Implantable electrode structure and manufacturing method therefor

Abstract

The present invention relates to an one-dimensional porous microfiber-based implantable electrode structure, wherein a first cell is mounted on a first portion of the one-dimensional porous microfiber, and a second cell is mounted on a second portion of the one-dimensional porous microfiber.

Description

Bio-implantable electrode structure and manufacturing method thereof

[0001] The present invention relates to a bio-implantable electrode structure and a method for manufacturing the same, and more particularly, to a microfiber-based bio-implantable electrode structure and a method for manufacturing the same.

[0002] The technological development of bioimplantable electrodes has evolved toward developing electrodes that can effectively interface with biological tissues such as nerves and muscles. Initially, simple metal wires or silicon-based electrodes were primarily used, boasting the advantages of relative ease of manufacture and high electrical conductivity. However, because biological tissue is soft and flexible, rigid metal or silicon electrodes frequently encountered mechanical mismatch after implantation, leading to inflammatory responses and tissue damage. Consequently, the development of electrodes utilizing flexible and biocompatible materials began in earnest.

[0003] Accordingly, methods have been developed to form electrodes by patterning metal circuits or conductive polymers on flexible polymer substrates such as polyimide and PDMS (polydimethylsiloxane). These electrodes have been widely utilized because they offer mechanical flexibility while maintaining a certain level of electrical performance of conventional metal electrodes. However, this technology also has various limitations, such as reduced adhesion between the electrode and tissue in long-term implant environments, in vivo foreign body reactions, and signal accuracy issues.

[0004] Recently, fiber-based electrodes, especially microfiber-based electrodes, which have a three-dimensional, porous structure that is more structurally similar to tissue and even considers cell interaction, are attracting attention as a new paradigm. Technology is evolving to directly culture cells on these microfiber electrodes or to selectively load specific cells. This means that electrodes can be utilized as active biointerface devices that go beyond the passive role of simply detecting signals and can even perform tissue regeneration or treatment. However, existing microfiber-based bioimplantable electrodes have limitations in several aspects, such as precise function control, implementation of complex physiological responses, and regulation of cell-to-cell interactions.

[0005] Accordingly, in order to overcome the limitations of existing technologies, the present invention has been made possible by mounting a first cell on a first part of a microfiber and a second cell on a second part, thereby resolving the simple functionality, intercellular interference, structural simulation limitations, and signal interpretation complexity of existing microfiber-based electrodes.

[0006] An object of the present invention to solve the above-mentioned problems is to provide a bio-implantable electrode structure based on one-dimensional porous microfibers that enables simultaneous implementation of cell transplantation and electrical stimulation, enables precise targeting based on heterogeneity between cells, enables precise separation and loading without interference between cells and maintains independent functions, improves cell viability, and has excellent tissue penetration and bioenvironment adaptability.

[0007] Another object of the present invention to solve the above-mentioned problems is to provide a method for manufacturing a bio-implantable electrode structure that enables simultaneous implementation of cell transplantation and electrical stimulation, enables precise targeting based on heterogeneity between cells, enables precise separation and loading without interference between cells and maintains independent functions, improves cell viability, and has excellent tissue penetration and bioenvironment adaptability.

[0008] However, the problem to be solved by the present invention is not limited to this, and may be expanded in various ways without departing from the spirit and scope of the present invention.

[0009] According to one embodiment of the present invention for achieving the above-described purpose, a bio-implantable electrode structure based on a one-dimensional porous microfiber may be provided with a first cell loaded on a first portion of the one-dimensional porous microfiber, and a second cell loaded on a second portion of the one-dimensional porous microfiber.

[0010] According to one aspect, the one-dimensional porous microfibers can be formed from an electrospun polymer.

[0011] According to one aspect, the electrospun polymer comprises at least one of polyurethane (PU), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polyhydroxyalkanoate (PHA), polyvinyl alcohol (PVA), hyaluronic acid (HA), polyethylene glycol (PEG), polycarbonate (PC), polyaniline (PANI), collagen, gelatin, chitosan, alginate, fibrin, decellularized extracellular matrix, poly(3,4-ethylenedioxythiophene):polystyrenesulfonic acid (PEDOT:PSS), and polypyrrole (PPy), and the polymer of the first portion and the polymer of the second portion of the one-dimensional porous microfibers may be the same or different.

[0012] According to one aspect, the first cell and the second cell are dopaminergic neurons, serotonergic neurons, acetylcholinergic neurons, norepinephrine neurons, glutamatergic neurons, GABAergic neurons, motor neurons, sensory neurons, pain receptor neurons, indirect motor neurons, neural stem cells, astrocytes, oligodendrocytes, microglia, Schwann cells, cardiomyocytes, skeletal muscle cells, myocytes, satellite cells, smooth muscle cells, cardiac fibroblasts, muscle stem cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, neural stem cells, cardiac progenitor cells, vascular progenitor cells, blood stem cells, retinal progenitor cells, muscle progenitor cells, retinal ganglion cells, photoreceptor cells, olfactory receptor cells, auditory hair cells, equilibrium sensory cells, taste receptor cells, vascular endothelial cells, vascular smooth muscle cells, macrophages, T cells, regulatory T cells, dendritic cells, natural killer cells, neutrophils, fibroblasts, hepatocytes, pancreatic cells beta cells, sebaceous cells, keratinocytes, osteoblasts, osteocytes or osteoclasts, and the first and second cells may be different from each other,

[0013] According to one aspect, the first part of the one-dimensional porous microfibers may form a core, and the second part of the one-dimensional porous microfibers may form a shell surrounding the core.

[0014] According to one aspect, the first portion of the one-dimensional porous microfibers may have microfibers oriented in a uniaxial direction, and the second portion of the one-dimensional porous microfibers may have microfibers that are not oriented.

[0015] According to one aspect, the one-dimensional porous microfibers may be coated with parylene.

[0016] According to one aspect, the one-dimensional porous microfibers may be perylene coated and then metal deposited.

[0017] According to one aspect, the one-dimensional porous microfibers may be formed into a one-dimensional thread shape by rolling or twisting an electrospun two-dimensional polymer microfiber film.

[0018] According to one aspect, the cross-section of the one-dimensional porous microfiber may include n layers from the center when the center is referred to as the first layer, and the first cell may be mounted on an odd-numbered layer among the n layers, and the second cell may be mounted on an even-numbered layer among the n layers.

[0019] According to one aspect, the cross-section of the one-dimensional porous microfiber may include n layers from the center when the center is referred to as the first layer, and the types of cells mounted on the n layers may all be different.

[0020] Another method for manufacturing a bio-implantable electrode structure according to an embodiment of the present invention for achieving the above-described object comprises: a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of coating the manufactured two-dimensional microfiber membrane with parylene; a third step of depositing a metal on the two-dimensional microfiber membrane coated with parylene; a fourth step of depositing a conductive polymer on the two-dimensional microfiber membrane with the metal deposited thereon; a fifth step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by mounting a first cell on the two-dimensional microfiber membrane with the conductive polymer deposited thereon; a sixth step of manufacturing a second two-dimensional microfiber membrane loaded with second cells by mounting a second cell on the two-dimensional microfiber membrane with the conductive polymer deposited thereon after performing the first to fourth steps; And a seventh step of manufacturing a one-dimensional porous microfiber by rolling or twisting after laminating the first two-dimensional microfiber film and the second two-dimensional microfiber film;

[0021] According to one aspect, the polymer forming the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane includes at least one of polyurethane (PU), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polyhydroxyalkanoate (PHA), polyvinyl alcohol (PVA), hyaluronic acid (HA), polyethylene glycol (PEG), polycarbonate (PC), polyaniline (PANI), collagen, gelatin, chitosan, alginate, fibrin, decellularized extracellular matrix, poly(3,4-ethylenedioxythiophene):polystyrenesulfonic acid (PEDOT:PSS), and polypyrrole (PPy), and the polymer forming the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane It can be the same or different.

[0022] According to one aspect, the first cell and the second cell are dopaminergic neurons, serotonergic neurons, acetylcholinergic neurons, norepinephrine neurons, glutamatergic neurons, GABAergic neurons, motor neurons, sensory neurons, pain receptor neurons, indirect motor neurons, neural stem cells, astrocytes, oligodendrocytes, microglia, Schwann cells, cardiomyocytes, skeletal muscle cells, myocytes, satellite cells, smooth muscle cells, cardiac fibroblasts, muscle stem cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, neural stem cells, cardiac progenitor cells, vascular progenitor cells, blood stem cells, retinal progenitor cells, muscle progenitor cells, retinal ganglion cells, photoreceptor cells, olfactory receptor cells, auditory hair cells, equilibrium sensory cells, taste receptor cells, vascular endothelial cells, vascular smooth muscle cells, macrophages, T cells, regulatory T cells, dendritic cells, natural killer cells, neutrophils, fibroblasts, hepatocytes, pancreatic cells A beta cell, a sebaceous cell, a keratinocyte, an osteoblast, an osteocyte or an osteoclast, and the first cell and the second cell may be different from each other.

[0023] According to one aspect, after the seventh step, a step of coating a decellularized extracellular matrix hydrogel on the manufactured one-dimensional porous microfibers may be further included.

[0024] According to one aspect, the first part of the one-dimensional porous microfibers loaded with the first cells may form a core, and the second part of the one-dimensional porous microfibers loaded with the second cells may form a shell.

[0025] According to one aspect, the first two-dimensional microfiber film can be electrospun to be oriented in a uniaxial direction, and the second two-dimensional microfiber film can be electrospun to form a random structure without being oriented.

[0026] According to one aspect, the metal deposited in the third step may include one or more of gold (Au), silver (Ag), copper (Cu), platinum (Pt), iridium (Ir), tantalum (Ta), titanium (Ti), ruthenium (Ru), palladium (Pd), nickel (Ni), cobalt (Co), iron (Fe), nickel-titanium alloy (NiTi), and gold-silver alloy (Au-Ag).

[0027] According to one aspect, the conductive polymer deposited in the fourth step is PEDOT:PSS (Poly(3,4-ethylenedioxythiophene):polystyrene sulfonate), PEDOT:Tos (Poly(3,4-ethylenedioxythiophene):tosylate), polypyrrole (PPy), polyaniline (PANI), poly(3-hexylthiophene) (P3HT), poly(3,4-propylenediothiophene) (PProDOT), polycarbazole, polyindole, poly(p-phenylene vinylene) (PPV), polyacetylene (PA), polyfuran, PEDOT:BF4 (Poly(3,4-ethylenedioxythiophene):tetrafluoroborate), PEDOT:Cl (Poly(3,4-ethylenedioxythiophene):chloride), PEDOT:PF6 (Poly(3,4-ethylenedioxythiophene):hexafluorophosphate), PEDOT-PEG copolymer, PEDOT-GO composite, PEDOT-CNT composite, PPy-chitosan composite, PPy-collagen composite, PANI-gelatin composite, PEDOT:PSS-gelatin hydrogel, PANI-PEG copolymer, PANI-PLA composite, PEDOT:PSS-hyaluronic acid hydrogel, PANI-alginate composite,It may include at least one of PEDOT:PSS-fibrin hydrogel and PEDOT:PSS-RGD peptide conjugate.

[0028] According to another embodiment of the present invention for achieving the above-described object, a method for manufacturing a bio-implantable electrode structure comprises: a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of coating the manufactured two-dimensional microfiber membrane with primary parylene; a third step of depositing a metal on the two-dimensional microfiber membrane coated with primary parylene; a fourth step of coating the two-dimensional microfiber membrane coated with secondary parylene to insulate the deposited metal surface; a fifth step of etching the two-dimensional microfiber membrane coated with secondary parylene to etch away a portion of the insulating film on the insulated metal surface, thereby exposing a portion of the metal surface of the two-dimensional microfiber membrane; a sixth step of depositing a conductive polymer on the exposed metal surface of the two-dimensional microfiber membrane; a seventh step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by loading first cells on the two-dimensional microfiber membrane on which the conductive polymer is deposited; After performing the first to sixth steps, the method may include an eighth step of manufacturing a second two-dimensional microfiber membrane having second cells mounted thereon by mounting second cells on the two-dimensional microfiber membrane on which the conductive polymer is deposited; and a ninth step of manufacturing a one-dimensional porous microfiber by laminating the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane and then rolling or twisting the laminate.

[0029] According to another embodiment of the present invention for achieving the above-described object, a method for manufacturing a bio-implantable electrode structure comprises: a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of coating the manufactured two-dimensional microfiber membrane with primary parylene; a third step of depositing a metal on the two-dimensional microfiber membrane coated with primary parylene; a fourth step of coating the two-dimensional microfiber membrane coated with secondary parylene to insulate the deposited metal surface; a fifth step of etching the two-dimensional microfiber membrane coated with secondary parylene to etch away a portion of the insulating film on the insulated metal surface, thereby exposing a portion of the metal surface of the two-dimensional microfiber membrane; a sixth step of depositing a conductive polymer on the exposed metal surface of the two-dimensional microfiber membrane; a seventh step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by loading first cells on the two-dimensional microfiber membrane on which the conductive polymer is deposited; The method may include an eighth step of manufacturing a plurality of two-dimensional microfiber membranes, each of which has different cells loaded thereon, by repeating the first to sixth steps; a ninth step of manufacturing a plurality of one-dimensional porous microfiber membranes, each of which has different cells loaded thereon, by rolling or twisting the plurality of two-dimensional microfiber membranes; and a tenth step of performing a multi-array process using the plurality of one-dimensional porous microfibers.

[0030] In one aspect, in the above 10th step, the multiple array process may be a braiding, weaving or knitting process.

[0031] In one aspect, the cells mounted on the plurality of one-dimensional porous microfibers are each different, and the cells may be dopaminergic neurons, serotonergic neurons, glutamatergic neurons, or GABAergic neurons.

[0032] The disclosed technology may have the following effects. However, this does not mean that a particular embodiment must include all or only the following effects, and therefore the scope of the disclosed technology should not be construed as being limited thereby.

[0033] According to the bio-implantable electrode structure and the manufacturing method thereof according to one embodiment of the present invention described above, by precisely separating and mounting different cells in specific areas within the electrode, each cell can perform its original function without interference between cells.

[0034] In addition, according to the bio-implantable electrode structure and the manufacturing method thereof according to one embodiment of the present invention, it is possible to separate and stably maintain the functions of heterogeneous cells, and to spatially control the interaction between cells to induce or suppress a specific physiological response.

[0035] In addition, according to the bio-implantable electrode structure and the manufacturing method thereof according to one embodiment of the present invention, the structure divided into specific regions within the electrode can independently collect or selectively stimulate bio-signals generated from each cell, thereby enabling precise signal analysis and control.

[0036] In addition, according to the bio-implantable electrode structure and the manufacturing method thereof according to one embodiment of the present invention, various functions such as nerve stimulation, tissue regeneration, and drug delivery can be performed simultaneously within a single electrode structure, thereby serving as the basis for implementing multifunctional bio-responses.

[0037] In addition, according to the bio-implantable electrode structure and the manufacturing method thereof according to one embodiment of the present invention, biocompatibility and functional integration can be maximized by reproducing an environment similar to a biological tissue by compartmentalizing the arrangement of cells like a biological tissue structure.

[0038] Figure 1 illustrates a bio-implantable electrode structure based on one-dimensional porous microfibers according to one embodiment of the present invention.

[0039] FIG. 2 is a schematic diagram showing selective monitoring of different types of neural cells using a one-dimensional porous microfiber-based bio-implantable electrode structure according to one embodiment of the present invention.

[0040] FIG. 3 is a schematic diagram showing a method for monitoring the activity of neural cells using a one-dimensional porous microfiber-based bio-implantable electrode structure according to one embodiment of the present invention.

[0041] FIG. 4 is a schematic diagram showing a manufacturing process of a one-dimensional porous microfiber-based bio-implantable electrode structure according to one embodiment of the present invention.

[0042] Figure 5 is an image showing the control of the orientation of microfibers during electrospinning.

[0043] Figure 6 is a schematic diagram showing a cross-section of a one-dimensional porous microfiber according to the present invention.

[0044] Figure 7 is a schematic diagram showing the diameter of electrospun microfibers according to the present invention.

[0045] Figure 8 is a schematic diagram showing the density of an electrospun microfiber film according to the present invention.

[0046] Figure 9 is a schematic diagram showing the orientation of an electrospun microfiber film according to the present invention.

[0047] Figure 10a is a schematic diagram showing the process of manufacturing one-dimensional microfibers by laminating and rolling or twisting an electrospun microfiber film according to the present invention.

[0048] Figure 10b is a schematic diagram showing the structure of a one-dimensional porous microfiber according to the present invention.

[0049] Figure 11a is a photograph showing a coating of parylene on microfibers according to the present invention.

[0050] Figure 11b shows a bare PU microfiber membrane, a polyurethane (PU) microfiber membrane with a primary perylene coating applied, and a PU microfiber membrane with a secondary perylene coating applied.

[0051] Figure 12 is a schematic diagram showing a traction platform on which a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention is mounted.

[0052] Figure 13 shows a schematic diagram of an automated device for rolling or twisting a two-dimensional microfiber membrane to manufacture one-dimensional porous microfibers according to the present invention.

[0053] Figure 14 is an image of an electrode array formed by depositing metal on a microfiber film according to the present invention.

[0054] Figure 15 is an image showing the results of depositing gold (Au) after the first perylene coating on a two-dimensional microfiber film according to the present invention, then depositing PEDOT:PSS, a conductive polymer, after the second perylene coating and oxygen plasma etching. Figure 16 is an image of one-dimensional porous microfibers (bundles) without cells, transplanted onto the skin of an SD rat (Sprague-Dawley rat).

[0055] Figure 17 is an image of human-derived dopaminergic neurons mounted on a two-dimensional microfiber membrane electrode (left) and a one-dimensional porous microfiber bundle electrode (right).

[0056] Figure 18 is an image showing the results of observing the activation response of muscle cells located in the thigh area of ​​an SD rat.

[0057] Figure 19 shows the braiding process and braiding form.

[0058] Figure 20 is an image of an electrode structure bundle (scaffold) manufactured using a braiding process for a bio-implantable electrode structure based on one-dimensional porous microfibers according to the present invention.

[0059] Figure 21 is an SEM image of a bundle of electrode structures manufactured by a braiding process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, at magnifications of 100 times (left), 150 times (center), and 500 times (right).

[0060] Figure 22 shows the weaving process and weaving form.

[0061] Figure 23 is an image of an electrode structure bundle (scaffold) manufactured using a weaving process for a bio-implantable electrode structure based on one-dimensional porous microfibers according to the present invention.

[0062] Figure 24 is an SEM image of a bundle of electrode structures manufactured by a weaving process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, at magnifications of 100 times (left), 150 times (center), and 500 times (right).

[0063] Figure 25 shows the knitting process and knitting form.

[0064] Figure 26 is an image of an electrode structure bundle (scaffold) manufactured by a knitting process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention.

[0065] Figure 27 is an SEM image of a bundle of electrode structures manufactured by a knitting process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, at magnifications of 100 times (left), 150 times (center), and 500 times (right).

[0066] The present invention can be modified in various ways and has various embodiments, and specific embodiments are illustrated in the drawings and described in detail.

[0067] However, this is not intended to limit the present invention to a specific embodiment, but should be understood to include all modifications, equivalents, or substitutes included in the spirit and technical scope of the present invention.

[0068] While terms such as "first" and "second" may be used to describe various components, these components should not be limited by these terms. These terms are used solely to distinguish one component from another. For example, without departing from the scope of the present invention, a first component may be referred to as a "second component," and similarly, a second component may also be referred to as a "first component." The term "and / or" includes any combination of multiple related items described herein or any item among multiple related items described herein.

[0069] When a component is referred to as being "connected" or "connected" to another component, it should be understood that it may be directly connected or connected to that other component, but that there may be other components intervening. Conversely, when a component is referred to as being "directly connected" or "connected" to another component, it should be understood that there are no other components intervening.

[0070] The terminology used in this application is only used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this application, it should be understood that the terms "comprise" or "have" indicate the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, but do not exclude in advance the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0071] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and will not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0072] Hereinafter, with reference to the attached drawings, preferred embodiments of the present invention will be described in more detail. In order to facilitate an overall understanding in describing the present invention, identical reference numerals will be used for identical components in the drawings, and redundant descriptions of identical components will be omitted.

[0073]

[0074] In this disclosure, "microfiber" may refer to any fiber structure having a diameter ranging from nanometers to micrometers, but it should be understood that the unit of microfiber is not limited thereto. That is, the "microfiber" according to the present invention may be a microfiber or a nanofiber.

[0075] In the present disclosure, the terms 'microfiber' and 'microfiber membrane' may be used interchangeably, and the terms 'coating' and 'deposition' may be used interchangeably.

[0076] In the present disclosure, the term 'bio-implantable electrode structure' refers to an electrode structure that can be inserted into a living body, and can be used as, for example, a neural electrode, a brain electrode, a muscle electrode, a heart electrode, etc., but is not limited thereto.

[0077]

[0078] The bio-implantable electrode structure according to the present invention is a bio-implantable electrode structure based on one-dimensional porous microfibers, wherein a first cell can be loaded on a first portion of the one-dimensional porous microfibers, and a second cell can be loaded on a second portion of the one-dimensional porous microfibers.

[0079] In this description, the one-dimensional porous microfibers according to the present invention are conveniently described as "first portion" and "second portion," but the one-dimensional porous microfibers according to the present invention may be separated, partitioned, and divided into two or more multiple portions. For example, the one-dimensional porous microfibers according to the present invention may include first to tenth portions.

[0080] In addition, in the present disclosure, the cells loaded on the one-dimensional porous microfibers according to the present invention are conveniently described as "first cells" and "second cells," but two or more types of cells may be used as the cells loaded on the one-dimensional porous microfibers according to the present invention. For example, the first to tenth cells may be loaded on the first to tenth portions of the one-dimensional porous microfibers according to the present invention, respectively.

[0081]

[0082] The bio-implantable electrode structure based on one-dimensional porous microfibers according to the present invention is intended to simultaneously implement cell-selective responsiveness and a signal amplification mechanism. The one-dimensional porous microfiber bundle according to the present invention is composed of a plurality of electrode channels whose electrical properties can be individually controlled, and each channel can induce adhesion and response of a specific cell type through surface modification of the electrode (e.g., charge density, surface energy, coating molecular pattern). For example, electrode A can be set to have a cell membrane potential response frequency band specific to neurons, and electrode B can be set to have a stimulation frequency band sensitive to microglia. This makes it possible to induce a response only in a selected cell group when stimulating, and to clearly distinguish differences in response according to cell type during monitoring.

[0083] In addition, the interior of the one-dimensional porous microfiber bundle (bundle) according to the present invention may be composed of hundreds to thousands of microfiber strands or microfiber bundles. Inside the one-dimensional porous microfiber bundle according to the present invention, cells (e.g., nerve cells, immune cells, stem cells, etc.) can be aligned in one direction and adhered and cultured, thereby increasing the possibility of forming electrical synapses and gap junctions between cells. These aligned cells exhibit electrically synchronized responses (synchronized firing), and when cells on the surface of the structure respond to external stimuli, the internal cell population also responds simultaneously, thereby naturally causing signal amplification. That is, cells cultured (or mounted) inside the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention can be arranged along the alignment direction of the microfibers, and when one cell responds due to the connectivity between cells, the surrounding homologous cells can induce a continuous response, thereby amplifying the signal.

[0084]

[0085] Furthermore, while conventional electrodes only capture the responses of a portion of surrounding cells, in the present invention, since the cells exist as an organized network within the structure, a diffuse response expansion (effect spread) can be induced, in which a single cell stimulus induces a response in multiple cells. This can lead to advantages such as high-efficiency response even with low-power stimulation (increased battery life), improved signal-to-noise ratio (SNR), and wavelength-based analysis of intercellular signal transmission. Furthermore, the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention can implement stimulation and response separately for each cell type, making it applicable to customized disease research and treatment (e.g., Parkinson's disease, dementia, peripheral nerve damage, etc.). In addition, since the cells are connected and aligned within the electrode structure, spatial / temporal expansion of the signal is possible, so that a strong physiological response can be induced even with a very small amount of stimulation. This means that the structure has the potential to be expanded into a multi-channel brain-machine interface (BMI), a high-precision biosignal collection device, or an electrode platform for smart therapy.

[0086]

[0087] In one aspect, the one-dimensional porous microfibers of the bio-implantable electrode structure according to the present invention can be formed from an electrospun polymer. The electrospun polymer may include, but is not limited to, polyurethane (PU), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polyhydroxyalkanoate (PHA), polyvinyl alcohol (PVA), hyaluronic acid (HA), polyethylene glycol (PEG), polycarbonate (PC), polyaniline (PANI), collagen, gelatin, chitosan, alginate, fibrin, decellularized extracellular matrix, poly(3,4-ethylenedioxythiophene):polystyrenesulfonic acid (PEDOT:PSS), polypyrrole (PPy), and the like. Additionally, the polymer of the first part and the polymer of the second part of the one-dimensional porous microfiber may be the same or different.

[0088] In one aspect, the first cell and the second cell of the bio-implantable electrode structure according to the present invention are dopaminergic neurons, serotonergic neurons, acetylcholinergic neurons, norepinephrine neurons, glutamatergic neurons, GABAergic neurons, motor neurons, sensory neurons, pain receptor neurons, indirect motor neurons, neural stem cells, astrocytes, oligodendrocytes, microglia, Schwann cells, cardiomyocytes, skeletal muscle cells, myocytes, satellite cells, smooth muscle cells, cardiac fibroblasts, muscle stem cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, neural stem cells, cardiac progenitor cells, vascular progenitor cells, blood stem cells, retinal progenitor cells, muscle progenitor cells, retinal ganglion cells, photoreceptor cells, olfactory receptor cells, auditory hair cells, equilibrium sensory cells, taste receptor cells, vascular endothelial cells, vascular smooth muscle cells, macrophages, T cells, regulatory T cells, dendritic cells, natural killer cells, neutrophils, It may be, but is not limited to, a fibroblast, a hepatocyte, a pancreatic beta cell, a sebaceous gland cell, a keratinocyte, an osteoblast, an osteocyte, or an osteoclast. In addition, the first cell and the second cell are different from each other.

[0089]

[0090] In one aspect, the first part of the one-dimensional porous microfibers may form a core, and the second part of the one-dimensional porous microfibers may form a shell surrounding the core.

[0091] In one aspect, the cross-section of the one-dimensional porous microfiber according to the present invention may include a first portion located at the center and a second portion surrounding the center, and further, the cross-section of the one-dimensional porous microfiber according to the present invention may include a first portion located at the center, a second portion surrounding the center, a third portion surrounding the second portion, a fourth portion surrounding the third portion, a fifth portion surrounding the fourth portion, a sixth portion surrounding the fifth portion, etc.

[0092] In one aspect, the cross-section of the one-dimensional porous microfiber according to the present invention may include n layers from the center, and when the center is referred to as the first layer, it may include n layers, and the polymers of the n layers may be the same or different. In addition, the types of cells loaded on the n layers may all be different, or identical cells may be loaded on odd-numbered layers and identical cells may be loaded on even-numbered layers.

[0093]

[0094] In one aspect, the first part of the one-dimensional porous microfibers may have microfibers oriented uniaxially, and the second part of the one-dimensional porous microfibers may have microfibers that are not oriented and formed in a random structure. Accordingly, the second part (outer skin) in which the microfibers are not oriented and formed in a random structure may have sufficient porosity and sufficient pore size, thereby improving connectivity or interaction with other external neural cells. In addition, the first part (center part) in which the microfibers are oriented uniaxially has orientation, thereby improving connectivity or interaction between internal cells (e.g., brain cells). Therefore, according to the bio-implantable electrode structure according to the present invention, even if only one dopamine is introduced from the outside, dopamine cells can activate the entire dopamine cluster within the bio-implantable electrode structure.

[0095] In one aspect, the one-dimensional porous microfiber according to the present invention can be coated with parylene.

[0096] In one aspect, the one-dimensional porous microfibers according to the present invention can be metal-deposited after being perylene-coated. The metals that can be deposited in the present invention may include, but are not limited to, gold (Au), silver (Ag), copper (Cu), platinum (Pt), iridium (Ir), tantalum (Ta), titanium (Ti), ruthenium (Ru), palladium (Pd), nickel (Ni), cobalt (Co), iron (Fe), nickel-titanium alloy (NiTi), gold-silver alloy (Au-Ag), and the like.

[0097] In one aspect, the one-dimensional porous microfiber according to the present invention can be coated with perylene, then metal is deposited, and then a conductive polymer is deposited. Conductive polymers that can be deposited in the present invention include PEDOT:PSS (Poly(3,4-ethylenedioxythiophene):polystyrene sulfonate), PEDOT:Tos (Poly(3,4-ethylenedioxythiophene):tosylate), polypyrrole (PPy), polyaniline (PANI), poly(3-hexylthiophene) (P3HT), poly(3,4-propylenediothiophene) (PProDOT), polycarbazole, polyindole, poly(p-phenylene vinylene) (PPV), polyacetylene (PA), polyfuran, PEDOT:BF4 (Poly(3,4-ethylenedioxythiophene):tetrafluoroborate), PEDOT:Cl (Poly(3,4-ethylenedioxythiophene):chloride), PEDOT:PF6 (Poly(3,4-ethylenedioxythiophene):hexafluorophosphate), PEDOT-PEG Copolymer (PEDOT-PEG copolymer), PEDOT-graphene oxide composite (PEDOT-GO composite), PEDOT-carbon nanotube composite (PEDOT-CNT composite), PPy-chitosan composite (PPy-chitosan composite), PPy-collagen composite (PPy-collagen composite), PANI-gelatin composite (PANI-gelatin composite), PEDOT:PSS-gelatin hydrogel (PEDOT:PSS-gelatin hydrogel), PANI-PEG copolymer (PANI-PEG copolymer), PANI-PLA composite (PANI-PLA composite), PEDOT:PSS-hyaluronic acid hydrogel (PEDOT:PSS-hyaluronic acid hydrogel),Examples of such materials include, but are not limited to, PANI-alginate composite, PEDOT:PSS-fibrin hydrogel, and PEDOT:PSS-RGD peptide conjugate.

[0098] In one aspect, the one-dimensional porous microfiber according to the present invention may be formed into a one-dimensional thread shape by rolling or twisting an electrospun two-dimensional polymer microfiber film. In this case, by stacking multiple electrospun two-dimensional polymer microfiber films and rolling or twisting them, the cross-section of the one-dimensional porous microfiber may include n layers from the center.

[0099] In one aspect, the one-dimensional porous microfibers according to the present invention may be coated with a decellularized extracellular matrix hydrogel to minimize the immune response and maximize tissue integration after the bio-implantable electrode structure is inserted into the body, but is not limited thereto. The decellularized extracellular matrix (ECM) hydrogel or decellularized organ extracellular matrix hydrogel according to the present invention, from which immune information has been removed, can effectively suppress the immune response in the body, and can be slowly absorbed in the tissue over the long term while maintaining biocompatibility. In addition, according to the present invention, the decellularized ECM can be processed into a powder form and then manufactured into a hydrogel form, and the protein composition ratio (collagen, laminin, proteoglycan, etc.) can be adjusted to use a hydrogel optimized for tissue regeneration and cell attachment.

[0100]

[0101] In addition, a method for manufacturing a bio-implantable electrode structure according to an embodiment of the present invention for achieving the above-described object may include a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of manufacturing a one-dimensional porous microfiber membrane by rolling or twisting the manufactured two-dimensional microfiber membrane; a third step of coating the manufactured one-dimensional porous microfiber with parylene; a fourth step of depositing a metal on the one-dimensional porous microfiber coated with parylene; a fifth step of depositing a conductive polymer on the one-dimensional porous microfiber on which the metal has been deposited; and a sixth step of loading cells on the one-dimensional porous microfiber on which the conductive polymer has been deposited.

[0102]

[0103] In addition, a method for manufacturing a bio-implantable electrode structure according to an embodiment of the present invention for achieving the above-described object comprises: a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of coating the manufactured two-dimensional microfiber membrane with parylene; a third step of depositing a metal on the two-dimensional microfiber membrane coated with parylene; a fourth step of depositing a conductive polymer on the two-dimensional microfiber membrane with the metal deposited thereon; a fifth step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by mounting a first cell on the two-dimensional microfiber membrane with the conductive polymer deposited thereon; a sixth step of manufacturing a second two-dimensional microfiber membrane loaded with second cells by mounting a second cell on the two-dimensional microfiber membrane with the conductive polymer deposited thereon after performing the first to fourth steps; And a seventh step of manufacturing a one-dimensional porous microfiber by rolling or twisting after laminating the first two-dimensional microfiber film and the second two-dimensional microfiber film;

[0104] In one aspect, after the seventh step, a step of coating a decellularized extracellular matrix hydrogel on the manufactured one-dimensional porous microfibers may be further included.

[0105] In one aspect, between the third and fourth steps, a second perylene coating step may be further included.

[0106] In one aspect, after the third step, a second perylene coating step and an etching step may be further included, and after the etching step, a fourth step may be performed.

[0107] In one aspect, by performing the etching step, the electrode layer, which is a metal-deposited portion, can be revealed.

[0108] In one aspect, when etching the secondary perylene coated portion, a shadow mask can be used to etch only a certain polymer portion.

[0109] In one aspect, the etching method may include, but is not limited to, plasma etching such as oxygen plasma etching, fluorine plasma etching, and chlorine plasma etching; wet etching such as acid wet etching and basic wet etching; dry etching such as reactive ion etching and ion beam etching; and electrochemical etching such as electrochemical peeling and anodic oxidation.

[0110] In addition, a method for manufacturing a bio-implantable electrode structure according to an embodiment of the present invention for achieving the above-described object comprises: a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of coating the manufactured two-dimensional microfiber membrane with primary parylene; a third step of depositing a metal on the two-dimensional microfiber membrane coated with primary parylene; a fourth step of coating the two-dimensional microfiber membrane coated with secondary parylene to insulate the deposited metal surface; a fifth step of etching the two-dimensional microfiber membrane coated with secondary parylene to etch away a portion of the insulating film on the insulated metal surface, thereby exposing a portion of the metal surface of the two-dimensional microfiber membrane; a sixth step of depositing a conductive polymer on the exposed metal surface of the two-dimensional microfiber membrane; a seventh step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by loading first cells on the two-dimensional microfiber membrane on which the conductive polymer is deposited; After performing the first to sixth steps, the method may include an eighth step of manufacturing a second two-dimensional microfiber membrane having second cells mounted thereon by mounting second cells on the two-dimensional microfiber membrane on which the conductive polymer is deposited; and a ninth step of manufacturing a one-dimensional porous microfiber by laminating the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane and then rolling or twisting the laminate.

[0111] In one aspect, the etching method may include, but is not limited to, plasma etching such as oxygen plasma etching, fluorine plasma etching, and chlorine plasma etching; wet etching such as acid wet etching and basic wet etching; dry etching such as reactive ion etching and ion beam etching; and electrochemical etching such as electrochemical peeling and anodic oxidation.

[0112]

[0113] In one aspect, the first part of the one-dimensional porous microfibers loaded with the first cells may form a core, and the second part of the one-dimensional porous microfibers loaded with the second cells may form a shell.

[0114] In one aspect, the first two-dimensional microfiber film can be electrospun to be oriented in a uniaxial direction, and the second two-dimensional microfiber film can be electrospun to form a random structure without being oriented.

[0115] In one aspect, the coating or deposition method used in the method for manufacturing the bio-implantable electrode structure according to the present invention includes, but is not limited to, physical vapor deposition (PVD), chemical vapor deposition (CVD), electrodeposition, solution-based deposition, and other deposition methods.

[0116] Physical vapor deposition (PVD) methods include thermal evaporation, electron beam evaporation, sputtering, DC sputtering, RF sputtering, and magnetron sputtering.

[0117] Chemical vapor deposition (CVD) methods include thermal chemical vapor deposition (TCVD), plasma-enhanced chemical vapor deposition (PECVD), atomic layer deposition (ALD), and metal-organic chemical vapor deposition (MOCVD).

[0118] Electrodeposition methods include electroplating and electropolymerization.

[0119] Solution-based deposition methods include sol-gel process, spin coating, dip coating, inkjet printing, spray coating, and microcontact printing.

[0120] Other deposition methods include vapor phase polymerization (VPP), sublimation deposition (SD), and Langmuir-Blodgett deposition (LBD).

[0121]

[0122] In one aspect, the polymer deposited or coated on the microfiber or microfiber film according to the present invention can be deposited or coated to provide functionalities such as insulation, conductivity, biocompatibility, piezoelectricity, hydrophobicity, and hydrophilicity, and the types of the polymer deposited or coated on the microfiber include Parylene, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), fluorinated ethylene propylene (FEP), perfluoroalkoxy (PFA), polyaniline (PANI), polypyrrole (PPy), poly(3,4-ethylenedioxythiophene) (PEDOT), poly(3,4-ethylenedioxythiophene):polystyrenesulfonic acid (PEDOT:PSS), polycaprolactone (PCL), polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), gelatin, chitosan, Examples include, but are not limited to, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polydimethylsiloxane (PDMS), polyvinylpyrrolidone (PVP), polydopamine (PDA), polyurethane (PU), and polystyrene (PS).

[0123] In one aspect, the microfibers or microfiber membrane according to the present invention may be coated (or deposited) with perylene. Parylene is a well-known bio-inert material that is chemically and biologically very stable, resulting in excellent biocompatibility and low tissue reactivity. Furthermore, it exhibits excellent electrical insulation properties and is mechanically flexible and strong. Furthermore, during the process of coating (or depositing) perylene, bonding between the microfibers occurs, resulting in a physically and electrically stable structure. In a microfiber membrane not coated with perylene, there may be areas where the microfibers are not bonded to each other.

[0124] In addition, instead of metal, oxides such as indium tin oxide (ITO), aluminum-doped zinc oxide (AZO), gallium-doped zinc oxide (GZO), fluorine-doped tin oxide (FTO), nickel oxide (NiO), zinc oxide (ZnO), copper oxide (CuO, Cu2O), titanium oxide (TiO2), manganese oxide (MnO2), vanadium oxide (V2O5), cobalt oxide (Co3O4), iron oxide (Fe2O3), iridium oxide (IrO2), ruthenium oxide (RuO2), and tantalum oxide (Ta2O5) may be deposited on the microfiber or microfiber film according to the present invention.

[0125] In one aspect, an electrode layer can be formed by depositing gold on microfibers or microfiber films according to the present invention.

[0126] In one aspect, when coating a polymer (e.g., perylene) on a microfiber or microfiber film according to the present invention, a chemical vapor deposition method (CVD) may be used, when depositing a metal (e.g., gold), a thermal deposition method may be used, and when depositing a conductive polymer, an electrical deposition method may be used, but the present invention is not limited thereto.

[0127] In one aspect, after a polymer is first coated on the microfibers or microfiber membrane according to the present invention, a metal may be deposited, and then a polymer may be secondarily coated. Here, the type of polymer and the deposition method used in the first polymer deposition and the second polymer deposition may be the same or different.

[0128]

[0129] In one aspect, the thickness of the electrospun two-dimensional microfiber film according to the present invention may be, but is not limited to, 200 nm or more and 800 nm or less, or 300 nm or more and 600 nm or less.

[0130] In one aspect, the diameter of the electrospun microfibers according to the present invention may be, but is not limited to, 100 nm to 2000 nm, or 200 nm to 1000 nm, or 300 nm to 800 nm.

[0131] In one aspect, the thickness of the polymer deposited or coated on the microfiber or microfiber film according to the present invention may be 30 to 1000 nm, preferably 50 to 900 nm, or 100 to 800 nm, or 200 to 600 nm, but is not limited thereto.

[0132] In one aspect, the thickness of the electrode layer made of metal deposited on the microfiber or microfiber film according to the present invention may be 10 to 500 nm, preferably 50 to 300 nm, or 50 to 200 nm, but is not limited thereto.

[0133] In one aspect, the pore size of the one-dimensional porous microfiber according to the present invention may be, but is not limited to, 200 nm to 10 μm, or 500 nm to 8 μm, or 600 nm to 6 μm, or 1 μm to 4 μm, or 3 μm to 5 μm.

[0134] In one aspect, the diameter of the one-dimensional porous microfiber according to the present invention may be, but is not limited to, 1 μm or more and 1000 μm or less, or 5 μm or more and 800 μm or less, or 5 μm or more and 500 μm or less, or 10 μm or more and 300 μm or less, or 50 μm or more and 200 μm or less.

[0135]

[0136] Hereinafter, a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention and a manufacturing method thereof will be described with reference to the drawings.

[0137]

[0138] Fig. 1 illustrates a one-dimensional porous microfiber-based bio-implantable electrode structure according to one embodiment of the present invention. The lower left of Fig. 1 is a schematic diagram showing a process of opening the skull to implant an electrode into the brain, implanting the bio-implantable electrode structure according to the present invention into the brain, and measuring the signal to communicate with the outside via a communication device. In addition, the right side of Fig. 1 shows that serotonin and dopamine cells mounted on the central and outer surfaces of the electrode, respectively, show different degrees of activation depending on the concentration of serotonin and dopamine activated in the brain.

[0139] Specifically, referring to FIG. 1, the one-dimensional porous microfiber of the present invention is composed of a central portion (first portion) and an outer portion (second portion), and the central portion is equipped with first cells, and the outer portion is equipped with second cells. The central portion may have microfibers oriented uniaxially, and thus has a relatively densely arranged cell and fiber structure. The outer portion has a random structure in which the microfibers are not oriented, and thus has porosity compared to the central portion. The one-dimensional porous microfiber-based bio-implantable electrode structure according to one embodiment of the present invention mimics a biological ECM (extracellular matrix).

[0140] Referring to Fig. 1, the same one-dimensional porous microfiber-based bio-implantable electrode structure can selectively induce two different physiological responses through stimulation. By controlling the pattern, waveform, or intensity of the electrical stimulation applied to the electrode by an external stimulation device, the activity state of the cells present inside can be changed, resulting in the secretion or response of different neurotransmitters (e.g., serotonin, dopamine). The enlarged view on the left side of Fig. 1 shows a state in which serotonin secretion is relatively higher than dopamine depending on the electrode stimulation conditions, which can induce an inhibitory or sedative physiological response. The enlarged view on the right side of Fig. 1 shows a state in which dopamine is higher than serotonin depending on the change in stimulation conditions, which can lead to an activation, reward response, or arousal state. In other words, according to the present invention, although the electrode structure is the same, by changing only the stimulation conditions, two opposing neurophysiological responses can be selectively induced with a single electrode.

[0141] Also, referring to Fig. 1, it is visually demonstrated that the same one-dimensional porous microfiber-based bio-implantable electrode structure can sense two different physiological states. The one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention can be inserted into biological tissue through a flexible thread-like structure to directly sense changes in the neurotransmitter environment. For example, cells mounted on the electrode can express receptors that can respond to neurotransmitters such as serotonin (5-HT) and dopamine, and changes in the concentration of these substances induce changes in cell membrane potential, which can be converted into electrophysiological signals by the electrode and detected. The enlarged view on the left side of Fig. 1 detects a state in which the serotonin concentration is higher than dopamine, which may indicate an inhibitory physiological state or a state of emotional depression. The enlarged view on the right side of Fig. 1 detects a state in which the dopamine concentration is higher than serotonin, which may reflect a positive physiological response such as activation of the reward system or a state of arousal. That is, according to the present invention, it is possible to precisely detect electrophysiological responses according to changes in neurotransmitter concentration in the external environment using only one identical electrode structure.

[0142]

[0143] Figure 2 is a schematic diagram illustrating selective monitoring of different neural cell types using a one-dimensional porous microfiber-based bio-implantable electrode structure according to one embodiment of the present invention. Specifically, Figure 2 is a schematic diagram showing an increase in the dopamine / serotonin secretion amount of cells mounted within the electrode according to the amount of dopamine / serotonin secretion in the brain, and the resulting electrical signal generation.

[0144] Specifically, referring to Fig. 2, when the concentration of a specific neurotransmitter (e.g., serotonin or dopamine) increases in the brain, the corresponding stimulus can be transmitted to the inside of the brain electrode, inducing a response from a specific group of nerve cells. Referring to the upper part of Fig. 2, when serotonin increases in the brain, only serotonin-sensitive cells mounted inside the electrode are selectively activated, and the activated serotonin-responsive cells induce a change in the electrode surface charge through changes in membrane potential, ion movement, etc., which can be converted into an electrical signal through the electrode, quantified, and output. Therefore, by using the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, a physiological response according to an increase in serotonin concentration can be accurately and selectively detected. Referring to the bottom of Fig. 2, when dopamine increases in the brain, only dopamine-sensitive cells mounted inside the electrode are selectively activated, and the activated dopamine-responsive cells induce changes in the electrode surface charge through membrane potential changes, ion movement, etc., which can be converted into electrical signals through the electrode and quantified and output. Therefore, by using the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, physiological responses according to increases in dopamine concentration can be accurately and selectively detected, and the dopamine activity status in the brain can be selectively and in real time monitored.

[0145]

[0146] FIG. 3 is a schematic diagram illustrating a method for monitoring the activity of neural cells using a one-dimensional porous microfiber-based bio-implantable electrode structure according to an embodiment of the present invention. Since a plurality of microfiber electrodes are arranged inside the one-dimensional porous microfiber-shaped electrode according to the present invention as illustrated in FIG. 3, when the one-dimensional porous microfiber bundle-shaped electrode is completed, a three-dimensional electrode array from a microscopic perspective can be formed inside it. That is, in the present invention, the one-dimensional porous microfiber bundle-shaped electrode can have a three-dimensional multi-electrode array.

[0147] Referring to the left side of Fig. 3, a one-dimensional porous microfiber-based bio-implantable electrode structure is inserted into the brain through the skull, and the electrode structure is a porous structure that mimics the ultra-flexible ECM (extracellular matrix). The one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention can be connected to an external device to implant and communicate neural activity in real time.

[0148] Referring to the upper right of Fig. 3, the present invention can perform neurochemical selectivity-based monitoring using a one-dimensional porous microfiber-based bio-implantable electrode structure. The three enlarged views in the upper right of Fig. 3 show the process in which a specific cell group within the electrode is selectively activated according to different neurotransmitters (e.g., serotonin, dopamine, etc.). Referring to the upper right of Fig. 3, when a specific neurochemical is introduced, only the cells that respond to it are activated, and the activated cells generate electrical signals, which can be detected by the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention. That is, using the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, it is possible to monitor the selective response of various neural cells within the electrode depending on the type of neurotransmitter.

[0149] The three enlarged views in the lower right corner of Fig. 3 illustrate the process by which cell responses vary depending on the depth and concentration distribution of the neurotransmitter within the electrode structure. Referring to the lower right corner of Fig. 3, when a neurotransmitter is introduced to a specific location, only cells at that depth partially respond, and as the concentration increases, cells in a wider area can be gradually activated. In other words, using the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, brain responses depending on the depth, concentration, and distribution of the neurotransmitter can be analyzed at high resolution.

[0150] In addition, by using the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, the directionality of a neuroactive substance flowing in from the outside or an electrical signal according to neural activity can be detected. In addition, while directionality cannot be determined with one electrode, with two (or more) electrodes, the direction of signal inflow can be determined at a one-dimensional (left-right) level through the arrival speed of the signal, and further, more precise spatial analysis is possible through the phase difference during the signal inflow process. In other words, the greater the number of electrodes and the more three-dimensionally they are distributed, the more effective and superior the spatiotemporal resolution can be.

[0151]

[0152] FIG. 4 is a schematic diagram illustrating a manufacturing process for a one-dimensional porous microfiber-based bio-implantable electrode structure according to an embodiment of the present invention. A method for manufacturing a bio-implantable electrode structure according to an embodiment of the present invention can manufacture a microfiber membrane based on a polymer, as illustrated in FIG. 4 . As a non-limiting example, a microfiber membrane can be manufactured by electrospinning polyurethane or a biocompatible polymer, but it should be noted that the present invention is not limited thereto. To this end, a polymer solution having a desired viscosity and concentration is prepared by dissolving the polymer in a solvent, which is then supplied to a syringe needle-shaped nozzle. After the syringe needle is positioned so that it faces a collector, a high voltage is applied between the syringe needle and the collector using a high voltage source, generating an electric field and drawing out the polymer solution in the form of thin fibers by the resulting electric force. These fibers are formed into microfibers as the solvent inside them evaporates, and the microfibers released from the syringe needle are deposited on the collector, thereby manufacturing a microfiber membrane. These microfiber films can be fabricated with an optimal final product structure by controlling the concentration and viscosity of the polymer solution and the electrospinning environment (voltage, temperature, humidity).

[0153]

[0154] Figure 5 is an image showing how to control the orientation of microfibers during electrospinning. Referring to Figure 5, when electrospinning is performed using a flat collector, a randomly oriented microfiber film can be produced, and when electrospinning is performed using a rotating collector such as a rotating drum collector, a microfiber film oriented in a uniaxial (or uniaxial) direction, i.e., a microfiber film oriented in a parallel or vertical direction, can be produced.

[0155] In one aspect, the first part of the one-dimensional porous microfiber according to the present invention can orient the microfibers in a single direction using a rotating drum collector during electrospinning, and the second part can form the microfibers in a random structure using a flat collector during electrospinning.

[0156]

[0157] Fig. 6 is a schematic diagram showing a cross-section of a one-dimensional porous microfiber according to the present invention. Referring to Fig. 6, the cross-section of the one-dimensional porous microfiber according to the present invention may include six layers from the center, and first cells may be loaded on the first layer (center) (100), the third layer (300), and the fifth layer (500), and second cells may be loaded on the second layer (200), the fourth layer (400), and the sixth layer (600). In addition, as illustrated in Fig. 1, the cross-section of the one-dimensional porous microfiber according to the present invention may include the first layer (center) loaded with first cells and the second layer (outer skin) loaded with second cells.

[0158]

[0159] Figure 7 is a schematic diagram illustrating the diameter of electrospun microfibers according to the present invention. As illustrated in Figure 7, the diameter of the microfibers that are electrospun to form a two-dimensional microfiber membrane according to the present invention can be appropriately adjusted to achieve suitable mechanical properties and flexibility. While a smaller microfiber diameter increases flexibility, the pore size decreases rapidly, which may affect cell loading.

[0160]

[0161] Figure 8 is a schematic diagram showing the density of an electrospun microfiber membrane according to the present invention. As illustrated in Figure 8, in the present invention, the density of the microfiber membrane formed by electrospinning into a two-dimensional microfiber membrane can be appropriately controlled to achieve suitable mechanical properties and flexibility. The higher the density of the microfiber membrane, the higher the density of the cells to be loaded. If the density is too high, the absolute amount of nutrients supplied to the cells may be reduced, which may affect the cell viability. According to the present invention, by appropriately controlling the density of the microfiber membrane, an ideal density that takes both cell viability and transfer rate into account can be realized.

[0162]

[0163] Figure 9 is a schematic diagram illustrating the orientation of an electrospun microfiber membrane according to the present invention. As illustrated in Figure 9, the present invention allows for the design of microfibers having an aligned structure that improves connectivity between internal cells and a random structure with porosity that improves connectivity with external cells by controlling the orientation of the electrospun two-dimensional microfiber membrane.

[0164]

[0165] Figure 10a is a schematic diagram showing the process of manufacturing one-dimensional microfibers by laminating and rolling or twisting electrospun microfiber membranes according to the present invention. The electrospun microfiber membranes according to the present invention can be laminated, and the laminated microfiber membranes can be of different types or of the same type, and the heterogeneous microfiber membranes can have different types of polymers and can have different orientations, densities, pore sizes, microfiber diameters, thicknesses, etc., but are not limited thereto.

[0166] Referring to FIG. 10a, the present invention utilizes the advantage of being able to precisely control the internal fiber orientation of a two-dimensional microfiber membrane, and by laminating heterogeneous fiber membranes, for example, oriented microfiber membranes and non-oriented microfiber membranes, and then rolling or twisting them together, it is possible to manufacture them in the form of one-dimensional microfibers (threads).

[0167] In one aspect, the first two-dimensional microfiber membrane of the present invention can improve connectivity or interaction between internal cells (e.g., brain cells) by being oriented in a uniaxial direction. In addition, the second two-dimensional microfiber membrane of the present invention can have sufficient porosity and sufficient pore size by being formed in a random structure, and can improve connectivity or interaction with other external neural cells.

[0168] Figure 10b is a schematic diagram illustrating the structure of a one-dimensional porous microfiber according to the present invention. Referring to Figure 10b, the second two-dimensional microfiber membrane, which is the outer layer of the present invention, can have a porous surface structure by being formed in a random structure. This porous surface structure is designed to allow neurotransmitters from the brain to be received through two routes. The first is direct secretion through synapses, and the second is a volume transmission route where they are secreted and diffused outside the synapse. This structure enables efficient mass transfer of small particles, and it is important to control the pore size to be 600 nm or more, considering the mean free path, so that the particles can move freely. Meanwhile, the first two-dimensional microfiber membrane, which is the center of the present invention, can maximize signal transmission between brain cells within the electrode by being oriented in a uniaxial direction. In this structure, even if only a small amount of neurotransmitter is introduced, a large number of neurons can be effectively activated based on the aligned fiber orientation. This also helps to ensure tensile durability during the brain transplantation process.

[0169]

[0170] Figure 11a is a photograph illustrating a perylene coating on microfibers according to the present invention. According to one aspect of the present invention, a porous microfiber membrane or microfibers may be coated with parylene. Parylene is a well-known bio-inert material that is chemically and biologically very stable, resulting in excellent biocompatibility and low tissue reactivity. It also exhibits excellent electrical insulation properties and is mechanically flexible and strong. As shown in Figure 11a, a microfiber membrane not coated with parylene may have unbonded portions between the microfibers. If unbonded spaces are formed between the microfibers, the distance between the microfibers may increase during subsequent metal deposition for electrode formation, resulting in electrode breakage. Therefore, to integrate the bonded portions of the microfibers, a perylene coating may be applied, as shown in Figure 11b.

[0171] Figure 11b shows a bare PU microfiber membrane, a PU microfiber membrane with a primary perylene coating, and a polyurethane (PU) microfiber membrane with a secondary perylene coating. Comparing Figures 11a and 11b, it can be seen that the joints of the microfibers are integrated. Although Figures 11a and 11b illustrate the perylene coating on the PU microfiber membrane, it should be understood that the material and thickness are not limited thereto, and the perylene coating can be applied to the microfiber membrane, microfiber bundle, or microfiber state, respectively, to integrate the joints between the microfibers.

[0172]

[0173] Meanwhile, the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention can be mounted on a 'traction platform' and inserted into a living body (e.g., a brain). Since the one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, having a diameter in the micron range, may have difficulty in inserting into a living body due to its own insufficient rigidity, a traction platform to assist insertion may be required. When such a traction platform is used, the one-dimensional porous microfiber-based bio-implantable electrode structure can be precisely positioned and safely delivered or positioned to the target tissue.

[0174] Fig. 12 is a schematic diagram showing a traction platform on which a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention is mounted. Referring to Fig. 12, a traction platform having a fine groove or step structure matching the diameter of the one-dimensional porous microfiber according to the present invention is manufactured so that the bio-implantable electrode structure can be easily fixed, and deformation of the bio-implantable electrode structure can be prevented during insertion thereof. In addition, when using the traction platform according to the present invention, traction force can be maintained during tissue insertion while minimizing tissue damage. In addition, according to the present invention, the traction platform can be manufactured using a bio-adhesive material, a biodegradable material, or a disposable insertion device so that it can be easily removed after temporarily working in the body.

[0175] In one aspect, biodegradable materials capable of forming a traction platform according to the present invention include polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) copolymer (PLGA), polycaprolactone (PCL), polydioxanone (PDO), polytrimethylene carbonate (PTMC), polyhydroxybutyrate (PHB), polyhydroxyalkanoate (PHA), polysebacic acid (PSA), polyanhydride, collagen, gelatin, hyaluronic acid (HA), chitosan, alginate, dextran, Examples of such materials include, but are not limited to, cellulose, carrageenan, fibrin, agarose, silk fibroin, elastin, pectin, starch, and decellularized organ hydrogels.

[0176]

[0177] Figure 13 is a schematic diagram of an automated device for rolling or twisting a two-dimensional microfiber membrane to manufacture one-dimensional porous microfibers according to the present invention. In the present invention, one-dimensional porous microfibers can be manufactured by rolling or twisting a two-dimensional microfiber membrane using a machine or device as illustrated in Figure 13, or one-dimensional porous microfibers can be manufactured by rolling or twisting a two-dimensional microfiber membrane by hand. Referring to Figure 13, in the rolling process, cells are cultured or mounted on the microfiber membrane, stacked in a single layer or multiple layers, and then rolled into a cylindrical shape to manufacture one-dimensional porous microfibers. Thereafter, a twisting process is performed to twist the ends of the cell-loaded structure. This is a deformation process that ensures structural stability of the cell-loaded electrode when implanted in the body. During the twisting process, the tensile force is precisely controlled in real time to prevent damage to cells, and a pore size of at least 3 micrometers or more is secured around the cells to prevent cell necrosis or compression.

[0178]

[0179] In one aspect, the one-dimensional porous microfibers according to the present invention can be assembled into a 3D structure using a fiber processing technique. Fiber processing techniques, which are multi-arrangement processes performed on the one-dimensional porous microfibers according to the present invention, include, but are not limited to, braiding, weaving, and knitting, and various fiber processing techniques or multi-arrangement processes can be performed.

[0180] In one aspect, after separate cells are loaded or independently cultured on each of the plurality of one-dimensional porous microfibers according to the present invention, they are structured (i.e., fiber-processed) to form a single electrode structure bundle, and this electrode structure bundle can be inserted or transplanted into a living body. For example, after neural cells such as dopaminergic neurons, serotonergic neurons, glutamatergic neurons, and GABAergic neurons are loaded or independently cultured on each of the plurality of one-dimensional porous microfibers or microfiber bundles according to the present invention, they are fiber-processed by braiding, weaving, knitting, etc., and structured to form a single electrode structure bundle, which can be inserted or transplanted into a living body.

[0181] In one aspect, a method for manufacturing a bio-implantable electrode structure according to an embodiment of the present invention comprises: a first step of manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; a second step of coating the manufactured two-dimensional microfiber membrane with primary parylene; a third step of depositing a metal on the two-dimensional microfiber membrane coated with primary parylene; a fourth step of coating the two-dimensional microfiber membrane coated with secondary parylene to insulate the deposited metal surface; a fifth step of etching the two-dimensional microfiber membrane coated with secondary parylene to etch away a portion of the insulating film on the insulated metal surface, thereby exposing a portion of the metal surface of the two-dimensional microfiber membrane; a sixth step of depositing a conductive polymer on the exposed metal surface of the two-dimensional microfiber membrane; a seventh step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by loading first cells on the two-dimensional microfiber membrane on which the conductive polymer is deposited; The method may include an eighth step of manufacturing a plurality of two-dimensional microfiber membranes, each of which has different cells loaded thereon, by repeating the first to sixth steps; a ninth step of manufacturing a plurality of one-dimensional porous microfiber membranes, each of which has different cells loaded thereon, by rolling or twisting the plurality of two-dimensional microfiber membranes; and a tenth step of performing a multi-array process using the plurality of one-dimensional porous microfibers.

[0182] In one aspect, in the above 10th step, the multiple array process may be a braiding, weaving or knitting process.

[0183] In one aspect, the cells mounted on the plurality of one-dimensional porous microfibers are each different, and the cells may be dopaminergic neurons, serotonergic neurons, glutamatergic neurons, or GABAergic neurons.

[0184] In one aspect, when electrospinning the plurality of two-dimensional microfiber films, electrospinning can be performed with different orientations.

[0185] In one aspect, at least one of the plurality of two-dimensional microfiber membranes may be uniaxially oriented, and at least one of the plurality of two-dimensional microfiber membranes may not be oriented.

[0186]

[0187] Hereinafter, a one-dimensional porous microfiber-based bio-implantable electrode structure and a manufacturing method thereof according to the present invention will be described with reference to examples.

[0188]

[0189] 1. Example 1: Fabrication of a one-dimensional porous microfiber-based bio-implantable electrode structure

[0190]

[0191] (1) Example 1-1: Preparation of a two-dimensional microfiber membrane

[0192] A two-dimensional microfiber membrane is manufactured through electrospinning using polyurethane as a fiber material.

[0193] Polyurethane pellets are mixed in a solvent of N,N-dimethylformamide (DMF):tetrahydrofuran (THF) in a weight ratio of 6:4 to prepare a 10 wt% solution.

[0194] The solution is placed in a syringe with a 22G needle and a syringe pump is used to extract a flow rate of 0.35 ml / hr. The tip of the syringe needle is positioned 12 cm from the collector, and a voltage of 10 kV is applied between the needle and the metal plate via a high-voltage source, after which electrospinning is performed.

[0195]

[0196] At this time, when a flat collector is used as the collector, a two-dimensional microfiber membrane having a random structure can be manufactured, and when a rotating drum collector is used, a microfiber membrane oriented (aligned) in a parallel direction can be manufactured.

[0197]

[0198] (2) Example 1-2: Transfer of two-dimensional microfiber membrane

[0199] To easily remove the two-dimensional microfiber membrane, a non-adhesive silicone-coated paper is attached to the collector. To remove the microfiber membrane from the silicone-coated paper, an OHP window is used. A 15 mm wide and 10 mm tall window is cut on the OHP film using a sheet cutter. Tape is attached to the edge of the window and the OHP window is placed on the silicone-coated paper on which the microfibers have been electrospun. The microfiber membrane is then removed through the adhesive strength of the tape and transferred to the OHP window.

[0200]

[0201] (3) Example 1-3: Primary Parylene Coating on an Electrospun Two-Dimensional Microfiber Film

[0202] A perylene organic polymer is vapor-deposited to a thickness of 200 to 600 nm onto the microfiber film transferred to the OHP window manufactured in Example 1-2. Parylene is coated on the surface of the microfiber strands, and during the deposition process, bonding between the fibers occurs, resulting in a physically and electrically stable structure.

[0203]

[0204] (4) Example 1-4: Metal deposition on a two-dimensional microfiber membrane coated with primary perylene

[0205] An electrode layer is formed by depositing gold (Au) to a thickness of 100 nm through thermal evaporation on the primary perylene-coated microfiber film manufactured in Example 1-3.

[0206] In one embodiment according to the present invention, as illustrated in FIG. 14, a metal is deposited on a microfiber film according to the present invention to form an electrode array.

[0207]

[0208] (5) Example 1-5: Secondary Parylene Coating on a Metal-Deposited Two-Dimensional Microfiber Film

[0209] In order to passivate the deposited electrode manufactured in Example 1-4, a secondary perylene coating is vapor-deposited to a thickness of 200 nm to 600 nm.

[0210]

[0211] (6) Example 1-6: Oxygen plasma etching on a two-dimensional microfiber membrane coated with a second perylene coating

[0212] A shadow mask made of OHP film material, in which holes of approximately 2 mm to 100 mm in size are formed, is arranged parallel to and brought into contact with the insulated electrode on the two-dimensional microfiber film coated with the secondary perylene as manufactured in Example 1-5. Thereafter, the electrode to which the mask was applied was exposed to an oxygen plasma process (plasma etching), thereby removing the insulating film, thereby leaving a large number of electrically active small-hole-sized regions arranged on the electrode surface.

[0213] The plasma process conditions are as follows: power 200 W, frequency 50 kHz, oxygen (O2) flow rate 100 sccm, reactive ion etching (RIE) mode, process time 7 min, and the process initial pressure 7 × 10 -3It started under torr conditions.

[0214]

[0215] (7) Example 1-7: Deposition of conductive polymer on oxygen plasma etched two-dimensional microfiber film

[0216] The surface of the oxygen plasma-etched two-dimensional microfiber film manufactured in Example 1-6 was deposited with a conductive polymer, PEDOT:PSS, through an electrochemical deposition method. During the deposition process of the conductive polymer, in order to improve adhesion with the electrode, currents of 0.2, 0.4, 0.6, and 0.8 μA were applied stepwise for 150 seconds each, and then a current of 1 μA was additionally applied for 600 seconds to form a surface coated with PEDOT:PSS.

[0217] In one embodiment of the present invention, FIG. 15 is an image showing the result of depositing gold (Au) after the first perylene coating on a two-dimensional microfiber film according to the present invention, then the second perylene coating, then oxygen plasma etching, and then depositing PEDOT:PSS, which is a conductive polymer.

[0218]

[0219] (8) Example 1-8: Cell loading on a two-dimensional microfiber membrane on which a conductive polymer has been deposited.

[0220] In Example 1-7, the conductive polymer-deposited two-dimensional microfiber membrane was prepared by applying cells (dopaminergic neurons obtained by dedifferentiating and redifferentiating cells obtained from human nasal cavity) and culture medium together with a pipette, thereby loading cells in an amount ranging from tens to millions per square centimeter.

[0221] In addition, after repeating Examples 1-1 to 1-7, the cells (iPSCs obtained from human nasal cavity and reverse-differentiated) and culture medium were applied together with a pipette to the two-dimensional microfiber membrane on which the newly manufactured conductive polymer was deposited, thereby loading the cells in an amount of tens to millions per square centimeter.

[0222] Thus, a first two-dimensional microfiber membrane loaded with dopaminergic neurons and a second two-dimensional microfiber membrane loaded with stem cells were prepared.

[0223]

[0224] (9) Example 1-9: Lamination of two-dimensional microfiber membranes

[0225] After laminating the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane manufactured in Example 1-8, rolling or twisting was performed to manufacture one-dimensional porous microfibers.

[0226]

[0227] 2. Example 2: Confirmation of the inflammatory response of a bio-implantable electrode structure based on one-dimensional porous microfibers.

[0228] The inflammatory response of the bio-implantable electrode structure based on one-dimensional porous microfibers according to the present invention was confirmed.

[0229] Figure 16 is an image of a non-cell-loaded, one-dimensional porous microfiber-based bioimplantable electrode structure (bundle) implanted into the skin of a Sprague-Dawley rat (SD rat). It can be confirmed that no significant inflammatory response occurred on the first day after implantation.

[0230]

[0231] 3. Example 3: Loading of dopamine-secreting neurons

[0232] Dopaminergic neurons derived from humans were loaded onto the two-dimensional microfiber membrane and one-dimensional porous microfiber according to the present invention.

[0233] Figure 17 shows images of human-derived dopaminergic neurons mounted on a two-dimensional microfiber membrane electrode (left) and a one-dimensional porous microfiber bundle electrode (right). Both images were taken after 8 weeks of culture, and the black dots represent neurons.

[0234]

[0235] 4. Example 4: Observation of muscle cell activation response

[0236] In Example 4, the activation response of muscle cells located in the thigh area of ​​SD rats was observed.

[0237] Figure 18 is an image showing the results of observing the activation response of muscle cells located in the thigh region of SD rats. The experiment was conducted under two conditions, injecting the neurotransmitter acetylcholine (Ach) and saline (control) to compare the responses of muscle cells. The graph in the lower left of Figure 18 shows the responses of muscle cells before and after injection of acetylcholine (1 mM). Immediately after injection, a clear electrical activity signal (voltage change) increases sharply, demonstrating a strong response of the muscle cells. In contrast, the graph in the lower right of Figure 18 shows that when saline was injected, there was no response, with the voltage signal remaining flat, indicating that the muscle cells did not respond. This suggests that cells possess inherent substance selectivity and respond only to specific neurotransmitters. Furthermore, the experimental results depicted in Figure 18 demonstrate that the same results can be applied even when muscle cells are replaced with brain cells and acetylcholine is replaced with other neurotransmitters, such as dopamine or serotonin.

[0238]

[0239] 5. Example 5: Fabrication of a bundle of electrode structures by braiding, weaving, and knitting a bio-implantable electrode structure based on one-dimensional porous microfibers.

[0240]

[0241] (1) Example 5-1: Manufacturing of electrode structure bundle using braiding

[0242] The braiding process is similar to braiding hair, interweaving three prepared one-dimensional porous microfiber-based bio-implantable electrode structures to form a structure. The tightly woven fibers provide high mechanical strength and structural stability, while maintaining consistent spacing and ensuring flexibility. These properties enable the fabrication of complex structures.

[0243] Figure 19 shows the braiding process and braiding form.

[0244] Figure 20 is an image of an electrode structure bundle (scaffold) manufactured using a braiding process for a bio-implantable electrode structure based on one-dimensional porous microfibers according to the present invention.

[0245] Figure 21 is an SEM image of a bundle of electrode structures manufactured by a braiding process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, at magnifications of 100 times (left), 150 times (center), and 500 times (right).

[0246]

[0247] (2) Example 5-2: Manufacturing of electrode structure bundle using weaving

[0248] The weaving process is similar to weaving fabric, arranging multiple one-dimensional porous microfiber-based bio-implantable electrode structures in a perpendicular direction to form a woven structure. This woven structure not only has high mechanical strength but can be formed at a consistent interval, providing a porous environment.

[0249] Figure 22 shows the weaving process and weaving form.

[0250] Figure 23 is an image of an electrode structure bundle (scaffold) manufactured using a weaving process for a bio-implantable electrode structure based on one-dimensional porous microfibers according to the present invention.

[0251] Figure 24 is an SEM image of a bundle of electrode structures manufactured by a weaving process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, at magnifications of 100 times (left), 150 times (center), and 500 times (right).

[0252]

[0253] (3) Example 5-3: Manufacturing of electrode structure bundle using knitting

[0254] The knitting process, similar to traditional knitting, weaves one-dimensional porous microfiber-based bio-implantable electrode structures into loops to form a continuous structure. These loop-woven fibers possess high flexibility and elasticity, and their strong inter-fiber bonding allows for stretchability.

[0255] Figure 25 shows the knitting process and knitting form.

[0256] Figure 26 is an image of an electrode structure bundle (scaffold) manufactured by a knitting process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention.

[0257] Figure 27 is an SEM image of a bundle of electrode structures manufactured by a knitting process using a one-dimensional porous microfiber-based bio-implantable electrode structure according to the present invention, at magnifications of 100 times (left), 150 times (center), and 500 times (right).

[0258]

[0259] As described above, the one-dimensional porous microfiber-based bio-implantable electrode structure and its manufacturing method according to the present invention compartmentalize and load different types of cells onto one-dimensional thread-shaped porous microfibers, and utilize them as bio-implantable electrodes. The bio-implantable electrode structure according to the present invention can simultaneously implement cell transplantation and electrical stimulation on a single platform, providing a complex and efficient therapeutic effect compared to existing treatment methods. In particular, by precisely separating and loading different cells through compartmental structures within the electrode, such as the first and second sections, each cell can stably perform its original function without intercellular interference. This compartmentalized structure is effective in spatially separating and maintaining the functions of heterogeneous cells, and also functions to control cell-to-cell interactions to selectively induce or suppress specific physiological responses. Furthermore, biosignals generated from each compartmentalized region of the electrode can be independently collected or selectively stimulated, enabling precise biosignal analysis and feedback control. This allows for expansion into a multifunctional platform capable of simultaneously implementing various bioreactions, such as nerve stimulation, tissue regeneration, and drug delivery, within a single electrode structure. In addition, by compartmentalizing the arrangement of cells into a living tissue structure, an environment similar to actual living tissue can be created, thereby maximizing biocompatibility and functional integration.

[0260] Meanwhile, the one-dimensional, thread-like porous microfibers used in the present invention possess unique advantages over conventional two-dimensional, planar membrane structures. The flexible, elongated fiber structure resembles the shape of actual biological tissue, facilitates penetration into tissues, and flexibly adapts to anatomically complex areas. Furthermore, the high surface-to-volume ratio increases the cell attachment area and activates cell-material interactions. The porous structure facilitates material diffusion, promoting the delivery of nutrients and oxygen and the excretion of metabolites, thereby positively affecting cell viability and functional maintenance. Due to these characteristics, the electrode of the present invention is advantageous for precise position control and ensuring stability after implantation, and also exhibits excellent mechanical compatibility with biological tissue and flexibility.

[0261] Therefore, the bio-implantable electrode structure according to the present invention is a highly functional platform that simultaneously secures structural flexibility and biocompatibility while integrating electrical and cell therapy functions, and is thus highly suitable for next-generation bioelectronic technology and precision medicine applications.

[0262]

[0263] Although the present invention has been described with reference to the drawings and embodiments, it does not mean that the scope of protection of the present invention is limited by the drawings or embodiments, and it will be understood that a person skilled in the art can modify and change the present invention in various ways without departing from the spirit and scope of the present invention as described in the following claims.

[0264] Although the present invention described above is described based on a series of functional blocks, it is not limited to the above-described embodiments and the attached drawings, and it will be apparent to those skilled in the art to which the present invention pertains that various substitutions, modifications, and changes are possible within a scope that does not depart from the technical spirit of the present invention.

[0265] The combination of the above-described embodiments is not limited to the above-described embodiments, and various combinations may be provided in addition to the above-described embodiments depending on implementation and / or needs.

[0266] In the above-described embodiments, the methods are described based on a flowchart as a series of steps or blocks. However, the present invention is not limited to the order of the steps, and some steps may occur in a different order or simultaneously with other steps described above. Furthermore, those skilled in the art will understand that the steps depicted in the flowchart are not exclusive, and other steps may be included, or one or more steps in the flowchart may be deleted without affecting the scope of the present invention.

[0267] The above-described embodiments include examples of various aspects. While not all possible combinations to illustrate the various aspects can be described, those skilled in the art will recognize that other combinations are possible. Accordingly, the present invention is intended to encompass all other alterations, modifications, and variations within the scope of the following claims.

Claims

1. 1 As a bio-implantable electrode structure based on a dimensional porous microfiber, A first cell is loaded on the first part of the above one-dimensional porous microfiber, A second cell is loaded on the second part of the above one-dimensional porous microfiber, Bio-implantable electrode structure.

2. In paragraph 1, The above one-dimensional porous microfibers are formed from an electrospun polymer. Bio-implantable electrode structure.

3. In paragraph 2, The electrospun polymer comprises at least one of polyurethane (PU), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polyhydroxyalkanoate (PHA), polyvinyl alcohol (PVA), hyaluronic acid (HA), polyethylene glycol (PEG), polycarbonate (PC), polyaniline (PANI), collagen, gelatin, chitosan, alginate, fibrin, decellularized extracellular matrix, poly(3,4-ethylenedioxythiophene):polystyrenesulfonic acid (PEDOT:PSS), and polypyrrole (PPy). The polymer of the first part and the polymer of the second part of the above one-dimensional porous microfiber are the same or different. Bio-implantable electrode structure.

4. In paragraph 1, The first cell and the second cell are dopaminergic neurons, serotonergic neurons, acetylcholinergic neurons, norepinephrine neurons, glutamatergic neurons, GABAergic neurons, motor neurons, sensory neurons, pain receptor neurons, indirect motor neurons, neural stem cells, astrocytes, oligodendrocytes, microglia, Schwann cells, cardiomyocytes, skeletal muscle cells, myocytes, satellite cells, smooth muscle cells, cardiac fibroblasts, muscle stem cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, neural stem cells, cardiac progenitor cells, vascular progenitor cells, blood stem cells, retinal progenitor cells, muscle progenitor cells, retinal ganglion cells, photoreceptor cells, olfactory receptor cells, auditory hair cells, equilibrium sensory cells, taste receptor cells, vascular endothelial cells, vascular smooth muscle cells, macrophages, T cells, regulatory T cells, dendritic cells, natural killer cells, neutrophils, fibroblasts, hepatocytes, pancreatic beta cells, Sebaceous gland cells, keratinocytes, osteoblasts, osteocytes or osteoclasts, The first and second cells are different from each other, Bio-implantable electrode structure.

5. In paragraph 1, The first part of the above one-dimensional porous microfiber forms a core, The second part of the above one-dimensional porous microfiber forms a shell surrounding the center, Bio-implantable electrode structure.

6. In paragraph 5, The first part of the above one-dimensional porous microfibers has microfibers oriented in a uniaxial direction, The second part of the above one-dimensional porous microfibers is a microfiber in which the microfibers are not oriented. Bio-implantable electrode structure.

7. In paragraph 1, The above one-dimensional porous microfibers are coated with parylene. Bio-implantable electrode structure.

8. In paragraph 7, The above one-dimensional porous microfibers are perylene coated and then metal deposited. Bio-implantable electrode structure.

9. In paragraph 8, The above one-dimensional porous microfibers are coated with perylene, then metal is deposited, and then a conductive polymer is deposited. Bio-implantable electrode structure.

10. In paragraph 2, The above one-dimensional porous microfibers are formed into a one-dimensional thread shape by rolling or twisting an electrospun two-dimensional polymer microfiber film. Bio-implantable electrode structure.

11. In paragraph 5, The cross-section of the above one-dimensional porous microfiber includes n layers from the center, when the center is referred to as the first layer. The first cell is mounted on an odd-numbered layer among the above n layers, The second cell is mounted on an even layer among the above n layers. Bio-implantable electrode structure.

12. In paragraph 5, The cross-section of the above one-dimensional porous microfiber includes n layers from the center, when the center is referred to as the first layer. The types of cells mounted on the above n layers are all different. Bio-implantable electrode structure.

13. A method for manufacturing a bio-implantable electrode structure, Step 1: Manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; A second step of coating the two-dimensional microfiber membrane manufactured above with parylene; A third step of depositing metal on the two-dimensional microfiber film coated with perylene; A fourth step of depositing a conductive polymer on the above metal-deposited two-dimensional microfiber film; A fifth step of manufacturing a first two-dimensional microfiber membrane loaded with first cells by loading first cells onto a two-dimensional microfiber membrane on which the conductive polymer is deposited; After performing the first to fourth steps, a sixth step of manufacturing a second two-dimensional microfiber membrane loaded with second cells by loading second cells onto the two-dimensional microfiber membrane on which the conductive polymer is deposited; and A seventh step of manufacturing a one-dimensional porous microfiber by laminating a first two-dimensional microfiber film and a second two-dimensional microfiber film and then rolling or twisting them; including, A method for manufacturing a bio-implantable electrode structure.

14. In paragraph 13, The polymer forming the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane includes at least one of polyurethane (PU), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polyhydroxyalkanoate (PHA), polyvinyl alcohol (PVA), hyaluronic acid (HA), polyethylene glycol (PEG), polycarbonate (PC), polyaniline (PANI), collagen, gelatin, chitosan, alginate, fibrin, decellularized extracellular matrix, poly(3,4-ethylenedioxythiophene):polystyrenesulfonic acid (PEDOT:PSS), and polypyrrole (PPy). The polymers forming the first two-dimensional microfiber membrane and the second two-dimensional microfiber membrane are the same or different. A method for manufacturing a bio-implantable electrode structure.

15. In paragraph 13, The first cell and the second cell are dopaminergic neurons, serotonergic neurons, acetylcholinergic neurons, norepinephrine neurons, glutamatergic neurons, GABAergic neurons, motor neurons, sensory neurons, pain receptor neurons, indirect motor neurons, neural stem cells, astrocytes, oligodendrocytes, microglia, Schwann cells, cardiomyocytes, skeletal muscle cells, myocytes, satellite cells, smooth muscle cells, cardiac fibroblasts, muscle stem cells, mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, neural stem cells, cardiac progenitor cells, vascular progenitor cells, blood stem cells, retinal progenitor cells, muscle progenitor cells, retinal ganglion cells, photoreceptor cells, olfactory receptor cells, auditory hair cells, equilibrium sensory cells, taste receptor cells, vascular endothelial cells, vascular smooth muscle cells, macrophages, T cells, regulatory T cells, dendritic cells, natural killer cells, neutrophils, fibroblasts, hepatocytes, pancreatic beta cells, Sebaceous gland cells, keratinocytes, osteoblasts, osteocytes or osteoclasts, The first and second cells are different from each other, A method for manufacturing a bio-implantable electrode structure.

16. In paragraph 13, After the seventh step, a step of coating a decellularized extracellular matrix hydrogel on the manufactured one-dimensional porous microfibers is further included. A method for manufacturing a bio-implantable electrode structure.

17. In paragraph 13, The first part of the above one-dimensional porous microfibers, in which the first cell is loaded, forms a core, The second part of the above one-dimensional porous microfibers, in which the second cells are loaded, forms a shell. A method for manufacturing a bio-implantable electrode structure.

18. In paragraph 13, The above first two-dimensional microfiber membrane is electrospun to be oriented in a uniaxial direction, The second two-dimensional microfiber film is electrospun to form a random structure without being oriented. A method for manufacturing a bio-implantable electrode structure.

19. In paragraph 13, The metal deposited in the third step includes at least one of gold (Au), silver (Ag), copper (Cu), platinum (Pt), iridium (Ir), tantalum (Ta), titanium (Ti), ruthenium (Ru), palladium (Pd), nickel (Ni), cobalt (Co), iron (Fe), nickel-titanium alloy (NiTi), and gold-silver alloy (Au-Ag). A method for manufacturing a bio-implantable electrode structure.

20. In paragraph 13, The conductive polymer deposited in the fourth step is PEDOT:PSS (Poly(3,4-ethylenedioxythiophene):polystyrene sulfonate), PEDOT:Tos (Poly(3,4-ethylenedioxythiophene):tosylate), polypyrrole (PPy), polyaniline (PANI), poly(3-hexylthiophene) (P3HT), poly(3,4-propylenediothiophene) (PProDOT), polycarbazole, polyindole, poly(p-phenylene vinylene) (PPV), polyacetylene (PA), polyfuran, PEDOT:BF4 (Poly(3,4-ethylenedioxythiophene):tetrafluoroborate), PEDOT:Cl (Poly(3,4-ethylenedioxythiophene):chloride), PEDOT:PF6 (Poly(3,4-ethylenedioxythiophene):hexafluorophosphate), PEDOT-PEG Copolymer (PEDOT-PEG copolymer), PEDOT-graphene oxide composite (PEDOT-GO composite), PEDOT-carbon nanotube composite (PEDOT-CNT composite), PPy-chitosan composite (PPy-chitosan composite), PPy-collagen composite (PPy-collagen composite), PANI-gelatin composite (PANI-gelatin composite), PEDOT:PSS-gelatin hydrogel (PEDOT:PSS-gelatin hydrogel), PANI-PEG copolymer (PANI-PEG copolymer), PANI-PLA composite (PANI-PLA composite), PEDOT:PSS-hyaluronic acid hydrogel (PEDOT:PSS-hyaluronic acid hydrogel), PANI-alginate composite (PANI-alginate composite),Comprising at least one of PEDOT:PSS-fibrin hydrogel and PEDOT:PSS-RGD peptide conjugate, A method for manufacturing a bio-implantable electrode structure.

21. A method for manufacturing a bio-implantable electrode structure, Step 1: Manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; A second step of coating primary parylene on the two-dimensional microfiber membrane manufactured above; A third step of depositing metal on the two-dimensional microfiber film coated with the first perylene; A fourth step of insulating the surface of the deposited metal by coating a secondary perylene on the two-dimensional microfiber film on which the metal has been deposited; A fifth step of etching the above-mentioned second perylene-coated two-dimensional microfiber film to etch away a portion of the insulating film on the insulated metal surface, thereby exposing a portion of the metal surface of the two-dimensional microfiber film; A sixth step of depositing a conductive polymer on the exposed metal surface of the two-dimensional microfiber film; A seventh step of manufacturing a first two-dimensional microfiber membrane having first cells loaded thereon by loading first cells onto a two-dimensional microfiber membrane on which the conductive polymer is deposited; After performing the first to sixth steps, an eighth step of manufacturing a second two-dimensional microfiber membrane loaded with second cells by loading second cells onto the two-dimensional microfiber membrane on which the conductive polymer is deposited; and A ninth step of manufacturing a one-dimensional porous microfiber by laminating the first two-dimensional microfiber film and the second two-dimensional microfiber film and then rolling or twisting them; including, A method for manufacturing a bio-implantable electrode structure.

22. A method for manufacturing a bio-implantable electrode structure, Step 1: Manufacturing a two-dimensional microfiber membrane by electrospinning a polymer solution; A second step of coating primary parylene on the two-dimensional microfiber membrane manufactured above; A third step of depositing metal on the two-dimensional microfiber film coated with the first perylene; A fourth step of insulating the surface of the deposited metal by coating a secondary perylene on the two-dimensional microfiber film on which the metal has been deposited; A fifth step of etching the above-mentioned second perylene-coated two-dimensional microfiber film to etch away a portion of the insulating film on the insulated metal surface, thereby exposing a portion of the metal surface of the two-dimensional microfiber film; A sixth step of depositing a conductive polymer on the exposed metal surface of the two-dimensional microfiber film; A seventh step of manufacturing a first two-dimensional microfiber membrane having first cells loaded thereon by loading first cells onto a two-dimensional microfiber membrane on which the conductive polymer is deposited; An eighth step of manufacturing a plurality of two-dimensional microfiber membranes, each loaded with different cells, by repeating steps 1 to 6; A ninth step of manufacturing a plurality of one-dimensional porous microfibers, each loaded with different cells, by rolling or twisting the plurality of two-dimensional microfiber membranes; and A tenth step of performing a multi-array process using the above plurality of one-dimensional porous microfibers; including, A method for manufacturing a bio-implantable electrode structure.

23. In paragraph 22, In the above 10th step, the multi-array process is a braiding, weaving or knitting process. A method for manufacturing a bio-implantable electrode structure.

24. In paragraph 22, The cells loaded on the above multiple one-dimensional porous microfibers are each different, The above cells are dopaminergic neurons, serotonergic neurons, glutamatergic neurons or GABAergic neurons. A method for manufacturing a bio-implantable electrode structure.

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