TW201713381A - Method of implantation of a medical device into neural tissue - Google Patents

Abstract

A method of providing a channel in nervous tissue filled with an aqueous gel for implantation of a microelectrode or other medical device lacking sufficient physical stability for direct implantation by insertion, comprises providing an apparatus comprising an oblong rigid pin covered by a dry gel forming agent; locating a target in the tissue; defining a straight insertion path a desired tissue insertion point and the target; aligning the pin with its end foremost with the insertion path; inserting the pin into the tissue to a position near or at the target; allowing sufficient time to pass for a gel to be formed around the pin, withdrawing the pin. Also disclosed is a corresponding channel; a method of implantation of a microelectrode or microprobe into nervous tissue via the channel; a corresponding method of implantation of living cells; a corresponding apparatus for forming the channel.

Description

Method of transplanting medical equipment into nerve tissue

The present invention relates to a method of transplanting a medical device or other object, such as a living cell, into a soft tissue (especially a nerve tissue) of a human or animal. Furthermore, the invention relates to a corresponding device, a method of providing the same, and an apparatus for use in the provision. The medical device or other object to which the present invention relates is not sufficiently physically stable when inserted into the tissue by insertion. In particular, the medical device of the invention is a microelectrode or microprobe such as an electrical or optical sensor.

Devices implanted into soft tissue include microelectrodes. Microelectrodes have a wide range of applications in medicine and related fields. In principle, electrical signals emitted by a single nerve cell or group of cells can be recorded. Single nerve cells or groups of cells can also be electrically stimulated with the device and monitored for response to the stimulus. This allows the user to select the nucleus that stimulates the therapeutic effect. Selective stimulation is expected to produce stronger results than non-selective stimuli. Stimulation of the brain or spinal cord is particularly valuable in the case of brain cell nuclear degradation or damage. Monitoring brain activity by a transplant device can be used to control local or systemic delivery of drugs or to control electrical stimulation of brain cell nuclei. In the present invention, the microelectrode is a flexible electrode including an elliptical electrode body, the conductor The diameter is in the sub-millimeter range, specifically 1 μm - 100 μm, which is not hard enough for precise insertion into the nerve tissue and tends to deviate from the desired path during insertion. This problem is solved in the present invention by encapsulating with a hard matrix instead of or at least a portion extending from the distal end or the apex to the proximal end, the matrix being dissolved in or at a rate substantially lower than the rate of insertion. degradation. Devices for insufficient physical stability for implantation into soft tissue also include various sensors such as glucose sensors (which can be used to control insulin administration), and fiber-optic radiation sensors.

The higher local concentration of matrix fragments caused by dissolution or degradation becomes a problem. It temporarily alters the natural environment of the target nerve cell or group of nerve cells and thus affects its behavior until the matrix solute is transported out of the insertion site. It takes time to remove the matrix solutes from the insertion site by convection or diffusion. Prior to removal of all or nearly all of the solute, the electrodes are unusable or can only be used to monitor nerve cells or groups of nerve cells under the influence of the solute. Single electrodes and electrode groups comprising a micro-elliptical metal electrode body encapsulated with a biosoluble or biodegradable matrix are disclosed, for example, in WO 2009/075625 A1.

Another problem is that in order to be sufficiently rigid to insert tissue, the matrix needs to be substantially larger in the radial direction than the electrode body. This requirement may result in a combination of radially upper electrode bodies/matrix, causing significant damage to the tissue inserted into the combination.

Another problem is that due to the different functional management and anatomy (especially brain tissue) of the tissue between the objects, the optimal position of the microelectrodes in the tissue may require repeated insertion and evaluation of the corresponding locations. Substrate-covered microelectrodes in the art do not readily accommodate repeated insertions because some matrix material is lost each time it is inserted, and the worst is that it loses a large amount of matrix material before the desired location of the tissue is obtained and the rigidity is compromised. This may be accompanied by a loss of matrix incorporation Pharmaceutical or biological materials that may have a negative impact on the tissue of interest.

A further problem or limitation of matrix-covered microelectrodes is that their rate of insertion into soft tissue is limited: in order to avoid excessive tissue damage, the microelectrodes must be inserted very slowly. The slower the insertion, the higher the risk that the matrix material and, if present, the pharmaceutically or other agent incorporated into the matrix will be lost in the insertion path and will not reach the desired location for release. This problem is especially noticeable when using probes containing frozen biological materials.

Another problem with the insertion of micro-electrodes covered by a matrix in the field is the bleeding of the wound caused by the microelectrode. This can cause localized clotting of blood to adhere to the surface of the substrate, significantly delaying its dissolution or degradation, and thus delaying the use of the microelectrode for its intended use.

Another important issue is neurological tissue stimulation caused by transplantation such as microelectrodes leading to neuronal loss and astrocyte proliferation (Lind G et al, J Scientific Reports 3 (2013); Article number 2942 DOI: doi: 10.1038/srep02942).

G Lind et al, J Neural Eng 7 (2010) 046005 (doi: 10.1088/1741-2560/7/4/046005) discloses the implantation of gelatin-embedded electrodes into brain tissue. Gelatin-coated metal microelectrodes or microelectrode bundles implanted in the brain show long-term functional improvement with a reduction in acute tissue response.

It is a primary object of the present invention to provide a method of the foregoing type that addresses one or more problems associated with the insertion of known microelectrodes and other objects into neural tissue. Neural tissue includes brain and spinal cord tissue as well as peripheral nerves, dorsal root ganglia, and Retinal tissue.

Other objects of the invention are to prevent or reduce or stop bleeding along the insertion path for medical devices or other objects in nerve tissue; to protect adjacent nerve cells from the negative effects of the transplant; to preserve the transplanted microelectrodes and other objects. The ability to correct position; another object of the invention is to provide an apparatus for the method; another object of the invention is to provide a method of producing the apparatus.

Other objects of the present invention will be apparent from the following description of the preferred embodiments of the invention.

The present invention is based on the discovery that a channel filled with a biocompatible aqueous gel (e.g., an aqueous gelatin gel) in a nerve cell can insert a medical device or other object into the implant of the neural tissue, the medical device or other object. Physical stability is insufficient for direct insertion into nerve tissue. Neural tissue includes brain and spinal cord tissue.

The passage of the present invention is preferably rotationally symmetrical, more preferably cylindrical and has a corresponding longitudinally extending central axis. The passage of the present invention is preferably straight or substantially straight, i.e., linear or substantially linear. The substantially linear/straight line indicates that when one end thereof is placed on the central axis, the straight line passing through the other end forms an angle with the central axis of not more than 10°, preferably not more than 5°. The length of the channel of the present invention is substantially greater than its width, specifically 5 or 10 or 20 or greater. The side and bottom surfaces (front) of the channel are formed by living tissue. For this or other reasons, the geometry of the channel can change over time. In particular, the diameter of the channel can shrink over time.

Biocompatible gel prevents radial shrinkage in the channel and is therefore stable The geometry of the channel, at least for a period of time when the gel is substantially unchanged (ie, degraded by enzymes or otherwise weakened). The use of a crosslinked gel extends the time of the substantially stable geometry, which can be adjusted by the degree of crosslinking.

Microstructures, such as thin filaments or electrodes or fibers, can be inserted (especially slowly inserted) into the biocompatible gel without substantially affecting their geometry. Slow insertion is a rate as fast as 5 mm/sec, specifically 1 or 2 mm/sec. This is in sharp contrast to the resistance of the soft tissue (especially nerve tissue) to the insertion. In general, the resistance of the aqueous gel of the present invention is 10 times or more lower than that of nerve tissue (especially meninges and other fibrous membrane layers), especially 25 times or more lower. The measure of resistance to penetration is the time required for a given size of elliptical needle to penetrate a defined depth under the influence of a constant force applied to the needle in an axially distal direction.

Biocompatible gels are translucent and are particularly advantageous in the use of visible and near-infrared radiation emitted by optical fibers disposed on channels.

The invention is also based on the discovery that the insertion of matrix stabilized microelectrodes or probes in the art can be improved by the method of the invention. Providing a channel of the type described above reduces (or even substantially reduces) the amount of matrix material that can be dissolved or degraded by body fluids required to maintain stability during insertion into soft tissue.

The aqueous gel of the present invention is formed in situ by contact with a gel forming agent and an aqueous medium, particularly an aqueous body fluid. For forming the channels of the present invention, the gel former is preferably used in a dry state, for example, in a state containing less than 20% by weight of water, especially less than 10% by weight or 5% by weight of water.

A preferred aspect of the invention is based on the discovery that the formation of an aqueous biocompatible gel (especially an aqueous gelatin gel) in the channel can have neuroprotective effects Including, it reduces the response of microglia to medical devices implanted in nerve tissue.

According to the present invention, gelatin from various animal sources can be used as a gel forming agent such as bovine, pig skin, poultry skin and tuna gelatin. Gelatin of mammalian origin is preferred because of its excellent gelling ability at body temperature. In order to form a long-term stable channel, it is preferred to use chemically cross-linked gelatin because of its slow degradation rate in vivo. Examples of effective gelatin crosslinkers are bis(vinylsulfonyl)methane and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide. Other useful crosslinking methods are UV irradiation. The rate of degradation in vivo can be controlled by the degree of crosslinking, which in turn can be controlled by the amount of crosslinker used or by exposure to UV radiation used to crosslink a given amount of gelatin.

Other aqueous biocompatible gels of the invention include sugar gels. Useful sugar gels herein include arabinogalactan gel, arabinoxylan gel, galactan gel, galactomannan gel, lichen polysaccharide gel, xylan gel, and fiber. a derivative such as hydroxymethylpropylcellulose, and the sugar gel is formed by contacting an aqueous medium (especially an aqueous body fluid) with a gel forming agent selected from the group consisting of arabinogalactan, arabinoxylan, Galacto, galactomannan, lichenin, xylan, hydroxymethylpropylcellulose, and other cellulose derivatives that form a gel upon contact with an aqueous medium.

Other aqueous biocompatible gels of the invention include protein gels. The protein gel of animal origin other than gelatin used in the present invention includes whey protein gel, soy protein gel, casein gel, which is selected from whey protein, soybean by an aqueous medium (especially aqueous body fluid). The protein, casein gel forming agent is contacted to form.

Other aqueous gels as used herein may be formed by contacting an aqueous medium (especially an aqueous body fluid) with a gel forming agent selected from the group consisting of arabinogalactan; arabinoxylan; galactan; galactomannan Glycan; lichen; xylan; cellulose derivative such as hydroxymethylpropylcellulose; whey protein; soy protein; casein; hyaluronic acid; chitosan; gum arabic; Sodium polyacrylate; carboxymethyl cellulose; sodium carboxymethyl cellulose; amylopectin; polyvinylpyrrolidone; karaya gum; pectin; xanthan gum; xanthan gum; alginic acid; polyoxymethylene; Amine; polyether; chitin; polyglycolic acid; polylactic acid; copolymer of polyglycolic acid and polylactic acid; copolymer of polylactic acid and polyethylene oxide; polyamine; polyanhydride; polycaprolactone; Maleic anhydride copolymer; polyhydroxybutyrate copolymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); polymer formed by copolymerization with sebacic acid or polyterephthalic acid Poly(glycolide-co-methylene carbonate copolymer; polyethylene glycol; polydio Ketone; polypropylene fumarate; poly(glutamic acid ethyl ester-co-glutamic acid); poly(glutamic acid tert-butoxycarbonylmethyl ester); polycaprolactone; poly(caprolactone- Co-butyl acrylate); polyhydroxybutyrate and copolymers thereof; poly(phosphazene); poly(D,L-lactide-co-caprolactone); poly(glycolide-co-caprolactone) Ester); poly(phosphate); poly(amino acid); poly(hydroxybutyrate); polydepsipeptide; maleic anhydride copolymer; polyphosphazene; polyimino carbonate; poly[(7.5% Methyl-trimethylene carbonate)-co-(2.5% trimethylene carbonate); polyethylene oxide; hydroxypropyl methylcellulose, poly(ethylene-co-vinyl acetate); Isobutylene-based copolymer of isobutylene and at least one other repeating unit (for example, butyl acrylate: butyl methacrylate); substituted styrene such as aminostyrene, hydroxystyrene, carboxystyrene, sulfonic acid styrene; polyethylene Homopolymer of base alcohol; polyvinyl alcohol and at least one other a copolymer of repeating units such as vinylcyclohexyl ether; hydroxymethyl methacrylate; hydroxy- or amino-terminated polyethylene glycol; acrylate-based copolymers such as methacrylic acid, methacrylamide, Methyl methacrylate; ethylene vinyl alcohol copolymer; an oxime-based copolymer of an alkyl or aryl siloxane and at least one repeating unit; polyurethane; acesulfate heparin; RGD peptide; polyethylene oxide; Chondroitin; YIGSR peptide; keratan sulfate; VEGF biomimetic peptide; peripherin (heparin sulfate proteoglycan 2); laminin α-1 chain peptide containing Ile-Lys-Val-Ala-Val (IKVAV); Heparin; a fibrin fragment.

The present invention also discloses an apparatus for forming a linear channel in a neural tissue for transplantation of a medical device or other object that is insufficiently physically stable for direct insertion into a nerve tissue. The device for forming a channel comprises an elliptical rigid needle having a front end and a rear end and a layer comprising the dry gel forming agent of the present invention or a layer consisting of a dry gel forming agent or consisting of the rigid needle and the layer The glue forming agent is located on a portion of the needle that extends in the distal direction from the front end and encloses the portion. In the present invention, a gel forming agent refers to a dry reagent which forms a gel by contacting an aqueous fluid such as an aqueous body fluid. The layer of the gel former has a water content of less than 20% by weight, preferably less than 10% by weight, most preferably less than 5% by weight or 2% by weight. A particularly preferred gel former is gelatin.

The needle is preferably rotationally symmetrical, in particular cylindrical, and comprises a central shaft. A "cylinder" includes a cylinder having an elliptical or similarly elliptical bottom surface. Preferably, the length of the layer of gel former corresponds at least to the depth of the channel formed in the tissue. Preferably, the length of the needle is greater than the length of the channel, for example 10% or 30% or more. The needle is made of a rigid material, in particular a material that is as rigid as possible, so that the radial dimension of the device is as small as possible to minimize its insertion into the tissue. Damage. Specific suitable materials include steel, titanium, tungsten, tantalum and niobium. Another particularly suitable material is an acrylate or epoxy polymer, preferably reinforced with fibers, particularly carbon fibers.

In accordance with a preferred aspect of the invention, the channel forming apparatus includes a fluid passageway in the needle that is disposed in the form of an axially disposed passageway that is communicable at a rear portion thereof and that does not cover the gel forming agent. The passage or passage extends from the rear end of the needle toward the front end and forms an opening near the front or front side thereof.

In accordance with a preferred embodiment of the present invention, the axially disposed passageway includes one or more radially extending passages that open in the cylindrical face of the needle but do not extend through the layer of gel former disposed thereon. According to a preferred refinement, the side opening of the radial passage can be plugged by a body fluid soluble material. According to another preferred refinement, the distal end of the axially extending channel can be embolized or permanently embolized in the same manner. An axial and/or radially extending passage is provided that allows injection of an aqueous fluid to affect the structure of the gel formed around the needle. Providing the channel also allows for the injection of an aqueous fluid containing a pharmaceutically active agent, or the continued injection of a fluid containing a different pharmaceutically active agent. It also allows for the injection of low viscosity aqueous gels which may include pharmaceutically active agents or other agents such as nutrients such as glucose.

Alternatively or additionally, the pharmaceutically active agent can be incorporated into a layer comprising or consisting of a gel forming agent. Preferred pharmaceutically active agents include coagulants, anticoagulants, antibiotics, osmotic pressure regulators, anti-inflammatory agents, nutrients, factors that stimulate growth, factors that stimulate cell differentiation, and hormones. Providing this channel (especially an axial channel) also allows for the injection of living cells.

According to another preferred aspect of the invention, the apparatus comprises an electrode device and/or a fiber optic device, either added to the axially disposed channel or independently present . The electrode device and/or fiber optic device allows for monitoring electrical activity and providing visual control during insertion and gel formation.

According to another preferred aspect of the invention, the layer comprising or consisting of a dry gel former can be covered by a layer of material that is reduced in tissue friction during transplantation. Providing the reduced friction layer (reducing friction layer) avoids or reduces damage caused by the transplant procedure. It also reduces the risk of bringing cells of the superficial tissue, such as meningeal fibroblasts, into the deep tissue during transplantation. Suitable friction reducing coating materials include polyvinyl alcohol, chitin, hyaluronic acid, and the agents disclosed in US 2008234790 A1, which is incorporated herein by reference.

The aqueous biocompatible gel in the neural tissue passage of the present invention may consist of more than one layer, especially two or three layers. The layer can be oriented radially and/or axially relative to the channel. The physical properties of the layered gel may vary, especially its swelling characteristics and/or its biodegradable properties and/or its pharmaceutically active agent content may vary.

According to a preferred embodiment of the invention, the gel comprises a radially disposed outer layer and an inner layer which is physically more stable than the inner layer, for example by cross-linking the uncrosslinked inner layer.

According to another preferred embodiment, an axially disposed physically stable outer gel layer (e.g., a crosslinked layer) surrounds the low viscosity gel inner layer or aqueous liquid layer. The aqueous gel layer can be formed by inserting a needle into a neural tissue that is covered by two or more layers placed on top of another layer, either radially or axially adjacent or both. .

The drug device or other object implanted into the nerve tissue by a channel filled with the gel of the invention (especially gelatin) as described herein is not reduced or at least This does not reduce the density of neurons in the adjacent nerve tissue of the graft.

According to the present invention, the passage of a drug device or other object filled with a gel (especially gelatin) filled with the gel of the present invention into the nerve tissue reduces bleeding of the channel wall.

According to the present invention, there is provided a method of providing an elliptical linear channel in a neural tissue of a human or mammal for implanting a medical device or other object into the tissue by insertion into the channel, the device being transplanted by direct insertion Insufficient physical stability when entering the tissue, the method comprising: providing a channel forming device comprising a rotationally symmetric, in particular cylindrical, rigid needle having a length that exceeds the usual length to be provided and having a front end and a rear An end portion of the needle extending from a front end thereof to a rear end thereof is encapsulated with a gel forming agent or a gel forming agent, the length of the extension corresponding at least to the length of the channel, wherein the gel forming agent is capable of being aqueous A dry reagent for forming an aqueous gel upon contact with a body fluid, encapsulated with a gel former or comprising a gel former comprising less than 20% by weight water, preferably less than 10% by weight water, especially less than 5% by weight or 2% by weight of water; inserting the needle with its front end forward into the nerve tissue; forming an aqueous gel around the needle by contact of the gel forming agent with the aqueous fluid; withdrawing the needle from the gel; Wherein the needle is sufficiently rigid to be inserted into the nerve tissue without a layer comprising a gel former or a gel former.

The cylindrical wall of the needle provided within the scope of the present invention has two or more layers of gel formers having different structures and characteristics, such as different biostability or different gel strengths formed. . The two or more layers may be placed on top of one another and/or adjacent each other in an axial direction. The gel formed in the channel of the present invention will reflect the layer of the gel forming agent on the needle or have a gel-like shape The location of the layer of the agent. For example, a first layer covering a portion of the cylindrical wall of the needle (and subsequently covered a second time) forms a centrally disposed cylindrical gel portion that is formed by the tubular gel portion when the needle is inserted into the nerve tissue to contact the body fluid surround.

In the present application, "other objects" include living cells and cell clusters, especially living cells and cell clusters in chilled aqueous suspensions.

According to a preferred aspect of the invention, a method of the aforementioned type is disclosed, comprising identifying a position of a target in a neural tissue relative to a front end of a channel to be provided in the tissue, the method comprising: i) providing an ellipse having a front end and a rear end A channel forming device for a rigid needle, the portion of the needle that is axially extending from the front end is covered by a gel forming agent; ii) provides contact with the tissue; iii) positions the spatial location of the target in the tissue; Iv) optionally locating a spatial location near the target; v) locating the spatial location of the insertion point on the contact surface of the tissue with respect to the device; vi) placing the front end of the needle on the insertion point while The direction of the needle corresponds to an insertion path defined by a line connecting the insertion point and the target or a spatial location proximate to the target; vii) inserting the front end of the needle into the tissue along the insertion path to the target or spatial position definition Depth; viii) for a sufficient time to allow gel formation around the needle; ix) optionally obtained by imaging techniques or by recording neural activity Information on gel formation; x) withdrawal of the needle from the gel.

A preferred device for transplantation is a microelectrode having insufficient physical stability. Optionally, the microelectrode can be a microelectrode bundle or a microelectrode comprised by an array.

A particularly preferred device for transplantation is an elliptical microelectrode. For a given diameter, the risk of microelectrode bending during insertion increases significantly with its length. Preferred objects for transplantation are living cells or clusters of cells, especially in chilled aqueous suspensions.

Suitable microelectrode materials in the art are known and comprise gold, platinum, tungsten, titanium, copper, silver, aluminum, and alloys thereof. Other suitable materials for the microelectrode include i) a conductive polymer and ii) a non-conductive polymer, including a polymer forming a natural fiber, a core of such a polymer covered by a conductive metal or metal alloy such as the aforementioned metal or metal alloy. .

By "elliptical" herein is meant a microelectrode in the form of a microfilament having a anterior (distal) end and a posterior (proximal) end, the length being a multiple of its diameter, such as 5 or 10 or 50 or 200 or 500. Multiple or more. The diameter of the microelectrode used in the present invention may range from the nanometer range, for example from 100 nm or 500 nm or from 1 μm or 2 μm or 5 μm to 20 μm or 50 μm or 100 μm. A microelectrode particularly suitable for use in the present invention is a microelectrode having insufficient physical stability for transplantation into a nerve tissue by inserting it into a tissue surface which is externally accessible and surgically formed. "Insufficient physical stability" means that the microelectrode is inserted with its front end forward into the nerve tissue with the risk that its front end is bent away from the desired path of insertion. This can result in the electrode tip not being placed as desired, such as not being placed in the desired spatial relationship with other optical or radially distinguishable elements of nerve cells or nerve cell clusters or nerve tissue. . In addition, "insufficient physical stability" includes elastic microelectrodes that are compressible and/or resilient.

Other preferred devices for implantation are optical fibers that are directly inserted into the soft tissue or have insufficient rigidity, which have one or more physical properties with the microelectrodes but differ in electrical conductivity. The fiber can be covered by a layer of conductive material, in addition to its end face allowing for the entry and exit of the radiation, thereby having the function of a microelectrode.

Another preferred device for transplantation is a microprobe or microsensor that is directly inserted into the soft tissue with insufficient physical stability or rigidity.

The method of the invention, whether or not it includes identifying the position of the target in the neural tissue relative to the leading end of the channel to be provided, the method may comprise a conductive needle, which may also serve as a temporary electrode comprising a metal, a metal alloy or a conductive a polymer or other electrically conductive non-metallic material such as carbon or a composition thereof, preferably a metal selected from the group consisting of gold, silver, copper, platinum, rhodium, titanium, chromium, tungsten, aluminum, and alloys thereof, tungsten, tantalum, and stainless steel. Any preference is particularly preferred; the protein or carbohydrate or mixture thereof acts as an agent capable of forming a gel upon contact with body fluids, preferably selected from the group consisting of gelatin, hyaluronic acid and pharmaceutically acceptable salts thereof, chemically modified gelatin and transparent Acidic acid, for example by cross-linking and/or partial hydrolysis, particularly preferred natural gelatin; electrically conductive wires in conductive form associated with or near the rear end of the needle; voltage monitoring devices or power supplies associated with the wires; contact energy with aqueous body fluids The pharmaceutically active agent contained in the gel-forming reagent is preferably a self-coagulating agent, an anticoagulant, an antibiotic, an osmotic pressure adjusting agent, or an anti-inflammatory agent. According to another preferred aspect of the invention, the device is or comprises a microelectrode and/or an optical fiber, a microprobe or a microsensor, such as an insulin or glucose probe, which is capable of monitoring/sensing biological agents in the tissue, such as insulin Or the concentration of glucose.

Alternatively, the process of the invention may comprise a substantially non-conductive hard needle, especially a needle of a polymeric material such as polycarbonate, polystyrene, polyvinyl chloride and polyacrylate. The needle may consist of or be covered by a material that facilitates withdrawal after formation of the aqueous gel. Parylene-C, anthrone rubber and Teflon® are particularly useful materials for this purpose.

According to a preferred aspect of the invention, a method for transplanting living cells to neural tissue is disclosed, comprising: i) providing an aqueous suspension of living cells in a syringe or tip or other device for injecting a suspension; ii) according to the present invention A method of forming a channel in a neural tissue of a human or mammal in which a linear graft channel is formed for transplantation of a medical device into the tissue, including or not including identifying a target in the neural tissue relative to a channel to be disposed. The position of the front end, iii) the desired depth of insertion of the syringe needle into the graft channel; iv) injection of an aqueous suspension of the living cells into the graft channel; v) withdrawal of the syringe or tip; The premise is that the injection can be made before and/or during the withdrawal.

According to a preferred aspect of the invention, the syringe needle may be covered with a material which forms a gel, such as gelatin, upon contact with the aqueous body fluid, and the linear graft passage of the present invention may be formed by using the thus-covered syringe needle as a needle.

According to another preferred aspect of the invention, the transplantation of living cells is disclosed A method of neural tissue, the method comprising identifying a position of a target in a neural tissue relative to a leading end of a channel to be disposed, comprising: i) providing a chilled aqueous suspension attached to a living cell inserted into the tip of the rod; ii) according to the present invention A method of forming a channel in a neural tissue of a human or mammal forms a linear graft channel in the tissue for transplantation of a medical device into the tissue, including or not including identifying a target in the neural tissue relative to a front end of the channel to be disposed Position, iii) inserting the rod at a desired depth into the graft channel with the tip facing forward; iv) melting the cryosus suspension; v) withdrawing the rod.

According to another preferred aspect of the present invention, a linear (preferably cylindrical) passage for transplanting a medical device in a neural tissue of a human or a mammal is disclosed, the passage being filled with a contact with a body fluid and a dry gel forming agent of the present invention In the formed gel, the gel former is especially selected from the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid, and salts thereof. The chemically modified gelatin and chemically modified hyaluronic acid fractions include hydrolytically degraded gelatin and hyaluronic acid and/or crosslinked gelatin and hyaluronic acid. However, the channels may, but are not preferred, other forms of cylindrical accidents; channels of square or other radial cross-section may be provided by the use of correspondingly formed needles. The cylindrical passage may comprise a cylindrical layer of two or more aqueous gels of the same diameter as the passage or a central cylindrical layer of aqueous gel surrounded by a peripheral layer of aqueous gel.

The term "cylindrical channel" consists of a cylinder with an elliptical radial section aisle.

The invention is described in more detail below with reference to a plurality of preferred embodiments, which are illustrated by a non-proportional rough drawing. The radial dimensions are significantly enlarged. All figures are axial or radial sections.

1‧‧‧Mammal brain/brain tissue

2‧‧‧Skull

3‧‧‧Dust film

4,4'‧‧‧Target nerve cells/cell clusters/microelectrodes

5‧‧‧through hole

6‧‧‧ surface

7,8‧‧‧ points / front end

9‧‧‧Insert track

10‧‧‧Laser beam

11‧‧‧Computed tomography (CT)

12‧‧ Magnetic resonance imaging (MRI)

13‧‧‧Control unit

21‧‧‧hard cylindrical needle

21'‧‧‧Before (far)

21" ‧ ‧ after (near) end

22,82,82’,82”‧‧• gelatin layer

22’‧‧‧ near end

23,23’‧‧• gelatin/gel

23', 75, 85, 86, 86" ‧ ‧ channels

24,24’‧‧‧Contour/Transplantation Channel

30‧‧‧Microelectrode

31‧‧‧Thin metal wire/electrode body

32‧‧‧Coupling components

33‧‧‧Metal wire

40‧‧‧Lock

41‧‧‧ clamp holder

51,61,71,81,81’,81”,101‧‧ needle

51’‧‧‧ front end

55,65‧‧‧ fiber

60, 70, 80, 90, 91,91’,91”,100,100a,100b,100c‧‧‧ equipment

66‧‧‧ gold layer

67‧‧‧paint

68‧‧‧insulated wire

70”, 80”, 90’‧‧‧ proximal end

72‧‧‧Dry gelatin layer

73,83,83’‧‧‧ flexible pipe

74, 84‧‧‧ thin layer

77,87‧‧‧ distal front

78,88,88’‧‧‧lateral/transverse cylindrical

80’, 90’‧‧‧ distal

89‧‧‧Reducing friction layer

92, 93‧‧‧ adjacent layers

102‧‧‧Inner/gel forming agent

102*, 103*, 104*‧‧‧ water-based gel

103*‧‧‧Tubular gel cylinder

103‧‧‧ outer layer

104‧‧‧First/Inner

105‧‧‧Neural tissue

1a-1f show a method of providing a channel for transplanting a medical device in a neural tissue of a human or mammal and a resulting channel, the method comprising identifying a position of a target in a neural tissue relative to a leading end of a channel to be disposed Figures 1c-1f show variants of the method of the invention in which the problem of the target is not identified by irradiation; Figures 1g, 1h show the method of grafting the microelectrode of the invention into neural tissue by the method of the invention The microelectrode is inserted into the channel, and the microelectrode thus implanted is shown; FIG. 2 shows the microelectrode implanted according to the method of the present invention, the position of which is fixed to the adjacent bone tissue; FIG. 3 shows the device according to the present invention for use in the nerve Channels are formed in the tissue for insertion of microelectrodes or other devices; Figure 4 shows the microelectrodes of Figures 1g-1j; Figure 5 shows a device according to the invention for forming channels in nerve tissue for insertion of microelectrodes or Other devices, the device comprising an optical fiber; Figure 6 shows a device according to the invention for forming a channel in a neural tissue for insertion of a microelectrode or Apparatus, the apparatus comprising an optical fiber and an electrode; Figures 7 and 7a show an apparatus according to the invention for forming a channel in a neural tissue for insertion into a microelectrode or other section along the axial direction A*-A* (Fig. 7; Fig. 7a shows the enlarged portion) a device comprising, in addition to a dry gelatin coated cylindrical needle and a fiber optic transfer electrode device, an axially extending passage in the needle for injecting fluid from a passage opening at a distal end face of the device The material is in the channel; Figures 8, 8a, 8b and 8c show a device according to the invention for forming a channel in the nerve tissue for axial A**-A** (Figure 8; Figure 8a shows The enlarged portion of the section) and the radial BB (Fig. 8b, 8c, further enlarged) section are inserted into the microelectrode or other device, the device including the dry gelatin coated cylindrical needle and the fiber optic transfer electrode device An axially extending passage in the needle for injecting fluid material into the passage from a passage opening at a distal end face of the apparatus, the apparatus further including a passage extending radially from the axially extending passage, The radially extending path of the variant of the device is shown in the stem of the plug Figure 8, 9a, 9b, 9c shows an apparatus according to the invention, corresponding to Figures 8, 8a, 8b and 8c, wherein a layer of friction reducing agent is provided on the gelatin layer; Figure 10 shows Figure 9 In a variant of the device, in the same part, the gelatin layer is covered by a first friction reducing layer (extending from the distal end of the needle in a proximal direction) and a second layer containing an anticoagulant (from the friction reducing layer) The proximal end is covered in a proximal direction; Figures 11, 11a, 11b, 11c show four embodiments of a cylindrical needle of the present invention, the needle being covered with a layer of one or more dry gel forming agents, Gel former for use in axial (channel axis) cross-sections in nerve tissue a corresponding cylindrical channel filled with an aqueous gel; Figures 12, 12a, 12b, 12c show four embodiments of a cylindrical channel filled with one or more layers of aqueous gel in the neural tissue of the present invention, respectively, by Figure 11, The needles implanted in the axial (channel axis) section shown in 11a, 11b, and 11c are produced.

Example 1. Determining the position of the target, the front (bottom) end of the channel, the rear (top or open) end of the channel, and providing guidance for inserting the channel forming device

Figure 1 is a cross-sectional representation of a mammalian brain 1 with adjacent portions of the skull 2 and the dura mater 3. A through hole 5 is provided in the skull 2, and the surface 6 of the brain tissue 1 can be released through the hole after the portion of the dura mater 3 is removed. A large number of nerve cells or cell clusters containing 100 or more cells 4 are shown in brain tissue 1. One of them 4' was identified as a target for possible nerve cells using a microelectrode. The position of the target nerve cell/cell cluster 4' is by using a combination of two image systems (such as computed tomography (CT) 11 and magnetic resonance imaging (MRI) 12) that are electrically connected to and controlled by the control unit 13. determine. Based on the position information, the microprocessor of the control unit 13 determines the insertion trajectory 9 of the channel forming device (20, Fig. 3) which is observed by the laser beam 10 controlled by the control unit 13. The control unit 13 also determines a point 7 on the path near the 4' cluster of target nerve cells, which corresponds to the distal end of the channel (23', Fig. 2) to be formed, defining the insertion depth of the channel forming device (20, Fig. 3). A point 8 on the insertion path 9 is also determined, at which the laser beam hits the free surface 6 of the brain tissue 4. Point 8 represents the point at which the channel forming device (20, Fig. 3) is inserted into the brain tissue 1.

Embodiment 2. First Embodiment of Channel Forming Apparatus of the Present Invention and Production Thereof

The channel forming apparatus 20 of the present invention is shown in Fig. 3 in an axial A-A section. The channel forming device 20 comprises a hard cylindrical needle 21 of rigid material and a gelatin layer 22 on a portion of the needle 21 that extends from its front (distal) end 21' to its rear (proximal) end 21". Gelatin Layer 22 can be replaced by a corresponding layer of other agent that can form a gel, such as hyaluronic acid or PEG or a combination of such agents, in contact with the body. The axial extension of layer 22 corresponds at least to the depth of the channel to be formed. The diameter of the needle 21 is smaller than the diameter of the channel to be formed and should be as small as possible. The thickness of the needle upper layer 22 is determined by the desired width of the channel to be formed. The needle 21 should taper towards its distal end, for example through the end. A sharp or rounded tip is formed, especially a conical rounded tip. The material of the needle 21 is not critical but should provide good adhesion to the layer 22 of gelatin or other agent that forms a gel upon contact with the aqueous body fluid. On the other hand, the material of the needle or the material covering the surface of the needle should be easy to release the formed aqueous gel after the dry gel forming agent contacts the aqueous body fluid, that is, should provide good for the formed aqueous gel. Adhesion. Use of polyfluorinated sulfonic acid For example, Teflon® covered needles 21 form acceptable damage. Other useful materials include various types of beryllium copper. Useful needle 21 materials include steel, aluminum, polycarbonate, polyether, glass, ceramic, and titanium, gold. , platinum and alloys thereof. They may be covered, for example, by a thin layer of polyfluorinated material or anthrone, or the surface thereof may be decylated.

The channel forming device 20 can be produced by, for example, providing an aqueous solution of gelatin and a needle 21 of stainless steel. The viscosity of the gelatin solution is controlled by temperature and concentration, making it significantly viscous but not gelled. Needle 21 is immersed in gelatin solution, then withdrawn, level set and rotated. Drying of the gelatin solution on needle 21 can be accelerated by heating and/or vacuum.

The immersion step is repeated until a desired thickness of gelatin layer 22 is formed on the needle 21. To avoid dissolution of dry gelatin, needle 21 is quickly withdrawn from the gelatin solution.

In another method of producing a channel forming apparatus, gelatin or other agent capable of forming a gel in contact with water is applied to the needle 21 by spraying with a corresponding aqueous solution.

In another method of producing a channel forming apparatus, a channel forming apparatus is produced using a mold of a desired shape. In a preferred embodiment, two sheets of acrylic material (Plexiglass®, each containing a semi-cylindrical molded portion of the same size, forming a cylindrical mold) are mounted adjacent to each other with their axes aligned around the cylindrical needle of the present invention. The shaft of the needle is centered in the mold. The sheets are held in adjacent positions by a plurality of screws disposed around the periphery of the mold. The radial dimension of the mold is slightly larger than the radial dimension of the needle. A channel is provided at one axial end of the mold through which a concentrated aqueous solution of the gel forming agent is injected into the space between the needle and the mold wall. The injection is carried out at a temperature at which the solution does not gel. The sheet of the mold is then slowly released by loosening the screw, allowing the contact air to dry. After drying to a water content of about 2% by weight, the needle covered with the dried gelling agent was removed from the mold. The gelling agent is then available material such Kollikoat ^® covered to prevent drying of the aqueous body fluid into contact with a gelling agent to prevent gelation starts and ends.

Example 3. Formation of a graft channel

Preferred embodiments for forming the graft channel of the present invention are shown in Figures 1b to 1f.

The channel forming device 20 of the present invention is placed with its front end 21' located at the insertion point 8 on the surface 6 of the contactable brain tissue 4, and its axis A-A juxtaposed with the insertion trajectory 9 (Fig. 1b). The pressure is then applied to the rear portion of the gel-free layer 22 of the device 20. The device 20 is inserted into the tissue 4 along the trajectory 9. Pressure and insertion can be done manually or by using a suitable micromanipulator (not shown). The device 20 is inserted into the desired depth, i.e., until its front end reaches the leading end 7 of the insertion trajectory or path (Fig. 1c). The insertion should be as fast as possible to avoid gelatin in layer 22 being dissolved by the aqueous body fluid during insertion. After full insertion, the device 20 is left in the fully inserted position (Fig. 1c) until the gelatin layer 22 is completely dissolved by the aqueous body fluid and a tubular layer of gelatin 23 is formed around the needle 21 (Fig. 1d). The combination of the needle 21 and the tubular layer of gelatin 23 constitutes the front channel shown in outline 24 of Figure 1d. Since the axial length of the gelatin layer 22 exceeds the insertion depth and thus exceeds the axial extension of its contact with the aqueous body fluid, the proximal end portion 22' of the gelatin layer 22 does not dissolve. In a subsequent step, the needle 21 is withdrawn from the gel 23 along the insertion path 9 (direction R). The withdrawal needle 21 removes the volume of the needle 21 from the volume of the front channel, thereby forming the channel of the present invention as shown by the contour 24' of Figure 1e. Figure 1f (enlarged view) shows the initial stage of exiting the needle 21, wherein the distal end portion of the gelatin 23' is shrunk to the diameter of the channel 24' and is cylindrical, while the adjacent portion of the gelatin 23 is still tubular. Upon complete withdrawal, a graft channel 24 filled with gelatin 23' is formed (Fig. 1e). When a physically stabilized microelectrode containing a soluble or degradable matrix in an aqueous body fluid is used, the gelatin content of channel 24 can be reduced.

By using cross-linked gelatin or other cross-linked gel former, channels filled with aqueous body fluids can be retained in the tissue after exiting the needle. The channel is surrounded by a cylindrical wall of the crosslinked gel. It is particularly useful for inserting physically unstable microelectrodes or other probes or sensors of the present invention into soft tissues.

Embodiment 4. A second embodiment of another apparatus of the present invention comprising a fiber optic device

A second embodiment 50 of the apparatus according to the invention is shown in FIG. Polypropylene The oleate needle 51 encloses an optical fiber 55 centered (axis A'-A') extending from the front end 51' of the needle in a proximal direction, causing the needle to be adjacent to the other end thereof, thereby The angle of intersection protrudes from the cylindrical wall of the needle. Or the fiber can extend through the entire needle and center the needle at its proximal end. The side wall of the needle 51 is covered by a layer 51 of dry gelatin which extends from the distal end 51' to a distal end where the optical fiber 55 projects from the cylindrical wall. The front end face of the needle 51 is not covered with gelatin. This allows the radiation to emerge from the front end of the fiber 55 without being blocked and/or inspected by tissue located before the front end of the needle 51.

Embodiment 5. A third embodiment of another apparatus of the present invention comprising an optical fiber and an electrode device

A third embodiment 60 of the apparatus according to the present invention is shown in FIG. It is a modification of the second embodiment, which also includes an electrode function. The electrode function is provided by a layer of conductive gold 66 on the needle 61 which encloses the centrally disposed fiber 65 and shares the central axis with the (A"-A" of the needle 61. The gold layer 66 is electrically insulated with paint 67 except for a short portion near its distal end. The gold layer 66 is electrically coupled to a control unit (not shown) via insulated conductors 68 that connect the gold layer 66 at its proximal end. The dried gelatin layer 62 covers the insulating and non-insulating portions of the gold layer 66.

Example 6. Microelectrode

A wide variety of microelectrodes can be used in the present invention. The design of the microelectrode other than it should be elliptical does not relate to the invention, and it is generally applicable to the transplantation described in the method of the invention. Figure 4 shows a microelectrode 30 consisting of a corrugated thin metal wire 31 having a free front (distal) end and having its other end (back, near) attached to the coupling element 32; the coupling element is preferably placed in the skull Significantly farther away. For example, the coupling element 32 in turn connects the thin insulation associated with the conduction of the wire 31. The metal wire 33, which may be electrically insulated except for its front end, serves as the active electrode tip. The physical stability of the microelectrode 30 is insufficient to allow its direct insertion into the brain tissue 1 due to deflection from its intended insertion path caused by its flexibility and uneven nerve tissue. The diameter of the microelectrodes used in the present invention is preferably in the sub-millimeter range, especially in the sub-200 μm range. The length of the microelectrodes used in the present invention is not critical and can be up to 100 mm or more.

Example 7. Microelectrode transplantation

Transplantation of the microelectrode 30 into brain tissue is shown in Figures 1g and 1h. The microelectrode 30 is initially placed over the channel 24' (shown in the outline) with its free front end adjacent the open end of the channel 24', approximately juxtaposed with the central axis BB of the channel 24' (Fig. 1e), and then partially inserted (direction F) The channel 24' (Fig. 1g) and, finally, fully inserted (Fig. 1h). Due to the nature of the gel 23', the radial error of the insertion of the microelectrode 4 can be corrected during insertion or by partial withdrawal and reinsertion. Other devices such as optical fibers can be implanted by the same method.

Example 8. Implanted and Positioned Microelectrodes

For long-term use, the location of the grafted microelectrode 30 or other device can be fixed. The principle of this fixation is shown in Figure 2. When the electrode body 31 is placed in the desired position, the coupling element 3 is held by a clamp holder 41 of an elastic flexible polymer which is mounted at a through hole in the lock 40 at the opening 5 of the skull 2 Glue with it. This arrangement protects the wound in the skull from infection. Other devices can be fixed in a corresponding manner.

Example 9. Evaluation of transplantation interactions with adjacent nerve cells

In order to evaluate the effect of gelatin surrounding the transplanted electrode in the tissue, the histological response of the transplanted rat brain after 6 weeks and the plate made of the transplanted SU-8 were compared. A test device (about 7 μm thick, 140 μm wide and 2.5 mm long) embedded with a thin layer (5-10 μm) of gelatin or not embedded.

All animal related programs of the surgical procedure were carried out according to local and international ethics, with the permission of the Lund and Malmö ethics committee, log number M258-11. All transplants (n-transplant = 16) were performed in magnetic Sprague-Dawley rats (number of rats = 8, Taconic, Denmark) weighing 200-250 g. Animals were anesthetized with an intraperitoneal injection of fentanyl (0.3 mg/kg body weight) and Domitorvet (metomixidine hydrochloride, 0.3 mg/kg) and placed in a stereotactic frame for surgery. Skin slitting is performed along the central suture of the skull to expose the anterior temporal point. An opening of about 2 mm diameter was formed, 1.0 mm from the front of the front point and 2.3 mm from the center line. Cut the dura mater with tweezers and a syringe. For ease of handling and transplantation, the test device was mounted on a stainless steel guide wire (about 3 mm long, 50 μm in diameter) using a sucrose solution as a binder and then transplanted into the skin layer with a micromanipulator to a depth of 2.0 mm. The gelatin encapsulating the test device was transplanted into one hemisphere in the rat (n=8) cerebral cortex and the unencapsulated test device was transplanted into the other hemisphere. After the sucrose is dissolved by physiologically cleaning the cortical surface, the retraction will be guided and removed, the opening of the skull is filled with FujiChem(R) rubber, and the implant is attached to the skull. The wound is then closed with a surgical staple. Animals received an anesthetic antidote (Antisedan, atmimethazole hydrochloride, 0.5 mg/kg b.w.) and Temgesic (buprenorphine, 50 μg/kg b.w.) for subcutaneous injection to reduce postoperative pain.

After 6 weeks, the animals were anesthetized with an overdose of pentobarbital (ip), and 150-200 ml of ice-cold 0.1 M phosphate buffer (PB) was perfused through the cardia, followed by perfusion of 4% poly in 0.1 M PB. Formaldehyde (PFA). The brain was fixed overnight in 4% PFA and then immersed in 30% sucrose for at least 24 hours for cryopreservation . They were then serially sectioned in a 30 μm horizontal plane using a low temperature thermostat (Microm HM560). The sections were stored in antifreeze in a non-floating manner.

Astrocyte proliferation, recruitment of neuronal bodies and microglia were assessed using standard non-floating immunohistochemistry (Lind et al. 2013). Briefly, brain sections were reacted overnight with primary antibody at room temperature. The primary antibody used is a rabbit polyclonal antibody that recognizes glial fibrillary acidic protein (GFAP, astrocytosine protein, 1:5000, Dako, Denmark) and recognizes CD68/ED1 (by active microglia) / Macrophage expression, 1:100, US Serotec (USA) or NeuN (expressed on neuronal cell nucleus, 1:100, Millipore, USA) murine monoclonal antibody. After repeated washing with PBS, brain sections (1:500, Invitrogen, USA) were further incubated with Alexa488-conjugated antibody of mouse IgG and Alexa594-conjugated antibody of rabbit IgG (room temperature protected from light for 2 hours) ) and wash with PBS.

A DS-Ril digital camera (Nikon Instruments, Japan) mounted on a Nikon Eclipse 80i microscope was used for histological fluorescence imaging analysis. Images were acquired and analyzed using NIS-Elements BR Software 3.2 (NIS-elements, Nikon Equipment Co., Japan). Different evaluation methods are used for different staining. Neuron NeuN staining was manually counted, and fluorescence intensity measurements were used for the glial markers GFAP and ED1 (Lind et al., 2013) as previously described. The region of interest (ROI) is located at 0-50 μm (inner ROI) and 50-200 μm (outer ROI) where the test device is located. A brain slice placed adjacent to the central portion of the test device is analyzed, which corresponds to the cortical blade 4. To analyze neuronal survival, matched NeuN-positive cells were also counted in the same ROI set in the untreated area of the cortex and served as a control.

Mark score test using Wilcoxon matching. A P value <0.05 was considered significant. Analysis was performed using GraphPad Prism 5.02 software (GraphPad Software, Inc., USA).

Significant astrocyte responses and significant microglial responses were limited to the intra-ROI of the transplanted test device. The microglia (ED1) density of the test device encapsulated in gelatin produced a statistically significant (p < 0.05) decrease compared to the unencapsulated experimental group. In contrast, no difference was observed between the stellate cell densities of the encapsulated and unencapsulated test devices. In all experimental groups, the density of neurons in the inner and outer ROIs was compared to the density of nerves in untreated tissues. Neuronal density was significantly reduced around the unencapsulated test device compared to the corresponding control (untreated brain) (P < 0.05). In contrast, the density of neurons in the tissue surrounding the gelatin-encapsulated test device was not reduced. The neuron density in any of the external ROIs was observed to be different from the control. The conclusion is that gelatin encapsulation significantly reduces the response of microglia to the transplant test device. Furthermore, the density of neurons in adjacent gelatin-encapsulated grafts did not decrease, while the number of neurons in adjacent tissues that did not encapsulate the grafts decreased significantly, indicating that the gelatin encapsulation is neuroprotective.

Embodiment 10. A fourth embodiment of the apparatus of the present invention, comprising a fluid pathway device for distal injection of fluid

A fourth embodiment 70 of the apparatus according to the present invention having a proximal end 70", a distal end 70' and a transverse cylindrical surface 78 are shown in Figures 7 and 7a. This is a modification of the third embodiment in which the center of the needle 71 is also (Axis A'-A') The axially extending passage 75 is in the form of a fluid passage means. The main cylindrical passage 75 is formed by a flexible tube 73 placed in the axial bore of the needle 71, the inner wall of which is composed of A thin layer 74 of high conductivity metal (e.g., silver or gold) is used. Layer 74 can be used as an electrode but can also be ignored. Tube 73 is preferably a transparent polymeric material such as an acrylate and is therefore capable of directing light and functioning as an optical fiber. At a short distance from the proximal end 70" of the device 70, the flexible tube 73 is completely away from the central axis A, -A', thereby projecting from the lateral face 78 of the needle 71. The dry gelatin layer 72 covers the portion of the lateral face 78 of the needle 71, Extending from the front end 70' to the vicinity of the distal end 70", but not covering the distal end face 77 of the needle 71 and thus not covering the distal opening of the channel 75.

Channel 75 can be used to inject fluid material emerging from its distal end. The fluid material can be, for example, an aqueous solution of a pharmaceutically active agent such as a neurotransmitter (e.g., dopamine or acetylcholine or histidine). The axial passage 75 can also be used as a suction fluid material, particularly during withdrawal of the needle 71 from the tissue. The fluid material may also contain nutrients such as glucose and may be oxidized to reduce hypoglycemia and ischemia following transplantation.

Embodiment 11. A fifth embodiment of the apparatus of the present invention, comprising a fluid pathway device for lateral injection of fluid

A fourth embodiment 80 of the apparatus according to the invention having a proximal end 80", a distal end 80' and a transverse cylindrical surface 78 are shown in Figures 8, 8a, 8b. This is a modification of the fourth embodiment, which is also in the needle 81 The central axial arrangement (axis A**-A**) of the extension channel 85 includes a fluid passage means. The primary cylindrical passage 85 is formed by a flexible tube 83 disposed in the axial bore of the needle 81, The inner wall of tube 83 is covered by a thin layer 84 of high conductivity metal (e.g., silver or gold). Layer 84 can be used as an electrode but is also negligible. Flexible tube 83 is preferably a transparent polymeric material such as acrylate and can therefore Light guides and use as an optical fiber. At a short distance from the proximal end 80" of the device 80, the flexible tube 83 is completely away from the central axis A**-A**, thereby projecting from the lateral face 88 of the needle 81. A dry gelatin layer 82 having a water content of about 2% by weight covers the needle 81, distal from the proximal end 80' The end 80" extends but does not cover the distal end face 87 of the needle 81 containing the distal opening of the flexible tube 83. The radially extending passage 86 branches from the axial passage 85. It can be used to convert the dry gelatin layer 82 to aqueous condensation. The fluid material emerging from its lateral face is injected after the glue. The fluid material may be, for example, an agent that accelerates the conversion of the dried gelatin layer 82 to the aqueous gel, but may also include or further include a pharmaceutically active agent such as a neurotransmitter (eg, dopamine or B). Choline or histidine).

The transverse passage 86 can also be used as a fluidic material, particularly during withdrawal of the needle 81 from the tissue. The axially disposed passageway 85 can be plugged or open at its distal end, and the plug (not shown) is comprised of a permanent material or a material that dissolves or degrades over time, such as cross-linked gelatin. A variant of the fifth embodiment lacking the metal layer 84 is also included in the invention, which is a variant lacking the flexible tube 83 or its extension from the distal end 80' in the proximal direction; in this case, flexibility The tube is replaced by a 83x high conductivity metal tube. Radially extending passages 86, such as four passages 86 disposed in a radial plane (Fig. 8b), extend from axially disposed passages 85 through the walls of flexible tube 83 and metal layer 84, but do not pass through the dry gelatin layer 82. The peripheral end portion of the radially-extended channel 86 can be plugged with a plug 87 (Fig. 8c) made of a soluble material in an aqueous fluid; this facilitates the covering of the needle 81 with gelatin to form a dry gelatin layer 82, thereby avoiding clogging of the radially extending channels. 86.

Embodiment 12. A first improvement of the fifth embodiment of the apparatus of the present invention including a friction reducing layer

Embodiment 90 of the apparatus of the present invention shown in Figures 9, 9a, 9b, 9c corresponds to embodiment 80 of Figures 8, 8a, 8b, 8c, except that it is on the same axially extending dry gelatin layer 82' A friction reducing layer 89 is included. Features indicated by reference numerals 81' and 83' to 88' and features of the embodiment shown in Figs. 8, 8a, 8b, 8c 81 and 83 to 88 are of the same category. The central axis A+-A+ corresponds to the central axis A**-A** of FIG. Reference numerals 90' and 90" indicate the distal end and the proximal end of the needle 81', respectively. The section B+-B+ corresponds to the section B-B of Fig. 8.

Embodiment 13. A second improvement of the fifth embodiment of the apparatus of the present invention including a friction reducing layer

Embodiment 91 of the apparatus of the present invention shown in Figure 10 corresponds to embodiment 80 of Figures 8, 8a, 8b, except that it also includes two adjacent layers 92, 93 on the dried gelatin layer 82', said drying The gelatin layer has the same axial extension as the total extension of layers 92,93.

The proximally disposed layer 92 comprises a coagulant that prevents bleeding from the channel formed by the insertion of the device 91 into the nerve tissue, while the distally disposed layer 93 is a friction reducing layer for insertion during insertion of the needle 81" The tissue damage is minimal. The features referred to by reference numerals 82", 86" to 88" are the same as those of the features 82 and 86 to 88 of the embodiment shown in Figures 8, 8a, 8b. The central axis A++-A++ corresponds to the central axis A**-A** of FIG. Reference numerals 91' and 91" indicate the distal end and the proximal end of the needle 81', respectively.

Embodiment 14. An embodiment of the device of the present invention, wherein the needle is covered by one or more layers of gel forming agent

Figures 11, 11a, 11b, 11c show the apparatus 100, 100a, 100b, 100c of the invention in a primary manner, wherein the cylindrical surface of the needle 101 (except for the portion extending a short distance from the proximal end) consists of one or more gel former layers Covered in different locations. In the embodiment 100 shown in FIG. 11, the needle 101 is covered by a layer of gel forming agent 102. In the embodiment 100a shown in Figure 11a, the needle 101 is covered by an inner layer 102 of gel forming agent, which in turn is covered by an outer layer 103 of gel forming agent. Figure 11b In embodiment 100b, the needle 101 is covered by a first layer 104 extending approximately halfway from its distal end and is adjacent to the proximal end of the first layer 104 and extends therefrom to near the proximal end of the needle 101. The second layer 102 is covered. In the embodiment 100c shown in Figure 11c, the needle 101 is covered by two inner layers 102, 104 which are arranged in the same manner as the layer of the embodiment of Figure 11b, which inner layer 102, 104 is then 103 coverage.

Example 15. Embodiment of a channel in a neural tissue of the invention filled with one or more layers of aqueous gel

Figures 12, 12a, 12b, 12c show, in a primary manner, channels in the neural tissue 105 of the present invention filled with one or more layers of aqueous gels 102*, 103*, 104*, respectively, from Figures 11, 11a, The respective dried gel former layers 102, 103, 104 on the needle 101 of the inventive device 100, 100a, 100b, 100c shown in 11b, 11c are formed by contact with aqueous body fluids oozing from the nerve tissue 105. The channel of Figure 12 is uniformly filled with a water-based gel 102*. The channel of Figure 12a is filled with a central gel cylinder 102* surrounded by a tubular gel cylinder 103* that abuts the cylindrical tissue wall of the channel. A portion extending from the bottom of the cylindrical passage of Fig. 12b to about half of its height is filled with a first aqueous gel 104*, and the remaining upper portion of the passage is filled with a second aqueous gel 102*. The central cylindrical portion of the channel of Figure 12c is filled with the first 104* and second 102* aqueous gels at the same location of Figure 12b and is covered by an aqueous gelled tubular layer 103 that extends the combined height of layers 102* and 104*. *surround. By employing the properties of a gel former, an aqueous gel can be designed, such as an aqueous gel having the desired viscosity or biodegradability. Non-gelling agents, such as pharmaceutically active agents and nutrients, may also be incorporated into the dry gel former to produce a corresponding aqueous gel containing a non-gelling agent.

1‧‧‧Mammal brain/brain tissue

2‧‧‧Skull

3‧‧‧Dust film

4,4'‧‧‧Target nerve cells/cell clusters/microelectrodes

5‧‧‧through hole

6‧‧‧ surface

7,8‧‧‧ points / front end

9‧‧‧Insert track

10‧‧‧Laser beam

21‧‧‧hard cylindrical needle

22‧‧‧ gelatin layer

Claims (49)

A method of providing an elliptical linear passage in a neural tissue of a human or mammal for implanting a medical device or other object into the tissue by insertion into the passage, the device being implanted into the tissue by direct insertion Insufficient physical stability, the method comprising: providing a channel forming device comprising a rotationally symmetric, in particular cylindrical, rigid needle having a length exceeding a channel length to be provided and having a front end and a rear end, the needle The portion extending from the front end to the rear end thereof is encapsulated with a layer of a gel former or a layer containing a gel forming agent, the length of the extension corresponding at least to the length of the channel, wherein the gel forming agent is capable of contacting the aqueous body fluid The drying agent forming the aqueous gel, the gel former layer or the gel-forming agent layer comprises less than 20% by weight of water, preferably less than 10% by weight of water, especially less than 5% by weight or 2% by weight Water; inserting the needle with its front end forward into the nerve tissue; forming an aqueous gel around the needle by contact of the gel forming agent with the aqueous fluid; withdrawing the needle from the gel; wherein the needle is It is rigid enough to insert nerve tissue in the absence of a layer comprising a gel former or a layer composed of a gel former. The method of claim 1, wherein the needle comprises two or more layers comprising a gel former or two or more layers consisting of a gel former, wherein the two or more layers Each contains a different gel former. The method of claim 1 or 2, wherein the needle is electrically conductive and/or comprises an axially extending electrical conductor and/or comprises an optical fiber. The method of claim 1 wherein the needle is metallic or comprises a metallic conductor or a conductive non-metallic material such as a conductive polymer or conductive carbon. The method of claim 1 wherein the needle comprises a centrally disposed axially extending channel from which optionally one or more channels extend radially. The method of claim 1, wherein the gel forming agent comprises a gel forming protein or a carbohydrate. The method of claim 6, wherein the protein is selected from the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid, and salts thereof. The method of claim 7, wherein the protein is gelatin. The method of claim 3, wherein the metal wire is electrically connected to the vicinity of the rear end or the rear end of the needle or metal conductor or conductive polymer. The method of claim 9, wherein the wire is for use in connection with a voltage monitoring device or a power source. The method of claim 3, wherein the needle is electrically insulated except for its front end. The method of claim 1, wherein the gel former layer or the gel forming agent-containing layer comprises a pharmaceutically active agent, especially a pharmaceutically active agent selected from the group consisting of coagulants, anticoagulants, antibiotics, osmotic pressure Modulators, anti-inflammatory agents, nutrients, factors that stimulate growth, factors that stimulate cell differentiation, hormones, cytokines. The method of claim 1, wherein the device comprises a microelectrode and/or an optical fiber. The method of claim 5, wherein the centrally disposed axially extending channel is designed to inject an aqueous fluid into the graft channel in an axial direction. The method of claim 14, wherein the axially extending channel is in fluid communication with one or more radially extending channels such that the fluid can be injected into the graft channel in a radial direction. The method of claim 1, wherein the gel forming agent is selected from the group consisting of: arabinogalactan; arabinoxylan; galactan; galactomannan; lichen polysaccharide; xylan; For example, hydroxymethylpropylcellulose; whey protein; soy protein; casein; hyaluronic acid; chitosan; gum arabic; carboxyvinyl polymer; sodium polyacrylate; carboxymethyl cellulose; Sodium; amylopectin; polyvinylpyrrolidone; karaya gum; pectin; xanthan gum; tragacanth; alginic acid; polyoxymethylene; polyimine; polyether; chitin; polyglycolic acid; Lactic acid; copolymer of polyglycolic acid and polylactic acid; copolymer of polylactic acid and polyethylene oxide; polydecylamine; polyanhydride; polycaprolactone; maleic acid Anhydride copolymer; polyhydroxybutyrate copolymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); a polymer formed by copolymerization with sebacic acid or polyterephthalic acid; (glycolide-co-trimethylene carbonate); polyethylene glycol; polydioxanone; polypropylene fumarate; poly(glutamic acid ethyl ester-co-glutamic acid); poly (valley Tert-butoxycarbonylmethyl ester); polycaprolactone; poly(caprolactone-co-butyl acrylate); polyhydroxybutyrate and copolymers thereof; poly(phosphazene); poly(D, L-lactide-co-caprolactone); poly(glycolide-co-caprolactone); poly(phosphate); poly(amino acid); poly(hydroxybutyrate); polyphenolic acid peptide Maleic anhydride copolymer; polyphosphazene; polyimino carbonate; poly[(7.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylene carbonate)]; polyepoxy Alkane; hydroxypropyl methylcellulose, poly(ethylene-co-vinyl acetate); isobutylene-based copolymer of isobutylene and at least one other repeating unit (eg butyl acrylate: butyl methacrylate); Styrene such as aminostyrene, hydroxystyrene, carboxyl styrene Sulfonic acid styrene; homopolymer of polyvinyl alcohol; copolymer of polyvinyl alcohol and at least one other repeating unit (for example, vinylcyclohexyl ether); hydroxymethyl methacrylate; hydroxyl- or amino-terminated poly Ethylene glycol; acrylate-based copolymers such as methacrylic acid, methacrylamide, hydroxymethyl methacrylate; ethylene vinyl alcohol copolymer; alkyl or aryl siloxane and at least one repeating unit of fluorenone Base copolymer; polyurethane; acesulfate heparin; RGD peptide; polyethylene oxide; chondroitin sulfate; YIGSR peptide; keratan sulfate; VEGF biomimetic peptide; peripherin (acetamide heparin proteoglycan 2); Lys-Val-Ala-Val (IKVAV) laminin alpha-1 chain peptide; modified heparin; fibrin fragment. A method of implanting a microelectrode into a neural tissue, the method comprising: i) providing a microelectrode having a front end and a rear end, the microelectrode being sufficiently rigid to be inserted into the nerve tissue; ii) forming a linear graft channel in the tissue by the method of any one of claims 1-15; iii) The microelectrode is inserted into the channel to a desired depth with the front end facing forward. A method of transplanting living cells into a neural tissue, the method comprising: i) providing an aqueous suspension of living cells in a syringe having a needle or a tip; ii) the method according to any one of claims 1-15 Forming a linear graft channel in the tissue filled with the aqueous gel; iii) inserting the syringe needle or tip into the graft channel to a desired depth; iv) injecting the aqueous suspension of living cells into the transplant The channel; v) exits the injection needle or tip; provided that the injection can be performed before and/or during withdrawal. A method of transplanting living cells into a neural tissue, the method comprising: i) providing a frozen suspension of living cells attached to the tip of the insertion rod; ii) filling according to any one of claims 1-15 A linear graft channel is formed in the tissue having the aqueous gel; iii) the rod is inserted into the graft channel at a desired depth with the tip facing forward; iv) the frozen suspension is thawed; v) the rod is withdrawn. An apparatus for forming a linear passage for transplanting a medical device in a nerve tissue, comprising an elliptical rigid needle having a front end and a rear end and a layer containing a dry gel forming agent or a layer composed of a dry gel forming agent, or The device consists of the rigid needle and the layer, a layer comprising or consisting of the gel forming agent disposed on a portion of the needle extending from the front end in a distal direction and enclosing the portion, wherein the layer or agent Containing less than 20% by weight of water, preferably less than 10% by weight of water, and most preferably less than 5% by weight of water, wherein the needle is sufficiently rigid to be capable of containing no dry gel former or by drying The layer composed of the gel forming agent is inserted into the nerve tissue. The device of claim 20, wherein the needle is cylindrical. The device of claim 20 or 21, wherein the needle is metallic or comprises a metal. The apparatus of claim 22, wherein the metal is selected from the group consisting of steel, titanium, tungsten, tantalum, and niobium. The device of claim 20 or 21, wherein the needle is a polymeric material or comprises the material. The apparatus of claim 24, wherein the polymer is an acrylate or epoxy polymer. The apparatus of claim 24, wherein the polymer is reinforced with fibers, especially with carbon fibers. The device of claim 20, the device comprising one or more devices selected from the group consisting of an electrode device, a fiber optic device, and a sensor device. The device of claim 21, wherein the needle comprises an axially extending channel having a distal end surface having an opening. The device of claim 28, the device comprising a channel extending radially from the axial passage. The device of claim 29, wherein the axially extending channel and/or the radially extending channel are respectively plugged at an opening of the distal end face or cylindrical face of the needle. The device of claim 30, wherein the plug is a material that is soluble or degradable in an aqueous fluid. The device of claim 20, wherein the agent is capable of forming a gel by contact with an aqueous body fluid comprising a gel forming protein or a carbohydrate. The device of claim 32, wherein the protein is selected from the group consisting of biocompatible coagulation A gel forming agent, especially an agent selected from the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid, and salts thereof. The device of claim 20, wherein the layer comprises a pharmaceutically active agent. The device of claim 34, wherein the pharmaceutically active agent is selected from the group consisting of: a coagulant, an anticoagulant, an antibiotic, an osmotic pressure regulator, an anti-inflammatory agent, a nutrient, a factor that stimulates growth, a factor that stimulates cell differentiation, hormone. The device of claim 20, wherein the device comprises a friction reducing layer disposed on all of the dried gel forming agent or portion thereof. The device of claim 20, wherein the device comprises a slow-dissolving layer disposed on the dried gel former or portion thereof. The device of claim 37, wherein the device comprises a friction reducing layer disposed on the slowing-down dissolution layer. The device according to claim 20, wherein the gel forming agent is selected from the group consisting of: arabinogalactan; arabinoxylan; galactan; galactomannan; lichen polysaccharide; xylan; For example, hydroxymethylpropylcellulose; whey protein; soy protein; casein; hyaluronic acid; chitosan; gum arabic; carboxyvinyl polymer; sodium polyacrylate; carboxymethyl cellulose; Sodium; amylopectin; polyvinylpyrrolidone; karaya gum; pectin; Xanthan gum; xanthan gum; alginic acid; polyoxymethylene; polyimine; polyether; chitin; polyglycolic acid; polylactic acid; copolymer of polyglycolic acid and polylactic acid; polylactic acid and polyepoxy Copolymer of alkane; polyamine; polyanhydride; polycaprolactone; maleic anhydride copolymer; polyhydroxybutyrate copolymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); a polymer formed by copolymerization with sebacic acid or polyterephthalic acid; poly(glycolide-co-trimethylene carbonate); polyethylene glycol; polydioxanone; polypropylene fumarate Poly(glutamic acid ethyl ester-co-glutamic acid); poly(glutamic acid tert-butoxycarbonylmethyl ester); polycaprolactone; poly(caprolactone-co-butyl acrylate); Hydroxybutyrate and its copolymer; poly(phosphazene); poly(D,L-lactide-co-caprolactone); poly(glycolide-co-caprolactone); poly(phosphate) Poly(amino acid); poly(hydroxybutyrate); polyphlegonic acid peptide; maleic anhydride copolymer; polyphosphazene; polyimino carbonate; poly[(7.5% dimethyl-trimethylene carbonate) )-co-(2.5% trimethylene carbonate)]; polyethylene oxide; hydroxypropyl methylcellulose, (Ethylene-co-vinyl acetate); an isobutylene-based copolymer of isobutylene and at least one other repeating unit (for example, butyl acrylate: butyl methacrylate); substituted styrene such as aminostyrene, hydroxystyrene , carboxystyrene, styrene sulfonic acid; homopolymer of polyvinyl alcohol; copolymer of polyvinyl alcohol and at least one other repeating unit (for example, vinylcyclohexyl ether); hydroxymethyl methacrylate; hydroxy- or Amino-terminated polyethylene glycol; acrylate-based copolymers such as methacrylic acid, methacrylamide, hydroxymethyl methacrylate; ethylene vinyl alcohol copolymer; alkyl or aryl siloxane and at least one Repeat unit of fluorenone-based copolymer; polyurethane; acesulfate heparin; RGD peptide; polyethylene oxide; chondroitin sulfate; YIGSR peptide; keratan sulfate; VEGF biomimetic peptide; peripherin (acetamide heparin proteoglycan 2 ); containing Ile-Lys-Val-Ala-Val (IKVAV) Laminin alpha-1 chain peptide; modified heparin; fibrin fragment. A method of reducing the response of microglia to the implantation of a medical device or other object into a neural tissue, comprising providing a biocompatible aqueous gel layer surrounding the graft device or object. The method of claim 40, wherein the layer of biocompatible gel is provided in the form of a channel extending from the surface of the neural tissue. The method of claim 41, wherein the medical device or other object is inserted into the tissue through the channel. The method of any one of claims 40-42, wherein the biocompatible gel is selected from the group consisting of gelatin, hyaluronic acid gum and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid gel And the glue of its salt. The method of claim 43, wherein the biocompatible gel is gelatin or chemically modified gelatin. A linear channel for transplanting a medical device in a neural tissue of a human or animal, the channel being filled with an aqueous gel formed in situ by contact with a dry biocompatible gel forming agent provided on body fluids and a solid support, The biocompatible gel is especially selected from the group consisting of gelatin, hyaluronic acid and salts thereof, chemically modified gelatin, chemically modified hyaluronic acid, and salts thereof, wherein the support is in the formation Remove after the channel. The linear nerve tissue channel of claim 45, wherein the channel is filled with a gel formed by contacting an aqueous body fluid and one or more gel forming agents selected from the group consisting of: arabinogalactan Arabian xylan; galactan; galactomannan; lichen polysaccharide; xylan; cellulose derivative such as hydroxymethylpropylcellulose; whey protein; soy protein; casein; hyaluronic acid Chitosan; gum arabic; carboxyvinyl polymer; sodium polyacrylate; carboxymethyl cellulose; sodium carboxymethyl cellulose; amylopectin; polyvinyl pyrrolidone; karaya gum; pectin; xanthan gum ;xanthine;alginic acid; polyoxymethylene; polyimine; polyether; chitin; polyglycolic acid; polylactic acid; copolymer of polyglycolic acid and polylactic acid; copolymerization of polylactic acid and polyethylene oxide Polyamide; polyanhydride; polycaprolactone; maleic anhydride copolymer; polyhydroxybutyrate copolymer; poly(1,3-bis(p-carbophenoxy)propane anhydride); a polymer formed by copolymerization of acid or polyterephthalic acid; poly(glycolide-co-) Methylene carbonate); polyethylene glycol; polydioxanone; polypropylene fumarate; poly(glutamic acid ethyl ester-co-glutamic acid); poly(glutamic acid tert-butoxycarbonyl group) Methyl ester); polycaprolactone; poly(caprolactone-co-butyl acrylate); polyhydroxybutyrate and its copolymer; poly(phosphazene); poly(D,L-lactide-co- -caprolactone); poly(glycolide-co-caprolactone); poly(phosphate); poly(amino acid); poly(hydroxybutyrate); polyphenolic acid peptide; maleic anhydride copolymer; Polyphosphazene; polyiminocarbonate; poly[(7.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylene carbonate)]; polyethylene oxide; hydroxypropyl methyl Cellulose, poly(ethylene-co-vinyl acetate); isobutylene and at least one other repeating unit (eg butyl acrylate: butyl methacrylate) Isobutylene-based copolymer; substituted styrene such as aminostyrene, hydroxystyrene, carboxystyrene, sulfonic acid styrene; homopolymer of polyvinyl alcohol; polyvinyl alcohol and at least one other repeating unit (eg ethylene) Copolymer of cyclohexyl ether); hydroxymethyl methacrylate; hydroxy- or amino-terminated polyethylene glycol; acrylate-based copolymers such as methacrylic acid, methacrylamide, hydroxymethyl methacrylate Ethylene vinyl alcohol copolymer; an alkyl or aryl siloxane and at least one repeating unit of fluorenone-based copolymer; polyurethane; acesulfate heparin; RGD peptide; polyethylene oxide; chondroitin sulfate; YIGSR peptide Keratin sulfate; VEGF biomimetic peptide; peripherin (acetamidine heparin proteoglycan 2); laminin α-1 chain peptide containing Ile-Lys-Val-Ala-Val (IKVAV); modified heparin; blood fiber Protein fragment. A linear channel as claimed in claim 45 or 46, wherein the channel is cylindrical. The linear channel of claim 47, wherein the channel comprises two or more cylindrical aqueous gel layers having the same diameter as the channels. The linear channel of claim 47, wherein the cylindrical central aqueous gel layer is surrounded by a peripheral aqueous gel layer.