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WO2025211847A1 - Structure d'électrode implantable et son procédé de fabrication - Google Patents

Structure d'électrode implantable et son procédé de fabrication

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Publication number
WO2025211847A1
WO2025211847A1 PCT/KR2025/004562 KR2025004562W WO2025211847A1 WO 2025211847 A1 WO2025211847 A1 WO 2025211847A1 KR 2025004562 W KR2025004562 W KR 2025004562W WO 2025211847 A1 WO2025211847 A1 WO 2025211847A1
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WO
WIPO (PCT)
Prior art keywords
cells
dimensional
microfiber
electrode structure
bio
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/004562
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English (en)
Korean (ko)
Inventor
이중호
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cellknit Inc
Original Assignee
Cellknit Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cellknit Inc filed Critical Cellknit Inc
Priority claimed from KR1020250043949A external-priority patent/KR20250148498A/ko
Publication of WO2025211847A1 publication Critical patent/WO2025211847A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like

Definitions

  • 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.
  • bioimplantable electrodes have evolved toward developing electrodes that can effectively interface with biological tissues such as nerves and muscles.
  • simple metal wires or silicon-based electrodes were primarily used, boasting the advantages of relative ease of manufacture and high electrical conductivity.
  • 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.
  • 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.
  • this technology also has various limitations, such as reduced adhesion between the electrode and tissue in long-term implant environments, foreign body reactions in the body, and issues with signal accuracy.
  • microfiber-based electrodes which have a three-dimensional, porous structure that is more structurally similar to tissue and even considers cell interaction
  • fiber-based electrodes which have a three-dimensional, porous structure that is more structurally similar to tissue and even considers cell interaction
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PU polyurethane
  • PCL polycaprolactone
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactide-co-g
  • 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,
  • 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.
  • 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.
  • the one-dimensional porous microfibers may be coated with parylene.
  • 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.
  • 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.
  • 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.
  • PU polyurethane
  • PCL polycaprolactone
  • PLA polylactic acid
  • PGA polyglycolic
  • 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,
  • a step of coating a decellularized extracellular matrix hydrogel on the manufactured one-dimensional porous microfibers may be further included.
  • 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.
  • 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.
  • 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).
  • 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):hexafluor
  • 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
  • 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
  • the multiple array process may be a braiding, weaving or knitting process.
  • 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 thus the scope of the disclosed technology should not be construed as being limited thereby.
  • each cell can perform its original function without interference between cells.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Figure 6 is a schematic diagram showing a cross-section of a one-dimensional porous microfiber according to the present invention.
  • Figure 10a is a schematic diagram showing how to manufacture one-dimensional microfibers by laminating and rolling or twisting an electrospun microfiber film according to the present invention.
  • Figure 10b is a schematic diagram showing the structure of a one-dimensional porous microfiber according to the present invention.
  • 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.
  • PU polyurethane
  • 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.
  • 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.
  • 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.
  • 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).
  • Figure 22 shows the weaving process and weaving form.
  • 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).
  • Figure 25 shows the knitting process and knitting form.
  • 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).
  • 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.
  • 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.
  • 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).
  • electrode A can be set to have a cell membrane potential response frequency band specific to neurons
  • 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.
  • 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.
  • cells e.g., nerve cells, immune cells, stem cells, etc.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-
  • 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.
  • 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.
  • the protein composition ratio (collagen, laminin, proteoglycan, etc.) can be adjusted to use a hydrogel optimized for tissue regeneration and cell attachment.
  • 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.
  • a second perylene coating step and an etching step may be further included, and after the etching step, a fourth step may be performed.
  • the electrode layer which is a metal-deposited portion, can be revealed.
  • a shadow mask when etching the secondary perylene coated portion, can be used to etch only a certain polymer portion.
  • 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.
  • 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.
  • 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.
  • 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, Cu 2 O), titanium oxide (TiO 2 ), manganese oxide (MnO 2 ), vanadium oxide (V 2 O 5 ), cobalt oxide (Co 3 O 4 ), iron oxide (Fe 2 O 3 ), iridium oxide (IrO 2 ), ruthenium oxide (RuO 2 ), and tantalum oxide (Ta 2 O 5 ) may be deposited on the microfiber or microfiber film according to the present invention.
  • ITO indium tin oxide
  • AZO aluminum-doped zinc oxide
  • GZO gallium-doped zinc oxide
  • FTO fluorine-doped tin oxide
  • NiO nickel oxide
  • ZnO zinc oxide
  • CuO copper oxide
  • an electrode layer can be formed by depositing gold on microfibers or microfiber films according to the present invention.
  • a chemical vapor deposition method 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m, or 500 nm to 8 ⁇ m, or 600 nm to 6 ⁇ m, or 1 ⁇ m to 4 ⁇ m, or 3 ⁇ m to 5 ⁇ m.
  • 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.
  • 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.
  • 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).
  • the same one-dimensional porous microfiber-based bio-implantable electrode structure can selectively induce two different physiological responses through stimulation.
  • 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.
  • Electrode 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.
  • the electrode structure is the same, by changing only the stimulation conditions, two opposing neurophysiological responses can be selectively induced with a single electrode.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a neurotransmitter when 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.
  • brain responses depending on the depth, concentration, and distribution of the neurotransmitter can be analyzed at high resolution.
  • the directionality of a neuroactive substance flowing in from the outside or an electrical signal according to neural activity can be detected.
  • 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.
  • the greater the number of electrodes and the more three-dimensionally they are distributed the more effective and superior the spatiotemporal resolution can be.
  • 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 .
  • 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.
  • 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.
  • 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).
  • Figure 5 is an image showing how to control the orientation of microfibers during electrospinning.
  • a flat collector 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.
  • Fig. 6 is a schematic diagram showing a cross-section of a one-dimensional porous microfiber according to the present invention.
  • 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).
  • 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.
  • 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.
  • FIG 8 is a schematic diagram showing the density of an electrospun microfiber membrane according to 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.
  • an ideal density that takes both cell viability and transfer rate into account can be realized.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG 10b is a schematic diagram illustrating the structure of a one-dimensional porous microfiber according to the present invention.
  • 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.
  • 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.
  • 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.
  • FIG 11a is a photograph illustrating a perylene coating on microfibers according to 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • each of the plurality of one-dimensional porous microfibers according to the present invention 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.
  • 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.
  • 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.
  • electrospinning when electrospinning the plurality of two-dimensional microfiber films, electrospinning can be performed with different orientations.
  • 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.
  • Example 1 Fabrication of a one-dimensional porous microfiber-based bio-implantable electrode structure
  • Example 1-1 Preparation of a two-dimensional microfiber membrane
  • 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.
  • a flat collector when 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.
  • a non-adhesive silicone-coated paper is attached to the collector.
  • 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.
  • Example 1-3 Primary Parylene Coating on an Electrospun Two-Dimensional Microfiber Film
  • 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.
  • 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.
  • a secondary perylene coating is vapor-deposited to a thickness of 200 nm to 600 nm.
  • 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.
  • the cells iPSCs obtained from human nasal cavity and reverse-differentiated
  • 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.
  • a first two-dimensional microfiber membrane loaded with dopaminergic neurons and a second two-dimensional microfiber membrane loaded with stem cells were prepared.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 5-1 Manufacturing of electrode structure bundle using braiding
  • Figure 19 shows the braiding process and braiding form.
  • 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.
  • 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).
  • 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.

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Abstract

La présente invention concerne une structure d'électrode implantable à base de microfibres poreuses unidimensionnelles, une première cellule étant montée sur une première partie de la microfibre poreuse unidimensionnelle, et une seconde cellule étant montée sur une seconde partie de la microfibre poreuse unidimensionnelle.
PCT/KR2025/004562 2024-04-05 2025-04-04 Structure d'électrode implantable et son procédé de fabrication Pending WO2025211847A1 (fr)

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KR1020250043949A KR20250148498A (ko) 2024-04-05 2025-04-04 생체 삽입형 전극 구조체 및 그 제조 방법
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KR20200119919A (ko) * 2019-03-19 2020-10-21 고려대학교 산학협력단 바이오 프린팅 기술을 이용한 신경도관의 제조방법 및 이에 따라 제조된 신경도관
KR20220042532A (ko) * 2020-09-28 2022-04-05 재단법인대구경북과학기술원 전도성 고분자를 이용한 나노 섬유 메쉬 생체 전극 및 이의 제조방법
KR20240033399A (ko) * 2022-09-05 2024-03-12 한양대학교 산학협력단 생체 삽입형 커패시터 전극 구조체

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009075625A1 (fr) * 2007-12-10 2009-06-18 Neuronano Ab Électrode médicale, faisceau d'électrodes et ensemble de faisceau d'électrodes
KR20180107158A (ko) * 2011-08-30 2018-10-01 코넬 유니버시티 금속 및 세라믹 나노 섬유들
KR20150084519A (ko) * 2014-01-14 2015-07-22 연세대학교 산학협력단 다층의 전기방사 섬유가 복합된 하이드로젤
KR20200119919A (ko) * 2019-03-19 2020-10-21 고려대학교 산학협력단 바이오 프린팅 기술을 이용한 신경도관의 제조방법 및 이에 따라 제조된 신경도관
KR102163164B1 (ko) * 2019-04-01 2020-10-08 재단법인대구경북과학기술원 나노섬유 메쉬 생체전극 및 이의 제조방법
KR20220042532A (ko) * 2020-09-28 2022-04-05 재단법인대구경북과학기술원 전도성 고분자를 이용한 나노 섬유 메쉬 생체 전극 및 이의 제조방법
KR20240033399A (ko) * 2022-09-05 2024-03-12 한양대학교 산학협력단 생체 삽입형 커패시터 전극 구조체

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