A probe for implanting into neural tissue comprising a microelectrode or a set of microelectrodes

Abstract

A microelectrode probe for implantation in soft tissue, comprising a sheath of flexible polymeric material divided by a wall into a distal and a proximal compartment, said distal and proximal compartments being filled with a matrix of biocompatible material dissolvable or degradable in aqueous body fluids, and comprising a centrally disposed electrically conductive core passing through the wall and attached to it. The core is insulated at its proximal portion, from which it extends to a holder for attachment to tissue other than said soft tissue. The sheath and the core extending distally from said holder are embedded in a kindred additional matrix. The invention also discloses a method for its manufacture, an array comprising two or more microelectrode probes and a microelectrode probe for incorporation into the array and a method for the manufacture of the array.

Description

Technical Field

[0001] This invention relates to probes comprising a single microelectrode or multiple sets of microelectrodes for implantation by insertion into soft tissue, particularly neural or endocrine tissue. The invention also relates to the use and manufacture of such probes. Background Technology

[0002] Implantable microelectrodes and microelectrode assemblies have wide applications in medicine and veterinary medicine.

[0003] Microelectrodes implanted in neural tissue, whether constituting a single implant or involving implants containing multiple microelectrodes (such as microelectrode bundles or microelectrode arrays), require electrical connection to a control device placed outside the tissue. This connection is typically provided by thin, insulated, flexible wires. These wires bridge various types and stiffnesses of tissue and are therefore affected by repetitive relative displacements caused by breathing, heartbeats, head and spinal movements. This tissue movement also affects other thin, flexible implants, such as microfibers, particularly optical microfibers.

[0004] One example where tissue movement relative to each other can be observed is when electrical leads bridge the skull and brain through spaces including the dura mater, arachnoid mater, cerebrospinal fluid, and pia mater. Other examples include leads bridging the spine and spinal cord; muscles and adjacent fibrous plates; and peripheral nerves and surrounding soft tissues. This relative movement of tissues can generate shear forces in their marginal areas, potentially leading to persistent local inflammation and tissue damage. Furthermore, these shear forces can affect the position of the active, non-insulated portions of implanted microelectrodes.

[0005] Purpose of the invention

[0006] One object of the present invention is to provide a microelectrode implanted in soft tissue, particularly nerve or endocrine tissue, which is electrically connected to a control device disposed outside the tissue, thereby avoiding or at least reducing tissue stimulation caused by movement of tissue adjacent to the implanted microelectrode or tissue adjacent to a wire electrically connected to the electrode control device disposed outside the implanted tissue.

[0007] Another objective of this invention is to prevent or reduce dislocation of implanted microelectrodes by influencing the force on the wires electrically connected to the electrode control device.

[0008] Another objective of this invention is to increase the lateral movement freedom of the implanted microelectrode.

[0009] In this invention, it is also desirable to avoid the transfer of aqueous body fluids between liquid reservoirs located at or around the proximal and distal ends or proximal and distal portions of the implanted microelectrode.

[0010] Another object of the present invention is to provide a microelectrode probe or a set of such probes for implantation in soft tissue, particularly neural or endocrine tissue, which can be converted into a microelectrode or microelectrode array by contact with aqueous body fluids.

[0011] Another object of the present invention is to provide a method for manufacturing the microelectrode probe and microelectrode probe array of the present invention. Invention Overview

[0013] This invention discloses a prototype microelectrode probe for implantation in soft tissues, particularly nerve or endocrine tissues, and a microelectrode formed from the prototype microelectrode probe after implantation.

[0014] The terms "distal" and "proximal" are used to describe microelectrodes, particularly certain portions of the microelectrode conductive core. The proximal segment (or portion) of the microelectrode conductive core is closer to the optional control device (or closer to the tissue separating a living organism from its environment [e.g., skin tissue]) than the distal segment (or portion). The distal and proximal segments (or portions) are separated by the intermediate portion of the microelectrode conductive core. The termination of the intermediate segment (or portion) and the beginning of the distal and proximal segments (or portions) [relative to the intermediate segment (or portion)] should not be understood as extremely specific locations, but rather as a continuous whole. Furthermore, the distal portion of the electrode core is located within the proximal and distal compartments. The proximal and distal compartments are separated by radially extending walls.

[0015] The term "flexible" is used to describe several components of the invention, particularly the conductor or core and the envelope or sleeve comprising or consisting of at least one layer (typically two or three layers) of flexible material. The flexibility of the core and the envelope or sleeve (a flexible polymer material) increases the degree of freedom of specific lateral movement of the implanted microelectrode. Therefore, the flexibility of the core and the envelope or sleeve helps to reduce irritation (e.g., inflammation) of soft tissues (e.g., nerves, endocrine tissues, and other soft tissues) in contact with the microelectrode after implantation, as well as the dissolution and / or degradation of the biocompatible matrix.

[0016] The microelectrode formed by the implanted probe comprises an oblong conductive microelectrode body or core, covered by an electrically insulating material layer, particularly an electrically insulating polymer material layer, except for its distal portion (which may be the distal terminal). At its proximal end, the microelectrode core is connected to an electrical connector in the form of a thin, flexible, electrically insulating wire, for direct or indirect connection to a control device placed outside the implanted tissue. Alternatively, the microelectrode core and the wire are integral, forming a single unit.

[0017] Electrically insulating materials can be composed of any material that provides electrical insulation capabilities, and are also suitable for methods of fabricating microelectrode probes. Typically, insulating materials should possess properties that enable them to be deposited by dip coating, spraying, vapor deposition, or casting, or any combination thereof. Exemplary insulating materials include biocompatible electrically insulating materials, such as various polymers, including polyurethane, polyethylene, and polymers called parylene, typically parylene C and parylene M.

[0018] The microprobe, formed after implantation into soft tissue, also includes a retainer comprising a proximal and a distal facet. Electrical connectors can be securely attached to the retainer and provide electrical connection to the microelectrode control device. Conversely, the retainer is attached directly or indirectly to tissue whose movement has little or no mechanical effect on the implanted microelectrode probe (microelectrode) or microelectrode array probe (microelectrode array) soft tissue.

[0019] This invention is based on the idea that direct contact between the implanted microelectrode core and adjacent soft tissues, particularly nerve tissue, as well as endocrine, exocrine, muscle, and connective tissues, can be avoided or at least reduced by a long, protective, rotationally symmetrical sheath or cannula made of flexible polymer material. This sheath or cannula laterally and remotely surrounds or encloses the microelectrode core while maintaining a certain distance from it, allowing the core to move within the sheath or cannula while preventing contact between the core and surrounding tissues. This avoidance of contact protects the microelectrode core from dislocations in adjacent nerve or endocrine tissues. Preferably, the distance between the core located at the center of the sheath or cannula (i.e., superimposed on its axis of rotation) and the inner wall of the sheath or cannula is more than twice the core diameter, particularly five times, or even ten, fifty, or more times, regardless of whether a polymer electrically insulating layer is used.

[0020] This invention is based on the additional insight that by arranging a separating wall of flexible polymer material in a radially extending manner, the radial direction including a direction perpendicular to the axis of rotational symmetry or any angular direction, dividing the interior of a sheath or cannula into distal and proximal compartments, while allowing the core to pass through the separating wall (preferably at or near its center) and fix it to the separating wall, movement of the core within the sheath or cannula is primarily restricted to lateral movement of its distal tip, while axial movement is impeded and thus limited. This arrangement provides the further advantage of preventing the flow of aqueous fluids between the distal and proximal ends of the sheath or cannula. Such flow needs to be restricted or prevented when the distal and proximal ends of the sheath or cannula are located in different tissues containing different aqueous fluids, and where exchange of aqueous fluids between tissues should be avoided. This is important, for example, in preventing cerebrospinal fluid from communicating with neural tissue near the uninsulated distal portion of the core. The core can penetrate the separating wall at any location; for example, the core can penetrate the separating wall at a non-central location, such as closer to the sheath or cannula than at the center of the separating wall.

[0021] This arrangement also allows for the delivery of drugs or other chemicals within the sheath or cannula of the microelectrode probe to the tissue. The drugs or other chemicals are located through at least one opening in the side or distal wall of the distal compartment near the sheath or cannula. This opening can be located at or near the distal end of the probe after implantation and conversion into a microelectrode, while avoiding delivery through a proximal opening. One or more openings may also be located anywhere within the distal compartment, such as in the middle of the distal compartment or near the proximal portion, i.e., near the wall separating the proximal and distal compartments.

[0022] The invention is also based on the concept of avoiding or at least reducing tissue inflammation caused by shear forces resulting from the cell or wire passing through such tissue, particularly through tissue that moves relative to each other and electrical connectors. This effect is achieved by providing a cell or wire whose length is much greater than the distance required between the sheath or housing that merely bridges the proximal and distal compartments of the microelectrode core, and by using highly flexible wires.

[0023] This invention discloses a microelectrode formed in situ when the microelectrode probe of this invention is implanted into nerve or endocrine tissue. Figure 5b The microelectrode is formed by dissolving or degrading a water-soluble or water-degradable matrix contained in the probe. Removal of the circumferential portion of the sheath or cannula of the proximal compartment and dissolution or degradation of the second matrix of the proximal compartment result in significant lateral movement of the microelectrode embedded in the soft tissue relative to the covering (see details). Figure 5b and Figure 6d ).

[0024] The present invention also discloses a microelectrode array formed when implanted into soft tissue, particularly neural or endocrine tissue, comprising two or more microelectrodes of the present invention, each microelectrode being housed in a protective sheath or cover (cannula) of a flexible polymer material. This microelectrode array is formed from a prototype microelectrode array probe of the present invention by contacting an aqueous body fluid, corresponding to the manner in which the prototype microelectrode probe of the present invention forms the microelectrodes of the present invention.

[0025] Therefore, this invention discloses a microelectrode probe implanted by insertion into soft tissue, particularly nerve and endocrine tissue, comprising a conductive core including a portion (or segment) located at the center of a rotationally symmetric sheath or sleeve of flexible polymer material, and attached to the sheath or sleeve by a wall of flexible polymer material extending in a vertical or angular direction relative to the rotation axis (of the microelectrode / microelectrode probe), separating the sheath or sleeve into a distal compartment and a proximal compartment; wherein the distal compartment comprises a (first) matrix of a first biocompatible material selected from one or more of carbohydrate materials, protein materials, and other materials, and wherein any of said materials is soluble or degradable in aqueous body fluids; wherein The proximal compartment includes a (second) matrix of a second biocompatible material selected from one or more of carbohydrate materials, protein materials, and other materials, wherein any of said materials is soluble or degradable in aqueous bodily fluids; wherein a core portion located in the proximal compartment extends proximally toward the compartment; wherein (a) the distal opening of the distal compartment is covered by a dome-shaped (spherical) covering or other covering of a flexible polymer material that narrows distally, said covering optionally being located on or attached to a (third) matrix of a third biocompatible material selected from one or more of carbohydrate materials, protein materials, and other materials, wherein any such material is soluble or degradable in aqueous bodily fluids;

[0026] The sleeve or tube has at least one distal opening and one proximal opening;

[0027] And the one or more of the said matrices are rigid materials when dried.

[0028] "Rigidity" refers to, but is not limited to, the stiffness that helps microelectrode probes (or prototype microelectrode probes) implant into soft tissues, especially nerve or endocrine tissues.

[0029] According to one embodiment of the microelectrode probe, there is no circumferential portion of the sheath or sleeve of the proximal compartment.

[0030] A distal opening refers to an opening in a sleeve or tube enclosing a distal compartment, or an opening in a cover covering the distal opening of a distal compartment. The opening may also be positioned to bridge the distal compartment and the cover. As is evident from the specification, the cover comprises a layer of flexible polymer material, also referred to as a third layer. The sleeve or tube enclosing the distal compartment is not limited to, but preferably comprises three layers of flexible polymer material, referred to as the first, second, and third layers. The third layer of the distal compartment and the distal opening cover of the distal compartment are preferably formed simultaneously during the fabrication of the microelectrode probe.

[0031] The materials for microelectrodes (e.g., the microelectrode core) can be any conductive material that meets the characteristics required for implantation in soft tissues, particularly endocrine and nervous tissues. Various metals are suitable, as are conductive non-metallic materials. Suitable materials are metals or metal mixtures that reduce or even avoid inflammatory reactions with the tissue surrounding the microelectrode, including platinum, iridium, gold, tungsten, stainless steel, copper, and silver, and mixtures thereof. Mercury alloys can also be used as microelectrode materials. Conductive non-metallic materials include various conductive polymers and carbon-containing materials such as graphene, graphite, and carbon nanotubes.

[0032] The core can be a single metal or two or more portions comprising different metals. Alternatively, the core can comprise two or more ultrafine metal wires. The thickness of one or more wires is preferably 10 nm to 100 nm or to 1 μm or 10 μm or even 100 μm. Two or more ultrafine wires can be wound together to maximize the surface area. In particular, the core portion extending proximally into the proximal compartment can be one or more materials different from the portions located in the proximal and distal compartments. The microelectrode core present in the distal compartment can exhibit a surface portion having a higher surface area than the average surface area of ​​the core in the distal compartment. Suitably, one or more portions exhibiting a higher surface area are located near one or more openings in the insulating layer. The core present in the distal compartment may also include uneven portions or protrusions near one or more openings. The uneven portions or protrusions are micrometer- or nanometer-scale.

[0033] The biodegradable material of the present invention, included in the device of the present invention, is completely or substantially completely degraded into degradation products soluble in aqueous bodily fluids within one or two weeks, or at most four weeks, after implantation of the device. "Substantially completely degradable" means at least 98% by weight, preferably at least 99% by weight or 99.5% by weight, of degradation.

[0034] The matrix material can be made from any biocompatible, soluble / degradable material. The biocompatible material (matrix material) is preferably gelatin or contains gelatin, with gelatin being a preferred protein material. The preferred carbohydrate material is glucose. Other preferred materials, i.e., materials other than carbohydrate and protein materials, are polyethylene glycol.

[0035] According to a first preferred embodiment, the core portion extending proximally into the proximal compartment includes a core retainer that can be fixed in a tissue different from the tissue to which the probe is implanted (especially bone or connective tissue). Preferably, the core retainer is attached directly or indirectly to a second biocompatible material.

[0036] According to a second preferred embodiment, the length of the core portion located between the proximal end of the distal compartment and the core retainer is 10% greater than the shortest distance between the proximal end of the distal compartment and the core retainer, particularly 20%, 50%, 100%, or more. Preferably, the core portion located between the proximal end of the distal compartment and the core retainer includes any spiral, serrated, or zigzag segment.

[0037] According to another preferred aspect of the invention, the microelectrode probe is embedded in a (fourth) matrix of a fourth biocompatible material selected from carbohydrate materials, protein materials, and other materials, wherein said material is soluble or degradable in aqueous body fluids. In this aspect, preferred variations of the microelectrode probe (or prototype microelectrode probe) are as follows: Figure 4i As shown. The outermost layer of the microelectrode probe in this aspect is primarily a flexible polymer material sheath or sleeve (in addition to optional distal and / or proximal openings).

[0038] According to another aspect of the invention, the sheath or sleeve and the distal segment of the core portion extending distally toward the distal compartment are embedded in a matrix of a fourth biocompatible material selected from carbohydrate materials, protein materials, and other materials, wherein said material is soluble or degradable in aqueous bodily fluids. The distal segment of the core portion corresponds to a cover (also referred to as a hemisphere or sphere) for the distal opening of the distal compartment, which narrows in the distal direction to cover the distal opening of the distal compartment.

[0039] The core retainer preferably comprises or is made of a rigid material and includes a distal facet and a proximal facet. Preferably, the proximal end segment of the core portion extends proximally into the proximal compartment to penetrate the core retainer from the distal end to the proximal facet. Preferably, the core retainer comprises a cylindrical tube with a diameter smaller than the diameter of the core retainer itself, particularly a cylindrical tube with a diameter equal to or smaller than the diameter of a hole in the bone where the core retainer will be mounted, the tube extending distally from the distal facet of the core retainer. This tube is made of the same or different material as the retainer and is stably resistant to degradation by aqueous body fluids. The term "rigid" when referring to the core retainer means providing proper core fixation while maintaining the function of the in-situ microelectrode. The retainer preferably imparts rigidity to the relevant tissue suitable for direct or indirect placement of the covering.

[0040] According to a fourth preferred aspect of the invention, the proximal compartment widens in a linear or non-linear manner in the proximal direction, particularly having a truncated conical shape. The lateral, proximal widening walls of the proximal compartment can also be curved, particularly convex. To improve fixation in tissue, the walls of the proximal terminal segment of the proximal compartment are preferably radially outwardly curved, for example, by 50 μm to 100 μm or more.

[0041] According to a fifth preferred aspect of the invention, the material or size, or both, of the core portion extending proximally into the proximal compartment is different from the material or size, or both, of the core portions located in the proximal and distal compartments.

[0042] The walls of the distal chamber comprise three layers of flexible polymer material, while the walls of the proximal compartment comprise two layers of flexible polymer material. Preferably, the innermost layer of the distal compartment wall, the radially extending wall, and the insulating layer on the core are integral. Also preferably, the dome-shaped covering and the flexible polymer material layer consisting of the sleeve or tube and its proximal extension are integral.

[0043] According to another embodiment, the prototype microelectrode probe or microelectrode probe (or microelectrode) comprises at least one bioactive substance, such as an anti-inflammatory substance, a neurotrophic substance, a sedative, or a neurotransmitter, such as glutamate, glycine, GABA, dopamine, norepinephrine, and acetylcholine. The bioactive substance is suitably contained in a distal compartment such that it can be released through one or more openings in the distal compartment. The bioactive substance may be added to the surface of a first matrix (made of a biocompatible material) and / or contained in the first matrix during the manufacture of the microelectrode probe. Furthermore, the bioactive substance may be applied to a core, specifically to a core portion located within the distal compartment.

[0044] The present invention also discloses a microelectrode probe device for inclusion in a microelectrode probe array, the microelectrode probe device comprising a conductive core located within a rotationally symmetric sleeve or tube of a flexible polymer material, including a proximal opening and a distal opening, particularly located at its center. The core is attached to the sleeve or tube by a flexible polymer material wall extending perpendicularly or at an angle relative to the rotation axis and separating the sleeve or tube into a distal compartment and a proximal compartment. The proximal compartment comprises a rigid second matrix containing or composed of one or more biocompatible carbohydrate materials, biocompatible protein materials, or biocompatible materials other than carbohydrate and protein materials. The distal compartment comprises a rigid first matrix containing or composed of one or more biocompatible carbohydrate materials, biocompatible protein materials, or biocompatible materials other than carbohydrate and protein materials. The core portion located in the proximal compartment extends proximally into the compartment. The distal compartment includes one or more openings. The matrix is ​​soluble or degradable in aqueous body fluids.

[0045] Preferably, the distal opening of the distal compartment is covered by a dome-shaped (spherical) covering or other covering that narrows in the distal direction, and said covering is a (single-layer) flexible polymer material, optionally supported by a third matrix of one or more biocompatible carbohydrate materials, biocompatible protein materials, or other biocompatible materials, wherein said dome-shaped covering or other covering that narrows in the distal direction, or the sidewall of said distal compartment, includes an opening or includes a combined opening; wherein the matrix material is soluble or biodegradable in aqueous body fluids. Preferably, the proximal compartment wall comprises two layers of flexible polymer material, wherein the distal compartment wall comprises three layers of flexible polymer material. The core portion extending proximally from the proximal compartment preferably includes any one of spiral, serrated, or zigzag segments; the portion forming the distal end sheath or sleeve comprises two or more layers, wherein the innermost layer is integral with a wall extending perpendicularly or at an angle relative to the axis of rotation, and an insulating layer on the core extends proximally from the wall.

[0046] According to the present invention, a microelectrode probe array is also disclosed, comprising two or more microelectrode probe devices of the present invention arranged in parallel or substantially parallel configurations, wherein the distal ends of the devices are preferably positioned in a plane extending perpendicularly to their axes, further comprising an array cover comprising or composed of a rigid material; wherein the proximal terminal portion of the core extending proximal to the proximal end of the proximal compartment is attached to the array cover and embedded together with the microelectrode probe devices containing them in a common rotationally symmetric rigid array matrix, the matrix being a biocompatible material soluble or biodegradable in aqueous body fluids, the material being selected from one or more of carbohydrate materials, protein materials, and materials other than carbohydrate and protein materials. Preferably, the array matrix extends to and is attached to the distal end face of the array cover. According to a preferred embodiment of the present invention, the diameter of the array matrix increases in the proximal direction from the axial plane cutting the proximal compartment. The proximal terminal segment of the core preferably penetrates the array cover and is electrically connected at or extends from the proximal end face of the array cover. According to a preferred aspect of the invention, except for an annular region adjacent to or near the array cover, the array includes a cover made of a flexible polymer material that covers and adheres to the increased diameter embedded portion. The cover is made of a material resistant to aqueous bodily fluids. Preferably, the cover is adhesively attached to the wall of the proximal compartment of the microelectrode probe device. In a preferred variation of the array according to the invention, two or more microelectrode probe devices are adhesively joined to each other at their sheath or sleeve wall. According to another preferred aspect of the invention, the array includes a rigid array housing that encloses all elements of the array located at the distal end of the array cover; wherein the array housing comprises or is composed of one or more biocompatible carbohydrate materials, biocompatible protein materials, other biocompatible materials soluble or degradable in aqueous bodily fluids, particularly gelatin.

[0047] The method for manufacturing a microelectrode probe of the present invention includes: providing a conductive wire (or ultrafine wire bundle) or polymer material fixed on opposite sides of a frame, the wire including a straight section at a proximal end and a middle section, particularly an intermediate spiral, serrated, or zigzag section extending between the straight sections; forming a first rigid matrix on a portion of the distal section of the wire; covering the first matrix and the portion of the wire not covered by the first matrix with a first layer of flexible polymer material; covering a portion of the wire with a material capable of forming a rigid second matrix, the first layer extending from the first matrix towards the proximal end and including the middle section of the wire; covering the first layer and the second matrix with a second layer of flexible polymer material; cutting the wire, the first layer, the second layer, and the first matrix near the distal end of the first matrix; optionally, by cutting... The generated first matrix deposits a material capable of forming a third matrix on the distal surface; optionally, the third matrix and the second matrix layer are covered with a third layer of flexible polymer material; a portion of the second and third layers is removed, or the second and third layers are removed from a circumferential region of the second matrix, the circumferential region covering a line portion extending proximally from the first matrix and including a midline portion; an opening is formed by removing a portion of the first, second, and third layers (the three layers enclosing the first matrix), or (or additionally) in the third layer enclosing the distal opening of the distal compartment; wherein the matrix material is selected from carbohydrate materials, protein materials, and other materials, wherein all matrix materials are biocompatible and soluble in aqueous body fluids, and capable of forming a rigid matrix upon drying. Preferably, the amount of the second matrix material applied to a designated portion of the first layer of flexible polymer material increases proximally. All layers of the flexible polymer material are also preferably composed of the same material.

[0048] During the manufacturing process, bioactive substances may be applied. After the first matrix is ​​applied, the bioactive substances may be applied to the surface of the first matrix. Alternatively, the bioactive substances may be applied to the core portion, which will be covered by the first matrix in subsequent steps. Another alternative method is to introduce the bioactive substances into the first matrix, i.e., to provide a first matrix comprising one or more bioactive substances. The bioactive substances may be included in the composition that forms the first matrix after application. Alternatively, the first matrix may be formed by sequentially applying a composition comprising one or more bioactive substances and a matrix to form a composition.

[0049] The method for manufacturing a microprobe array according to the present invention includes providing two or more microelectrode probes in any of the disclosed embodiments, placing the probes parallel or substantially parallel; optionally attaching their covers to each other by an adhesive; embedding the probes in a rigid first array matrix having proximal and distal ends; covering the proximal portion of the array matrix extending from the proximal end of the array matrix with a layer of flexible polymer material resistant to degradation by aqueous bodily fluids; removing an annular region of the flexible polymer material layer between its proximal and distal ends; and covering the flexible polymer material layer and the annular region with a second rigid array matrix; wherein the first and second array matrices are independently selected from one or more biocompatible materials selected from carbohydrate materials, protein materials, and other materials, and wherein the matrix material is soluble or degradable in aqueous bodily fluids. Preferably, the distal ends of the probes are disposed on a plane. According to a preferred aspect of the invention, the method includes providing the array with a cover including a distal facet and a proximal facet, such that the array matrix is ​​adhesively attached to the distal facet of the cover. Furthermore, the proximal ends of the preferred cover and the second array matrix are cylindrical and centered relative to a common axis of rotation, and the diameter of the cover is larger than the diameter of the cylindrical portion of the second array matrix. According to another preferred aspect, the method of the invention includes forming the distal portion of the second array matrix in a gradually tapering manner. When embedding the microelectrode probe into the first array matrix, it is preferably positioned such that its axis of rotation comprises an angle of less than 10° relative to the array axis, particularly less than 5°, 2°, or 1°, or parallel to the array axis.

[0050] The invention will now be described in more detail with reference to various preferred embodiments shown in the figures, which are not to scale for clarity. Brief description of the attached diagram Attached Figure Description

[0052] Figure 1 The nerve tissue site for implanting the microelectrode probe of the present invention is located in a cross section perpendicular to the bone protecting the site;

[0053] Figure 2 Figure 1 The site, in the same section after providing a round hole in the bone;

[0054] Figure 2a A rough schematic diagram of the microelectrode probe of the present invention in axial cross-section;

[0055] Figure 3 Figure 2 The position, in the Figure 2a Immediately after implantation of the microelectrode probe, at the same cross-section;

[0056] Figures 4a-4h A process for manufacturing the microelectrode probe of the present invention, which is shown in an axial cross-section Figure 4i The diagram shows the continuous early stages of the microelectrode probe. Figure 4h (Also known as prototype equipment)

[0057] Figure 4i The microelectrode probe of the present invention is located in the axial section.

[0058] Figure 4j Figure 4i The various microelectrode probes shown, including the anchoring cover, are located in the same cross section.

[0059] Figure 5 The microelectrode probe of the present invention is implanted in nerve tissue in an axial section prior to complete radial dissolution of the second matrix portion.

[0060] Figure 5a Implanted neural tissue in the intermediate stage of transforming into the microelectrode of this invention Figure 5 The prototype microelectrode probe, whose cross-section is similar to... Figure 5 same.

[0061] Figure 5b Depend on Figure 5 The microelectrode of the present invention (in-situ microelectrode) is formed in situ using a microelectrode probe. Figure 5 , 5a In the same cross section.

[0062] Figure 5c Figure 5 A partial view that has a changing overlay within the same view.

[0063] Figure 6a A simplified schematic diagram of the microelectrode probe of the present invention, including a soluble coating, is shown in perspective.

[0064] Figure 6b Figure 6a The microelectrode probe, after being implanted into nerve tissue and having its covering dissolved by aqueous body fluid, is in an intermediate stage of transformation into the microelectrode of this invention. Figure 6a In the same view.

[0065] Figure 6c In the same view by Figure 6a The matrix material is composed of microelectrode probes.

[0066] Figure 6d ,6e through complete dissolution Figure 6b The microelectrode of the present invention, formed in situ from the supporting matrix material in the intermediate stage, is in the same cross section. Figure 6d It shows the angular dislocations in the microelectrode core; Figure 6e It also shows how to deform a flexible covering by means of an adjacent covering.

[0067] Figure 7 The array of four microelectrode probes of the present invention is shown in the same cross section as in FIG. 6, and the microelectrode probes are illustrated in a similar simplified manner.

[0068] Figure 7a Figure 7 The radial section AA of the array.

[0069] Figure 7b The microelectrode probes of the present invention, used for addition to a microelectrode probe array, are shown in a simplified perspective view, excluding portions of their matrix material.

[0070] Figure 7c Various Figure 7 The 7a microelectrode probe array, in conjunction with Figure 7a In the same cross section. Detailed Implementation

[0071] Example 1

[0072] Implantation and tissue environment principles. Figure 1 , 2 Figures 2a and 3 schematically illustrate the implantation of microelectrode probes into neural tissue. Here, neural tissue 3 is brain tissue protected by skull 1, which is separated by a thin layer 2 comprising several sublayers, such as the dura mater, arachnoid mater, pia mater, and cerebrospinal fluid. Neural tissue 3 is prone to displacement relative to skull 1 due to head movements; displacement parallel to skull 1 (arrows b, b') is generally greater than displacement perpendicular to it (arrows a, a'). The intermediate tissue between skull 1 and brain tissue 3 also displaces, but not necessarily to the same degree.

[0073] Prior to implanting the device of the present invention, access to the desired location in the brain is achieved by drilling a round hole 8 in the skull. Figure 2 ).

[0074] In the next step, the device of the present invention, for example... Figure 2a The microelectrode probe 10 or microelectrode probe array of the present invention is inserted into brain tissue 3 through the hole 8. Figure 3Upon implantation, the microelectrode probe 10 transforms into the microelectrode of the present invention (in-situ microelectrode) through contact with aqueous body fluids. Once the matrix material is completely dissolved or degraded, a fully functional in-situ electrode is formed. The microelectrode probe 10 includes a cover 7 anchored to and protecting the skull opening 8. The microelectrode 10 includes a metal or other conductive core 6, 6', 6" attached to and extending from the distal end 6 through the intermediate portion 6' and penetrating the cover 7 to the proximal end 6", 6" which extends from the proximal end face of the cover 7 for electrical communication with a microelectrode control unit (not shown) placed outside the body or implanted subcutaneously. The distal portion 6 of the core 6, 6', 6" is housed in a flexible polymer material cannula or sheath comprising a proximal compartment 4 and a distal compartment 9, separated by a radially extending wall 10a that is penetrated and attached to the distal portion 6 of the electrode core. The portion of the core 6 housed in the distal compartment 9 (i.e., the distal end located in wall 10a) is not electrically insulated, while the remainder of the core 6', 6" is insulated. The length of the intermediate portion 6' of the core is preferably much greater than the distance between the proximal end of the distal compartment and its connection point with the cover 7. A control unit may be mounted on or included within the cover 7 (not shown). The intermediate portion 6' allows the core 6 and its associated insulating or encapsulating elements to move relative to the housing 7 if displaced due to movement of surrounding tissue. Therefore, the length of the intermediate portion 6' is designed to be substantially greater than the distance between its connection point with the housing and its distal end, which is the end that connects to the proximal end of the distal portion of the core 6 or is integral with the proximal end of the distal portion of the core 6 [6', 6"]. The distal end of the intermediate core 6' is located at the proximal end of the distal compartment. The following embodiments describe in detail the microelectrode probe of the present invention and its fabrication.

[0075] Example 2

[0076] The fabrication process of the microelectrode of this invention is helpful for understanding the structure of the microelectrode probe of this invention and the microelectrode formed therefrom during implantation. Such a process... Figures 4a to 4h Or as shown in 4j.

[0077] At the beginning ( Figure 4aThe ends of metal wires 15, 16, and 17 are fixed to opposite sides 11 and 12 of rectangular frames 11, 12, 13, and 14. Wires 15, 16, and 17 include long and short straight end portions 15 and 17, and pre-bent intermediate spiral, zigzag, or zigzag extendable portions 16. Typically, wires 15, 16, and 17 are a few micrometers thick, for example, from 1 μm to 20 μm, particularly from 2 μm to 12 μm. Wires 15, 16, and 17 can be a single piece or composed of two or more segments with different compositions, for example, the first segment 15 is platinum or iridium, and the second segments 16 and 17 are gold. A bundle of ultrafine metal wires or conductive polymer material can be used instead of individual wires 15, 16, and 17 to improve flexibility.

[0078] In the second step, the middle portion of the long straight section 15 is coated with low-molecular-weight carbohydrates (e.g., glucose) or peptides or mixtures thereof by electrospinning under dry conditions (preferably at 10% or less humidity) to form a basic cylindrical layer 18 attached to the long straight section 15. Figure 4b The thickness of this layer is 5 μm to 100 μm, particularly from 20 μm to 50 μm. Alternatively, the layer can be formed by dip coating, spraying, or casting.

[0079] In the third step, the blank portions of the metal wires 15, 16, 17 and the surface of the carbohydrate layer 18 are covered by a layer 19 of an insulating polymer material such as parylene C or parylene M through vacuum pyrolysis and deposition (as shown in Figure 4C). The preferred thickness of the insulating layer 19 is 10 μm or less, especially 4 μm or less, for example 1 μm-2 μm.

[0080] In the fourth step, a layer of gelatin 20 is applied, for example by spraying or casting, to a portion of lines 15, 16, 17 extending from the proximal end of the carbohydrate layer covered with insulating polymer 19 toward the proximal end of the short straight end portion 17 in the middle portion. Figure 4d In the proximal direction, the diameter of the gelatin layer 20 increases from approximately the diameter of the carbohydrate layer 18 to twice or more the diameter of the carbohydrate layer, but a constant diameter of the gelatin layer is also feasible.

[0081] In the fifth step, the entire prototype device is covered with a second layer 21 of an electrically insulating polymer, such as parylene C, having a thickness similar to that of the first insulating layer 19. Figure 4e ).

[0082] In step six (the result is as follows) Figure 4f As shown), in section FF ( Figure 4eThe prototype device is radially cut at point 22' to give it a flat distal end face 22'. The new distal end of the wire portion of the distal portion of the core 15 is located at the center of face 22' and is radially surrounded by carbohydrate layer 18 and insulating layers 19, 21.

[0083] In the optional seventh step, a certain volume of, for example, gelatin 22 is added to the surface 22' by, for example, casting. Figure 4g This certain volume is suitable for addition in the form of a hemisphere 22 or other structural form that narrows in the distal direction, so as to form the distal portion of the distal compartment after the layer in step 8 is added.

[0084] In step 8, the entire prototype device 30 is covered with an additional layer 23 of an electrically insulating polymer such as parylene C. Figure 4h The thickness of the third layer 23 is similar to that of the first layer 19 and the second layer 21.

[0085] In two consecutive ninth and tenth steps (the order of which is interchangeable), the prototype device 30 is thus produced. Figure 4h ) was converted into the prototype microelectrode probe 30' of this invention. Figure 4i In polymer layers 19, 21, and 23, laser evaporation is performed near the distal ends of lines 15, 16, and 17. Figure 4h Hole 24 is formed at point G in the middle, and then near... Figure 4h The prototype device 30 uses near-end laser milling to evaporate the circumferential bands of polymer layers 21 and 23. Figure 4h (at point H in the middle) to form an annular region 25 that is not covered by the insulating polymer.

[0086] The location and axial extent of the circumferential zone may vary depending on the type of tissue to be penetrated by the microelectrode probe.

[0087] The openings 24 of the polymer layers 19, 21, and 23 can be formed at any location, allowing the carbohydrate layer 18 surrounding the distal portion of the core 15 to communicate with the outside.

[0088] In the final step, gelatin is applied by spraying it in a dry atmosphere (optionally under reduced pressure) to cover the surface. Figure 4i The prototype microelectrode probe 30′ is used to form Figure 4j The microelectrode probe 30 of the present invention includes an outer gelatin layer 27. It is less preferable to form the gelatin layer 27 by casting, because the high humidity generated in the material covered by the casting solution is detrimental to the structure of the material. Figure 4jThe cylindrical microelectrode probe 30” of the present invention is shown, which includes a distal circular end formed therefrom. Its gelatin layer 27 does not cover the proximal face or proximal end portion of the prototype device 30”. At its proximal end or end portion, the prototype device may optionally include a rigid cover 28 of polymer or other suitable material to facilitate its installation in a bone (e.g., skull) hole covering the tissue to be implanted. For ease of installation, the radial extension of the cover 28 is suitably larger than the diameter of the cylindrical portion of the microelectrode probe 30”. At its proximal end, the proximal portions 17 of the polymer-covered microelectrode cores 15, 16, 17 (19, 21', 23) are securely fixed to the cover 28 using, for example, adhesive, penetrating the cover 28 to reach their proximal face for electrical connection with an electrode control device (not shown).

[0089] Figure 5 The implanted brain is shown in an axial section. Figure 4j The microelectrode probe 30” is implanted into the brain through a hole in the skull 31, and its covering 28 is attached to the bone 31. The components of the microelectrode probe 30” are numbered and... Figure 4j The numbers are the same. The implanted microelectrode probe 30” shows that it penetrates and is adjacent to three different tissues numbered 34, 35, and 36 from proximal to distal. The regions of tissues 34 and 35 and 35 and 36 that are adjacent to each other are numbered 32 and 33, respectively.

[0090] After implantation, the soluble and (if present) biodegradable material of the microelectrode probe 30” comes into contact with an aqueous body fluid, which may have different compositions depending on the tissues from which it flows 34, 35, 36.

[0091] Figure 5c shown Figure 5 The type of microelectrode probe differs from the former because its cover 28 is provided by a short, tapered tubular portion 28' protruding from its distal side. The diameter of the tubular portion 28' is adapted to fit into and remain in the bone hole into which the microelectrode probe 30 is to be inserted.

[0092] Figure 5a The implanted microelectrode probe 30″ is shown in the intermediate stage 30”a of the transformation into the in-situ microelectrode of the present invention, wherein the gel-like covering 27 has been partially dissolved by an aqueous body fluid to form a gelatin-rich aqueous layer 29 surrounding the remaining portion of the microelectrode probe.

[0093] Upon further contact with aqueous body fluids, the remaining soluble or degradable carbohydrates 18 and gel-like materials 22, 27, and 26 of the microelectrode probe 30”a dissolve in or are degraded by the aqueous body fluids, thereby forming the in-situ microelectrode 30”b of the present invention. Figure 5bOver time, an aqueous fluid surrounding the microelectrode 30"b, containing dissolved and / or degraded carbohydrates 18 and gel-like materials 22, 27, 26, is absorbed by adjacent tissues 34, 35, 36, thereby allowing tissue adjacency to the flexible polymer covering (19, 21) 23. Conversely, similar fluids 35', 36' remain within the covering 23 for extended periods, separated by a wall portion w into a proximal portion P containing fluid 35' flowing from tissue 35 and a distal portion D containing fluid 36' flowing from tissue 36. Electrical contact between the distal portions 15 of the electrode bodies 15, 16, and 17 and the adjacent tissue 36 is provided by a side window or aperture 24 near the distal end of the microelectrode. An extendable helical portion 16 bridges the boundary 32 between tissues 34 and 35, which are easily slidable relative to each other. Dislocations in the electrode cores 15, 16, and 17 caused by sliding tissue movement are compensated by the extendable nature of the helical portion 16 of the intermediate electrode core portion, which prevents or reduces dislocations in the distal electrode portions 15, particularly near their distal ends near the window 24.

[0094] Example 3

[0095] Figure 6a The microelectrode probe 40 of the present invention is shown in a simplified perspective view, comprising distal chambers 46, 52 having cylindrical portions 46 and hemispherical portions 52, and a cylindrical proximal chamber 47. Chambers 46, 52, and 47 are separated by radially extending walls 43. The microelectrode probe 40 is substantially rotationally symmetric with respect to a central axis CC extending in the proximal / distal direction. The walls 44, 50, and 45 of chambers 46, 52, and 47 are respectively... Figure 6b The partition wall 43 is a flexible polymer material, such as parylene C. Chambers 46, 52, and 47 are filled with one or more biocompatible carbohydrate and protein materials, such as glucose and gelatin; for example, the cylindrical portions 46 of the proximal chamber 47 and the distal chambers 46, 52 are filled with carbohydrate material, while the hemispherical portions 52 of the distal chambers 46, 52 are filled with gelatin. Preferably, in the probe without a drawn outer shell ( Figure 6b Near the distal end 40', the walls 44, 50 of the distal chambers 46, 52 include openings or windows 49, but may also include two or more windows located in any desirable position on the walls 44, 50 of the distal chambers. The chambers 46, 52, 47 are embedded in a shell 53 of a biocompatible material, particularly a material capable of forming a gel in contact with aqueous bodily fluids (e.g., gelatin). Figure 6a , Figure 6cThe housing 53 is rotationally symmetrical about the central axis CC and has a rounded distal tip. The microelectrode probe 40 also includes conductive electrode cores 41, 41a, particularly of a metal or metal alloy such as gold, which are centered about the central axis CC. A first electrical conductor or extension 41' is connected to the proximal end of the electrode core portion 41a. The first electrical conductor or extension 41' extends proximally to a circular cover 56, where it may terminate at a coupling point 58 and continue proximally as a second electrical conductor or extension 41"; or the electrode cores 41, 41a and their first 41' extension, or the electrode cores 41, 41a and their two extensions 41', 41" may be integral, such as a single wire. A first lead wire or extension 41' passes through the cover 56 and continues as a proximal portion 41" of the cover 56 to a microelectrode control device (not shown) or terminates at a coupling device 58 attached to the cover 56 for coupling a separate lead wire 41" to the control device. A first extension 41' of the electrode cores 41, 41a, or a first lead wire 41' connecting the cores 41, 41a and the cover 56, located between the proximal end of the proximal chamber 47 and the cover 56, has a length substantially greater than that required for a direct connection, for example including helical or bent portions to allow for the absorption of distance variations between the proximal chamber 47 and the cover 56 without tautening the corresponding chamber walls 44, 50, 45 of the chambers 46, 52, 47.

[0096] Figure 6b This represents a variation of the microelectrode probe 40' of the present invention, which lacks a shell made of biocompatible material.

[0097] The biocompatible material filling the proximal chamber 47 extends to the distal face of the covering 56. It is optionally widened in the proximal direction to form a truncated conical portion 48. While the distal end of the distal portion of the electrode core 41 (extending from the distal end of the core 41 to the partition wall 43) is not electrically insulated, the proximal end of the distal portion of the electrode core 41a (extending to the wall 43) and the proximal ends of its extensions or the wires 41', 41" attached to it are insulated. The flexible transverse wall 43 is made of the same or similar polymeric material as the other chamber walls 44, 45, 50. The distal end of the electrode core 41 is located at approximately the same axial level as the window 49, and when the microelectrode probe 40 or 40' is transformed into the implanted microelectrode (40", 40"') of the present invention, Figure 6d , 6e When the electrode core 41 is in contact with the adjacent soft tissue through the window 49, it can be electrically connected.

[0098] Flexible polymer wall portions 51 and 51' of the same polymer material as the wall 45 of the proximal chamber 47 extend in the form of truncated cones between the proximal end of the proximal chamber 47 and the distal end face of the covering 58, forming a truncated cone chamber 48 that encapsulates the solid matrix of the biocompatible material. The flexible polymer wall portions 51 and 51' of the truncated cone chamber 48 are separated from each other by annular regions 42 of width z, in which the matrix of the biocompatible material lacks the protection of the polymer walls.

[0099] For clarity, Figure 6c The diagram shows chambers or chamber portions 52, 46, 47, 48 filled with biocompatible material and a shell 53 of biocompatible material, without all other components.

[0100] Figure 6d , 6e The microelectrodes 40”, 40”' of the present invention, formed in soft tissue by dissolving or degrading a biocompatible material shell 53 and biocompatible material-filled chambers 52, 46, 47, 48, are shown in a simplified manner and in two modified stages. The flexible nature of the polymer material and the thickness of the covering walls 50, 44, 45, 51, 51' allow the microelectrodes 40”' to adapt to the displacement of adjacent tissue, that is, without providing substantial resistance to the movement of adjacent tissue. Figure 6d In 6e, Figure 6a and 6b The distal chambers 46 and 52 are designated by reference numeral 54 to indicate that they are filled with bodily fluids entering through window 49, while Figure 6a The proximal chambers 47 and 48 of 6b are designated as reference numerals 55 and 57 to indicate that they are filled with bodily fluid entering through an annular opening at region 42, which lacks the polymer wall of the proximal chamber portion 48; the same bodily fluid also enters through the same opening into the flat chamber 59 defined by the flexible polymer wall portion 51' and the distal face of the cover 56.

[0101] Example 4

[0102] Microelectrode array probe: Microelectrode array probe 60 such Figure 7 and 7aAs shown, the device includes four microelectrode probes, each comprising an elongated electrode core 62, 62a; 64, 64a; 66, 66a; 68, 68a, made of metal or other conductive material, connected at its proximal end to flexible wires 72, 74, 76, 78. The proximal portions of wires 72, 74, 76, 78 pass through a circular housing or lock 70 made of polymer material and are attached to microcontacts 71, 73, 75, 77 by welding to their proximal surfaces. Microcontacts 71, 73, 75, 77 serve as contact points for external leads, providing electrical connection to a microelectrode control device (not shown), or as contact points for internal leads, providing electrical connection to an implanted microelectrode control device (not shown). Cores 62, 62a; 64, 64a; 66, 66a; 68, 68a are located in cylindrical sleeves or tubes 61, 63, 65, 67 of flexible polymer material, having an open proximal end and including a hemispherical distal end extension. Approximately halfway between their proximal and distal ends, the sleeves or tubes 61, 63, 65, 67 are separated into proximal and distal compartments by radially extending walls 81, 83, 85, 87 of the same flexible polymer material. Although the core portions 62, 64, 66, 68 (i.e. located in the distal compartments) of the radial extension walls 81, 83, 85, 87 are not insulated, the core portions 62a, 64a, 66a, 68a (and located in the proximal compartments) of the radial extension walls 81, 83, 85, 87 are insulated, especially using polymer materials of the same or similar kind as the sheaths or sleeves 61, 63, 65, 67 or the radial extension walls 81, 83, 85, 87.

[0103] Figure 7b Microelectrode probe 40a, of the same type as probes 61, 63, 65, and 67, is shown; probe 40a shows... Figure 7b Details not shown due to space constraints. Figure 7bIn the figures, reference numeral 41 identifies the non-insulated distal portion of electrode cores 41, 41a, while reference numeral 41a identifies their insulated proximal portion. An insulated conductor 41′ is connected to the proximal end of core portion 41a. Flexible polymer walls 44, 45 define cylindrical proximal and distal compartments 46, 47, separated by radially extending circular walls 43 of the same or similar polymer material. Electrode cores 41, 41a pass through and are attached to the center of wall 43. At their distal ends, the wall 44 of distal compartment 46 engages with a wall 50 of the same or similar flexible polymer material, defining a hemispherical distal extension 52 of compartment 46. Laterally elliptical or circular openings 49 are provided at the boundary regions of the walls 44, 50 of distal compartment 46 and their distal extension 52. In addition to the radially extending wall 43, flexible polymer walls 44, 45, and 50 form a coating on a solid matrix of carbohydrates, proteins, or other biocompatible materials soluble in aqueous body fluids, which fill compartments 46, 52, and 47 and are respectively confined by walls 43, 44, 50 and 43, 45.

[0104] exist Figure 7 , 7a In the microelectrode array probe 60, microelectrode probes 61, 63, 65, and 67 are symmetrically arranged parallel to the central rotation axis EE, and their distal and proximal ends are in the same plane. The compartments of the microelectrode probes 61, 63, 65, and 67 are filled with a matrix of rigid carbohydrates and / or proteins and / or other biocompatible materials soluble in aqueous body fluids; the microelectrode probes 61, 63, 65, and 67 are embedded in cylindrical array matrices 69 and 79 of the same or similar types of materials, forming circular distal tips 83a, which widen along the direction of the outer shell 70 from the axial horizontal plane 91 located near the radially extending walls 81, 83, 85, and 87, so that the distal end face is close to and adheres to the outer shell 70. Except for the annular region w near or adjacent to the distal end face of the outer shell 70, the widened portion of the carbohydrate and / or protein material is covered by a layer or outer cover 99, 99', which is the same as or covered by a similar polymer material as the polymer material forming the walls of the microelectrode probes 61, 63, 65, 67, thereby defining truncated conical proximal array compartments 80, 80', the distal and proximal portions of which are separated by the region of width w. The region of width w thus forms an annular window composed of the truncated conical outer covers 99, 99'.

[0105] exist Figure 7In the radial section 7a of the microelectrode probe array 60, the distal edge 91 of the truncated conical outer casing 99, 99' is shown horizontally. The walls of the proximal compartments are identified by reference numerals 92, 94, 96, 98 and cover the first cylindrical carbohydrate or protein matrix or other kind of matrix 82, 84, 86, 88 of the proximal portions 62a, 64a, 64a, 66, 66a, 68a (or: the proximal portions of the distal portions of the cores) of the electrode cores 62, 62a; 64, 64a; 66, 66a; 68, 68a arranged around the center. The compartments defined by their walls 92, 94, 96, 98 are enclosed in the array matrix 69 and thus held in position within the outer casing 99, 99'. The truncated conical array matrix 69 of carbohydrate or protein or other material extends toward the distal ends of the microelectrode probes 61, 63, 65, 67 to form rounded distal tips.

[0106] Figure 7c As shown Figure 7 , 7a The variation 90 of the microelectrode probe array 60 differs from the microelectrode probe array 60 in that cylindrical walls 92', 94', 96', 98' surrounding the distal portions of the centrally located electrode cores 62a', 64a', 66a', 68a' are attached to each other in pairs by adhesive means such as glues 93, 93', 93", 93"', including polymer materials of the same or similar type as those constituting the cylindrical walls. Alternatively or separately, walls 92', 94', 96', 98' may be attached to adjacent truncated conical flexible polymer walls 99 (e.g., at adhesive points 97).

[0107] Figure Labels

[0108] letter

[0109] a,a',b,b' Organizational dislocation direction

[0110] Inclination angle of axis E α

[0111] w Width of the annular region without polymer covering

[0112] C Central axis

[0113] E Inclined central axis

[0114] F Cutting plane

[0115] H. Annular region without polymer layers 21, 23

[0116] G. Circular regions without polymer layers 19, 21, and 23

[0117] D. Remote compartment

[0118] O Covered compartment

[0119] P proximal compartment

[0120] z Width of the annular region without polymer covering

[0121] number

[0122] 1. Skull

[0123] 2. Thin soft tissue layer

[0124] 3. Nervous (brain) tissue

[0125] 4. Proximal compartment of the sleeve

[0126] 5. Gelatin layer (third matrix)

[0127] 6 distal core segment, 6' intermediate core segment, 6' proximal core segment

[0128] 7. Covering

[0129] 8. Openings or holes in the skull

[0130] 9 sleeves distal compartment

[0131] 10.10: Schematic diagram of electrode probe; 10a: Radial compartment wall

[0132] 11. The upper side of frames 11, 12, 13, and 14

[0133] 12. Lower side of the frame

[0134] 13. Left side of the frame

[0135] 14. Right side of the frame

[0136] The long, straight ends (far ends) of lines 15, 16, and 17.

[0137] 16. Intermediate extendable section

[0138] 17. Short, straight end (proximal) segment

[0139] 18 First matrix layer (cylindrical carbohydrates, etc.) layer

[0140] 19. Polymer material insulation layer (first layer of polymer material)

[0141] 20 Second matrix layer (widened along the proximal direction)

[0142] 21 Second layer polymer material; 21' Second insulating layer

[0143] 22 gelatin hemispheres, 22' circular end face or distal opening of the distal compartment (third matrix).

[0144] 23 Third layer polymer material'

[0145] 24. Holes or windows in polymer layers 1-3

[0146] 25. Lacks the annular region of polymer layers 2 and 3, with a high H.

[0147] 26. Proximal region protected by polymer layers 2 and 3

[0148] 27. Gelatin layer (fourth matrix)

[0149] 28 Rigid coverings

[0150] 29. Aqueous layer formed by gelatin layer 27

[0151] 30 Prototype microelectrode probe, 30', 30” microelectrode probe, 30”a Microelectrode probe during the disintegration of gelatin layer 27; 30”b In-situ formed microelectrode.

[0152] 31 Skull

[0153] 32 First (proximal) tissue boundary

[0154] 33 Second (remote) organizational boundary

[0155] 34 Proximal soft tissue layer

[0156] 35. Intermediate soft tissue layer

[0157] 36 Distal soft tissue layer

[0158] 37. Solution of matrix 26 in aqueous body fluid originating from proximal layer 34

[0159] 38. Matrix 26 in a solution of aqueous body fluid derived from the intermediate layer 35

[0160] 39. Solution of matrix 18 in an aqueous body fluid originating from distal layer 36

[0161] 40 Microelectrode probes

[0162] 41 Electrode core, distal end, non-electrically insulated portion; 41a Proximal end, electrically insulated portion; 41' Flexible conductor; 41” Flexible conductor extension.

[0163] 42. Matrix cross-sectional boundary not covered by the flexible polymer layer

[0164] 43. Partition wall

[0165] 44 The wall of the distal chamber 46

[0166] 45 The wall of the distal segment of the proximal chamber 47

[0167] 46. ​​Proximal segment of the distal chamber

[0168] 47. Distal segment of the proximal ventricle

[0169] 48. The distal segment of the truncated cone portion of the proximal chamber

[0170] 49 windows

[0171] 50 The wall of the dome-shaped distal end section 52 of the distal chamber

[0172] 51. The wall of the distal segment of the truncated conical segment of the proximal ventricle; 51' The wall of the proximal portion of the truncated segment of the proximal ventricle.

[0173] 52. The distal dome-shaped section of the distal chamber

[0174] 53 Gelatin Shell

[0175] 54. The proximal segment of the distal compartment filled with aqueous body fluid.

[0176] 55' The distal portion of the proximal compartment filled with aqueous body fluid; 55' The proximal portion of the proximal compartment filled with aqueous body fluid

[0177] 56. Coverings

[0178] 57. The distal segment of the truncated cone portion of the proximal chamber filled with aqueous body fluid.

[0179] 58. Covering opening

[0180] 59. The proximal segment of the truncated cone portion of the proximal chamber filled with aqueous body fluid.

[0181] 60 Array of four microelectrode probes

[0182] 61 First microelectrode probe

[0183] 62 First electrode core, uninsulated distal portion; 62a Proximal insulated portion

[0184] 63 Second microelectrode probe

[0185] 64 Second electrode core, uninsulated distal portion; 64a Proximal insulated portion

[0186] 65 Third microelectrode probe

[0187] 66 Third electrode core, uninsulated distal portion; 66a Proximal insulated portion

[0188] 67 Fourth microelectrode probe

[0189] 68 Fourth electrode core, uninsulated distal portion; 68a Proximal insulated portion

[0190] 69 array substrate

[0191] 70 Array Housing

[0192] 71 First Micro-Contact Point

[0193] 72 First Flexible Conductor

[0194] 73 Second Micro-contact Point

[0195] 74 Second Flexible Conductor

[0196] 75 Third micro-contact point

[0197] 76 Third Flexible Conductor

[0198] 77 Fourth micro-contact point

[0199] 78 Fourth Flexible Conductor

[0200] 79 Second Array Substrate

[0201] 80' Array compartment, distal portion; 80' proximal portion

[0202] 81 Radial wall of the first microelectrode probe

[0203] 82 Matrix of the proximal compartment of the first microelectrode probe

[0204] 83 Radial wall of the second microelectrode probe

[0205] 84 Matrix of the proximal compartment of the second microelectrode probe

[0206] 85. Radial wall of the third microelectrode probe

[0207] 86 Matrix of the proximal compartment of the third microelectrode probe

[0208] 87 Radial wall of the fourth microelectrode probe

[0209] 88 Matrix of the proximal compartment of the fourth microelectrode probe

[0210] 89. The compartment of the fourth microelectrode probe

[0211] The variation of array 60 is the same as array 60, marked with a '.

[0212] 91. The far-end boundary of the far-end section 99 of the outer cover 99 and 99'.

[0213] 92 Outer casing of the proximal compartment of the first microelectrode probe

[0214] 93. Adhesive fixation of the proximal outer casing of the first and fourth microelectrode probes

[0215] 93', 93”, 93”' probes 1, 2; 2, 3; 3, 4 outer covers fixed with glue;

[0216] 94 Outer casing of the proximal compartment of the second microelectrode probe

[0217] 95 -

[0218] 96. Outer casing of the proximal compartment of the third microelectrode probe

[0219] Glue spots on the wall at 97, 98, and 99

[0220] 98. Outer casing of the proximal compartment of the fourth microelectrode probe

[0221] Shorten the distal wall portion of the conical outer cannula;

[0222] 99' Proximal wall portion

[0223] 83a Circular distal tip

Claims

1. A microelectrode probe for implantation by insertion into soft tissue, comprising a conductive core including a portion located at the center of a sleeve or cannula of a flexible polymer material and connected to the sleeve or cannula by a separation wall of the flexible polymer material extending radially or at an angle relative to a rotation axis and dividing the sleeve or cannula into a distal compartment and a proximal compartment, the conductive core passing through the separation wall and being secured thereto; in, The distal compartment is filled with a matrix of a first biocompatible material, the first biocompatible material being selected from one or more carbohydrate materials and protein materials, and any of the first biocompatible materials being soluble or degradable in aqueous body fluids; The proximal compartment is filled with a matrix of a second biocompatible material, the second biocompatible material being selected from one or more of carbohydrate materials and protein materials, and any of the second biocompatible materials being soluble or degradable in aqueous body fluids. The conductive core portion located in the proximal compartment extends toward the proximal end of the proximal compartment; The distal opening of the distal compartment is covered by a covering that narrows in the distal direction, the covering being made of a flexible polymer material. The sleeve or cannula has at least one distal opening and at least one proximal opening; and Wherein, when dried, the matrix is ​​a rigid material, and, The flexible polymer material described herein is resistant to degradation by aqueous bodily fluids.

2. The microelectrode probe of claim 1, wherein the covering is located on or attached to a matrix of a third biocompatible material.

3. The microelectrode probe of claim 1 or 2, wherein the conductive core portion extending to the proximal end of the proximal compartment includes a conductive core retainer capable of being fixed in a tissue different from the tissue in which the probe is implanted.

4. The microelectrode probe of claim 3, wherein the conductive core holder is directly or indirectly connected to the second biocompatible material.

5. The microelectrode probe as described in claim 4, wherein, The length of the conductive core portion located between the proximal end of the proximal compartment and the conductive core holder is 10% greater than the shortest distance between the proximal end of the proximal compartment and the conductive core holder.

6. The microelectrode probe as described in claim 5, wherein, The conductive core portion located between the near end of the proximal compartment and the conductive core holder includes a spiral or serrated section.

7. The microelectrode probe as described in claim 5, wherein, The conductive core portion located between the proximal end of the proximal compartment and the conductive core holder includes a tortuous section.

8. The microelectrode probe of claim 1, wherein the microelectrode probe is encapsulated in a fourth matrix composed of a fourth biocompatible material selected from carbohydrate materials and protein materials, and wherein the fourth biocompatible material is soluble or degradable in aqueous body fluids.

9. The microelectrode probe of claim 3, wherein the conductive core retainer is composed of or contains a rigid material, the conductive core retainer further includes a distal end face and a proximal end face, and wherein the proximal end portion of the conductive core portion extends to the proximal side of the proximal compartment, penetrating the conductive core retainer from the distal end face to the proximal end face.

10. The microelectrode probe of claim 1, wherein the proximal compartment widens in a linear or nonlinear manner in the proximal direction.

11. The microelectrode probe of claim 10, wherein the proximal compartment is a truncated cone.

12. The microelectrode probe of claim 11, wherein the proximal portion of the wall of the proximal compartment is curved.

13. The microelectrode probe of claim 1, wherein the conductive core comprises metal wires, each metal wire having a thickness of 10 nm to 100 µm.

14. The microelectrode probe of claim 3, wherein the material of the conductive core portion extending to the proximal end of the proximal compartment and outside the proximal compartment is different from the material of the conductive core portions located in the proximal compartment and the distal compartment.

15. The microelectrode probe of claim 1, wherein the distal compartment wall comprises three layers of flexible polymer material, and the proximal compartment wall comprises two layers of flexible polymer material.

16. The microelectrode probe of claim 15, wherein the innermost layer of the distal compartment, the radially extending separation wall, and the insulating layer on the conductive core are integral.

17. The microelectrode probe of claim 1, wherein, The covering and the flexible polymer material layer included in the sleeve or tube, as well as its proximal extension, are integral.

18. The microelectrode probe of claim 1, wherein at least one bioactive substance is filled in the distal compartment.

19. The microelectrode probe of claim 1, wherein one or more materials of the conductive core portion extending to the proximal end of the proximal compartment and outside the proximal compartment are the same as or different from one or more materials of the conductive core portions located in the proximal compartment and the distal compartment.

20. A microelectrode probe device for incorporating a microelectrode probe array, the probe device comprising a conductive core located in a rotationally symmetric sleeve or tube of a flexible polymer material and connected to the sleeve or tube by a separation wall of the flexible polymer material, the separation wall extending perpendicularly or at an angle relative to a rotation axis and dividing the sleeve or tube into a distal compartment and a proximal compartment, the sleeve or tube including a proximal opening and a distal opening, the conductive core passing through the separation wall; in, The proximal compartment is filled with a rigid second matrix, which includes one or more biocompatible carbohydrate materials and biocompatible protein materials. The distal compartment is filled with a rigid first matrix, which includes one or more biocompatible carbohydrate materials and biocompatible protein materials. The conductive core portion located in the proximal compartment extends towards the proximal end of the proximal compartment. The distal compartment includes one or more openings; The biocompatible carbohydrate and protein materials of the first and second matrices are soluble or degradable in aqueous body fluids. The flexible polymer material described herein is resistant to degradation by aqueous bodily fluids.

21. The microelectrode probe device of claim 20, wherein the distal opening of the distal compartment is covered by a cover that narrows in the distal direction, wherein the cover is made of a flexible polymer material, wherein the cover that narrows in the distal direction or the sidewall of the distal compartment includes an opening, or the cover that narrows in the distal direction and the sidewall of the distal compartment both include an opening.

22. The microelectrode probe device of claim 21, wherein the distal compartment wall comprises three layers of flexible polymer material, and the proximal compartment wall comprises two layers of flexible polymer material.

23. The microelectrode probe device of claim 20, wherein the conductive core portion located between the proximal end of the proximal compartment and the conductive core holder comprises a helical or serrated section.

24. The microelectrode probe of claim 20, wherein, The conductive core portion located between the proximal end of the proximal compartment and the conductive core holder includes a tortuous section.

25. The microelectrode probe device of claim 20, wherein the sheath or sleeve portion forming the distal portion comprises multiple layers, wherein the innermost layer is integral with a separation wall extending perpendicularly or at an angle relative to the axis of rotation, and is integral with an insulating layer on the conductive core.

26. The microelectrode probe device of claim 20, wherein the conductive core comprises metal wires, each metal wire having a thickness of 10 nm to 100 µm.

27. The microelectrode probe device of claim 20, wherein the distal compartment contains at least one bioactive substance.

28. A microelectrode probe array comprising a plurality of microelectrode probe devices of any one of claims 20-27 arranged substantially in parallel, the distal ends of the microelectrode probe devices being located in a plane extending perpendicularly to their axes, and further comprising an array cover comprising or being composed of a rigid material; in, The proximal end portion of the conductive core, extending proximal to the proximal end of the proximal compartment, is attached to the array cover. The proximal end segment of the conductive core passes through the array cover and extends from the proximal end face of the array cover. It is encapsulated together with the microelectrode probe device constituting the array in a rotationally symmetric rigid array matrix, which is a biocompatible material that is soluble or biodegradable in aqueous body fluids and is selected from one or more carbohydrate materials and protein materials.

29. The array of claim 28, wherein the array matrix extends to and is attached to the distal surface of the array cover.

30. The array of claim 28, wherein the diameter of the array matrix increases in the proximal direction starting from the axial plane of the transverse proximal compartment.

31. The array of claim 28, further comprising an outer cover made of a flexible polymer material outside the edge of the array cover or in an annular region near the array cover, which covers and is attached to the array matrix with a gradually increasing diameter.

32. The array of claim 31, wherein the outer casing is adhesively attached to the proximal compartment wall of the microelectrode probe device.

33. The array of claim 31, wherein a plurality of microelectrode probe devices are adhesively attached to each other at their sheath or sleeve wall.

34. The array of claim 28, further comprising a rigid array housing that encapsulates all components of the array and is disposed at the distal end of the array cover; wherein, The array housing comprises one or more biocompatible carbohydrate materials and biocompatible protein materials.

35. The array of claim 28, wherein the array housing comprises gelatin.

36. A method for manufacturing a microelectrode probe as described in any one of claims 1 to 19, comprising: Provide a conductive wire of metal or polymer material fixed on opposite sides of a frame, the wire comprising a proximal and distal straight section and an intermediate section extending between the straight sections; A first rigid matrix is ​​formed on a portion of the remote section of the line; The first rigid matrix and the line portion not covered by the first rigid matrix are covered by a first layer of flexible polymer material; The first layer is covered on a portion of the line with a material capable of forming a rigid second matrix, the portion of which extends from the first rigid matrix toward the proximal end; The first and second substrates are covered with a second layer of flexible polymer material; Cut the metal wire, the first layer, the second layer, and the first rigid matrix near the distal end of the first rigid matrix; A material capable of forming a third matrix is ​​deposited on the distal surface of the first rigid matrix produced by cutting; The third matrix and the second layer are covered with a third layer of flexible polymer material; Remove the second and third layers of the circumferential annular region of the second matrix, the second matrix covering the line portion extending from the first rigid matrix in a proximal direction and including the middle line portion; An opening is formed by removing a portion of the first, second, and third layers, and an opening is formed in the third layer that encloses the distal opening of the distal compartment; The matrix material is selected from carbohydrate materials and protein materials, wherein the material is biocompatible and soluble in aqueous body fluids, and can form a rigid matrix when dry, and wherein the flexible polymer material can resist degradation by aqueous body fluids.

37. The method of claim 36, wherein the amount of the second matrix applied to a given portion of the first layer of flexible polymer material increases in the proximal direction.

38. The method of claim 36 or 37, wherein all flexible polymer material layers are made of the same material.

39. A method for manufacturing an array of microelectrode probe devices as described in any one of claims 20-27, comprising: The probes are placed in a basically parallel position; The probe covers are connected to each other using adhesive. The probe is encapsulated in a rigid first array matrix with proximal and distal ends; A layer of flexible polymer material is used to cover the proximal portion of the array matrix extending from the proximal end of the array matrix. This flexible polymer material is resistant to degradation by aqueous body fluids. Remove the annular region of the flexible polymer material layer between its proximal and distal ends; A second rigid array matrix covers a flexible polymer material layer and an annular region; wherein the first and second array matrices are independently selected from one or more biocompatible materials selected from carbohydrate materials and protein materials, and wherein the matrix materials are soluble or degradable in aqueous body fluids.

40. The method of claim 39, wherein the distal end of the probe lies in a plane.

41. The method of claim 39 or 40, further comprising providing an array with a cover having a distal face and a proximal face, wherein the array matrix is ​​in close proximity to the distal face of the cover.

42. The method of claim 41, wherein the proximal ends of the cover and the second array matrix are cylindrical and centered on a common axis of rotation, and the diameter of the cover is greater than the diameter of the cylindrical portion of the second array matrix.

43. The method of claim 39, further comprising forming a distal end portion of the second array matrix in a gradually tapering manner.

44. The method of claim 42, wherein the probe is arranged parallel to the array axis or its probe axis is arranged at an angle of less than 10° and greater than 0° relative to the array axis.

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