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WO2015092109A1 - Microsonde neuronale et procédé de fabrication de celle-ci - Google Patents

Microsonde neuronale et procédé de fabrication de celle-ci Download PDF

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Publication number
WO2015092109A1
WO2015092109A1 PCT/ES2014/070940 ES2014070940W WO2015092109A1 WO 2015092109 A1 WO2015092109 A1 WO 2015092109A1 ES 2014070940 W ES2014070940 W ES 2014070940W WO 2015092109 A1 WO2015092109 A1 WO 2015092109A1
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WIPO (PCT)
Prior art keywords
layer
polymer
micro
probe
providing
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English (en)
Spanish (es)
Inventor
Rosa Villa
Elisabet PRATS ALFONSO
Gemma Gabriel Buguña
Philippe Godignon
Maria Victoria SANCHEZ VIVES
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Consejo Superior de Investigaciones Cientificas CSIC
Institucio Catalana de Recerca i Estudis Avancats ICREA
Institut d'Investigacions Biomèdiques August Pi i Sunyer
Original Assignee
Consejo Superior de Investigaciones Cientificas CSIC
Institucio Catalana de Recerca i Estudis Avancats ICREA
Institut d'Investigacions Biomèdiques August Pi i Sunyer
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Publication of WO2015092109A1 publication Critical patent/WO2015092109A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
    • A61B5/293—Invasive
    • 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
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
    • 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
    • A61N1/0526—Head electrodes
    • A61N1/0529—Electrodes for brain stimulation
    • 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
    • A61N1/0551—Spinal or peripheral nerve electrodes
    • 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
    • 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
    • A61N1/0404—Electrodes for external use
    • A61N1/0472—Structure-related aspects
    • A61N1/0476—Array electrodes (including any electrode arrangement with more than one electrode for at least one of the polarities)

Definitions

  • the present invention relates to a method of manufacturing at least one flexible, biocompatible and implantable neuronal microprobe in the brain, and also relates to such a micro-probe.
  • neuronal micro-probes have already had a significant positive effect on our understanding of the brain to reveal the functioning of biological neuron networks.
  • the neuronal micro-probes provide an electrical connection between the biological neuronal tissue and physical devices and corresponding electronic control systems.
  • Neural micro-probes can be implanted in different areas of the brain to record signals from specific parts of the brain and / or to stimulate those parts. Neural micro-probes are currently used in many clinical settings for the diagnosis of brain diseases, such as seizures, epilepsy, migraine, Alzheimer's disease and dementia. These devices also help patients affected by paralysis, since they can handle computers or robots from the patient's neuronal activity.
  • a neuronal micro-probe can be mounted on a support to facilitate its handling and connection and to have a better control of the instrumentation.
  • i Metal materials also have the disadvantage of having too low signal / noise ratios.
  • the biocompatibility of neuronal microbes also plays an important role in minimizing rejection of the foreign body in determining the long-term functionality of neuronal micro-probes after implantation.
  • a manufacturing process of at least one flexible, biocompatible and implantable neuronal micro-probe comprises the steps of:
  • - providing a temporary assembly comprising providing a layer of a rigid substrate and providing a layer of a soluble polymer on said rigid substrate layer;
  • - providing at least one microelectrode assembly on said temporary assembly comprising providing a layer of a first polymer and engraving on said first polymer layer at least one opening, and providing a layer of a two-dimensional conductive material on said first polymer layer and engraving on said layer of two-dimensional conductive material at least one microelectrode provided with at least one contact area; - providing a finishing assembly on said microelectrode assembly; Y
  • the rigid substrate can be a silicon wafer, silicon carbide or glass. These materials are commonly used in electronic assemblies because of their good strength, low cost and wide availability.
  • the rigid substrate provides the necessary solid surface without which it would not be possible to uniformly add the ultra thin layers of flexible polymers and two-dimensional conductive material.
  • the solid surface is also necessary for high definition etching of the openings in the polymer and high definition etching of the microelectrodes in the two-dimensional conductive material.
  • a preferred embodiment of two-dimensional conductive material is graphene.
  • Graphene has a two-dimensional atomic structure and is only one atom thick.
  • the two-dimensional conductive material layer can be obtained by means of vapor deposition or by synthesis on silicon carbide.
  • uniform large surface graphene poly-crystalline films can be produced by vapor deposition on copper sheets or films.
  • the transfer process may require the addition of a polymethyl methacrylate (PMMA) protective layer that would not affect the manufacturing process of a flexible neuronal micro-probe described herein.
  • PMMA polymethyl methacrylate
  • graphene layers can be produced either on the silicon face or on the carbon face of a silicon carbide wafer by sublimation of silicon atoms, thus leaving a graphitized surface that can be transferred for use
  • the two-dimensional conductive material may be a metal, for example gold, titanium, aluminum, chromium or copper.
  • Providing the assembly of a microelectrode layer may comprise providing a layer of ultra-fine microelectrodes engraved on the two-dimensional conductive material and an ultra-thin insulating polymer layer with specifically assigned openings to provide access to the microelectrode contact areas and to delineate the perimeter. outside of the micro probe.
  • Microelectrodes and openings can be etched using positive or negative photo resistant polymers recorded by photolithography.
  • the Microelectrodes and openings can be etched by reactive ionic etching, in which case the polymer does not need to be a photo-resistant polymer.
  • microelectrode assembly at the top of the first microelectrode assembly provides two distinct layers of microelectrodes. If necessary, these layers of microelectrodes can be internally connected to each other at one or more points based on engraving openings in the layer of insulating polymer present between them.
  • the finishing assembly serves to add a range of features to the flexible, biocompatible and implantable neuronal micro-probe, including the provision of access to microelectrode contact areas from one or more outer faces of the micro-probe, and the provision of one or more fluidic microchannels for drug administration.
  • the soluble polymer is dissolved in a solution in order to discard the rigid substrate and to retain the micro-probe.
  • the method comprises the joint and simultaneous manufacture of at least two of said biocompatible and implantable flexible neuronal micro-probes.
  • the same procedure can be used to manufacture multiple neuronal micro-probes on top of the same rigid substrate, which can form individual matrices of multiple micro-probes or can form multiple independent individual micro-probes.
  • providing a finishing assembly comprises providing a layer of a second polymer on said at least one microelectrode assembly.
  • the finishing assembly can simply be a final layer of unrecorded polymer.
  • the resulting micro-probe will only have access to microelectrode contact areas provided in one or more layers from only one outer face of the micro-probe.
  • providing a finishing assembly further comprises engraving at least one opening in the second polymer layer.
  • recording openings in the polymer can provide the necessary access to the microelectrode contact areas from a second outer face of the micro probe.
  • these openings can also delineate the outer perimeter of the micro-probe or, in case of adding a microchannel for fluids, these openings can be used to create one or more of said fluidic microchannels in the micro-probe.
  • providing a finishing assembly further comprises:
  • a fluidic microchannel for the neuronal administration of drugs provided with at least one outlet on a surface of the micro-probe can be included therein by providing one or more microelectrode assemblies and recording openings to form the fluidic channel in the layers of microelectrode assemblies.
  • a rigid substrate layer is provided separately, which is coated with a soluble polymer layer.
  • the rigid substrate provides the solid platform necessary to provide a uniform layer of a third polymer over the soluble polymer layer.
  • This independent assembly can then be turned around and attached to the upper second polymer layer of the microelectrode assembly to cover and close the microchannel (s) for fluids.
  • providing a layer of a third polymer further comprises engraving at least one opening therein. Engraving the third polymer can serve to form a microchannel, delineate access to contact areas and microchannel outputs and also the perimeter of the neuronal micro-probe.
  • the first polymer, the second polymer and the third polymer may be of the same polymeric material.
  • the soluble polymer may be poly-acrylic acid (PAA) and the solvent solution thereof may be water.
  • PAA poly-acrylic acid
  • water-soluble polymers include polyacrylic acid, dextran, polymethacrylic acid, polyacrylamide, polyethyleneimine, polyvinyl alcohol and polyethylene oxide.
  • Another type of solvent solution may be acetone.
  • the process allows a wide range of polymers to be used for the different layers although it also allows all the polymer layers to be of the same material.
  • the polymers can be positive or negative photo-resistant polymers, in which case etching can be done by photolithography.
  • one or more of the polymers may be SU-8 which is a negative photoresin.
  • Another polymer may be the thermoplastic COP polymer, which is an epoxy copolymer of glycidyl methacrylate and ethyl acrylate.
  • Other examples of polymers include, among others: PET (polyethylene terephthalate), PEN (polyethylene naphthalate), PMMA (polymethyl methacrylate), PC (polycarbonate), PE (polyethylene), or PS (polystyrene).
  • a flexible, biocompatible and implantable neuronal micro-probe comprises at least one layer of a two-dimensional conductive material sandwiched between two layers of polymeric material, said layer of two-dimensional conductive material comprising at least one microelectrode provided with at least one area contact, so that at least one of said two layers of polymeric material comprises at least one opening to access said microelectrode contact area from at least one outer face of the micro-probe.
  • the neuronal micro-probe comprises two key materials, the two-dimensional conductive material, preferably of graphene, and the insulating layer, preferably of SU-8 polymer. Both materials can be provided in ultra-thin layers. They are strong, flexible, compatible for use in magnetic resonance systems, biocompatible, and have a high signal / noise ratio.
  • the neuronal micro-probe may comprise one or more layers of microelectrodes, each with one or more contact contact areas on one or more surfaces of the micro probe. Therefore, the flexible and implantable biocompatible neuronal micro-probe can be used in a wide range of bio-neuronal applications, including short-term or long-term in-vivo implantation, for simultaneous and precise stimulation and detection of neuronal signals. between two or more microelectrodes, or precise multi-neuronal detection located on one or more sides of the same neuronal micro-probe.
  • the flexible, biocompatible and implantable neuronal micro-probe is also compatible with MRI systems, since it can be used within them for having non-metallic electrodes.
  • the micro-probe can be classified as "conditional on magnetic resonance," which is defined as a device or implant that can contain magnetic components, conductors or radio frequency reagents, which are safe to operate in close proximity to the MRI system. Consequently, said neural micro-probes can be connected to the instrumentation and control electronics using "zero insertion force" (ZIF) connectors for integrated circuits and magnetic resonance compatible cables.
  • ZIF zero insertion force
  • the two-dimensional conductive material layer comprises at least two microelectrodes. A minimum of two microelectrodes is necessary to stimulate neurons.
  • a neuronal micro-probe with at least two microelectrodes can stimulate and detect neuronal signals and offer more precise measurements and tight control.
  • the micro-probe comprises at least two layers of the two-dimensional conductive material, each of which in turn comprises at least one microelectrode.
  • the ability to pack multiple microelectrodes within a small surface area or volume offers more precise measurements because, otherwise, it is difficult to specifically identify the location of specific neurons.
  • the micro-probe may comprise two or more layers of microelectrodes with multiple electrodes per layer.
  • each layer of polymeric material comprises at least one opening to access the microelectrode contact area from at least two outer faces of the micro-probe.
  • the micro-probe can be used to stimulate neurons and detect neuronal signals on two or more faces of the same micro-probe, in order to increase the number of measurement points within a small area with greater precision and accuracy in neuronal research, measurement and control.
  • the two-dimensional conductive material is graphene.
  • graphene is a layer with a thickness of a single carbon atom that combines a minimum thickness with high mechanical resistance, high thermal and electrical conductivities, and such flexibility that it can be wrapped around delicate fabrics. It is also biocompatible and does not cause adverse biological reactions when implanted in human or animal living tissue. Graphene is also compatible with magnetic resonance imaging, since it does not cause interference or adverse reactions when used in a magnetic resonance imaging device. This is particularly useful for use with patients with long-term implanted neuronal micro-probes.
  • the polymeric material is SU-8.
  • the SU-8 is a very viscous polymer that can extend with a thickness that varies from less than 1 micrometer to more than 300 micrometers, and still be processed with standard photolithography by which it can be recorded in high resolution. It is also biocompatible and compatible with MRI systems.
  • the micro-probe comprises at least one microchannel for the application of neuronal drugs, thus allowing simultaneous neuronal stimulation, signal recording and administration of drugs to the brain.
  • Figure 1 represents a first embodiment of a manufacturing method of a flexible, biocompatible, flexible neuronal micro-probe and implantable
  • Figure 2 represents a second embodiment of the manufacturing process
  • Figure 3 represents a third embodiment of the manufacturing process
  • Figure 4 represents a first flow chart in relation to the manufacturing process
  • Figure 5 represents a second flow chart in relation to the manufacturing process
  • Figure 6 represents a flexible, biocompatible and implantable neuronal micro-probe
  • Figure 7 represents two micro-probes
  • Figure 8 represents a series of twenty-six micro-probes
  • Figure 9 represents a flexible, biocompatible and implantable neuronal micro-probe with a fluidic microchannel.
  • Figure 1 illustrates a first embodiment of a manufacturing process for a flexible, biocompatible and implantable neuronal micro-probe, and provided with a microelectrode layer and at least two openings to access the microelectrode contact areas from an outer face. of the micro-probe.
  • FIG. 1 (a) A layer of a rigid substrate 100, for example a glass or silicon wafer, is shown in Figure 1 (a).
  • Figure 1 (b) shows a layer of a soluble polymer 10, for example poly-acrylic acid (PAA), provided on the rigid substrate layer 100.
  • PAA poly-acrylic acid
  • the assembly formed by the rigid substrate layer and the layer of soluble polymer will be called temporary assembly 180.
  • a layer of a first polymer 130, for example SU-8, provided on temporary assembly 180 is shown in Figure 1 (c).
  • the first polymer layer 130 has been etched by photolithography (140 ) to form two openings 151 and 152.
  • Figure 1 (e) shows a layer of a two-dimensional conductive material 160, such as graphene, provided on the first polymer layer 130.
  • the assembly formed by the first polymer layer and the two-dimensional conductive material layer will be referred to as microelectrode assembly 190.
  • the two-dimensional conductive material layer 160 has been etched by photolithography (140) to form one or more microelectrodes.
  • Figure 1 (g) illustrates a microelectrode etched by photolithography in the two-dimensional conductive material layer 160.
  • FIG. 1 (h) A layer of a second polymer 170, for example SU-8, provided on the microelectrode assembly 190 is shown in Figure 1 (h).
  • the second polymer layer 170 is also called finishing assembly 195.
  • Figure 1 (h) also illustrates the immersion of at least the temporary assembly 180 in a solution 120, for example water, to dissolve the soluble polymer layer 1 10 in order to discard the rigid substrate 100.
  • Figure 1 (i) represents a cross-sectional view of a flexible, biocompatible and implantable micro-probe and provided with a microelectrode 160 and at least two openings 151 and 152 to access the microelectrode contact areas from an outer face of the micro-probe.
  • Figure 2 illustrates a second embodiment of the manufacturing process of a flexible, biocompatible and implantable neuronal micro probe, and provided with two microelectrode assemblies and four openings for accessing the contact areas of each microelectrode from two outer faces of the micro -probe.
  • a layer of a rigid substrate 200 for example a glass or silicon wafer, is shown in Figure 2 (a).
  • a layer of a soluble polymer 210, for example poly-acrylic acid (PAA), provided on the rigid substrate layer 200 is shown in Figure 2 (b).
  • the assembly formed by the rigid substrate layer and the polymer layer soluble will be called temporary assembly 280.
  • a layer of a first polymer 230, for example SU-8, provided on the temporary assembly 280 is shown in Figure 2 (c).
  • the first polymer layer 230 has been etched by photolithography (240 ) to form two openings 251 and 252.
  • the first microelectrode assembly 290 The assembly formed by the first polymer layer and the first layer of two-dimensional conductive material will be called the first microelectrode assembly 290.
  • the layer of Two-dimensional conductive material 260 has been recorded by photolithography (240) to form one or more microelectrodes.
  • Fig. 2 (g) illustrates a microelectrode engraved on the first layer of two-dimensional conductive material 260.
  • the second layer of two-dimensional conductive material 261 has been etched by photolithography (240) to form one or more microelectrodes
  • Figure 2 (j) illustrates a microelectrode engraved on the second layer of two-dimensional conductive material 261.
  • FIG. 2 (k) A layer of a second polymer 270, provided on the second microelectrode assembly 291, is shown in Figure 2 (k).
  • the second polymer layer 270 is also called finishing assembly 295.
  • the second polymer layer 270 has been etched by photolithography (240).
  • Figure 2 (1) illustrates two openings 253 and 254 etched in third polymer 270.
  • Figure 2 (m) illustrates the immersion of at least the temporary assembly 280 in a solution 220, for example water, to dissolve the soluble polymer layer 210 in order to discard the rigid substrate 200.
  • a solution 220 for example water
  • Figure 2 (n) represents a cross-sectional view of a flexible, biocompatible and implantable micro-probe and provided with two microelectrode assemblies 290 and 291 and four openings 251, 252, 253, 254 for accessing the contact areas of each microelectrode from two outer faces of the micro-probe.
  • Figure 3 illustrates a third embodiment of the manufacturing process of a flexible, biocompatible and implantable neuronal microprobe and provided with a microelectrode layer and at least two openings for accessing the microelectrode contact areas from an outer face of the micro -probe.
  • the micro-probe also comprises a fluidic channel with at least two outputs on said surface of the micro-probe.
  • a layer of a rigid substrate 300 for example a glass or silicon wafer, is shown in Figure 3 (a).
  • PAA poly-acrylic acid
  • the assembly formed by the rigid substrate layer and the soluble polymer layer It will be called temporary assembly 380.
  • a layer of a first polymer 330, for example SU-8, provided on the temporary assembly 380 is shown in Figure 3 (c).
  • the first polymer layer 330 has been etched by photolithography (340 ) to form four openings 356, 357, 358 and 359.
  • Figure 3 (e) shows a layer of a two-dimensional conductive material 360, for example graphene, provided on the first polymer layer 330.
  • the assembly formed by the first polymer layer and the two-dimensional conductive material layer will be called assembly of microelectrode 390.
  • the layer of two-dimensional conductive material 360 has been etched by photolithography (340) to form one or more microelectrodes.
  • a layer of a second polymer 370, for example SU-8, provided on the microelectrode assembly 390 is shown in Figure 3 (g).
  • the second polymer layer 370 has been etched by photolithography (340) to form openings 355 , 358 and 359 etched in the second polymer 370 representing the fluid channel and the two outputs, respectively.
  • a layer of a rigid substrate 305 for example a silicon wafer, silicon carbide or glass, is shown separately in Figure 3 (h).
  • a layer of a soluble polymer 315, polyacrylic acid (PAA), provided on this rigid substrate layer 305 is shown in Figure 3 (i).
  • the assembly formed by the rigid substrate layer and the soluble polymer layer will be called assembly temporary 385.
  • a layer of a third polymer 375, for example SU-8, provided on said temporary assembly 385 is shown in Figure 3 (j).
  • Figure 3 (k) illustrates the union of the third polymer layer 375 with the second polymer provided on the microelectrode assembly 390.
  • the second polymer layer 370, the third polymer layer 375 and the assembly Temporal 385 together form a finishing assembly 395.
  • Figure 3 (k) also illustrates the immersion of the two temporary assemblies 380 and 385 in a solution 320, for example water, to dissolve the layers of soluble polymer 310 and 315 in order to discard the rigid substrates 300 and 305.
  • a solution 320 for example water
  • Figure 3 (1) represents a cross-sectional view of a flexible, biocompatible and implantable micro-probe and provided with a microelectrode layer 360 and at least two openings 356 and 357 to access the microelectrode contact areas from an outer face of the micro-probe.
  • the micro-probe also comprises a fluidic channel 355 with at least two outputs 358 and 359 on a surface of the micro-probe.
  • Figure 4 illustrates a first flow chart in relation to an embodiment of the manufacturing process of a flexible, biocompatible and implantable neuronal micro-probe.
  • a rigid substrate layer is provided, for example a glass or silicon wafer.
  • a soluble polymer layer for example poly-acrylic acid (PAA) is provided on the rigid substrate layer.
  • PAA poly-acrylic acid
  • a layer of a first polymer for example SU-8, is provided on the temporary assembly.
  • This first polymer layer can be etched by photolithography or by reactive ions (RIE) to form one or more openings. Such openings may provide contact access between the outside of the micro-probe and the microelectrode contact areas. Another opening may partially define a fluid channel or an inlet or outlet associated with the fluid channel. However, another opening can also delineate the outer perimeter of the flexible micro-probe.
  • RIE reactive ions
  • a layer of a two-dimensional conductive material for example graphene
  • the whole of the first polymer layer and the two-dimensional conductive material layer is called the microelectrode assembly.
  • the two-dimensional conductive material layer can be etched by photolithography or by reactive ions (RIE) to form one or more microelectrodes in the two-dimensional conductive material layer itself.
  • RIE reactive ions
  • step 450 the procedure allows, if necessary, the addition of an additional microelectrode assembly based on repeating steps 430 and 440. Providing an additional microelectrode assembly results in a second layer of one or more microelectrodes.
  • step 430 contact access between two microelectrodes can be provided on two different layers based on engraving openings in the first polymer if step 430 is repeated.
  • step 450 another microelectrode assembly can still be added to form a micro-probe with three layers of one or more microelectrodes.
  • steps 460 and 480 are directed to provide a finishing assembly.
  • a layer of a second polymer is added to the uppermost layer of the microelectrode assembly.
  • openings in the second polymer layer can be etched by photolithography or by reactive ions. Such openings can provide contact access between an outer face of the micro-probe and the microelectrode contact areas.
  • Another opening may partially define a fluid microchannel or an inlet or outlet associated with said fluid microchannel.
  • another opening can also delineate the outer perimeter of the flexible micro-probe.
  • step 470 in some embodiments it may be a requirement to have a fluid microchannel and then the procedure follows in step 480. In other embodiments there may be no need for a fluid channel, in which case the procedure may jump directly to stage 490.
  • step 480 the assembly is attached to a cover assembly obtained at the output of the flow chart of Figure 5.
  • the cover assembly provides a cover for the fluidic microchannel.
  • the rigid substrate (s) is discarded by dissolving the soluble polymer, for example polyacrylic acid, in a solution, for example water.
  • step 495 the procedure ends.
  • Figure 5 illustrates a second flow chart in relation to the manufacturing process of a flexible, biocompatible and implantable neuronal micro-probe.
  • step 500 the procedure to provide said cover assembly is initiated.
  • a separate layer of rigid substrate is provided in step 510, for example a wafer made of glass or silicon.
  • a separate layer of soluble polymer for example poly-acrylic acid (PAA) is provided on the separated layer of rigid substrate.
  • PAA poly-acrylic acid
  • a layer of a first polymer for example SU-8, is provided on the temporary assembly.
  • This first polymer layer can be etched by photolithography or by reactive ions (RIE) to form one or more openings.
  • RIE reactive ions
  • Such openings can provide contact access between the outside of the micro-probe and the contact areas of microelectrodes.
  • Another opening may partially define a fluid channel or an inlet or outlet associated with said fluid channel.
  • another opening can also delineate the outer perimeter of the flexible micro-probe.
  • step 540 the procedure ends.
  • Figure 6 illustrates a single flexible, biocompatible and implantable neuronal micro-probe 600 comprising 10 610 microelectrodes in one layer.
  • the microelectrodes and their contact areas 651 and 652 are engraved on the two-dimensional conductive material.
  • the outer perimeter 640 of the micro-probe is delineated by etching the polymer.
  • Figure 7 illustrates two flexible, biocompatible and implantable neuronal micro-probes 700 and 710, each comprising 4 microelectrodes 720 in one layer.
  • the microelectrodes and their contact areas 751 and 752 are engraved on the two-dimensional conductive material.
  • the micro-probes are placed on top of a temporary assembly 730 comprising a rigid substrate, such as a silicon wafer.
  • the outer perimeter 740 of the micro-probe is delineated based on etching the polymer.
  • Figure 8 illustrates a matrix of twenty-six micro-probes 800 and 801, biocompatible and implantable flexible neurons, arranged on a temporary assembly 830 comprising a rigid substrate, such as a silicon wafer.
  • Figures 9 (a) and (b) represent a flexible, biocompatible and implantable neuronal micro-probe 910, provided with a fluidic microchannel 960.
  • Figure 9 (a) illustrates a cross-section of a neuronal micro-probe 910 provided with the microchannel fluid 960 and an inlet 930 and outlets 940 and 950 for the fluid.
  • Figure 9 (b) illustrates the same micro probe 910 seen from the outside with the fluid outlets 940 and 950 visible.

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  • Radiology & Medical Imaging (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Micromachines (AREA)
  • Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)

Abstract

La présente invention concerne un procédé de fabrication d'au moins une microsonde neuronale souple, biocompatible et implantable qui comprend les étapes consistant à: former une couche d'un substrat rigide (100); former une couche d'un polymère soluble (110) sur ladite couche de substrat rigide; former une couche d'un premier polymère (130); graver dans ladite couche de premier polymère au moins une ouverture (151; 152); former une couche d'un matériau conducteur bidimensionnel (160) sur ladite couche de premier polymère; graver dans ladite couche de matériau conducteur bidimensionnel au moins une microélectrode pourvue d'au moins une zone de contact; former un assemblage de finition (195) sur la microélectrode; et dissoudre ledit polymère soluble dans une solution (120). La microélectrode obtenue (160) est intercalée entre deux couches de matériau polymère (190, 195), dont une comprend une ouverture (151; 152) permettant d'accéder à ladite zone de contact.
PCT/ES2014/070940 2013-12-20 2014-12-19 Microsonde neuronale et procédé de fabrication de celle-ci Ceased WO2015092109A1 (fr)

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ES201331895A ES2541552B1 (es) 2013-12-20 2013-12-20 Micro-sonda neuronal y procedimiento de fabricación de la misma
ESP201331895 2013-12-20

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EP3375482A1 (fr) * 2017-03-14 2018-09-19 Scriba Nanotecnologie S.r.l. Dispositif multifonctionnel implantable actif sur un échafaudage biodégradable/biorésorbable et ses procédés de fabrication
WO2025021483A1 (fr) * 2023-07-24 2025-01-30 The University Court Of The University Of Glasgow Microsonde neuronale et son procédé de fabrication

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WO2011159923A2 (fr) * 2010-06-18 2011-12-22 The Regents Of The University Of Michigan Électrodes à micro-composants implantables
WO2012075120A2 (fr) * 2010-11-30 2012-06-07 University Of South Florida Électrodes de graphène sur dispositif de prothèse neuronale implantable sur le long terme en carbure de silicium (3c-sic) cubique plan
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WO2012075120A2 (fr) * 2010-11-30 2012-06-07 University Of South Florida Électrodes de graphène sur dispositif de prothèse neuronale implantable sur le long terme en carbure de silicium (3c-sic) cubique plan
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3375482A1 (fr) * 2017-03-14 2018-09-19 Scriba Nanotecnologie S.r.l. Dispositif multifonctionnel implantable actif sur un échafaudage biodégradable/biorésorbable et ses procédés de fabrication
WO2025021483A1 (fr) * 2023-07-24 2025-01-30 The University Court Of The University Of Glasgow Microsonde neuronale et son procédé de fabrication

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ES2541552A1 (es) 2015-07-21

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