1).

For the function of the electrode implant, it is important to have a fixed spatial relationship between the implant and the recording/stimulation site on the measured entity. In daily life, the body exhibits significant movement and, therefore, the tissue. Movement is caused by, for example, respiration, heartbeat, intestinal activity, skeletal activity such as rotating the head relative to the body. Movement may also be caused by external forces on the body. Relative movement between the tissue and the electrodes may thus cause changes in the recorded physiological signals, such as transmitters, such as electrical or chemical signals. For example, an action potential corresponds to a voltage change on the order of 100mV across a neuron membrane. This potential change fades rapidly with distance from the cell. Thus, movement of the electrodes relative to the measured cell can result in a significant change in the magnitude of the measured action potential. Similarly, when electrodes are used for electrical stimulation, changes in the position of the electrodes relative to the tissue may result in changes in the neurons being stimulated. It is therefore important that the site on the medical-treatment electrode (where the recording or stimulation in the tissue is performed) follows the movement of the tissue in which the medical-treatment electrode is embedded as faithfully as possible. In addition to attenuating the effects of the recorded signals or stimuli, movement between the implant and the tissue may cause damage to the tissue, which in turn may trigger a tissue reaction and loss of function of the implant. Mechanical stability between the electrode and the tissue is very important for intracellular recordings, as movement of the electrode relative to the cell can easily damage the membrane and allow leakage of extracellular fluid into the cell and vice versa. Today, there is no known electrode implant designed or adapted for simultaneous intracellular recordings in many neurons over a long period of time, such as days, weeks, or months, in a freely moving animal or human body.

Ultra-thin electrodes that are flexible and thereby overcome some of the problems associated with tissue and inter-electrode movement are known in the prior art (WO 2007/040442). By embedding such electrodes in a dissolvable hard matrix, it is possible to implant them into soft tissue without any additional support such as a syringe. Such ultra-thin electrodes should be made of materials that are not degraded by tissue or easily oxidized, which results in high electrical resistance and a resulting reduced signal-to-noise ratio. Examples of suitable conductors are noble metals such as gold and platinum. Generally, an alloy of platinum and iridium is used as a material for an implant for stimulation.

It is also important that the electrodes are anchored in the tissue close to the tissue being measured or stimulated in order to achieve a physically stable contact with the cells in the nervous system. Electrodes with conductive barbs and electrode pads equipped with holes through which tissue can grow and thereby be firmly attached to the electrode are known in the prior art (WO 2007/040442; WO2008/091197; WO 2009/075625). However, the implant may cause chronic inflammation and even infection and may have to be removed. When the electrode is withdrawn from a tissue anchoring device known in the art, such as a barb or a hole in the electrode body specifically allowing tissue to grow therein, extensive damage to the tissue may result. Accordingly, it is desirable to address the problem of how to anchor a medical-treatment electrode in soft tissue such that the medical-treatment electrode is physically stabilized in the tissue and may also be withdrawn from the tissue with reduced tissue damage.

Object of the Invention

It is an object of the present invention to provide a microelectrode which is stabilized against displacement in the implanted tissue.

It is another object of the invention to provide a microelectrode bundle comprising such electrode(s).

It is a further object of the present invention to provide a microelectrode array and a microelectrode bundle array comprising such electrode(s).

Other objects of the present invention will become apparent from the following summary of the invention, the preferred embodiments illustrated in the drawings and the appended claims.

Disclosure of Invention

The invention is based on the observation that in order to optimally resist displacement within the soft tissue in which it is implanted, the microelectrode should approximate a certain weight of that tissue. By such approximation, the electrode "floats" in the tissue and may be referred to as a floating microelectrode. The floating nature of the electrode allows it to follow the displacement of the surrounding tissue as it is accelerated or decelerated. Stabilization according to the present invention is thus stabilization against displacement within the tissue, not against being withdrawn from the tissue by mechanical anchoring means such as barbs, spikes, etc. It is, of course, feasible to additionally provide the present invention with such means to resist being withdrawn from the tissue. Stabilization according to the present invention is particularly useful for electrodes implanted within delicate non-fibrous soft tissue (tissue such as the brain, spinal canal, and bone marrow).

The microelectrode of the invention is intended to record electrical signals induced in tissue, in particular in neural tissue, but can also be used for electrical stimulation of tissue.

Thus, disclosed according to the present invention is a medical microelectrode which is resistant to displacement in soft tissue due to inertia.

The electrode comprises an electrically conductive tubular lead comprising or consisting of a metal and/or an electrically conductive polymer. The tubular guide has an exterior face and an interior face. The outer face of the tubular guide may be porous but not in a form that allows external bodily fluids to penetrate into the lumen. Thus, the small hole does not penetrate the exterior face or is sealed at a desired depth (e.g., by applying a polymer coating in the luminal surface of the tubular guide). The tubular guide has a front or distal end, a rear or proximal end, and a sealed lumen disposed between the front and rear ends. The lumen of the tubular guide is empty or comprises one or more voids and one or more portions partially or fully filled with a filler. The density of the filler at 20 ℃ 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. Preferably, the filler is composed of or comprises a polymer, in particular a polymer with closed pores. The polymer is preferably soft, in particular elastically soft.

Optionally, the electrode comprises or consists of a linear guide. The linear guide may be porous or non-porous. In embodiments where the guide is a wire-like guide, the insulation on the guide may be a porous polymer material that includes sealed pores (i.e., pores that do not absorb bodily fluids). Optionally, a porous polymer material comprising sealed pores is provided on the thin, non-porous insulating layer on the wire guide. The volume of the porous insulating material is selected to compensate for the high density of the wire-like guides.

The density of the electrode at a temperature of 20 ℃ is preferably 0.80 to 1.15, more preferably 0.90 to 1.07, even more preferably from 0.95 to 1.03, most preferably 0.99 ± 0.02. Optionally, a portion of the exterior face of the electrode is electrically insulated. A cylindrical or elliptical cross-section of the guide is preferred, but guides with other cross-sections, such as triangular, square or hexagonal, are not excluded from the invention. In the present application, the rectangular guide portion has an aspect ratio of 5 or more, specifically 10 or more, and most preferably 20 or more. The preferred lead diameter is from 1 μm to 200 μm. The lead is preferably made of a metal selected from gold, silver, platinum, and copper, or an alloy including one or more of these metals. Alternatively, the guide portion is made of a conductive modified body of carbon such as a carbon nanotube or a conductive polymer. The guide may also comprise a combination of these materials.

According to a preferred aspect of the invention, the electrodes are wholly or partially embedded in a matrix dissolvable or degradable in the body fluid.

According to another preferred aspect of the invention, the electrode comprises electronic amplification means and/or microprocessor means, it being required that the combination of the electrode and the electronic amplification means and/or microprocessor means has a density at 20 ℃ of 0.80 to 1.15, in particular from 0.90 to 1.07, more in particular from 0.95 to 1.03, more even 0.99 ± 0.02. Preferably, the electronic amplification means/microprocessor means is located at or near the rear end of the electrodes.

Optionally, electronic amplification and/or microprocessor means are provided separate from the electrodes implanted in the tissue. Electrical communication between the electrode and the electronic amplifying and/or microprocessor device placed at a distance from the electrode is provided by an insulated electrical conductor, such as an ultra-thin insulated wire mounted at or near the rear end of the electrode at one end and at the electronic amplifying/microprocessor device at the other end; the preferred thickness of the wire is 50 μm or less. Preferably, the conductor has the same density as the electrode density, i.e. a density of about 1, in particular from 0.9 to 1.1. The density of the wire-type electrical conductor may be controlled by providing the wire-type electrical conductor with a buoyant member (such as, for example, a spongy polymer insulating coating) having a density < 1. It is also preferred for the electronic amplification/microprocessor means to be separate from the electrodes, to have the same density as the electrode density, i.e. a density of about 1, in particular from 0.9 to 1.1. The electronic amplification/microprocessor means of the electrodes may be powered by, for example, a power source (such as a battery implanted within the tissue or external to the tissue); the electrical connection between the power supply and the electronic amplification/microprocessor means of the electrodes is provided by electrical conductors of the type described above (made buoyant by providing them with a buoyant member).

The microprocessor means separate from the electrodes is preferably located in the soft tissue of the human or animal, but may also be located outside the human or animal. The amplifying/microprocessor means may comprise a source of electrical energy, such as a battery, or may be connected by electrical leads to an external power source. The amplifying/microprocessor means may also include means for transmitting radiation to and/or receiving radiation from a control unit located externally of the patient or animal. The electrode of the present invention can be in electrical communication with a microprocessor device placed within the tissue of a human or animal at a distance from the electrode or placed externally to the human or animal. The microprocessor means may comprise a source of electrical energy, such as a LiH battery. The microprocessor may also include means for sending radiation to and/or receiving radiation from a control unit disposed external to the patient or animal.

According to another preferred aspect of the invention, the electrode may comprise an anchoring device disposed at or near the electrode front end, preferably integral with the electrode. Since the electrode of the present invention is not susceptible to dislocation caused by sudden displacement of the tissue in which it is embedded, the need to anchor the electrode within the tissue is less emphasized than with conventional microelectrodes having a density substantially greater than 1. A rough electrode surface or rough parts thereof, such as rough electrode tips, may be sufficient for anchoring.

According to yet another preferred aspect, the electrode may be or comprise a porous, electrically conductive material. Preferred porous, electrically conductive materials are sintered metal powders, particularly titanium, aluminum, and alloys thereof. Other porous, electrically conductive materials include or consist of carbon nanotubes and/or fullerene and/or graphite lamellae down to the graphite monolayer. The pores of such material, which open at the surface of the electrode, may be sealed by, for example, an electrically insulating material such as a polyurethane or polyimide coating, or by an electrically conductive material such as a layer deposited by electrolysis of gold or other noble metal, at the electrically non-insulating portion(s) of the electrode.

Alternatively, the electrode may comprise a porous, non-conductive material. Preferred porous, non-conductive materials include porous organic polymers (such as porous polyurethane), and porous ceramic materials (such as sintered alumina) on which a conductive layer comprising or consisting of a metal or metal alloy is deposited by, for example, ion sputtering.

The pores of the porous conductive or non-conductive material of the electrode of the invention may be open or closed. If the openings are sealed by a non-conductive lacquer or a thin metal layer deposited thereon, for example by ion sputtering or other suitable technique, they are protected from the intrusion of liquid-like body fluids. In order to provide the entire electrode with the preferred density of the invention at 20 ℃ of from 0.80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03, even 0.99 ± 0.02, the porosity of the porous conductive or non-conductive material of the electrode is chosen to compensate completely or at least substantially partially for the density of >1 of the bulk electrode material. To achieve a preferred density, the porous electrode material of the present invention may advantageously be combined with an electrode having a sealed cavity and/or comprising a buoyant member attached to the surface of the electrode.

According to the invention, an electrode bundle comprising two or more electrodes of the invention is also disclosed. The electrode bundle comprises a non-permanent bundling means, preferably in the form of a material dissolvable or degradable in a body fluid, wherein two or more electrodes are enclosed in a substantially parallel configuration. Accordingly, the electrode of the present invention may be included in such an electrode bundle. It is preferred that the electrode bundle has a density at 20 ℃ of from 0.80 to 1.15, in particular from 0.90 to 1.07, more in particular from 0.95 to 1.03, and even 0.99 ± 0.02.

In accordance with yet another preferred aspect of the present invention, an electrode lead is disclosed comprising a plurality of conductive layers with a layer of non-conductive low density polymer material spaced therebetween; such guides can be made by electro-spin coating, for example gold nanowires revolving parallel to or around the low density polymer fiber. The ends of the lead are fused by laser radiation or any other suitable heat source, establishing electrical contact between the conductive layers such that they constitute a single electrode lead.

The electrode of the invention may further comprise useful features known from prior art microelectrodes.

According to the present invention, further disclosed is an electrode array comprising two or more electrodes and/or electrode bundles of the present invention. According to an advantageous aspect of the invention, the electrode array is partially or completely enclosed in a material that is soluble or degradable in body fluids. It is preferred that the electrode array has a density of from 0.80 to 1.15, particularly from 0.90 to 1.07, more particularly from 0.95 to 1.03, and even 0.99 + -0.02 at 20 ℃. Thus, the electrodes of the present invention may be included in such an electrode array.

Embodiments of the invention of the electrodes with materials intended to be dissolved or degraded once the electrode is implanted allow tiny and flexible microelectrodes and bundles or arrays containing them to be inserted into tissue without putting their integrity at risk.

Electrode embedding material is ignored when considering determining the density of the electrode of the present invention.

According to another important aspect, the present invention teaches that, in addition to the entire electrode being designed such that its density is close to that of the soft tissue (i.e., about 1.0), it is important to design the electrode such that the high-density member and the low-density member are distributed as uniformly as possible over the entire electrode. Most often, the electrodes of the present invention may be rectangular; in a rectangular electrode configuration, therefore, there areIt is advantageous to compensate for density separation along the electrodes. This type of compensation avoids influencing the preferred orientation of the portion of the electrode in the tissue due to gravity, such as for example the gravity of an electrode of the invention having a relatively high density of front portions pointing downwards in a state of flow in the tissue and a relatively lower density of rear portions pointing upwards in the same state (or vice versa). The high-density member includes a metal electrode lead, a micro-signal amplifier or other electronic device attached to the electrode lead at a rear end thereof, or the like; the low density member includes a buoyant member disposed on or within a void in the electrode guide. Of importance is also the choice of material, in particular the metallic material of the electrode lead, which comprises a composite of metals. Therefore, it is preferable that the electrode of the present invention is density-balanced. By "density equalization" is understood not only that the high density portion of the electrode is equalized by the low density portion to obtain an electrode having the desired density as a whole, but that the equalization of density is localized to portions of the electrode, under the need for equalization. The means for equalizing the electrodes of the present invention is the center of gravity (C) of the same shaped electrodes having the same density_g) And center of gravity (C)_g') The distance between them. In the balanced electrode of the invention having a front end and a rear end separated by a distance L, the center of gravity C_gAnd C_g'The distance L therebetween is less than 25%, preferably less than 15%, more preferably less than 10% of the distance L.

According to the invention, an electrode bundle and an electrode array comprising one or more electrodes of the invention are also disclosed. An electrode bundle comprises two or more electrodes of the invention bundled by a bundling means which may be permanent or temporary. "permanent" and "temporary" refer to the state of the electrode bundle once implanted. A permanent bundling means is a means designed to maintain the integrity of the electrode bundle during the period of time that the electrodes are used within the tissue, whereas a temporary means is a means designed to maintain such integrity during the insertion of the electrode bundle into the tissue, rather than during the period of time that the electrodes are used within the tissue. The permanent bundling means comprises, for example, a binder or sheath surrounding two or more electrodes of the invention disposed in parallel proximal proximity at the trailing end, which binder or sheath is not readily dissolved or degraded by body fluids. The temporary bundling means may comprise, for example, a gel attached to at least the tail of the electrode disposed adjacent the tail end thereof, the gel being dissolvable in body fluid.

For ease of implantation, the electrode bundle and electrode array of the present invention may be partially or fully enclosed by a material that is dissolvable or degradable in body fluids. This type of enclosure may also fulfill the function of the temporary electrode bundling means of the invention. The partial enclosure at least partially encloses the front of the electrodes of the electrode bundle or electrode bundle array.

The invention will now be described in more detail with reference to a number of preferred embodiments shown in the drawings. Figures 1-11 of the drawings are not to scale and are intended only to clearly illustrate the basic features of the present invention.

Drawings

Figure 1 shows a first embodiment of the electrode of the invention in an axial (a-a) section;

FIGS. 1-8 show a variation of the embodiment of FIG. 1 in the same view;

FIG. 9 shows a second embodiment of the electrode of the present invention in axial (B-B) cross-section;

FIG. 10 shows, in the same view, a variant of the embodiment of FIG. 9;

FIG. 11 shows the electrodes of FIG. 10 embedded in a dissolvable matrix body;

fig. 12a-12f show examples of electrode leads of the present invention in radial cross-section.

Detailed Description

The first embodiment of the medical microelectrode 1 shown in fig. 1 comprises a conductive tubular lead 2 of silver and 20% copper alloy. At its front end 3, the guide 2 is closed and has a sharp point 11. At its rear end 4, the cavity 5 of the guide 2 is sealed by a polyethylene plug 6 disposed in the cavity 5 at the rear end 4. A thin insulated (not shown) wire 9 is conductively attached to the outer surface of the lead 2 at the rear end 4 of the lead 2 by solder 10. A wire 9 connects the electrode 1 to an electrode control unit (not shown) comprising a microprocessor means.

In a first variant 101 of the microelectrode of fig. 1, shown in fig. 2, the polyethylene plug 6 is placed in the cavity 105 at a distance from the rear end 104 and the point 111 of the lead 102 of aluminum alloy, thereby dividing the cavity 105 in a ratio of about 2:1 into a sealing part extending from the plug towards the front end 103 and an opening part extending from the plug 104 towards the rear end 104. The open portion of the chamber 105 is filled with compressed glucose powder 107. Once the electrode 101 is inserted into the soft tissue, the liquid bodily fluid contacts the powder 107 and slowly dissolves. Filling the open portion of the cavity 105 with a material that is soluble in a liquid-like liquid avoids the air-filled pouch from remaining in the open portion of the cavity 105.

In a second variant 201 of the microelectrode of fig. 1, shown in fig. 3, the entire cavity of the electrode lead 202 of gold/silver alloy with the dots 211, extending from the closed front end 203 to the open rear end 204, is filled with polyurethane foam 208 with closed pores.

A third variant 301 of the microelectrode of fig. 1, shown in fig. 4, differs from the variant of fig. 3 in that only the rear end 304 of the cavity 305 is partially filled with polyurethane foam 308. The front end portion of the cavity 305 is thereby sealed with a gap. Likewise, the electrode lead 302 is pointed 311 at its front end 303 and open at its rear end 304.

The fourth microelectrode variation 401 shown in FIG. 4 differs from the microelectrode of FIG. 1 in that the front end 403 of the lead 402 has a blunt tip 411. At the front end 404, the cavity 405 is closed by a polyethylene plug 406. A thin insulated (not shown) wire 409 welded to the outer surface of the lead 402 provides electrical communication between the electrode and an electrode control unit (not shown).

The fifth variant 501 of the microelectrode of fig. 1, shown in fig. 6, differs from the microelectrode of fig. 2 in that its tip 511 is provided with anchoring means 512 in the form of barbs for securing the electrode against accidental withdrawal once inserted into soft tissue. Reference numerals 502, 503, 504, 506, 507 identify components corresponding to those labeled 202, 203, 204, 206, 207 in fig. 2.

A sixth variation 601 of the microelectrode of FIG. 1, shown in FIG. 7, comprises a tubular platinum alloy lead 602 closed at its front end 603 by a pointed tip 611 and open at its rear end 604. The cavity is filled with a polymer foam. At its rear end, the lead portion 602 is provided with a signal amplifier 613, and an insulated ultra-thin wire 609 extends from the signal amplifier 613. The line 609 provides an electrical connection between the signal amplifier 613 and an electrode control unit (not shown). The lead 602 and signal amplifier 613, except for its pointed front end 603 tip, are encapsulated by a conductive lacquer 615.

A seventh variation 701 of the microelectrode of FIG. 1, shown in FIG. 8, comprises a rotationally symmetric tubular lead 702 except for a pointed tip 711 of a front end 603. The cavity 702 is partially filled with a polymer foam such that a first foam portion 708 extending from the rear end 704 of the guide 702 to the front end 703 and a second foam portion 708' extending from the front end 703 to the rear end 704 delimit a middle portion 705 of the void of the guide cavity.

A second embodiment 801 of a medical microelectrode, illustrated in fig. 9, comprises a solid state electrode lead 802 of titanium having a front end 803 and a rear end 804, the front end 803 being provided with a pointed tip 811. Except at its tip 811, the guide 802 is closed by a buoyant layer 814 of polymer foam with closed pores, which adjoins the guide 802 and is tightly bonded thereto. The buoyant layer 814 has substantially the same form as the sleeve on the lead 802. At the rear end of the lead portion 802, an electric signal amplifier 813 sealed by a thin paint layer 815 is provided. The amplifier 813 is in electrical communication with an electrode control unit (not shown) via an insulated ultra-thin metal wire 809.

In fig. 10, a modification 901 of the second embodiment of the medical microelectrode of the invention is shown. The buoyant layer includes two portions 914, 914 'that are spaced apart, a first portion 914 disposed proximate the front end 903 of the tungsten electrode lead 902 and a second portion 914' disposed proximate the back end 904 of the tungsten electrode lead 902. The surface of the lead portion 902 extending between the portions 914, 914' is insulated by a lacquer 915. Therefore, only the rotationally symmetric tip 911 is uninsulated. At its rear end, electrode 901 has an ultra-thin electrically insulated wire 909 soldered thereto, providing electrical communication with an electrode control unit (not shown) disposed internally or externally at a distance from one end of electrode 901.

FIG. 11 shows the electrodes of FIG. 10 incorporated into the body of carbohydrate matrix 920 through which microelectrodes 901 can be inserted into soft tissue without compromising its physical integrity. Once inserted, the matrix body 902 may be dissolved by the liquid-like body fluid, thereby establishing physical contact of the electrodes with the tissue. The matrix body 920 is rotationally symmetric and is disposed around the electrode 901 such that its rotation axis coincides with the rotation axis of the electrode 901. At its front end, the matrix body 902 has pointed tips 921.

Sizing of the electrodes of the invention

The choice of radial dimensions of the electrode of the invention to bring the density of the electrode close to 1.0 is shown in a number of examples as follows. The outer diameter of the electrode was set to 100 μm. By multiplying the thickness of the electrode layer by a desired size factor, the radial dimension of the thicker or thinner electrode is obtained. In an example where the axial length of the electrode tip is assumed to be negligible relative to the full length of the electrode lead.

Example 1

A tubular silver guide, fig. 12 a; d_Ag= 10.4. Inner (cavity) diameter: 95 μm. Density (calculated): 1.01.

Example 2

Tubular gold lead, fig. 12 b; d_AuAnd 19.3. Inner (cavity) diameter: 97.3 μm. Density (calculated): 1.03.

Example 3

Tubular double-layered guide, fig. 12 c. Outer layer of gold, d_Au=19.3, inner titanium, d_Ti= 4.5. Inner (cavity) diameter: 92 μm; thickness of the titanium layer: 7 μm; thickness of gold layer: 1 μm. Density (calculated) 0.986.

Example 4

Tubular double-layered guide, fig. 12 d. Outer layer of gold, d_Au=19.3, inner titanium, d_Ti= 4.5. Inner (cavity) diameter: 92 μm; thickness of the titanium layer: 7.5 μm; thickness of gold layer: 0.5 μm. Cavity-filled polyurethane foam, d_PUF= 0.20. Density (calculated): 0.963.

Example 5

Gold wire leader covered with polyurethane foam with closed pores, fig. 12 e. d_Au=19.3;d_PUF= 0.24. Diameter of gold wire: 40 μm. Density (calculated): 1.00.

Example 6

A tubular titanium guide covered with polyurethane foam with closed pores, fig. 12 f. d_Ti=4.5;d_PUF= 0.20. Outer diameter of titanium guide portion: 70 μm; inner (cavity) diameter: 53 μm. Density (calculated): 1.04.

Example 7

A porous nickel lead was fabricated by an electroforming method of US7,393,446B2 using polystyrene beads having a diameter of about 60 μm. Outer diameter of the guide portion: 500 μm. A guide having a density of about 1.1 can be manufactured as one of a series of guides manufactured by changing the duration of electroforming. Once the cellular metal structure with open pores was formed, the polystyrene matrix was removed by soaking in acetone. The cylindrical porous nickel leads were rinsed with propanol, dried, and then electrogilded to a coating thickness of about 10 μ to maintain these small dimensionsThe holes are open. The guide was rinsed thoroughly with water, then propanol, and then dried. One end of the guide was carefully heated with an acetylene lamp so that it shrunk to form a blunter thin-tipped insulated copper wire that was attached by welding to the other end of the guide. Except for the constricted tip portion, the electrode lead portion was immersed in a solution of polyurethane (in THF)Solution grade SG-85A, Lubrizol Corporation, cleveland, ohio) (20%, w/w)) to close these pores and insulate the major portion of the electrode lead. Other dip-coated materials for use in the present invention, such asIncluding polyether urethane ureas containing a softer portion made of polytetramethylene oxide and a harder portion made of 4, 4' -diphenylmethane diisocyanate and ethylenediamine (BPS-215, Thoratec corporation, pleisonon, ca).

Production of the electrode of the invention

The tubular electrode of the present invention may be made of a corresponding metal microtube. The microtubes of the noble metals can be obtained, for example, by electroplating a noble metal such as silver, gold, platinum, etc. and also copper to a less expensive noble metal such as aluminum or iron, followed by dissolving the less expensive noble metal by a strong non-oxidizing acid such as hydrochloric acid. The forward end of the microtube may be collapsed by heating a short section of the original tube to slightly below its melting point, then stretching its end in the opposite direction at this temperature, then raising the temperature to the melting point so that the finely drawn section is drawn. The tube is then pulled apart and two pointed, sharp or rounded (depending on the material and processing conditions) microtubes are obtained, which can be cut to the desired length. Alternatively, the microtube may be closed at one end by welding, optionally flattening the end portion before welding. The rear end of the microtube with the front end closed may be sealed by, for example, a slightly conical polyethylene or polypropylene plug that is pushed into the open end for a desired distance. Filling the cavities of the microtubes with the polymer foam is done by injecting a solution or suspension of the prepolymer in a highly volatile solvent such as propane or butane, followed by gentle heating of the filled microtubes. A solid filler in granular form can be poured into the cavity and, if necessary, compressed there by a piston of suitable dimensions.

Conductive polymers suitable for use in the present invention include polyethylene dioxythiophene, polyaniline, polyacetylene, and polypyrrole.

The wire-like electrodes can be covered with the polymer foam by, for example, placing the wire-like electrodes in a closed compartment comprising a container filled with the above-mentioned prepolymer solution or suspension, immersing the wire-like electrodes in the solution or suspension, removing them from the solution or suspension, closing the container, admitting air, in particular humid air, into the compartment, storing the thus covered electrodes in a humid environment until the polymer has completely solidified. The thickness of the polymer layer with closed pores on the wire can be controlled by controlling the viscosity of the polymer solution or suspension in the container and/or the temperature of the solution or suspension and/or the type of solvent.

An ultra-thin insulating layer can be obtained by applying an electrically insulating varnish to the desired part of the electrode. Alternatively or additionally, for example, an insulating coating of parylene-C may be used.

The electrode of the present invention comprising a porous metal structure may, for example, be manufactured by the method described in US7,393,446B2.

The electrodes of the invention may be bundled or stacked in substantially the same manner as described in WO2007/040442a 1. The electrodes of embodiments of the present invention may also be incorporated into arrays as described in WO2008/091197a 1. Suitable steps for bonding the electrode of the invention and the electrode bundle or array of electrode bundles of the invention to a rigid matrix body dissolvable in body fluids are disclosed in WO2009/075625a 1.

Method for embedding microelectrodes of the invention in a dissolvable matrix

The method for embedding a microelectrode of the present invention comprises providing a holding device, holding the electrode and optionally additional components to be embedded (such as optical fibers, contractile members, etc.) in the holding device in a desired configuration, applying a sleeve over the thus held electrode and attachment except for its proximal coupling part, applying a solution or suspension of a first matrix material over the electrode such that the part of the electrode to be embedded is covered, allowing the solvent or dispersion of the matrix solution or suspension to evaporate or harden, respectively, removing the sleeve, and releasing the electrode from the holding device. In order to embed the electrodes in the two matrix materials to form respective matrix compartments (each enclosing a portion of an electrode), a suitable portion of the electrode held by the holding means as described above is coated with a solution or suspension of the first matrix material, the solvent/dispersant of which is then evaporated, and then the remaining portion of the electrode to be coated is coated with a solution or suspension of the second matrix material, followed by evaporation of the solution/suspension of the second matrix material and release of the electrode from the holding means. In the present method, the electrodes are preferably placed in a sheath of a low wettability, smooth material (such as polyfluorocarbon polymers or silicone rubber) and fixed therein. To assist the evaporation of the solvent, the material of the sleeve is advantageously porous, in particular microporous. After the matrix material(s) are applied and dried, the electrodes are removed from the sleeve. Drugs or drug combinations can be incorporated into the matrix, as desired.

An alternative method of embedding the electrodes of the invention in two matrix materials to form different matrix compartments comprises embedding the entire electrode in a first matrix material, dissolving a portion of the first matrix material, preferably a distal portion extending from the distal end, covering the non-embedded distal portion of the electrode by a second matrix material, e.g. by means of a sleeve applied over the non-embedded distal portion, filling the sleeve with a solution or suspension of the second matrix material, evaporating the solvent to dry/harden the second matrix material, and removing the sleeve.

The electrodes of the present invention are coated by using a single coating technique or a combination of coating techniques, such as by dip coating, spin coating, melt processes including extrusion, compression molding, and injection molding, or a combination of different techniques.

In a representative example of a step-wise procedure, the electrode is first dip coated with a suitable absorbable polymer or blend of polymers (specifically collagen, gelatin, polyvinyl alcohol, and starch) dissolved in a suitable solvent. Other polymers may also be used. The thickness of the polymer layer is controlled in a manner known to those skilled in the art. The coating is then subjected to a drying step. The dip coating and drying steps may be performed once or may be repeated depending on the desired 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 should be one in which the polymer swells (swell) and the drug dissolves. After a suitable contact time, such as from less than one second to 5 minutes or more, the electrodes are removed from the solution and the matrix is dried by evaporation of the solvent (possibly under reduced pressure).

In one-pot procedures, the electrodes are submerged in a solution of the polymer at the optimum concentration and the selected drug for the desired coating thickness and, optionally, the desired drug loading. Then, possibly under reduced pressure, the electrode is removed from the solution and the solvent is evaporated.

Alternatively, the coating is generated by spin coating, wherein 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 in the invention are hydrogel coatings made of partially hydrolyzed water soluble polymers such as polyvinyl alcohol, polyacrylic acid, and derivatives of polyacrylic acid, e.g., poly (isopropylacrylamide). The increase in temperature causes these hydrogels to shrink, thereby expelling the drug or drug combination incorporated in the coating. Alternatively, the temperature sensitive hydrogel is an interpenetrating hydrogel network of poly (acrylamide) and poly (acrylic acid), and the increase in temperature causes the hydrogel to expand, thereby allowing the drug to diffuse out of the gel.

The invention also includes the use of polymers or polymer blends for electrically triggered release, such as polyvinyl alcohol/chitosan.

The electrode bundles and the electrodes and electrode bundle arrays of the present invention may be embedded in a matrix in substantially the same manner as described above for the individual electrodes.

Use of

The invention also relates to the use of matrix-embedded electrodes, matrix-embedded electrode bundles, or an array of matrix-embedded electrode bundles for long-term neurostimulation and multichannel recording of neuronal electrical activity and neurotransmitter concentrations by measurement of redox reactions and damaged tissue for scientific, medical and animal care purposes.

According to a preferred aspect of the invention, the microelectrode bundle, the microelectrode or the array of microelectrode bundles of the invention is used for a patient or an animal for: recording signals from nerves remaining after brain and/or spinal cord damage; stimulating neurons to compensate for lost function; pain relief by stimulating analgesic brainstem centres; providing relief or reduction of tremors or other motor symptoms in parkinsonism; reducing or reducing chorea and other involuntary movements by stimulation within basal neurons or associated nuclei; improving memory by stimulating cholinergic and/or monoaminergic nuclei in the case of alzheimer's disease or other degenerative diseases; control of mood, aggression, anxiety, fear, sensation, excessive behavior, impotence, feeding disturbances by stimulation of the limbic center or other brain areas; providing patient rehabilitation after stroke or brain/spinal cord injury by stimulating remaining connections or reduced motor nerve channels in the cerebral cortex; providing reestablishment of control of spinal functions such as bladder and bowel emptying by stimulating relevant portions of the spinal cord after spinal cord injury; providing control over spasticity by stimulating the central or appropriate cerebellar region of inhibited spinal descent; the re-establishment of somatosensory, auditory, visual, olfactory sensations is provided by stimulation of the relevant nuclei in the spinal cord and brain.

According to another preferred aspect of the invention, the microelectrode bundle, the microelectrode or the array of microelectrode bundles of the invention is used for combined monitoring and stimulation of a patient or an animal, in particular for: monitoring epileptic seizures by coupling to an electrode implanted epileptogenic lesion for delivery of an epileptic drug or electrical stimulation; compensating for lost connections in the locomotor system by recording central locomotor commands, followed by stimulating the more distantly injured execution part of the locomotor system; blood glucose concentrations were recorded to control hormone release.

According to yet another preferred aspect of the invention, the microelectrode bundle, and the array of microelectrodes or microelectrode bundles of the invention are used in a patient or animal for locally damaged tissue, in particular tumors or abnormally active or epileptogenic nervous tissue, by passing a current of sufficient magnitude through said electrode, electrode bundle, or array of electrode bundles.

In biomedical research, the use of the microelectrodes, microelectrode bundles, and arrays of microelectrodes or microelectrode bundles of the present invention can be used to study normal and pathological function of the brain and spinal cord, particularly over extended periods of time.

In a patient having a neuroprosthetic device, the microelectrodes, bundles of microelectrodes, and arrays of microelectrodes or bundles of microelectrodes of the present invention can be used to interface between a nerve and the device.

The microelectrodes, bundles of microelectrodes, and arrays of microelectrodes or bundles of microelectrodes of the present invention can be used to control the function of endocrine or exocrine organs, such as to control hormone secretion, in a patient or animal.

The microelectrodes, bundles of microelectrodes, and arrays of microelectrodes or bundles of microelectrodes of the present invention can be used to control the function of one or more skeletal or cardiac muscles in a patient or animal.

Claims (40)

1. A medical microelectrode for implantation in soft tissue of a human or animal, resistant to displacement within the tissue due to inertia, the microelectrode having a leading end, a trailing end and a density at 20 ℃ of from 0.80 to 1.15, the microelectrode comprising any one of:

an electrically conductive tubular guide comprising a metal and/or an electrically conductive polymer, the tubular guide having an outer surface and a sealed cavity;

a conductive linear guide comprising a metal and/or a conductive polymer, the linear guide having a surface and a buoyant member attached to the surface having a density of less than 1.0;

wherein the outer surface or a portion of the surface, respectively, is electrically insulating.

2. The microelectrode of claim 1, wherein the density of the microelectrode is from 0.90 to 1.07.

3. The microelectrode of claim 1, wherein the density of the microelectrode is from 0.95 to 1.03.

4. The microelectrode of claim 1, wherein the density of the microelectrode is 0.99 ± 0.02.

5. The microelectrode of claim 1, wherein the cavity is a void.

6. The microelectrode of claim 1, wherein the cavity comprises one or more portions filled with a filler, and one or more void portions.

7. The microelectrode of claim 6, wherein the filler has a density of 0.8 or less.

8. The microelectrode of claim 6, wherein the filler has a density of 0.6 or less.

9. The microelectrode of claim 6, wherein the filler comprises a porous material.

10. The microelectrode of claim 6, wherein the filler comprises a polymer.

11. The microelectrode of claim 10, wherein the polymer is flexible.

12. The microelectrode of claim 10, wherein the polymer comprises closed pores.

13. The microelectrode of claim 12, wherein the polymer has a density of less than 0.8 at 20 ℃.

14. The microelectrode of claim 12, wherein the polymer has a density of less than 0.6 at 20 ℃.

15. The microelectrode of claim 1, wherein the buoyant member comprises: a polymer comprising blocked pores.

16. The microelectrode of claim 15, wherein the polymer has a density of less than 0.8 at 20 ℃.

17. The microelectrode of claim 15, wherein the polymer has a density of less than 0.6 at 20 ℃.

18. The microelectrode of claim 15, wherein the polymer is flexible.

19. The microelectrode of claim 1, wherein the microelectrode is wholly or partially embedded in a matrix that is dissolvable or degradable in a body fluid.

20. The microelectrode of claim 1, comprising electronic amplification means and/or microprocessor means, with the proviso that the combination of microelectrode and electronic amplification means and/or microprocessor means has a density of 0.80 to 1.15 at 20 ℃.

21. The microelectrode of claim 20, wherein the density of the microelectrode is from 0.90 to 1.07.

22. The microelectrode of claim 20, wherein the density of the microelectrode is from 0.95 to 1.03.

23. The microelectrode of claim 20, wherein the density of the microelectrode is 0.99 ± 0.02.

24. The microelectrode of claim 20, wherein the electronic amplification and/or microprocessor device is located at or near the rear end.

25. The microelectrode of claim 1, attached to an ultra-thin insulated wire at or near a rear end of the microelectrode for electrical communication with an electronic amplification device and/or a microprocessor device placed at a distance from an end of the insulated wire.

26. The microelectrode of claim 25, wherein the ultra-thin insulated wire is integral with the microelectrode.

27. The microelectrode of claim 20, wherein the electronic amplification means and/or microprocessor means are located in the soft tissue of the human or animal.

28. The microelectrode of claim 20, wherein the electronic amplification means and/or microprocessor means comprises a source of electrical energy.

29. The microelectrode of claim 20, wherein the electronic amplification means and/or microprocessor means comprise means for sending radiation to and/or receiving radiation from a control unit placed outside the patient or animal.

30. The microelectrode of claim 1, comprising an anchoring device disposed at or near the front end of the microelectrode.

31. The microelectrode of any of claims 1 to 30, comprising a porous material that is sealed.

32. An electrode bundle comprising two or more microelectrodes according to any of claims 1 to 30.

33. The electrode bundle of claim 32 wherein the electrode bundle is wholly or partially encapsulated in a material that is dissolvable or degradable in body fluids.

34. The electrode bundle of claim 32 comprising a sealed porous material.

35. The electrode bundle of claim 33 comprising a sealed porous material.

36. An electrode array comprising two or more microelectrodes according to any of claims 1 to 30.

37. The electrode array of claim 36, comprising a sealed porous material.

38. An electrode array comprising two or more electrode bundles according to claim 32.

39. An electrode array comprising two or more electrode bundles according to claim 33.

40. The electrode array of claim 39, wherein the electrode array is partially or fully encapsulated in a material that is dissolvable or degradable in a body fluid.