Substrate, electrode element, and electrode system for implanted microelectrodes, and manufacturing method thereof

Abstract

A substrate for an implanted microelectrode for implantation into tissue, such as a nerve, or in contact with a single cell for applying and / or recording electrical signals to and / or from the tissue or single cell is provided, the substrate comprising a first layer and a second layer deposited on at least a portion of a first surface of the first layer, the first layer and the second layer each extending in the x-direction and the y-direction, the first layer and the second layer stacked in the z-direction, (i) the first layer is based on a first mixture, the first mixture comprising a first component comprising at least one of: (a) a first photoinitiator, (b) a first monomer, a first oligomer, or a first polymer, the first monomer, (i) a first component, the first monomer or first oligomer or first copolymer comprising a first functional group, the first functional group being capable of being activated by a first photoinitiator such that the first component can be photopolymerized via the first functional group; and (ii) the second layer is based on a second mixture, the second mixture comprising: (c) a second photoinitiator; (d) a second component comprising a second monomer or second oligomer or second polymer, the second monomer or second oligomer or second copolymer comprising a first functional group, the first functional group being capable of being activated by a first photoinitiator such that the first component can be photopolymerized via the first functional group; and a second component, the second oligomer or second polymer being an acid and comprising a second functional group, the second functional group being capable of being activated by a second photoinitiator such that the second component can be linearly photopolymerized via the second functional group; (e) a base, the base being capable of neutralizing the second monomer or the second oligomer or the second polymer, thereby forming a salt; and (f) a third component comprising at least one of a third oligomer or third polymer, the third oligomer or third polymer comprising two functional groups, the two functional groups being a third functional group and a fourth functional group, each of the third functional group and the fourth functional group being capable of being activated by a second photoinitiator such that the third component can crosslink the second component via the third functional group and the fourth functional group; and wherein the swelling volume of the first layer is less than the swelling volume of the second layer.

Description

[Technical field]

[0001] The present disclosure relates to a substrate for an implanted microelectrode for implantation in a tissue, such as a nerve, or in contact with a single cell for applying and / or recording an electrical signal to and / or from the tissue or single cell. The present disclosure further relates to an electrode element comprising the substrate, and an electrode system comprising the electrode element. The substrate for the implanted microelectrode can bend or, more specifically, bend or fold on itself when in contact with a liquid containing water molecules. The present disclosure further relates to a method for manufacturing the substrate, the electrode element, and the electrode system. [Background technology]

[0002] In current practice, implanted microelectrodes are used for neuroscience, to alleviate symptoms of neurological disorders such as Parkinson's disease or epilepsy, or to restore bodily functions after injury. Implanted microelectrodes are introduced into the patient's body via surgery and used to record from or stimulate neural target tissues and nerves. An example of an implanted microelectrode is a stimulation electrode used for deep brain stimulation. Other examples are cuff electrodes used to interface with nerves and electrodes used in electrocorticography.

[0003] Patent Document 1 discloses a microelectrode having a layered structure including a layer containing a polymer compound having an aromatic ring (polymer compound layer) and a layer containing a conductive material (conductive layer), in which the polymer compound layer has a thickness of 10 to 900 nm, the conductive layer has a thickness of 0.3 to 10 nm, and the microelectrode has a three-dimensional curved shape.

[0004] Microelectrodes with such small dimensions (in the nano- and micrometer range) are generally difficult to handle during operation, for example when implanting the microelectrode in tissue. A further challenge can be to accurately fabricate such three-dimensional microelectrodes. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US2021 / 0270764 A1 Summary of the Invention [Problem to be solved by the invention]

[0006] The technical problems to be solved can be summarized as providing a substrate for implanted microelectrodes, and an electrode element / electrode system including the substrate, that provides a stable, reliable and controlled structure and allows for more precise handling by the user. [Means for solving the problem]

[0007] The substrate for the implanted microelectrode according to the present disclosure includes a first layer or flexible non-swelling base layer and a second layer or swelling layer deposited on at least a portion of the first surface of the first layer. The substrate is preferably a thin film or flexible polymeric compound or compounds for forming and / or attaching the implanted microelectrode thereon. The implanted microelectrode may be, for example, a cuff electrode capable of forming an interface with a nerve having a diameter of about 50 to 500 μm. During implantation, mechanical actuation of the implanted microelectrode according to the present disclosure may be initiated by contacting with an external stimulus, i.e., a liquid including water, which may cause the implanted microelectrode to deform, curve, bend, or fold itself, for example, around the nerve, to form a close and stable interface with the biological tissue. The implanted microelectrode may have a small area that is conductive for contacting the biological sample, which area may be in the micrometer or millimeter range. Implanted microelectrodes can be used, for example, to record signals from neural tissue in the mV or V range, or to stimulate neural tissue with current pulses in the μA to mA range or voltage pulses in the mV or V range.

[0008] Each of the first and second layers extends in the x and y directions and / or in the xy plane, and the first and second layers are stacked in the z direction. The x, y and z axes and / or directions are of a three-dimensional Cartesian coordinate system that are mutually orthogonal. The direction in which the layers (1, 2) are stacked is the z direction. The first and second layers overlap each other in the z direction. Thus, the first layer is based on a first mixture and / or the first layer is obtained by photopolymerization (and / or curing) of the first mixture. Photopolymerization is a light-induced reaction that converts a liquid mixture of one or more monomers and / or oligomers and / or polymers into a solid and / or cured polymer. This reaction may require the use of a suitable photoinitiator, which is a photosensitive molecule that generates active species or radicals upon irradiation with UV, visible or infrared light. The first mixture comprises a first photoinitiator and a first component comprising at least one of a first monomer or a first oligomer or a first polymer, the first monomer or the first oligomer or the first copolymer comprising a first functional group. A monomer generally comprises a single unit of a compound. An oligomer comprises two or more units of the same or structurally similar compound, i.e., a number of units of the same or structurally similar compound greater than or equal to 2 and less than about 30 or 30, and a polymer comprises more units of the same or structurally similar compound. The photoinitiator can be activated by exposure to light to form a radical. The first functional group can be activated by the first photoinitiator, more specifically by the radical formed from the first photoinitiator, so that the first component can be photopolymerized via the first functional group. The first layer is obtained by curing the first mixture, more specifically by exposing the first mixture to light such as UV light and / or visible light and / or infrared light, more preferably to light having a wavelength in the range of 200 to 400 nm.

[0009] The second layer is based on a second mixture and / or the second layer is obtained by photopolymerization (and / or curing) of the second mixture. The second mixture comprises a second photoinitiator and a second component comprising a second monomer or a second oligomer or a second polymer, the second monomer or the second oligomer or the second polymer being an acid and comprising a second functional group. The second photoinitiator can be activated by exposure to light to form a radical. The second functional group can be activated by the second photoinitiator, more specifically by the radical formed from the second photoinitiator, so that the second component can be linearly photopolymerized (and / or linked together to form a linear polymer chain) via the second functional group. The second mixture further comprises a base capable of neutralizing the second monomer or the second oligomer or the second polymer, thereby forming a salt, and a third component comprising at least one of the third oligomer or the third polymer, the third oligomer or the third polymer comprising two or more functional groups, the two functional groups being a third functional group and a fourth functional group. Each of the third functional group and the fourth functional group can be activated by the second photoinitiator, more specifically by the radicals formed from the second photoinitiator, so that the third component can crosslink the second component via the third functional group and the fourth functional group. The second layer is obtained by curing the second mixture, more specifically by exposing the second mixture to light, such as UV light and / or visible light and / or infrared light, more preferably light having a wavelength in the range of 200 to 400 nm, so as to form a swelling or superabsorbent layer. Because the swelling capacity of the first layer is smaller than the swelling capacity of the second layer, the substrate may be able to curve and / or bend and / or fold itself when contacted with (and / or immersed and / or submerged in) a liquid comprising water molecules. In particular, the substrate may be able to curve itself when the second layer contacts and swells with a liquid, more particularly when it swells by absorbing a component of the liquid comprising water molecules.When contacted with a liquid, the substrate may be capable of curving such that one side of the first layer (and / or the inner surface of the substrate) is concave and one side of the second layer (and / or the outer surface of the substrate) is convex. When contacted with a liquid and / or immersed and / or submerged in a liquid, the substrate preferably curves and / or bends and / or folds itself such that the radius of curvature of the folded or curved substrate is defined in the z-direction and / or in the direction from the second layer to the first layer and / or in the direction from the first surface to the second surface of the first layer, the second surface being opposite the first surface in the z-direction. The first layer (and / or the first mixture) and the second layer (and / or the second mixture) are preferably one or more electrically insulating materials. The first layer preferably has a z-thickness of 5 to 200 μm, more preferably 50 to 80 μm, and the second layer preferably has a z-thickness of 5 to 200 μm, more preferably 40 to 80 μm. The radius of curvature of the folded or curved substrate is preferably 50 to 1000 μm, more preferably 50 to 150 μm.

[0010] The substrate of the present disclosure may have one or more of the following advantages: The photopolymerization process may allow to control the size, shape, and thickness of the first and second layers. The first and second layers may be produced with thicknesses ranging from micrometers to millimeters, and lateral dimensions ranging from micrometers to centimeters. Furthermore, the first and second mixtures utilized to obtain the substrate according to the present disclosure may be suitable for modern fabrication techniques such as 3D printing. The second layer may generate high osmotic pressure in the polymer network caused by free ions inside the cured polymer network, allowing high swelling of the second layer. As a result, the second layer acts as a superabsorbent layer with a high swelling capacity that allows strong deformation of the substrate. For such reason, the second layer, or the swelling or superabsorbent layer, expands in terms of volume when in contact with a liquid containing water molecules, which creates stress on the first layer or the flexible non-swelling base layer. The stress is relieved by bending or folding of the substrate, since the first / second layer undergoes a smaller / larger volume change than the second / first layer, respectively. The first layer is flexible and / or elastic in the sense that it can fold and / or bend without breaking. The second layer (superabsorbent layer) of the substrate of the present disclosure swells intensely, which allows for small folding radii in the micrometer or millimeter range, generally allowing for a reliable, stable and controlled self-curving or self-folding mechanism of the substrate. The folding is triggered by contact of the substrate and / or the second layer to a liquid containing water molecules (by contact and / or exposure by immersion and / or soaking in the liquid), so the substrate provides a stable and reliable mechanism of self-folding or self-assembly that is controllable by an external stimulus. This feature may be further advantageous when the substrate is used for implanted microelectrodes, such as microelectrodes or cuff electrodes for bioelectronics, in that the implanted microelectrodes can encase biological samples, such as neural tissue, through self-folding during implantation, without the need for any additional measures that would otherwise have to be performed manually by an operator. The substrate of the present disclosure may be further advantageous in that the folding or curving is reversible.More precisely, when the substrate (or at least the second layer) in the folded state is allowed to dry after contact with a liquid containing water molecules, the substrate returns to an unfolded or uncurved state.

[0011] The first functional group and / or the second functional group and / or the third functional group and / or the fourth functional group may be an acrylate group or a methacrylate group, respectively. Alternatively, the first, second, third and fourth functional groups may be selected from epoxy groups, or aromatic ring structures, or sulfhydryl (thiol) groups or alkene (ene) groups for thiol-ene click reactions. Each of the first, second, third and fourth functional groups may contain one or more covalent bonds, preferably C=C double bonds, that can be cleaved and photopolymerized. The radicals for this reaction are generated from the first and second photoinitiators contained in the first and second mixtures, respectively, and undergo photolysis under irradiation with light, such as UV light and / or visible light and / or infrared light, more preferably light having a wavelength in the range of 200 to 400 nm. The concentration of the photoinitiator added to the mixture is preferably in the range of 0.1 to 2% w / w.

[0012] The first and second photoinitiators may be the same or different. In particular, the second photoinitiator may be selected from the group comprising photoinitiators that are miscible in the second mixture containing the acid. Examples of the first and / or second photoinitiator may be B(2,4,6-trimethylbenzoyl)phenylphosphine oxide / ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate (Omnirad 2100) or phenylbis(2,4,6-trimethylbenzoyl)-phosphine oxide (Omnirad 819DW).

[0013] The second monomer or second oligomer or second polymer of the second mixture may be selected from the group including acrylic acid, methacrylic acid, ethylene acrylic acid, and polyacrylic acid.

[0014] The third component may comprise a third oligomer and / or a third polymer, preferably having two or more functional groups, which may be acrylate and / or methacrylate functional groups. More preferably, the third oligomer / third polymer is a bifunctional oligomer / polymer having two acrylate groups or two methacrylate groups. The third oligomer or third polymer is preferably a hydrophilic oligomer or polymer that is miscible in aqueous solution and may be selected from the group including methylenebisacrylamide, diethylene glycol diacrylate, triethylene glycol diacrylate, tetraethylene glycol diacrylate, and polyethylene glycol diacrylate or dimethacrylate, generally having ethylene glycol blocks in number greater than or equal to two.

[0015] The substrate is preferably biocompatible, i.e. the materials of the first and second layers of the substrate do not cause significant cytotoxic effects or show less than 30% metabolic inhibition in a cytotoxicity test based on WST-8. Sub-layers and / or adhesive layers may be stacked between the first and second layers.

[0016] Preferably, at least one of the second, third and fourth functional groups can form a covalent bond with the first functional group. Unreacted functional groups can still be present in the cured polymer network after a certain level of curing (and / or amount of curing applied). This feature can be further advantageous in that the first layer and the second layer can be firmly bonded together via covalent bonds, even without the use of an adhesive layer.

[0017] Preferably, the swelling capacity (Q w1 ) versus the swelling capacity of the second layer (Q w2 ) is preferably Q w2 / Q w1 = 5 or more (i.e., Q w1 :Q w2 = 1:5 or more), more preferably Q w2 / Q w1 = 10 or more (i.e. Q w1:Q w2 =1:10 or more), more preferably Q w2 / Q w1 = 20 or more (i.e. Q w1 :Q w2 = 1:20 or more). This ratio is preferably w2 / Q w1 = 5 to 20, more preferably Q w2 / Q w1 = 10 to 20. The swelling capacity of the first (second) layer is obtained by dividing (i) the mass of the first (second) layer after the first (second) layer has been contacted with a liquid containing water molecules and / or has been swollen and / or saturated with the components of the liquid by (ii) the initial mass of the first (second) layer (i.e., the mass of the first (second) layer before contact with the liquid). The second layer is a superabsorbent layer with high swelling capacity, which allows for strong deformation of the substrate and generally allows for a reliable, stable and controlled self-bending and self-folding mechanism of the substrate.

[0018] Preferably, the second layer entirely covers the first surface of the first layer. Each of the first and second layers has a length in the x direction and a width in the y direction. Preferably, the length of the second layer is less than the width of the second layer and the length of the second layer is less than the length of the first layer. Preferably, the second layer extends over at least 60%, more preferably at least 80%, of the total extent of the first layer in the y direction and more preferably the width of the first layer may be equal to the width of the second layer.

[0019] Preferably, the substrate comprises a plurality of second layers deposited on a first surface of the first layer, the plurality of second layers being spaced apart from each other in the x-direction. Preferably, the length of the first layer is greater than the width of the first layer, or the length of the first layer is less than the width of the first layer. The first surface of the first layer may be rectangular or rhomboidal. Preferably, the first layer comprises a groove or a depression or a recessed portion formed in the first surface of the first layer and / or the second surface of the first layer, the second surface being opposite the first surface in the z-direction, the groove extending in the x-direction, preferably the groove extending over at least 60%, more preferably at least 80%, or more preferably the entire extent of the first layer in the x-direction. Preferably, the first layer has a third surface in the yz-plane and a fourth surface in the yz-plane opposite the third surface in the x-direction, and the groove extends along the x-direction from the third surface of the first layer all the way to the fourth surface of the first layer. The groove preferably extends through the first layer in the x-direction. The thickness of the first layer in the z-direction at the recessed portion is smaller than in other parts of the first layer, and the width of the groove is in the y-direction and is less than the length of the groove in the x-direction. As a result, the groove has a longitudinal direction extending in the x-direction.

[0020] A substrate according to the present disclosure may have one or more of the following further advantages: The direction of bending or folding of the substrate can be more precisely controlled by the multiple second layers, such that the substrate bends or folds along the longer side of the second layer. More precisely, if the longer side and / or the main longitudinal direction of the second layer run parallel to the y direction, the substrate will bend or fold itself when in contact with (and / or immersed and / or submerged in) a liquid containing water molecules, such that the axis of curvature and / or bending and / or folding is defined in or parallel to the x direction and the radius of curvature is defined in the yz plane.

[0021] Preferably, the first layer includes a plurality of grooves, the plurality of grooves being spaced apart from one another in the y-direction. Preferably, the second layer extends at least partially into the grooves, more preferably fills the grooves. The second layer may fill the grooves where they overlap or cross each other, thereby promoting adhesion between the stacked layers. Preferably, the width direction of the second layer (and / or the length direction of the second layer and / or the main machine direction of the second layer) and the length direction of the grooves (and / or the longer direction of the grooves or the direction in which the grooves extend) are mutually perpendicular.

[0022] The substrate of the present disclosure may further have one or more of the following advantages: The curvature or folding direction of the substrate along the length direction of the second layer and / or the longer direction of the second layer and / or the main longitudinal direction of the second layer is facilitated and made more pronounced by the one or more grooves, and furthermore, it is possible to precisely control the curvature direction and achieve smaller curvature radii.

[0023] Preferably, the first monomer or the first oligomer or the first polymer is a polyurethane or a silicone, and the first functional group is an acrylate or a methacrylate group. Preferably, the second component comprises a second monomer, the second monomer is an acrylic acid or a methacrylic acid, and the second functional group is an acrylate or a methacrylate group.

[0024] Preferably, the second component comprises a further monomer or further oligomer comprising a fifth functional group, which may be activated by a second photoinitiator, so that the second component may be linearly photopolymerized via the second and fifth functional groups. The substrate according to the present disclosure may be further advantageous in that the swelling properties of the cured polymer network of the second layer may be further controlled by copolymerizing the second monomer, second oligomer, or second polymer with the further monomer or further oligomer. The further monomer or further oligomer may be a hydrophilic acrylic monomer or oligomer, and may be selected from the group comprising (meth)acrylated carboxylic acids, amides, and alcohols.

[0025] Preferably, the fifth functional group is a methacrylate group and the further monomer is hydroxyethyl methyl acrylate (HEMA). The substrate according to the present disclosure may have one or more of the following advantages: The methyl group in the methacrylate group may cause steric hindrance, and the reactivity of the further monomer with respect to photopolymerization may be reduced compared to the further monomer containing an acrylate group as the fifth functional group, or compared to the second monomer, second oligomer, or second polymer containing an acrylate group as the second functional group. The reaction rate of the photopolymerization of the second mixture can be more precisely controlled, which is particularly important for the processability of the second mixture with modern 3D printing techniques, where precise control of the layer hardening, polymerization depth, and gelation of the material is required.

[0026] Preferably, the base comprises NaOH and / or KOH, the third oligomer or third polymer is a polyethylene glycol, the third functional group is an acrylate or methacrylate group, and the fourth functional group is an acrylate or methacrylate group.

[0027] Preferably, the molar ratio of the second monomer or second oligomer or second polymer to the further monomer or further oligomer is in the range of 1000:1 to 1:1, more preferably 1000:1 to 2:1, and / or the molar ratio of the second monomer or second oligomer or second polymer to the base is in the range of 10:1 to 10:6. More preferably, the molar ratio of the second monomer or second oligomer or second polymer to the base is in the range of 10:3 to 10:4.

[0028] Preferably, the degree of neutralization of the acid with respect to the base is 10 to 60%, or more preferably 30 to 40%. The degree of neutralization of the neutralization reaction of the acidic second monomer or second oligomer or second polymer with the base is the ratio of the number of neutralized second monomer or second oligomer or second polymer molecules after the neutralization reaction with the base to the initial number of acidic second monomer or second oligomer or second polymer molecules. The degree of neutralization is the molar ratio of the initially present acidic second monomer or second oligomer or second polymer molecules to the base.

[0029] Preferably, the molar ratio of the second component to the third component is in the range of from 1000:1 to 2:1, more preferably from 200:1 to 20:1.

[0030] Preferably, the first mixture and / or the second mixture further comprises a further photoinitiator and / or a quencher and / or a light absorber. An example of an absorber or photosensitizer is 4-hydroxybenzophenone (HMBS) or 2-isopropylthioxanthone (ITX). An example of a quencher or free radical quencher is 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). The concentration of the absorber contained in the mixture is preferably in the range of 0% to 10% w / w. The concentration of the quencher contained in the mixture is preferably in the range of 0% to 2% w / w.

[0031] Preferably, the system according to the present disclosure comprises a substrate as described above and a third layer extending from the first layer in the x- and y-directions and / or in the xy-plane, the third layer being integrally formed with the first layer, the third layer being preferably based on the first mixture.

[0032] Preferably, an electrode element implantable in a biological sample comprises the above substrate and a first conductive layer deposited on a second surface of the first layer. The second surface extends in the x-direction and the y-direction and is opposite the first surface in the z-direction. Thus, the second layer, the first layer and the first conductive layer are stacked in this order in the z-direction. The second layer, the first layer and the first conductive layer overlap each other in the z-direction.

[0033] The electrode element of the present disclosure may have one or more of the following advantages: Since the folding of the electrode element's substrate is induced by contacting the electrode element and / or the electrode element's substrate and / or the second layer of the substrate with a liquid containing water molecules and / or by immersing and / or dipping the electrode element in the liquid, the electrode element provides a reliable and stable mechanism for self-folding or self-assembly that is controllable by an external stimulus. This feature may be further advantageous in that when the electrode element is used for implantation in a biological sample, the electrode element may envelop biological tissue, such as nerve tissue, through self-folding during implantation in a controlled and reliable manner. Furthermore, the second layer of the electrode element's substrate may provide stronger volume expansion than the first layer of the substrate, thereby enabling the electrode element to reliably and stably provide a small folding or bending radius in the micrometer or millimeter range. This may generate a stable and intimate interface to biological tissue or nerve, thereby enabling improved signal recording and stimulation efficiency.

[0034] Preferably, the first conductive layer comprises a metal film and / or a nanoparticle conductor and / or a conductive polymer. The conductive layer can be deposited via sputtering (e.g., gold or platinum) and / or solution processing and / or vapor deposition, via solution processing techniques, and / or by printing and sintering a metal nanoparticle-based paste or ink, and / or by printing a conductive polymer-based paste or ink. The electrode elements described above may include one or more of any of the features of the substrate.

[0035] Preferably, the electrode system comprises the above-mentioned electrode element and a third layer extending from the first layer of the substrate of the electrode element in the x-direction and y-direction and / or in the xy-plane. The third layer is integrally formed with the first layer. The third layer is preferably based on the first mixture, i.e. the third layer is obtained by curing the first mixture via exposure to light. The electrode system further comprises a second conductive layer deposited on the third layer, the second conductive layer being connected to the first conductive layer, in particular the second conductive layer being mechanically or physically connected to the first conductive layer.

[0036] The electrode system of the present disclosure may have one or more of the following advantages: The electrode system provides a controlled, reliable and stable mechanism for self-folding or self-assembly, since the folding of the substrate of the electrode element of the electrode system is induced by contacting the electrode system and / or the electrode element of the electrode system and / or the substrate of the electrode element and / or the second layer of the substrate with a liquid containing water molecules and / or by immersing and / or submerging the electrode system and / or the electrode element in the liquid. This feature may be further advantageous in that, when the electrode system is embedded in a biological sample, the electrode element of the electrode system may encapsulate biological tissue, such as neural tissue, during the embedding procedure in a controlled and reliable manner through self-folding. Furthermore, the second layer of the substrate of the electrode system may undergo a stronger volume expansion compared to the first layer of the substrate, thereby enabling the electrode element of the electrode system to interface with biological tissue reliably and stably. The electrode elements of the electrode system can provide a stable, close interface to biological tissue or nerves, which can improve the signal recording and stimulation efficiency provided by the electrode system when the second conductive layer of the electrode system is connected to external amplification and / or stimulation circuitry and / or a pulse generator.

[0037] The third layer may have a thickness greater than the first layer. An electrode system according to the present disclosure may be further advantageous in that a connector may be more easily attached to the second conductive layer, thereby improving the reliability of the electrode system.

[0038] Preferably, the electrode system further comprises a fourth layer or passivation layer deposited on the third surface of the second conductive layer. The fourth layer is preferably one or more electrically insulating materials. The third layer, the second conductive layer and the fourth layer are stacked in this order in the z-direction. The fourth layer is preferably based on the first mixture, i.e. the fourth layer is obtained by curing the first mixture by exposure to light. The above electrode system may comprise one or more of any of the features of the electrode element and the substrate.

[0039] According to the present disclosure, there is provided a method for manufacturing the above substrate, the method including forming a first layer by exposing a first mixture to light, and forming a second layer on the first layer by exposing a second mixture to light. The steps of forming the first layer and forming the second layer on the first layer can be performed by using a mask-based photolithography technique or by using 3D printing such as stereolithography.

[0040] Preferably, the step of forming the first layer includes a step of forming a groove. The step of forming the first layer may include a first step of forming a groove by exposing the first mixture to light, while obtaining the first layer, so that the first mixture receives a lower amount of light at the local location of the groove compared to the remaining part of the first mixture, by exposing the first mixture to light using a light pattern or mask. Then, the uncured residue of the first mixture can be removed.

[0041] According to the present disclosure, the method for manufacturing the above electrode element includes all the steps of the above method for manufacturing the substrate, and preferably further includes the step of forming a first conductive layer on the first layer.

[0042] A method for producing the electrode system includes all the steps of the method for producing the electrode element, and further includes forming a third layer by exposing the first mixture to light, and forming a second conductive layer. The third layer and the first layer can be formed simultaneously by exposing the first mixture with a light pattern or mask, or more preferably by exposing with a grayscale pixelated mask generated by a digital micromirror device and / or a stereolithographic printer. [Brief description of the drawings]

[0043] In the following detailed description, preferred embodiments of the present disclosure are described with reference to the accompanying drawings. [Figure 1] FIG. 2A is a perspective view that generally illustrates a substrate according to a first embodiment of the present disclosure, and FIG. 2B is a perspective view that generally illustrates a substrate according to a second embodiment of the present disclosure. [Diagram 2] FIG. 1A is a top view that generally illustrates a substrate according to a first embodiment, and FIG. 1B is a top view that generally illustrates a substrate according to a second embodiment. [Diagram 3] FIG. 1(a) is a perspective view that generally illustrates a folded or curved substrate according to a first embodiment, and FIG. 1(b) is a perspective view that generally illustrates a folded or curved substrate according to a second embodiment. [Figure 4] FIG. 1(a) is a side view that generally illustrates a substrate according to a first or second embodiment, and FIG. 1(b) is a side view that generally illustrates a folded or curved substrate according to a first or second embodiment of the present disclosure. [Diagram 5] FIG. 13(a) is a perspective view that illustrates a schematic diagram of a first layer of a substrate having a groove according to a third embodiment, and FIG. 13(b) is a perspective view that illustrates a schematic diagram of a substrate having a first layer having a groove according to the third embodiment. [Figure 6] FIG. 13(a) is a top view that illustrates a schematic of a first layer of a substrate having a groove according to a third embodiment, and FIG. 13(b) is a top view that illustrates a schematic of a substrate having a first layer having a groove according to the third embodiment. [Figure 7] FIG. 13 is a perspective view that diagrammatically illustrates a folded or curved substrate in which a first layer has a groove according to a third embodiment; [Figure 8] FIG. 1(a) is a side view that diagrammatically illustrates a substrate according to a third embodiment, in which a first layer has a groove on a first surface, and FIG. 1(b) is a side view that diagrammatically illustrates a substrate according to a third embodiment, in which a first layer has a groove on a second surface. [Figure 9] FIG. 1(a) is a side view that illustrates a schematic of a folded or curved substrate according to a third embodiment, in which a first layer has a groove on a first surface; FIG. 1(b) is a side view that illustrates a schematic of a folded or curved substrate according to a third embodiment, in which a first layer has a groove on a second surface; [Figure 10] (a) is a diagram showing an image of a folded or curved substrate according to a second embodiment, (b) is a diagram showing an example of a folded or curved system according to an embodiment of the present disclosure, and (c) is a diagram showing an example of a folded or curved system according to an embodiment of the present disclosure. [Figure 11] 1A is a side view that illustrates a schematic of an electrode element according to one embodiment; FIG. 1B is a side view that illustrates a schematic of a folded or curved electrode element according to one embodiment; FIG. [Figure 12] FIG. 1A is a perspective view illustrating a schematic of an electrode system according to one embodiment; FIG. 1B is a side view illustrating a schematic of an electrode system according to one embodiment of the present disclosure; and FIG. 1C is a side view illustrating a schematic of a folded or curved electrode system according to one embodiment. [Figure 13] 1A to 1C are top views showing an example of a curved electrode system according to an embodiment. [Figure 14] 1(a)-(e) are schematic diagrams illustrating a method for producing a substrate and / or electrode system according to the present disclosure. [Figure 15] (a) is a schematic diagram illustrating neutralization of a second monomer or second oligomer or second polymer with a base according to one embodiment; (b) is a schematic diagram illustrating the resulting cured polymer network of the second layer before contacting and / or swelling with a liquid comprising water molecules according to one embodiment; and (c) is a schematic diagram illustrating the resulting cured and swollen polymer network of the second layer in contact with a liquid comprising water molecules according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] 1. Substrate <First embodiment> FIG. 1a (perspective view) and FIG. 2a (top view, xy-plane) show a substrate A according to a first embodiment. The substrate A comprises a first layer 1 and a second layer 2. The first layer 1 is a polymer-based flexible layer that can serve as a base layer, on which further structures, such as electrodes, can be formed. The first layer 1 may comprise non-swelling polyurethane or hydrophobic molecules, such as silicone. The second layer 2 is a swelling or superabsorbent layer, which can induce a self-curving process of the substrate A. The first and second layers 1, 2 are based on a first mixture 10 and a second mixture 20, respectively. More specifically, the first (second) layer 1 (2) is obtained by photopolymerization (and / or curing) of the first (second) mixture 10 (20).

[0045] Each of the first layer 1 and the second layer 2 extends in the x-direction and the y-direction. The first layer 1 and the second layer 2 overlap each other in the z-direction. More specifically, as shown in Fig. 1a and Fig. 2a, the second layer 2 may entirely cover the first surface 1-1 of the first layer 1. The first layer 1 has a length l1 in the x-direction and a width w1 in the y-direction. The width w1 of the first layer 1 is preferably shorter than the length l1 of the first layer 1. Correspondingly, the second layer 2 has a length l2 in the x-direction and a width w2 in the y-direction, and the width w2 of the second layer 2 is preferably shorter than the length l2 of the second layer, which may be further advantageous in controlling the curvature direction of the substrate A, as described below. The length l1 of the first layer 1 is equal to the length l2 of the second layer, and the width w1 of the first layer 1 is equal to the width w2 of the second layer 2.

[0046] Figure 3a shows the substrate A shown in Figures 1a and 2a in a folded or curved state. As shown in Figure 3a, the swelling capacity Q of the first layer 1 w1 is the swelling capacity Q of the second layer 2 w2, the substrate A is able to curve itself when in contact with a liquid containing water molecules. The substrate curves such that one side of the first layer 1 is concave and one side of the second layer 2 is convex. More precisely, the substrate A according to the first embodiment curves or folds itself such that the second surface 1-2 of the first layer 1, which is opposite to the first surface 1-1, becomes an inner surface of the substrate A.

[0047] <Self-folding mechanism of substrate> With reference to FIGS. 1a, 2a, 3a, 15a to 15c, the working principle of the liquid-induced self-bending (or self-folding) mechanism of substrate A is described below.

[0048] The second layer 2 is based on a second mixture 20. The second mixture 20 comprises a base and a second monomer or second oligomer or second polymer that is an acid. The acidic second monomer or second oligomer or second polymer is neutralized by the base: the hydrogen atoms of the OH groups of the acidic second monomer or second oligomer or second polymer are released and the ions of the base condense with the second monomer or second oligomer or second polymer to form a salt of the second monomer or second oligomer or second polymer. As a result, the ions of the base can be released again from the salt molecules of the second monomer or second oligomer or second polymer when dissolved in an aqueous solution. Since both the remaining unneutralized molecules of the acidic second monomer or second oligomer or second polymer and the neutralized molecules of the second monomer or second oligomer or second polymer contain a second functional group, they can be photopolymerized together linearly through the second functional group. In this linear polymerization reaction, the radicals generated from the photoinitiator open and bond to one end of the C=C double bond in the second functional group of the molecule of the second monomer or second oligomer or second polymer, or the salt molecule of the second monomer or second oligomer or second polymer. This generates a new radical that bonds to another molecule of the second monomer or second oligomer or second polymer, or the salt molecule of another second monomer or second oligomer or second polymer, and continues as a chain reaction to form a polymer chain containing condensed base ions.

[0049] The second mixture 20 further comprises a third component, the third component comprising at least one of a third oligomer or a third polymer, the third oligomer or the third polymer comprising two or more functional groups, the two functional groups being a third functional group and a fourth functional group, such that the third component can crosslink the second component through the third and fourth functional groups to form a crosslinked polymer network to obtain the second layer when the second mixture is cured by exposure to light. When this cured polymer network of the second layer is immersed in water, the ions of the condensed base can enter the solution but remain within the polymer network of the second layer because the O-ions are bound thereto. This salt solution within the cured polymer network of the second layer creates an osmotic pressure, which draws the water molecules outside the polymer network into the polymer network, causing a high level of swelling of the second layer.

[0050] Figures 15a to 15c illustrate schematic chemical structures of the second layer according to the first embodiment: Figure 15a shows schematic neutralization of the second monomer of the second mixture 20 (here acrylic acid as an example of the second monomer) with the base of the second mixture 20 (here NaOH as an example of the base). The degree of neutralization or molar ratio of the second monomer to the base is preferably in the range of 10:1 to 10:6. The hydrogen atom of the OH group of the second monomer (acrylic acid) is released and the ion (Na+) of the base (NaOH) condenses with the second monomer (acrylic acid) to form the salt of the second monomer (sodium acrylate) and water molecules. The Na of the base + The ions may be released again from the salt of the second monomer (sodium acrylic acid salt) when the second layer 2 is in contact with a liquid containing water molecules.

[0051] 15b shows a schematic diagram of the cured polymer network of the resulting second layer 2 of the substrate A before contacting with liquid and / or swelling with a liquid containing water molecules. As shown in FIG. 15b, the remaining unneutralized second monomer (acrylic acid) and the neutralized second monomer (sodium acrylic acid salt) can photopolymerize together linearly through the second functional groups and form one or more linear polymer chains D. A third oligomer or third polymer of a third component in the second mixture 20 can crosslink the linearly photopolymerized second monomer and / or linear polymer chains D to form one or more crosslinker chains F.

[0052] Figure 15c shows a schematic diagram of the polymer network of Figure 15b when in contact with a liquid containing water molecules. + The ions are released from the neutralized and photopolymerized second monomer and can go into solution when the second layer 2 is in contact with a liquid containing water molecules. However, solvated Na + The ions remain in the polymer network of the second layer 2 because the O-ions are bound thereto. This salt solution in the cured polymer network of the second layer 2 creates an osmotic pressure that draws water molecules from the outside of the second layer 2 into the polymer network of the second layer 2, causing a high level of swelling of the second layer 2. As illustrated in FIG. 15c, the mesh of the cured polymer network of the second layer 2, which comprises one or more crosslinker chains F and one or more linear polymer chains D, is stretched and expands in volume, which creates stress on the first layer or the flexible non-swelling base layer comprising polyurethane. The first / second layer undergoes a smaller / larger volume change than the second / first layer, respectively, so that the stress is relieved by bending or folding the substrate. The second layer 2 thus serves as a superabsorbent layer that can allow for strong deformation of the substrate A, as illustrated in FIG. 3a.

[0053] The self-bending mechanisms and / or approaches disclosed herein generally serve to provide substrates, electrode elements, and electrode systems for implanted microelectrodes that allow for achieving a stable, reliable, and controlled mechanism of self-bending or self-folding, which is common across the following embodiments of the present disclosure.

[0054] <Second embodiment> 1b, 2b and 4a show a substrate A according to an embodiment of the present disclosure (side views of the first and second embodiments are identical to each other). The substrate A according to the second embodiment differs from the first embodiment in the configuration / shape of the second layer 2. According to the second embodiment, the second layer 2 only partially covers the first surface 1-1 of the first layer 1. The width w2 of the second layer 2 may be equal to the width w1 of the first layer 1, or the width w2 of the second layer 2 is at least 60%, or more preferably at least 80%, of the width w1 of the first layer 1. The width w1 of the first layer 1 may be equal to the width w2 of the second layer 2. According to the second embodiment, the length l2 of the second layer 2 is shorter than the length l1 of the first layer 1, so that the second layer 2 has a longer side in the y direction (i.e., the width w2 is longer than the length l2). The substrate A preferably comprises a plurality of second layers 2 deposited on the first surface 1-1 of the first layer 1, the plurality of second layers 2 being spaced apart from one another in the x-direction. Figure 2b shows three second layers 2 forming a striped pattern on the first surface 1-1 of the first layer 1. The specific number of second layers 2 shown in Figure 2b is merely an example and may be less or more.

[0055] 3b and 4b show the substrate A according to the second embodiment in a folded or curved state after contact with a liquid and swelling with the liquid, including water molecules. As in the first embodiment, the swelling capacity Q of the first layer 1 is w1 is the swelling capacity Q of the second layer 2 w2, the substrate A can bend itself when in contact with a liquid containing water molecules, such that one side of the first layer 1 becomes concave and one side of the second layer 2 becomes convex. More specifically, the substrate A bends or folds itself so that the second surface 1-2 of the first layer 1 becomes the inner surface of the substrate A. The direction and / or axis of bending or folding of the substrate A can be more precisely controlled by the shape or geometry of the one or more second layers 2: the substrate A is bent or folded along the longer side and / or the main longitudinal direction and / or the width w2 of the one or more second layers 2. More precisely, as shown in Figs. 1b, 2b, and 3b, the longer side and / or the main longitudinal direction of the one or more second layers 2 are along the width w2 of the one or more second layers 2 and / or run parallel to the y direction. The bending or folding of substrate A is therefore controlled by one or more second layers 2 such that substrate A bends or folds itself along the y direction. More precisely, as shown in Figures 3b and 4b, substrate A bends or folds itself such that the axis of curvature is defined in the x direction, more precisely in a direction parallel to the x direction, and the radius of curvature is defined in the yz plane.

[0056] <Third embodiment> 5a and 6a show a perspective view and a top view, respectively, of a first layer 1 according to a third embodiment. The first layer 1 according to the third embodiment has at least one groove 1a or a depression or recessed portion in a first surface 1-1 of the first layer 1 to facilitate and support the self-folding process of the substrate A. The first layer 1 may include multiple grooves 1a. The specific number of grooves 1a shown in Figs. 5a and 6a is merely an example and may be less or more.

[0057] Each of the plurality of grooves 1a in the first surface 1-1 of the first layer has a width w 1a The first layer 1 has a width w1 in the y direction and a length l1 in the x direction, and the width w 1ais smaller than the width w1 of the first layer 1. The grooves 1a of the plurality of grooves 1a are spaced apart from each other in the y direction. The grooves extend over at least 60% of the total extent of the first layer in the x direction, and as illustrated in FIG. 5a, the grooves 1a preferably extend through the first layer 1 along the entire length (l1) of the first layer 1 in the x direction and / or parallel to the x direction. The thickness of the first layer 1 in the z direction at the grooves 1a is smaller than in other parts of the first layer 1. FIGS. 5a and 6a show three grooves 1a forming a striped pattern on the first surface 1-1 of the first layer 1.

[0058] 5b and 6b show a perspective view and a top view, respectively, of the substrate A according to the third embodiment. FIG. 8a further shows a side view of the substrate A according to the third embodiment. The substrate A includes a first layer 1 having a plurality of grooves 1a that facilitate and support the self-folding process of the substrate, and further includes a second layer 2. The first layer 1 and the second layer 2 are stacked in the z direction such that the first layer 1 and the second layer 2 overlap each other. More specifically, the substrate A includes a second layer 2 having a longer side and / or a main longitudinal direction in the y direction. If the width w1 of the first layer 1 is longer than the length l1 of the first layer 1, the second layer 2 may entirely cover the first layer 1, as in the first embodiment. Preferably, the substrate A includes a plurality of second layers 2 spaced apart from each other in the x direction. The grooves 1a in the first layer 1 have a width w1 smaller than the width w1 of the first layer 1. 1a5b, the first layer 1 has a first surface 1-1 having a longer side and / or a main longitudinal direction extending in the x-direction. The longer side and / or main longitudinal direction of the second layers 2 and the longer side and / or main longitudinal direction of the grooves 1a are mutually perpendicular. Furthermore, the grooves 1a open from the top of the first layer 1 toward the second layers 2, so that the second layers 2 extend into and / or fill the grooves 1a. As shown in FIG. 5b, the second layers 2 fill the grooves 1a at the positions where the grooves 1a and the second layers 2 overlap or cross each other. FIGS. 5b and 6b show three second layers 2 forming a striped pattern on the first surface 1-1 of the first layer 1. The specific number of second layers 2 shown in FIGS. 5b and 6b is merely an example and may be less or more.

[0059] 7 and 9a show perspective and side views, respectively, of a folded or curved substrate A according to the third embodiment. The self-curving or self-folding of the substrate A (when contacted with a liquid containing water molecules) is along the longer side or main longitudinal direction of the second layers 2 and perpendicular to the longer side and / or main longitudinal direction of the grooves 1a. The axis of curvature is in the x-direction and / or parallel to the x-direction. More specifically, the substrate A curves or folds itself such that one side of the first layer 1 becomes concave (and / or the second surface 1-2 of the first layer 1 becomes the inner surface of the substrate A) and one side of the second layer 2 becomes convex.

[0060] Fig. 8b shows a side view of a substrate A according to a variant of the third embodiment, in which the first layer 1 has a number of grooves 1a on the second surface 1-2. Fig. 9b shows the substrate A of the variant of the third embodiment, which is curved or folded. The substrate A curves or bends or folds itself when in contact with a liquid containing water molecules, such that one side of the first layer 1 becomes concave and one side of the second layer 2 becomes convex. More specifically, the second surface 1-2 with the grooves 1a is an inner surface of the substrate A.

[0061] <Further modification examples> According to the first to third embodiments, the second layer 2 may be deposited directly on the first layer 1. Alternatively, the substrate A according to the first to third embodiments may comprise one or more further sub-layers between the first layer 1 and the second layer 2, such as an adhesion layer.

[0062] <Manufacturing method> The method includes forming a first layer 1 by exposing a first mixture 10 to light. In particular, the first mixture 10 can be placed on a transparent support or glass slide 70 by drop casting or spin coating. The first mixture 10 is then irradiated with a light pattern from below the support 70 to obtain a first layer 1. For the third embodiment (see FIG. 5a), one or more grooves 1a can be formed by applying different exposure times and / or light doses to different positions of the first mixture 10. At one or more positions of the one or more grooves 1a, a shorter exposure time and / or a lower light dose is applied than in other parts of the first layer 1, so that the first layer 1 at the one or more grooves 1a has a smaller thickness in the z direction than in other parts of the first layer 1. Thus, one or more grooves 1a are formed on the surface (extending in the x and y directions) of the first layer 1.

[0063] After exposing the first mixture 10 to light, the uncured residues of the first mixture 10 are removed. The method further comprises forming a second layer 2 on the first layer 1 by exposing the second mixture 20 to light. The second mixture 20 is then deposited on the first layer 1 and exposed to light through the support 70 and the cured first layer 1. The patterning of the second layer 2 (e.g. the second layer in the form of a plurality of stripes according to the second or third embodiment) can also be formed by exposing a patterning structure, i.e. by exposing only a part of the second mixture 20 to light, and then removing the uncured residues of the second mixture 20 from the surface of the first layer 1. For a variant of the third embodiment (see FIG. 8b), after curing the first layer 1, the first layer 1 is inverted, the second mixture 20 is deposited on the surface without the grooves 1a, and the second layer 2 is further patterned as described above. Alternatively, the grooves 1a on the second surface 1-2 of the first layer 1 can be made by molding from a transparent support or master that contains the positive structure for the grooves 1a.

[0064] <Example> In the following, an example of the substrate A of the present disclosure prepared according to the above embodiment is described. The materials and conditions used in the example are merely examples and do not limit the embodiment.

[0065] Fig. 10a shows examples of substrates according to the second embodiment, which are in a folded or curved state after contacting and swelling with deionized water (the example substrates are therefore saturated, the first and / or second layers being saturated with liquid components). According to the examples, the first layer 1 is based on a first mixture comprising a polyurethane 3D printing resin (Luxaprint® flex Detax), which is an example of a first mixture 10 comprising a first component. The second layer 2 is based on a second mixture 20, which contains the second monomer acrylic acid (50% molar ratio), the further monomer HEMA (25% molar ratio), the base NaOH (30% stock in deionized water, 25% molar ratio), the third oligomer or crosslinker PEGDA (Mn500, 1% molar ratio), the photoinitiator Omnirad2100 (1% molar ratio), the quencher TEMPO (0.02% molar ratio), and the light absorber ITX (0.025% molar ratio). Both the first layer 1 and the second layer 2 were obtained by curing the first mixture 10 and the second mixture 20, respectively, by exposing them to light with a wavelength of around 365 nm. The first layer 1 has a length l1 of 3 mm and a width w1 of 1.5 mm, and eight second layers 2, each having a length l2 of 0.18 mm and a width w2 of 1.5 mm, were formed on the first layer 1. Each of the first and second layers has a thickness of 0.05 mm. In the folded state, the example substrate exhibits a curvature radius of 0.5 mm.

[0066] FIG. 10b shows four examples of systems (examples 1, 2, 3, 4, from the rightmost to the leftmost in FIG. 10b, respectively) with a substrate A having a morphology according to the second embodiment. FIG. 10b shows side views of these examples, i.e. in the x-direction and yz-plane. Each of the system examples includes a further layer (third layer) extending in the x-direction and y-direction from the first layer 1 of the substrate A, which is integrally formed with the first layer 1. The system example shown in FIG. 10b has the substrate A in a folded state after contact with a liquid (here deionized water at room temperature) and swelling with the liquid containing water molecules (the substrate of the system example is therefore saturated, and the first and / or second layers are saturated with the components of the liquid). In each of the system examples, the substrate A is located at the end of the system along the y-direction (i.e. at the top of the system example in FIG. 10b).

[0067] Each of the one or more first layers 1 of Examples 1-4 has a width w1 of 0.6 mm in the y direction, a length of 0.8 mm in the x direction, and a thickness (t1) of 76 μm in the z direction. The third layer extending from the substrate A has a thickness of 0.15 mm in the z direction. Each of Examples 1-4 has a number of second layers 2 of 3. Each of the second layers 2 has a length l2 of 0.15 mm in the x direction, a width w2 of 0.6 mm in the y direction, and the second layers are separated from each other by a distance of 0.15 mm in the x direction. System Examples 1-4 differ from each other in the thickness (t2) of the second layer 2, as summarized in Table 1.

[0068] FIG. 10c shows four further examples of the system in a folded or curved state (Examples 5, 6, 7, and 8, from the far right to the far left in FIG. 10c, respectively). Examples 5-8 have the same configuration as Examples 1-4, except for the thickness (t1) of one or more first layers 1 and the thickness (t2) of the second layer 2. Each first layer 1 has a thickness (t1) of 87 μm in the z-direction. Examples 5-8 differ from each other in the thickness (t2) of the second layer 2, as summarized in Table 2.

[0069] According to examples 1-4 shown in FIG. 10b and examples 5-8 shown in FIG. 10c, a first mixture 10 is prepared comprising the polyurethane 3D printing resin (Luxaprint flex Detax) described above with respect to FIG. 5a. To provide a second mixture 20, a second monomer acrylic acid (50% molar ratio), a further monomer HEMA (25% molar ratio), a base NaOH (30% stock in deionized water, 25% molar ratio), a third oligomer or crosslinker PEGDA (Mn500, 1% molar ratio), a photoinitiator Omnirad2100 (1% molar ratio), a quencher TEMPO (0.02% molar ratio), and a light absorber ITX (0.025% molar ratio) are mixed together. A good swelling capacity Q of the second layer 2 is obtained. w2 For this reason, the degree of neutralization or the molar ratio of the second monomer to the base is preferably in the range of 10:1 to 10:6. Furthermore, for a stable polymer network structure, the molar ratio of the second monomer to the third oligomer is preferably 1000:0.1 to 2:1.

[0070] To produce examples 1-8, the first mixture 10 and the second mixture 20 are processed using a stereolithographic printer (Miicraft50X, LED with a wavelength of 365 nm). A small amount (1-2 ml) of the first mixture 10 is provided and / or drop cast and / or pipetted onto a support 70 (glass slide) provided in an empty tank of the printer. The first mixture is exposed with a light pattern by using the printer so as to simultaneously form the first layer 1 and the third layer 4. For examples 1-4, the first mixture 10 is exposed with an exposure time of 1 second and / or 1 mW cm at the location of the first layer 1. -2 to obtain a thickness t1 of 76 μm, with an exposure time of 10 s and / or an irradiance of 1 mW cm at the location of the third layer 4. -2 For examples 5 to 8, the first mixture 10 is cured at the location of the first layer 1 with an exposure time of 2 seconds and / or an irradiance of 2 mW cm -2to obtain a thickness t1 of 87 μm. Uncured residues of the first mixture 10 are removed by washing with isopropanol. A small amount (50-500 μl) of the second mixture 20 is then provided on the first surface 1-1 of the first layer 1. One or more of the second layers 2 of Examples 1-4 and Examples 5-8 are produced by subjecting the second mixture 20 provided on the first surface 1-2 to different exposure times in the range of 30 to 50 seconds and / or irradiances of 3 to 5 mW cm. 2 After curing, the residues of the second mixture are removed by washing with isopropanol. The thicknesses of the first layer(s) 1 and the second layer(s) 2 of these examples were measured using a confocal laser scanning microscope (Keyence VK-X250).

[0071] The produced examples are placed on a holder and immersed in deionized water for at least 10 minutes. According to examples 1-4 shown in FIG. 10b and examples 5-8 shown in FIG. 10c, the substrate A of the example system or systems is curved on itself such that the second surface 1-2 of the first layer (1) forms an inner layer of the curved or folded substrate A. The curved or folded examples 1-8 are examined using an optical microscope to measure the radius of curvature. The results of the measured thickness of the first layer 1, the thickness of the second layer 2, and the achieved radius of curvature of examples 1-4 are shown in Table 1. The results of the measured thickness of the first layer 1, the thickness of the second layer 2, and the achieved radius of curvature of examples 5-8 are shown in Table 2.

[0072] The results in Tables 1 and 2 show that one or more substrates A according to the present disclosure provide a stable, reliable, and controlled mechanism of self-bending or self-folding. For both thicknesses t1 of the first layer 1, the larger the thickness t2 of the second layer 2, the smaller the bending radius obtained. Examples 1 to 8 demonstrate that by setting the thickness of one or more second layers 2, a small bending radius in the micrometer range suitable for wrapping / grasping biological samples such as nerve fibers having diameters typically in the range of tens to hundreds of μm and attaching electrodes can be reliably and stably achieved.

[0073] [Table 1]

[0074] [Table 2] 2. Electrode element 11a and 11b show schematic side views of electrode element B and folded or curved electrode element B, respectively. Electrode element B comprises substrate A according to the first embodiment or the second embodiment or the third embodiment. Electrode element B further comprises a first conductive layer 3 deposited on the second surface 1-2 of the first layer 1 of substrate A. The first conductive layer 3 may serve as part of an embedded microelectrode and may directly and / or physically contact a biological sample in use. The second layer 2 of substrate A, the first layer 1 of substrate A and the first conductive layer 3 are stacked in this order in the z-direction and overlap each other. As shown in FIG. 11b, electrode element B curves itself when in contact with a liquid containing water molecules such that the first conductive layer 3 becomes an inner layer of substrate A. The axis of curvature is defined in the x-direction, more precisely in a direction parallel to the x-direction, and the radius of curvature is defined in the yz-plane.

[0075] To manufacture the electrode element B, a substrate A according to the first or second or third embodiment is first prepared according to a method for manufacturing the substrate A. A first conductive layer 3 is deposited on the second surface 1-2 of the first layer 1 of the substrate A, for example by a metal sputtering process or a printing process.

[0076] 3.Electrode system 12a, 12b and 12c show diagrammatically an electrode system C comprising an electrode element B. As explained above, the electrode element B comprises a first conductive layer 1 for direct and / or physical contact with a biological sample and comprises a substrate A according to the first or second or third embodiment. The electrode system C further comprises a third layer 4 extending in the x and y directions from the first layer 1. The third layer 4 is integrally formed with the first layer 1 of the electrode element B, the third layer 4 being preferably based on a first mixture 10, just like the first layer 1. The third layer 4 and the first layer 1 can be obtained by curing the first mixture 10, more precisely, simultaneously by curing the first mixture 10. The electrode system C further comprises a second conductive layer 5 deposited on the third layer 4, the second conductive layer 5 being connected to the first conductive layer 3. More precisely, the second conductive layer 5 is mechanically or physically connected to the first conductive layer 3. The second conductive layer 5 can be formed simultaneously with the first conductive layer 3, for example in a metal sputtering process. The second conductive layer 5 can serve as a feed line and a contact pad for electrically connecting the first conductive layer 3 to further equipment. In this embodiment, two feed lines (i.e., the second conductive layer 5) are provided and connected to one first conductive layer 3, which may be more advantageous for conducting electrical conductivity tests. The two feed lines are merely optional, and the first conductive layer may be connected to only one feed line.

[0077] The electrode system C preferably further comprises a fourth layer 6, which may be an insulating and / or passivation layer 6 on the surface of the second conductive layer 5 for shielding a part of the second conductive layer. The third layer 4, the second conductive layer 5 and the fourth layer 6 are stacked in this order in the z-direction. In particular, the third layer 4, the second conductive layer 5 and the fourth layer 6 overlap each other. The fourth layer 6 may be based on the first mixture 10 and / or the fourth layer 6 is obtained by curing the first mixture 10.

[0078] 12c, electrode element B of electrode system C can curve or fold itself when in contact with a liquid containing water molecules (when at least the second layer 2 of substrate A contacts the liquid and is swollen by the liquid) with an axis of curvature defined in the x direction and / or parallel to the x direction and a radius of curvature defined in the yz plane. Electrode element B of electrode system C curves or folds itself such that the first conductive layer 3 forms an inner layer of the curved or folded electrode element B.

[0079] <Manufacturing method> 14a-e are schematic diagrams illustrating a method for manufacturing an electrode system C integrating an electrode element B with a substrate A according to the first or second or third embodiment. As shown in FIG. 14a, the method comprises the step of forming a first layer 1 and a third layer 4 by exposing a first mixture 10 to light. In particular, the first mixture can be placed on a transparent support or glass slide 70 by drop casting or spin coating. The first mixture 10 is then irradiated with a light pattern (indicated by arrows) from below the support 70 to obtain the first layer 1 and the third layer 4. As shown in FIG. 14b, by applying a longer exposure time and / or a higher light amount (represented in FIG. 14a by a long arrow) to the first mixture 10 at the position of the third layer 4 compared to the position of the first layer 1 (represented in FIG. 14a by a short arrow), the thickness of the third layer 4 in the z-direction is formed to be greater than the thickness of the first layer 1.

[0080] After exposing the first mixture 10 to light, the uncured residue of the first mixture 10 is removed. As shown in FIG. 14c, the method further includes forming a second layer 2 on the first layer 1 by exposing the second mixture 20 to light. There, the second mixture 20 is deposited on the first layer 1 and exposed to light through the support 70 and the cured first layer 1, as shown by the arrow. Curing the first layer 1 with a shorter exposure time than the third layer 4 can be particularly advantageous in that when both the first mixture 10 and the second mixture 20 include first and second components having (meth)acrylate functional groups, the first layer 1 and the second layer 2 can be covalently bonded to each other through the (meth)acrylate functional groups, which can provide strong adhesion between the first layer 1 and the second layer 2 even without an adhesive layer between the first layer 1 and the second layer 2.

[0081] As shown in Fig. 14d, after curing the second mixture 20, the uncured residue of the second mixture 20 is removed to obtain a second layer 2. As shown in Fig. 14e, the formed first layer 1, second layer 2, and third layer 4 are turned upside down on a support 70, and the method further includes forming a first conductive layer 3 on the first layer 1 and forming a second conductive layer 5 on the third layer 4.

[0082] <Example> In the following, examples are described for the electrode system C according to the present disclosure. The materials and conditions used in these examples are merely illustrative and do not limit the present embodiment.

[0083] 13a-c show a part of an example of a curved electrode system C according to an embodiment (an image of this example is shown in the top row and a corresponding schematic diagram is shown in the bottom row). The first layer 1, the second layer 2 and the third layer 3 of the electrode system C are obtained from the first mixture 10 and the second mixture 20, respectively, as described for the example in Figs. 10a-c. The substrate A integrated in the example electrode system C shown in Figs. 13a-c has a number of second layers of 3. The first layer 1 has a width w1 of 0.6 mm in the y direction, a length l1 of 0.8 mm in the x direction and a thickness of 80 μm in the z direction. The thickness of the third layer 4 in the z direction is 0.15 mm. The third layer 4, which extends from the first layer 1 in the x and y directions, is integrally formed with the first layer 1. Each of the second layers 2 of this exemplary electrode system C has a length l2 of 0.15 mm in the x direction, a width w2 of 0.6 mm in the y direction, is separated from each other by a distance of 0.15 mm in the x direction, and has a thickness of 40 μm in the z direction.

[0084] The first conductive layer 3 and the second conductive layer 5 are obtained by simultaneously sputtering gold to a thickness of about 80 nm on the second surface 1-2 of the first layer 1 and on the surface of the third layer 4, respectively, so that the second conductive layer 5 is physically connected to the first conductive layer 3. The sputtered conductive layers 3, 5 are patterned by using a nanosecond laser to form two separate electrodes as shown in Fig. 13a-c. A fourth layer 6 (passivation layer) was obtained by spin-coating the first mixture 10 on the surface of the second conductive layer 5 and curing the first mixture 10 to partially passivate the electrodes on the third layer 4 and to form contact pads for connecting amplification and stimulation circuits (not shown).

[0085] As shown in Fig. 13a-c, the electrode element B (i.e. the first conductive layer 3 and the substrate A) of the exemplary electrode system C curves itself after contact with a liquid (here deionized water at room temperature) and swelling with the liquid containing water molecules (the substrate of the exemplary electrode system is therefore saturated and the first and / or second layers are saturated with the components of the liquid) with an axis of curvature defined in the x-direction, more precisely in a direction parallel to the x-direction. Fig. 13a shows the electrode system C before folding, i.e. before immersion in the liquid. The electrode system C is immersed in the liquid and Fig. 13b shows the electrode system C 40 seconds after immersion in the liquid, where the substrate A on which the first conductive layer 3 is deposited starts to deform, such that the outer edge (edge ​​in the y-direction) of the substrate A rises in the z-direction and approaches further to the second conductive layer 5 in the y-direction. 13c shows the electrode system C in a fully folded state (60 seconds after immersion in the liquid). As shown by way of example, the first conductive layer 3 forms the inner layer of the curved or folded electrode element B. [Explanation of symbols]

[0086] A: Substrate B: Electrode element C: Electrode system 1: First layer 1a: Groove 1-1: First surface 1-2: Second surface 2: Second layer 3: First conductive layer 4: Third layer 5: Second conductive layer 6: Fourth layer 10: First mixture 20: Second mixture 70:Support

Claims

1. A substrate for an implantable microelectrode for embedding in tissues such as nerves or for contacting single cells to apply and / or record electrical signals to and / or from the tissue or the single cell, a first layer, and a second layer deposited on at least a part of a first surface of the first layer comprising, each of the first layer and the second layer extending in the x and y directions, and the first layer and the second layer being stacked in the z direction, (i) the first layer is based on a first mixture, the first mixture comprising (a) a first photoinitiator, (b) a first component comprising at least one of a first monomer or a first oligomer or a first polymer, the first monomer or the first oligomer or the first polymer comprising a first functional group, the first functional group being activatable by the first photoinitiator, so that the first component is a first component capable of being photopolymerized via the first functional group, comprising, (ii) the second layer is based on a second mixture, the second mixture comprising (c) a second photoinitiator, (d) a second component comprising a second monomer or a second oligomer or a second polymer, the second monomer or the second oligomer or the second polymer being an acid and comprising a second functional group, the second functional group being activatable by the second photoinitiator, so that the second component is a second component capable of being linearly photopolymerized via the second functional group, (e) a base capable of neutralizing the second monomer or the second oligomer or the second polymer to thereby form a salt, (f) a third component comprising at least one of a third oligomer or a third polymer, the third oligomer or the third polymer comprising two functional groups, the two functional groups being a third functional group and a fourth functional group, each of the third functional group and the fourth functional group being activatable by the second photoinitiator, so that the third component is a third component capable of crosslinking the second component via the third functional group and the fourth functional group, comprising, The swelling capacity (Q ｗ１ ) of the first layer is smaller than the swelling capacity (Q ｗ２ ) of the second layer, substrate.

2. The substrate according to claim 1, wherein at least one of the second functional group, the third functional group, and the fourth functional group is capable of forming a covalent bond with the first functional group.

3. The swelling capacity (Q ｗ１ ) of the first layer with respect to the swelling capacity (Q ｗ２ ) of the second layer is preferably Q ｗ２ / Q ｗ１ = 5 or more, more preferably Q ｗ２ / Q ｗ１ = 10 or more, more preferably Q ｗ２ / Q ｗ１ = 20 or more. The substrate according to claim 1 or 2

4. The substrate according to any one of claims 1 to 3, wherein the second layer entirely covers the first surface of the first layer.

5. Each of the first layer and the second layer has a length in the x direction and a width in the y direction, The length of the second layer is shorter than the width of the second layer, The substrate according to any one of claims 1 to 3, wherein the length of the second layer is shorter than the length of the first layer.

6. The substrate according to claim 5, comprising a plurality of the second layers deposited on the first surface of the first layer, the plurality of second layers being spaced apart from each other in the y direction.

7. The length of the first layer is longer than the width of the first layer, or The substrate according to any one of claims 1 to 6, wherein the length of the first layer is shorter than the width of the first layer.

8. The first layer includes grooves formed on the first surface or the second surface of the first layer, the second surface being on the opposite side of the first surface in the z direction, The substrate according to any one of claims 1 to 7, wherein the grooves extend in the x direction.

9. The substrate according to claim 8, wherein the first layer includes a plurality of the grooves, the plurality of grooves being spaced apart from each other in the x direction.

10. The substrate according to claim 8 or 9, wherein the second layer at least partially enters into the grooves.

11. The substrate according to any one of claims 8 to 10, wherein the width direction of the second layer and the longitudinal direction of the grooves are perpendicular to each other.

12. The first monomer or the first oligomer or the first polymer is polyurethane or silicone, and / or The substrate according to any one of claims 1 to 11, wherein the first functional group is an acrylate group or a methacrylate group.

13. The second component includes the second monomer, the second monomer being acrylic acid or methacrylic acid, and / or The substrate according to any one of claims 1 to 12, wherein the second functional group is an acrylate group or a methacrylate group.

14. The second component includes a further monomer or a further oligomer containing a fifth functional group, Since the second functional group and the fifth functional group can be activated by the second photoinitiator, the second component can be linearly photopolymerized via the second functional group and the fifth functional group. The substrate according to any one of claims 1 to 13.

15. The fifth functional group is a methacrylate group, and / or The further monomer is hydroxyethyl methyl acrylate (HEMA). The substrate according to claim 14.

16. The base contains NaOH and / or KOH, and / or The third oligomer or the third polymer is polyethylene glycol. Further, the third functional group is an acrylate group or a methacrylate group, The fourth functional group is an acrylate group or a methacrylate group. The substrate according to any one of claims 1 to 15.

17. The molar ratio of the second monomer or the second oligomer or the second polymer to the further monomer or the further oligomer is in the range of 1000:1 to 1:1, more preferably 1000:1 to 2:1, and / or The molar ratio of the second monomer or the second oligomer or the second polymer to the base is in the range of 10:1 to 10:6, more preferably 10:3 to 10:

4. The substrate according to any one of claims 14 to 16.

18. The degree of neutralization of the acid with respect to the base is 10 to 60%, or more preferably 30 to 40%. The substrate according to any one of claims 1 to 17.

19. The molar ratio of the second component to the third component is in the range of 1000:1 to 2:1, more preferably 200:1 to 20:

1. The substrate according to any one of claims 1 to 18.

20. The first mixture and / or the second mixture further contains a further photoinitiator and / or a quencher and / or a light absorber. The substrate according to any one of claims 1 to 19.

21. A system comprising the substrate according to any one of claims 1 to 20, A third layer extending in the x direction and the y direction from the first layer Including, The third layer is integrally formed with the first layer. The third layer is preferably based on the first mixture. A system.

22. An electrode element that can be embedded in a biological sample, The electrode element includes the substrate according to any one of claims 1 to 21, The electrode element is (iii) A first conductive layer deposited on a second surface of the first layer, the second surface extending in the x and y directions and being on the opposite side of the first surface in the z direction, the second layer, the first layer, and the first conductive layer being stacked in this order in the z direction, the electrode element including the first conductive layer.

23. The electrode element according to claim 22, wherein the first conductive layer includes a metal film and / or a nanoparticle conductor and / or a conductive polymer.

24. An electrode system including the electrode element according to claim 22 or 23, (iv) A third layer extending from the first layer in the x and y directions, the third layer being integrally formed with the first layer, the third layer preferably being based on the first mixture, the third layer, (v) A second conductive layer deposited on the third layer and connected to the first conductive layer, the second conductive layer including the electrode system.

25. A method for manufacturing a substrate according to any one of claims 1 to 20, the method including: forming the first layer by exposing the first mixture to light; forming the second layer on the first layer by exposing the second mixture to light. including the method.

26. The method according to claim 25, wherein the step of forming the first layer includes the step of forming a groove according to any one of claims 8 to 11.

27. A method for manufacturing the electrode element according to claim 22 or 23, the method including all the steps according to claim 24 or 25, and the method further including: forming the first conductive layer on the first layer.

28. A method for manufacturing the electrode system according to claim 24, the method including all the steps according to claim 27, and the method further including: forming the third layer by exposing the first mixture to light; forming the second conductive layer including the method.

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