WO2010103174A1 - A carbon fiber multichannel electrode for measuring electrical and chemical activity in biological tissue and a process for making the electrode - Google Patents

A carbon fiber multichannel electrode for measuring electrical and chemical activity in biological tissue and a process for making the electrode Download PDF

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Publication number
WO2010103174A1
WO2010103174A1 PCT/FI2010/050162 FI2010050162W WO2010103174A1 WO 2010103174 A1 WO2010103174 A1 WO 2010103174A1 FI 2010050162 W FI2010050162 W FI 2010050162W WO 2010103174 A1 WO2010103174 A1 WO 2010103174A1
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Prior art keywords
electrode
multichannel
bunch
tip
tips
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PCT/FI2010/050162
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French (fr)
Inventor
Mikko VÄHÄSÖYRINKI
Arto Piironen
Original Assignee
Oulun Yliopisto
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Publication of WO2010103174A1 publication Critical patent/WO2010103174A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848—Needles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/685—Microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes

Definitions

  • a carbon fiber multichannel electrode for measuring electrical and chemical activity in biological tissue and a process for making the electrode
  • the invention relates to a method for manufacturing multichannel electrode from carbon fiber.
  • the manufactured multichannel electrode comprises several adjacent needle-like microelectrodes utilized either in electrical or chemical stimulations or measurements in biological tissue.
  • neurons can also communicate among each other utilizing chemical signaling in form of transmitters or hormones. Both communication methods can be measured outside the cells in the extracellular space.
  • electrical impulses called action potentials.
  • Neurons can also communicate among each other utilizing chemical signaling in form of transmitters or hormones. Both communication methods can be measured outside the cells in the extracellular space.
  • studying the nervous system it is important to understand how nerve cells cooperate as a network. This requires simultaneous recording from many adjacent or nearby neurons with a single cell resolution. It is also desirable that both electrical and chemical activity can be measured simultaneously.
  • the same communication methods are also utilized in other types of biological tissues e.g. muscle tissue. Al- though nervous system is discussed from here on as an example application, the invention is not restricted to neuron measurements but it is generally applicable to different types of biological tissue.
  • Stimulation can be accomplished by leading electrical current via a tip of an electrode to the nervous system. It is also possible to inject a chemical substance to the tissue as a chemical stimulus.
  • the electrochemical measurements can be utilized with carbon fiber electrodes.
  • a substance concentration is transformed to electrical signals through oxidation or reduction processes on the surface of the electrode.
  • multichannel electrodes have been developed for measuring electrical activity in nervous system. They are accomplished mainly by utilizing semiconductor technology to produce a planar electrode matrix or a matrix with cylinder or needle-like electrodes protruding from the surface.
  • These multichannel electrodes are different from the present invention in regard to their material, fabrication methods, size limitations and general electrode geometry. These electrodes do not in general enable chemical stimulation or electrochemical measurements.
  • Patent US 4959130 discloses a carbon fiber microelectrode comprising a sharp tip suitable for electrochemical measurements. Otherwise the depicted microelectrode is insulated against chemical and mechanical influences.
  • the tip of the elec- trode can be 0.1 ⁇ m. Two of such electrodes are utilized for electrical stimulation with typical distance of about 2 mm in between. The large separation between two electrodes makes the method unsuitable for manufacturing multichannel electrodes.
  • Carbon has also been used as material in multichannel electrodes developed for measuring neural activity.
  • Publication US 2005/0230270 discloses a flat microelectrode array consisting of carbon nanotube electrodes which are integrated to a silicon substrate. A distance between two adjacent nanotubes can be adjusted from 10 ⁇ m to 100 ⁇ m. However, the planar geometry of the microelectrode array prevents its use in applications that require penetration into the tissue.
  • Publication US 2006/0135862 discloses a microelectrode array consisting of several sharpened carbon fiber needles where individual needles are separated with about 100 ⁇ m distance. The large separation between the individual needles makes it unsuitable for measurements of small neurons with a single neuron resolution. The mentioned methods do not enable chemical stimulation or discuss pos- sibility of electrochemical measurements.
  • Needle-like electrodes such as the present invention, have been developed that are suitable for measuring neural activity.
  • Publication US 1993/5215088 discloses a three-dimensional needle-like electrode array placed on a planar platform.
  • Publication US 1995/5413103 discloses a microprobe consisting of one or more electrically insulated metal wires mounted in a row-like order with a clamping structure.
  • Publication US 2006/6993392 discloses another row-like multichannel metal micro wire electrode where wires are mounted on a printed circuit board.
  • the methods above utilize needles with diameters of tens to hundreds of ⁇ m and/or individual needles separated by the distance of typically hundreds of micrometers.
  • the large size of these electrode arrays prevents their use in measur- ing activity with a single neuron resolution in tissue with small and/or densely packed neurons.
  • the mentioned electrodes are also not suitable for chemical stimulation or electrochemical measurements.
  • the multichannel electrodes known in the art do not provide means for measuring electrical activity of densely packed small neurons in the tissue below the surface (e.g. 1 -10 ⁇ m adjacent objects) or for measuring electrical activity in small experimental animals such as a fruit fly.
  • the multichannel electrodes known in the art also do not provide a possibility for electrical and chemical stimulation or for the electrochemical measurements. Therefore, there exists a need for an ultra-small needle-like multichannel electrode suitable for recording electrical activity, chemical signals and for stimulating chemically and electrically. Summary of the invention
  • An object of the invention is to provide a manufacturing method and an ultra-small multichannel electrode for measuring electrical and chemical activity in biological tissue.
  • the objects of the invention are achieved by a multichannel carbon fiber electrode where several distinct 0.1-20 ⁇ m electrode tips can locate 5-50 ⁇ m from each other.
  • An advantage of the invention is that the size and density of the multichannel elec- trade is suitable for measuring activity of small and densely packed objects such as neurons.
  • Another advantage of the invention is that the electrodes have needle-shaped sharp form.
  • Another advantage of the invention is that the number of distinct measurement channels can be varied.
  • Another advantage of the invention is that the lengths of the individual needles as well as the size and separation of the electrodes can be varied.
  • Another advantage of the invention is that it can be utilized both in electrical and in electrochemical measurements.
  • Another advantage is that it provides for electrical and/or chemical stimulation by one and the same multichannel electrode.
  • a further advantage of the invention is that the structure is mechanically and chemically resistant.
  • the multichannel electrode according to the invention is characterized in that the multichannel electrode comprises electrically insulated carbon fibers integrated as a bunch and that one end of the integrated bunch comprises at least two needle- shaped electrode tips whose distance is predetermined in a range of 5-50 ⁇ m.
  • the method for manufacturing a multichannel electrode for electrical and chemical measurement of neuron is characterized in that it comprises: - integrating several tubular covers as a bunch;
  • the multichannel electrode comprises of several electrically insulated carbon fibers integrated together.
  • the second ends of the carbon fibers are advantageously first individually connected to a conductor such as a copper wire with a conductive adhesive.
  • carbon fibers having a diameter of 5-10 ⁇ m are electrically insulated with a suitable dielectric such as electrophoretic deposition paint and integrated together to form a cylindrical electrode array by inserting integrated fiber-conductor assembly into a tubular cover and securing them in place with an adhesive. Conductor wires are connected to a suitable connector.
  • a suitable dielectric such as electrophoretic deposition paint
  • each one of the hollow tubes is loaded with a 5-10 ⁇ m carbon fiber- conductor assembly.
  • the integrated bunch of hollow capillary tubes is drawn from the end where the tips of the carbon fibers are by a drawing machine known in the art. Due to the drawing the outer diameter of the bunch of the hollow capillary tubes in the drawn end is reduced considerably, wherefrom several separate carbon fiber tips extend. Conductor wires are connected to a suitable connector.
  • the tips of the carbon fibers are advantageously sharpened by electrochemical and electrical means.
  • the electrode tips After shaping the electrode tips they are advantageously individually isolated in a controlled manner with a suitable dielectric such as electrophoretic depositon paint.
  • a suitable dielectric such as electrophoretic depositon paint.
  • the distance between two adjacent carbon fiber tips of the manufactured multichannel electrode may be 5-50 ⁇ m.
  • the electrodes may advantageously be coated with a suitable material such as a conductive polymer or a biological substance.
  • Connector of the multichannel electrode may be connected to a proper measurement apparatus.
  • Fig. 1 a shows a schematic representation of a multichannel electrode according to the invention before drawing
  • Fig. 1 b shows a schematic representation of a multichannel electrode according to the invention after drawing
  • Fig. 1 c shows a schematic representation of a multichannel electrode according to the second embodiment of the invention before drawing
  • Fig. 2 shows as an example a tip of the multichannel electrode of Fig. 1 b;
  • Fig. 3 shows an exemplary flow chart of the main stages of the method for manufacturing a multichannel electrode according to the first embodiment of the invention.
  • Fig. 4 shows an exemplary flow chart of the main stages of the method for manufacturing a multichannel electrode according to the second embodiment of the invention.
  • Fig. 1 a illustrates an example of a semi-finished multichannel electrode 1 according to the invention.
  • the exemplary semi-finished multichannel electrode 1 comprises three exemplary carbon fiber electrodes 18 in three tubular covers 16.
  • the length of the carbon fiber 18 may be about 30 mm and its diameter may be about 5-10 ⁇ m.
  • Each of the carbon fibers may advantageously be bonded to a copper wire before insertion to a tubular cover.
  • the free ends of the carbon fibers extend a bit from the capillary tube 16.
  • the capillary tube 16 may be made of glass or plastic.
  • the inner diameter of the capillary tube 16 may advantageously be 0.6 mm and the outer diameter 1.2 mm.
  • each of the capillary tubes 16 contains a carbon fiber-copper wire assembly 14-18.
  • a bunch of capillary tubes according to the invention comprises several capillary tubes. The integration of the bunch may be accomplished either before or after inserting the fiber-wire assembly 14 in the capillary tubes 16.
  • one or more of the capillary tubes 16 may be left empty. In that embodiment the empty capillary tubes may be utilized to inject a chemical substance to a research object. After inserting the carbon fibers 18 and attached copper wires 14 in the capillary tubes 16, an adhesive is added to secure the wires to the capillary tubes.
  • Fig. 1 b illustrates an example of a finished multichannel electrode 10 according to the invention.
  • the exemplary multichannel electrode 10 of Fig. 1 b comprises three exemplary carbon fiber electrodes.
  • the multichannel electrode 10 is manufactured from the semi-finished electrode 1 of Fig. 1 a by drawing the heated outer end of the capillary tube bunch 2 in a draw bench known in the art.
  • One possible drawing machine is model PE-21 manufactured by Narishige Co. Ltd.
  • the drawing of the capillary tube bunch 2 is accomplished in an area depicted by reference 100 in Fig. 1 b.
  • the other ends of the copper wires 14 may be connected to a connector 12.
  • the connector 12 may be connected by some connecting means to a proper measurement apparatus.
  • Fig. 1 c is depicted an example of a semi-finished multichannel electrode tip 20a according to the second embodiment of the invention. It comprises carbon fibers 18a of 5-10 ⁇ m which are electrically insulated with a suitable dielectric 17 such as electrophoretic deposition paint and integrated together to form a cylindrical electrode array 2a.
  • the electrode array 2a is advantageously inserted into a tubular cover 16a and secured in place with an adhesive.
  • Conductor wires are connected to a suitable connector (not shown in Fig. 1 c).
  • the exemplary semi-finished multichannel electrode according to the second embodiment comprises three exemplary insulated carbon fibers 18a in a plastic tubular cover 16a secured in place with an adhesive. Diameter of one carbon fiber is advantageously about 5 ⁇ m and its length about 30 mm.
  • Each of the carbon fibers 18a may advantageously be bonded before the insulation to a copper wire with an electrically conductive adhesive.
  • the insulation of the copper wire may be Teflon, for example.
  • Fig. 2 illustrates in more detail the needle-shaped tip 20 of Fig. 1 b.
  • the electrode tips 181 , 182 and 183 extend from the capillary tubes 161 a, 161 b and 161 c.
  • the tips may advantageously be cut to a length of 1-5 mm.
  • the tips 181 , 182 and 183 of the carbon fibers may be further shaped by chemical and electrical processes.
  • the shape of the readymade tip may be for example a cone or a cylinder.
  • the tips of the carbon fibers are covered by some insulating material known in the art, such as electrophoretic depositon paint.
  • some insulating material known in the art, such as electrophoretic depositon paint.
  • Fig. 3 shows as an exemplary flow chart the main steps of a manufacturing process whereby the multichannel electrode according to the first embodiment of the invention may be made.
  • Fig. 3 shows as an exemplary flow chart the main steps of a manufacturing process whereby the multichannel electrode according to the first embodiment of the invention may be made.
  • some of the process steps may be accomplished in another order than depicted in Fig. 3. Therefore the manufacturing process depicted in Fig. 3 is only illustrative.
  • step 30 it is decided how many channels the multichannel electrode comprises. In this step it is also decided if one or some of the capillary tubes of the multichan- nel electrode are left empty. An empty capillary tube may be utilized for injecting some chemical to a biological tissue under study.
  • step 31 an electrical connection between the carbon fiber and copper wire is accomplished by using two-component glue which is electrically conducting in cured state.
  • step 32 a composite of a carbon fiber and copper wire is inserted in a capillary tube of the multichannel electrode. The composite is inserted in the capillary tube so that an end of the carbon fiber extends about 10-50 mm from the capillary tube. After insertion of the composite an adhesive is added to secure it to the ca- pillary tube. An oven may be used for curing the adhesive. The curing fastens the copper wire constantly to the capillary tube.
  • step 33 several capillary tubes are integrated as a bunch.
  • the bunch of the capillary tubes may also be manufactured before the composites are inserted in the capillary tubes.
  • the bunch of capillary tubes including the composites are also heat-treated in one go.
  • step 34 one end of the capillary tube bunch is drawn for reducing its outer diameter to 10-100 ⁇ m.
  • the drawing may be accomplished for example by a drawing bench model PE-21 manufactured by Narishige Co. Ltd. After the drawing the free ends of the carbon fibers extend about 10 mm from the capillary tubes.
  • step 35 the free ends of the carbon fibers may be cut to a length of 1-5 mm.
  • step 36 the length of the free ends of the carbon fibers are shortened to 5- 50 ⁇ m and their tips may be shaped to conical shape.
  • the length of the conical part of the electrode tip may vary between 0.1 and 20 ⁇ m.
  • the length of the conic- al part of the electrode tip may be determined during the shortening and shaping process.
  • the tips of the carbon fibers are first inserted in a loop made of inert material, for example platinum, gold or silver.
  • the loop retains a liquid which is electrically con- ductive such as a salt solution.
  • a DC voltage of approximately 100V is applied between the electrode and the loop.
  • the electrode is advanced in the solution using a micromanipulator. As soon as the tip of the electrode touches the solution, a high current density is created at the contact and the electrode is rapidly shortened. By advancing the electrode in the solution with a constant velocity, the ex- posed tip can be adjusted to a desired length, typically 100 micrometers.
  • the same loop is dried and a high voltage between 600 and 2000 V is applied to it.
  • the high voltage corrodes the carbon fiber tip in a controlled manner enabling it to be manufactured to desired shape and length.
  • the electrode tips may be coated by an insulating material such as electrophoretic depositon paint.
  • a drop of electrophoretic depositon paint is applied to a hook made of platinum.
  • the electrode is positioned in the drop so that the area to be insulated is immersed in the coating solution.
  • a DC voltage of 1-6 V is applied between the electrode and the solution for a desired time, typically around 30-90 s. This causes the paint to adhere to the carbon fiber.
  • the adhered paint is then heat-cured in an oven.
  • the aim for this optional step is to ascertain that the tips of the carbon fibers do not have an electrical connection. It also enables accurate customization of the electrode size and distance between the two electrodes.
  • step 38 the insulation may be removed from a defined portion or area of each tip.
  • the length of the naked portion of the electrode tip may advantageously be 1 ⁇ m.
  • the removal of the insulation may be accomplished either by electrical, chemical or mechanical means.
  • a measured signal level may advantageously be increased by decreasing the electrically conductive portion of the electrode tip, i.e. by shortening the naked portion of the electrode tip.
  • the electrode tips may be coated with various substances which are needed in a special application.
  • Some examples of the possible coating material are carbon nanotubes, conductive polymers, metals of different kind, Na- fion ® or synthetic or biological molecules.
  • the multichannel electrode according to the invention is ready.
  • the multichannel electrode may in addition to carbon fiber electrodes also comprise empty capillary tube or tubes. These empty capillary tubes may be used to inject a chem- ical substance to an issue under study.
  • Fig. 4 shows as an exemplary flow chart the main steps of a manufacturing process whereby the multichannel electrode according to the second embodiment of the invention may be made.
  • Fig. 4 shows as an exemplary flow chart the main steps of a manufacturing process whereby the multichannel electrode according to the second embodiment of the invention may be made.
  • some of the process steps may be accomplished in another order than depicted in Fig. 4. Therefore the manufacturing process depicted in Fig. 4 is only illustrative.
  • step 40 it is decided how many channels the multichannel electrode comprises.
  • step 41 an electrical connection between the carbon fiber and copper wire is accomplished by using two-component glue which is electrically conducting in cured state.
  • step 42 the carbon fiber is insulated with suitable dielectric such as electropho- retic deposition paint.
  • step 43 several insulated carbon fibers are integrated as a bunch.
  • step 44 a composite of a carbon fibers and copper wires is inserted in a capil- lary tube of the multichannel electrode.
  • the composite is inserted in the capillary tube so that an end of the carbon fiber extends about 10-50 mm from the capillary tube.
  • an adhesive is added to secure it to the capillary tube.
  • An oven may be used for curing the adhesive. The curing fastens the copper wire constantly to the capillary tube.
  • step 45 the free ends of the carbon fibers may be cut to a length of 1-5 mm.
  • step 46 the free ends of the carbon fibers are shortened to 5-50 ⁇ m and their tips may for example be shaped to conical shape.
  • the tips of the carbon fibers are first inserted in a loop made of inert material for example platinum, gold or silver.
  • the loop retains a liquid which is electrically conductive such as a salt solution.
  • a DC voltage of approximately 100V is applied between the electrode and the loop.
  • the electrode is advanced in the solution using a micromanipulator. As soon as the tip of the electrode touches the solution, a high current density is created at the contact and the electrode is rapidly short- ened. By advancing the electrode in the solution with a constant velocity, the exposed tip can be adjusted to a desired length, typically 100 micrometers.
  • the same loop is dried and a high voltage between 600 and 2000 V is applied to it.
  • the high voltage corrodes the carbon fiber tip in a controlled manner enabling it to be manufactured to desired shape and length.
  • the electrode tips may be coated by an insulating material such as elec- trophoretic depositon paint.
  • a drop of electrophoretic depositon paint is applied to a hook made of platinum.
  • the electrode is positioned in the drop so that the area to be insulated is immersed in the coating solution.
  • a DC voltage of 1-6 V is applied between the electrode and the solution for a desired time, typically around 30-90 s. This causes the paint to adhere to the carbon fiber.
  • the adhered paint is then heat-cured in an oven.
  • the aim of this optional step is to ascertain that the tips of the carbon fibers do not have an electrical connection. It also enables accurate customization of the electrode size and distance between the two electrodes.
  • step 47 the insulation may be removed from a defined portion or area of each tip.
  • the removal may be accomplished ei- ther by electrical, chemical or mechanical means.
  • the electrode tips may be coated with various substances which are needed in a special application.
  • Some examples of the possible coating material are carbon nanotubes, conductive polymers, metals of different kind, Na- fion ® or synthetic or biological molecules.
  • step 49 the multichannel electrode according to the second embodiment of the invention is ready.
  • glass was used as an exemplary material of the capillary tubes.
  • the material may be substituted for example by a proper plastic.

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Abstract

The invention relates to a multichannel electrode used in measuring electrical and chemical activity in biological tissue and a method for manufacturing the multi-channel electrode. For manufacturing the multichannel electrode a carbon fiber and a conductor are first attached together. Electrodes are electrically insulated from each other by directly applying insulation on their surface, or by inserting them in capillary tubes made of glass or plastic. Insulated single electrodes are then integrated into a bunch. If capillary tubes are used as insulator, the bunch is drawn to a fine tip by using heat. In both variations, distance between the tips of the electrodes is 5-50 micrometers. Electro active area at the tip can be precisely adjusted using electrochemical etching and partial insulation with suitable dielectric such as electrophoretic deposition paint. The tips may additionally be coated with suitable material such as carbon nanotubes, conductive polymer, metals of different kind, or synthetic or biological molecules.

Description

A carbon fiber multichannel electrode for measuring electrical and chemical activity in biological tissue and a process for making the electrode
Field of the invention
The invention relates to a method for manufacturing multichannel electrode from carbon fiber. The manufactured multichannel electrode comprises several adjacent needle-like microelectrodes utilized either in electrical or chemical stimulations or measurements in biological tissue.
Background of the invention
In a nervous system information between neurons is transmitted by electrical impulses called action potentials. Neurons can also communicate among each other utilizing chemical signaling in form of transmitters or hormones. Both communication methods can be measured outside the cells in the extracellular space. When studying the nervous system it is important to understand how nerve cells cooperate as a network. This requires simultaneous recording from many adjacent or nearby neurons with a single cell resolution. It is also desirable that both electrical and chemical activity can be measured simultaneously. The same communication methods are also utilized in other types of biological tissues e.g. muscle tissue. Al- though nervous system is discussed from here on as an example application, the invention is not restricted to neuron measurements but it is generally applicable to different types of biological tissue.
In some cases it is desirable to stimulate nervous tissue in experimental investigations. Stimulation can be accomplished by leading electrical current via a tip of an electrode to the nervous system. It is also possible to inject a chemical substance to the tissue as a chemical stimulus.
It is also possible to electroporate different kinds of electrically charged substances or molecules such as fluorescent and color substances, medicines and drug molecules, DNA or RNA molecules and different kinds of proteins and their precursors to the nerve cells by utilizing electrical stimulus.
In addition to electrical measurements also the electrochemical measurements can be utilized with carbon fiber electrodes. In these measurements a substance concentration is transformed to electrical signals through oxidation or reduction processes on the surface of the electrode. Several kinds of multichannel electrodes have been developed for measuring electrical activity in nervous system. They are accomplished mainly by utilizing semiconductor technology to produce a planar electrode matrix or a matrix with cylinder or needle-like electrodes protruding from the surface. Another generally known so- lution for manufacturing multichannel electrodes involves twisting four electrically insulated metal wires to a cylindrical bundle and cutting their ends in plane to form an array of circle shaped electrodes that are separated by the thickness of the insulation (= wire tetrode). These multichannel electrodes are different from the present invention in regard to their material, fabrication methods, size limitations and general electrode geometry. These electrodes do not in general enable chemical stimulation or electrochemical measurements.
Patent US 4959130 discloses a carbon fiber microelectrode comprising a sharp tip suitable for electrochemical measurements. Otherwise the depicted microelectrode is insulated against chemical and mechanical influences. The tip of the elec- trode can be 0.1 μm. Two of such electrodes are utilized for electrical stimulation with typical distance of about 2 mm in between. The large separation between two electrodes makes the method unsuitable for manufacturing multichannel electrodes.
Carbon has also been used as material in multichannel electrodes developed for measuring neural activity. Publication US 2005/0230270 discloses a flat microelectrode array consisting of carbon nanotube electrodes which are integrated to a silicon substrate. A distance between two adjacent nanotubes can be adjusted from 10 μm to 100 μm. However, the planar geometry of the microelectrode array prevents its use in applications that require penetration into the tissue. Publication US 2006/0135862 discloses a microelectrode array consisting of several sharpened carbon fiber needles where individual needles are separated with about 100 μm distance. The large separation between the individual needles makes it unsuitable for measurements of small neurons with a single neuron resolution. The mentioned methods do not enable chemical stimulation or discuss pos- sibility of electrochemical measurements.
Needle-like electrodes, such as the present invention, have been developed that are suitable for measuring neural activity. Publication US 1993/5215088 discloses a three-dimensional needle-like electrode array placed on a planar platform. Publication US 1995/5413103 discloses a microprobe consisting of one or more electrically insulated metal wires mounted in a row-like order with a clamping structure.
Publication US 2006/6993392 discloses another row-like multichannel metal micro wire electrode where wires are mounted on a printed circuit board.
Publication US 1996/5524338 discloses a microelectrode where conductive core is sharpened and coated with a dielectric material. A small area of the conductor is exposed by ablating the dielectric material with ultraviolet laser beam. Same method is used to manufacture multichannel electrodes that consist of multiple strands of a fine wire twisted together to form helical strands. Conductors of these strands can be exposed with ultraviolet laser beam to form electrode sites.
The methods above utilize needles with diameters of tens to hundreds of μm and/or individual needles separated by the distance of typically hundreds of micrometers. The large size of these electrode arrays prevents their use in measur- ing activity with a single neuron resolution in tissue with small and/or densely packed neurons. The mentioned electrodes are also not suitable for chemical stimulation or electrochemical measurements.
In summary, to study function of the nervous system it is desirable that activity of adjacent or nearby neurons could be measured at the same time with a single neuron resolution. It is also desirable that neurons could be electrically and chemically stimulated during the measurements by utilizing the same electrode. However, the multichannel electrodes known in the art do not provide means for measuring electrical activity of densely packed small neurons in the tissue below the surface (e.g. 1 -10 μm adjacent objects) or for measuring electrical activity in small experimental animals such as a fruit fly. The multichannel electrodes known in the art also do not provide a possibility for electrical and chemical stimulation or for the electrochemical measurements. Therefore, there exists a need for an ultra-small needle-like multichannel electrode suitable for recording electrical activity, chemical signals and for stimulating chemically and electrically. Summary of the invention
An object of the invention is to provide a manufacturing method and an ultra-small multichannel electrode for measuring electrical and chemical activity in biological tissue. The objects of the invention are achieved by a multichannel carbon fiber electrode where several distinct 0.1-20 μm electrode tips can locate 5-50 μm from each other.
An advantage of the invention is that the size and density of the multichannel elec- trade is suitable for measuring activity of small and densely packed objects such as neurons.
Another advantage of the invention is that the electrodes have needle-shaped sharp form.
Another advantage of the invention is that the number of distinct measurement channels can be varied.
Another advantage of the invention is that the lengths of the individual needles as well as the size and separation of the electrodes can be varied.
Another advantage of the invention is that it can be utilized both in electrical and in electrochemical measurements.
Another advantage is that it provides for electrical and/or chemical stimulation by one and the same multichannel electrode.
A further advantage of the invention is that the structure is mechanically and chemically resistant.
The multichannel electrode according to the invention is characterized in that the multichannel electrode comprises electrically insulated carbon fibers integrated as a bunch and that one end of the integrated bunch comprises at least two needle- shaped electrode tips whose distance is predetermined in a range of 5-50 μm.
The method for manufacturing a multichannel electrode for electrical and chemical measurement of neuron is characterized in that it comprises: - integrating several tubular covers as a bunch;
- drawing an end of the bunch, from which the conductive electrodes extend, to a needle shape;
- cutting ends of the conductive electrodes to a length of 1-5 mm; and
- adjusting a length and shape of a tip of the conductive electrode by electro- chemical treatment. Some advantageous embodiments of the invention are disclosed in the dependent claims.
The idea of the invention is basically as follows: The multichannel electrode comprises of several electrically insulated carbon fibers integrated together. The second ends of the carbon fibers are advantageously first individually connected to a conductor such as a copper wire with a conductive adhesive.
In the first advantageous embodiment carbon fibers having a diameter of 5-10 μm are electrically insulated with a suitable dielectric such as electrophoretic deposition paint and integrated together to form a cylindrical electrode array by inserting integrated fiber-conductor assembly into a tubular cover and securing them in place with an adhesive. Conductor wires are connected to a suitable connector.
In the second advantageous embodiment several hollow tubes are first fused together. Each one of the hollow tubes is loaded with a 5-10 μm carbon fiber- conductor assembly. The integrated bunch of hollow capillary tubes is drawn from the end where the tips of the carbon fibers are by a drawing machine known in the art. Due to the drawing the outer diameter of the bunch of the hollow capillary tubes in the drawn end is reduced considerably, wherefrom several separate carbon fiber tips extend. Conductor wires are connected to a suitable connector.
In either one of the embodiments the tips of the carbon fibers are advantageously sharpened by electrochemical and electrical means.
After shaping the electrode tips they are advantageously individually isolated in a controlled manner with a suitable dielectric such as electrophoretic depositon paint. The distance between two adjacent carbon fiber tips of the manufactured multichannel electrode may be 5-50 μm.
The electrodes may advantageously be coated with a suitable material such as a conductive polymer or a biological substance.
Connector of the multichannel electrode may be connected to a proper measurement apparatus.
Brief description of the drawings
Further scope of applicability of the present invention will become apparent from the detailed description given hereafter. It should be understood, however, that the detailed description and specific examples, while indicating advantageous em- bodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The invention is described in detail below. Reference is made to the accompany- ing drawings in which
Fig. 1 a shows a schematic representation of a multichannel electrode according to the invention before drawing;
Fig. 1 b shows a schematic representation of a multichannel electrode according to the invention after drawing;
Fig. 1 c shows a schematic representation of a multichannel electrode according to the second embodiment of the invention before drawing;
Fig. 2 shows as an example a tip of the multichannel electrode of Fig. 1 b;
Fig. 3 shows an exemplary flow chart of the main stages of the method for manufacturing a multichannel electrode according to the first embodiment of the invention; and
Fig. 4 shows an exemplary flow chart of the main stages of the method for manufacturing a multichannel electrode according to the second embodiment of the invention.
Detailed description
In the following description, considered embodiments are merely exemplary, and one skilled in the art may find other ways to implement the invention. Although the specification may refer to "an", "one" or "some" embodiment(s) in several locations, this does not necessarily mean that each such reference is made to the same embodiment(s), or that the feature only applies to a single embodiment. Sin- gle features of different embodiments may also be combined to provide other embodiments.
Fig. 1 a illustrates an example of a semi-finished multichannel electrode 1 according to the invention. The exemplary semi-finished multichannel electrode 1 comprises three exemplary carbon fiber electrodes 18 in three tubular covers 16. The length of the carbon fiber 18 may be about 30 mm and its diameter may be about 5-10 μm. Each of the carbon fibers may advantageously be bonded to a copper wire before insertion to a tubular cover.
The free ends of the carbon fibers extend a bit from the capillary tube 16. The capillary tube 16 may be made of glass or plastic. The inner diameter of the capillary tube 16 may advantageously be 0.6 mm and the outer diameter 1.2 mm.
In the example of Fig. 1 a there are three capillary tubes 16 which are integrated into a bunch 2. In the example of Fig. 1 a each of the capillary tubes 16 contains a carbon fiber-copper wire assembly 14-18. A bunch of capillary tubes according to the invention comprises several capillary tubes. The integration of the bunch may be accomplished either before or after inserting the fiber-wire assembly 14 in the capillary tubes 16.
In some embodiments one or more of the capillary tubes 16 may be left empty. In that embodiment the empty capillary tubes may be utilized to inject a chemical substance to a research object. After inserting the carbon fibers 18 and attached copper wires 14 in the capillary tubes 16, an adhesive is added to secure the wires to the capillary tubes.
Fig. 1 b illustrates an example of a finished multichannel electrode 10 according to the invention. The exemplary multichannel electrode 10 of Fig. 1 b comprises three exemplary carbon fiber electrodes.
The multichannel electrode 10 is manufactured from the semi-finished electrode 1 of Fig. 1 a by drawing the heated outer end of the capillary tube bunch 2 in a draw bench known in the art. One possible drawing machine is model PE-21 manufactured by Narishige Co. Ltd. The drawing of the capillary tube bunch 2 is accomplished in an area depicted by reference 100 in Fig. 1 b. The other ends of the copper wires 14 may be connected to a connector 12. The connector 12 may be connected by some connecting means to a proper measurement apparatus.
In Fig. 1 c is depicted an example of a semi-finished multichannel electrode tip 20a according to the second embodiment of the invention. It comprises carbon fibers 18a of 5-10 μm which are electrically insulated with a suitable dielectric 17 such as electrophoretic deposition paint and integrated together to form a cylindrical electrode array 2a. The electrode array 2a is advantageously inserted into a tubular cover 16a and secured in place with an adhesive. Conductor wires are connected to a suitable connector (not shown in Fig. 1 c). The exemplary semi-finished multichannel electrode according to the second embodiment comprises three exemplary insulated carbon fibers 18a in a plastic tubular cover 16a secured in place with an adhesive. Diameter of one carbon fiber is advantageously about 5 μm and its length about 30 mm. Each of the carbon fibers 18a may advantageously be bonded before the insulation to a copper wire with an electrically conductive adhesive. The insulation of the copper wire may be Teflon, for example. The diameter of the insulated copper wire is advantageously 0.5 mm.
Fig. 2 illustrates in more detail the needle-shaped tip 20 of Fig. 1 b. After drawing, the electrode tips 181 , 182 and 183 extend from the capillary tubes 161 a, 161 b and 161 c. The tips may advantageously be cut to a length of 1-5 mm. Then the tips 181 , 182 and 183 of the carbon fibers may be further shaped by chemical and electrical processes. The shape of the readymade tip may be for example a cone or a cylinder.
In one advantageous embodiment the tips of the carbon fibers are covered by some insulating material known in the art, such as electrophoretic depositon paint. By doing so, it can be ascertained that the tips of the carbon fibers are electrically separated from each other and the size of the electrode and the distance between two electrodes can be accurately controlled. Then in the next step some of the insulation may be removed from desired areas of the tips. A distance between the electrode tips 181 , 182 and 183 is adjustable. The distance may vary between 5 and 50 μm. Advantageously, in biological measurements the distance between the utilized electrode tips may be set in a range of 5-20 μm.
Fig. 3 shows as an exemplary flow chart the main steps of a manufacturing process whereby the multichannel electrode according to the first embodiment of the invention may be made. However, it is evident to a man skilled in the art that some of the process steps may be accomplished in another order than depicted in Fig. 3. Therefore the manufacturing process depicted in Fig. 3 is only illustrative.
In step 30 it is decided how many channels the multichannel electrode comprises. In this step it is also decided if one or some of the capillary tubes of the multichan- nel electrode are left empty. An empty capillary tube may be utilized for injecting some chemical to a biological tissue under study.
In step 31 an electrical connection between the carbon fiber and copper wire is accomplished by using two-component glue which is electrically conducting in cured state. In step 32 a composite of a carbon fiber and copper wire is inserted in a capillary tube of the multichannel electrode. The composite is inserted in the capillary tube so that an end of the carbon fiber extends about 10-50 mm from the capillary tube. After insertion of the composite an adhesive is added to secure it to the ca- pillary tube. An oven may be used for curing the adhesive. The curing fastens the copper wire constantly to the capillary tube.
In an optional step 33 several capillary tubes are integrated as a bunch. However, it is evident to a man skilled in the art that the bunch of the capillary tubes may also be manufactured before the composites are inserted in the capillary tubes. In that embodiment the bunch of capillary tubes including the composites are also heat-treated in one go.
In step 34 one end of the capillary tube bunch is drawn for reducing its outer diameter to 10-100 μm. The drawing may be accomplished for example by a drawing bench model PE-21 manufactured by Narishige Co. Ltd. After the drawing the free ends of the carbon fibers extend about 10 mm from the capillary tubes.
In step 35 the free ends of the carbon fibers may be cut to a length of 1-5 mm.
In step 36 the length of the free ends of the carbon fibers are shortened to 5- 50 μm and their tips may be shaped to conical shape. The length of the conical part of the electrode tip may vary between 0.1 and 20 μm. The length of the conic- al part of the electrode tip may be determined during the shortening and shaping process. These two processes of step 36 may be accomplished for example in two sub sequential steps.
The tips of the carbon fibers are first inserted in a loop made of inert material, for example platinum, gold or silver. The loop retains a liquid which is electrically con- ductive such as a salt solution. A DC voltage of approximately 100V is applied between the electrode and the loop. The electrode is advanced in the solution using a micromanipulator. As soon as the tip of the electrode touches the solution, a high current density is created at the contact and the electrode is rapidly shortened. By advancing the electrode in the solution with a constant velocity, the ex- posed tip can be adjusted to a desired length, typically 100 micrometers.
In the next step the same loop is dried and a high voltage between 600 and 2000 V is applied to it. The high voltage corrodes the carbon fiber tip in a controlled manner enabling it to be manufactured to desired shape and length. In an optional step 37 the electrode tips may be coated by an insulating material such as electrophoretic depositon paint. A drop of electrophoretic depositon paint is applied to a hook made of platinum. Using a micromanipulator and a microscope, the electrode is positioned in the drop so that the area to be insulated is immersed in the coating solution. A DC voltage of 1-6 V is applied between the electrode and the solution for a desired time, typically around 30-90 s. This causes the paint to adhere to the carbon fiber. The adhered paint is then heat-cured in an oven. The aim for this optional step is to ascertain that the tips of the carbon fibers do not have an electrical connection. It also enables accurate customization of the electrode size and distance between the two electrodes.
If step 37 is utilized, then in an optional step 38 the insulation may be removed from a defined portion or area of each tip. The length of the naked portion of the electrode tip may advantageously be 1 μm. The removal of the insulation may be accomplished either by electrical, chemical or mechanical means. A measured signal level may advantageously be increased by decreasing the electrically conductive portion of the electrode tip, i.e. by shortening the naked portion of the electrode tip.
In an optional step the electrode tips may be coated with various substances which are needed in a special application. Some examples of the possible coating material are carbon nanotubes, conductive polymers, metals of different kind, Na- fion® or synthetic or biological molecules.
In step 39 the multichannel electrode according to the invention is ready. The multichannel electrode may in addition to carbon fiber electrodes also comprise empty capillary tube or tubes. These empty capillary tubes may be used to inject a chem- ical substance to an issue under study.
Fig. 4 shows as an exemplary flow chart the main steps of a manufacturing process whereby the multichannel electrode according to the second embodiment of the invention may be made. However, it is evident to a man skilled in the art that some of the process steps may be accomplished in another order than depicted in Fig. 4. Therefore the manufacturing process depicted in Fig. 4 is only illustrative.
In step 40 it is decided how many channels the multichannel electrode comprises.
In step 41 an electrical connection between the carbon fiber and copper wire is accomplished by using two-component glue which is electrically conducting in cured state. In step 42 the carbon fiber is insulated with suitable dielectric such as electropho- retic deposition paint.
In step 43 several insulated carbon fibers are integrated as a bunch.
In step 44 a composite of a carbon fibers and copper wires is inserted in a capil- lary tube of the multichannel electrode. The composite is inserted in the capillary tube so that an end of the carbon fiber extends about 10-50 mm from the capillary tube. After insertion of the composite an adhesive is added to secure it to the capillary tube. An oven may be used for curing the adhesive. The curing fastens the copper wire constantly to the capillary tube.
In step 45 the free ends of the carbon fibers may be cut to a length of 1-5 mm.
In step 46 the free ends of the carbon fibers are shortened to 5-50 μm and their tips may for example be shaped to conical shape. These two processes can be accomplished for example in two sub sequential steps.
The tips of the carbon fibers are first inserted in a loop made of inert material for example platinum, gold or silver. The loop retains a liquid which is electrically conductive such as a salt solution. A DC voltage of approximately 100V is applied between the electrode and the loop. The electrode is advanced in the solution using a micromanipulator. As soon as the tip of the electrode touches the solution, a high current density is created at the contact and the electrode is rapidly short- ened. By advancing the electrode in the solution with a constant velocity, the exposed tip can be adjusted to a desired length, typically 100 micrometers.
In the next step the same loop is dried and a high voltage between 600 and 2000 V is applied to it. The high voltage corrodes the carbon fiber tip in a controlled manner enabling it to be manufactured to desired shape and length.
In step 47 the electrode tips may be coated by an insulating material such as elec- trophoretic depositon paint. A drop of electrophoretic depositon paint is applied to a hook made of platinum. Using a micromanipulator and a microscope, the electrode is positioned in the drop so that the area to be insulated is immersed in the coating solution. A DC voltage of 1-6 V is applied between the electrode and the solution for a desired time, typically around 30-90 s. This causes the paint to adhere to the carbon fiber. The adhered paint is then heat-cured in an oven. The aim of this optional step is to ascertain that the tips of the carbon fibers do not have an electrical connection. It also enables accurate customization of the electrode size and distance between the two electrodes.
If step 47 is utilized, then in an optional step 48 the insulation may be removed from a defined portion or area of each tip. The removal may be accomplished ei- ther by electrical, chemical or mechanical means.
In an optional step the electrode tips may be coated with various substances which are needed in a special application. Some examples of the possible coating material are carbon nanotubes, conductive polymers, metals of different kind, Na- fion® or synthetic or biological molecules.
In step 49 the multichannel electrode according to the second embodiment of the invention is ready.
In the description above glass was used as an exemplary material of the capillary tubes. However, instead of using glass in the capillary tubes the material may be substituted for example by a proper plastic.
Some advantageous embodiments according to the invention were described above. The invention is not limited to the embodiments described. The inventional idea can be applied in numerous ways within the scope defined by the claims attached hereto.

Claims

Claims
1. A multichannel electrode (10) for measuring electrical and chemical activity in biological tissue, in which each measurement channel comprises: - an electrically insulated carbon fiber electrode (18, 18a) comprising a shaped tip at a first end of the conductive electrode;
- a conductor (14) connected to a second end of the conductive electrode (18, 18a); and
- at least one tubular protective cover (16, 16a, 17) covering a connection point of the conductive electrode (18, 18a) and the conductor (14), characterized in that the multichannel electrode (10) comprises electrically insulated carbon fibers (18, 18a) integrated as a bunch (2, 2a) and that one end of the integrated bunch comprises at least two needle-shaped electrode tips (18a, 181 , 182, 183) whose distance is predetermined in a range of 5-50 μm.
2. The multichannel electrode according to claim 1 , characterized in that the tips of the multichannel electrode (10) are configured to be used in measuring electrical and/or chemical activity in biological tissue.
3. The multichannel electrode according to claim 1 or 2, characterized in that the electrode tips (181 , 182, 183) have a shape of a cone or a cylinder.
4. The multichannel electrode according to claim 3, characterized in that a length of the conical part of the electrode tips (181 , 182, 183) is in a range of 0.1 - 20 μm.
5. The multichannel electrode according to claim 4, characterized in that it is configured to be used in electrical stimulation or electroporation.
6. The multichannel electrode according to claim 2, characterized in that the integrated bunch (2) comprises an empty tubular protective cover (16) which is configured to be used for injecting chemicals to the target tissue.
7. The multichannel electrode according to claim 1 , characterized in that the in- tegrated bunch (2) of carbon fibers (18a) is covered by a common tubular cover (16a).
8. The multichannel electrode according to claim 1 , characterized in that each of the carbon fibers (18) is covered by an individual tubular cover (16) which tubular covers are integrated together as a bunch (2).
9. The multichannel electrode according to claim 8, characterized in that one end of the integrated bunch (2) of tubular covers (16) is reduced by drawing to form a needle-shaped tip (20).
10. The multichannel electrode according to claim 8 or 9, characterized in that the tubular protective cover (16, 16a) is glass or plastic.
1 1. A method for manufacturing a multichannel electrode for electrical and chemical measurement in biological tissue, the method comprising:
- attaching (31 ) a conductive electrode and a conductor mechanically and electri- cally to a composite;
- inserting (32) the composite of the conductive electrode and the conductor in a tubular cover so that the conductive electrode extends from the tubular cover; and
- connecting the composite and the tubular cover together by heating, characterized in that the method further comprises: - integrating (33) several tubular covers into a bunch;
- drawing (34) an end of the bunch, from which the conductive electrodes extend, to a needle shape;
- cutting (35) ends of the conductive electrodes to a length of 1-5 mm; and
- adjusting (36) a length and shape of a tip of the conductive electrodes by elec- tro-chemical treatment.
12. The method according to claim 1 1 , characterized in that the adjusting the length and shape of the tip comprises:
- inserting the tip in a loop made of inert material which loop retains electrically conductive liquid;
- applying a direct current from the loop to rapidly corrode the tip to a predetermined length and form by oxidation; and
- drying the loop and applying high voltage of 600-2000 V to electrically corrode the tip to desired length and shape.
13. The method according to claim 1 1 , characterized in that the method further comprises:
- insulating (38) the tips of the conductive electrodes; and - removing a part of the insulation from the tips mechanically, chemically or electrically.
14. The method according to claim 13, characterized in that the method further comprises coating the electrode tip with a special substance such as carbon nano- tubes, conductive polymer or organic molecules.
15. The method according to claim 1 1 , characterized in that to the bunch of the several tubular covers is integrated also at least one empty tubular cover to pro- vide means for injecting substances to the biological tissue.
PCT/FI2010/050162 2009-03-09 2010-03-02 A carbon fiber multichannel electrode for measuring electrical and chemical activity in biological tissue and a process for making the electrode WO2010103174A1 (en)

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