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WO2016047811A1 - Timbre favorisant la cicatrisation - Google Patents

Timbre favorisant la cicatrisation Download PDF

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Publication number
WO2016047811A1
WO2016047811A1 PCT/JP2015/078126 JP2015078126W WO2016047811A1 WO 2016047811 A1 WO2016047811 A1 WO 2016047811A1 JP 2015078126 W JP2015078126 W JP 2015078126W WO 2016047811 A1 WO2016047811 A1 WO 2016047811A1
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Prior art keywords
patch
wound healing
electrode
positive electrode
negative electrode
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English (en)
Japanese (ja)
Inventor
松彦 西澤
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Tohoku Techno Arch Co Ltd
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Tohoku Techno Arch Co Ltd
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    • 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
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents

Definitions

  • the present invention relates to a wound healing patch, and more particularly, to a wound healing patch that can easily perform wound healing by electricity with high safety and low cost.
  • Non-Patent Documents 1 and 2 Treatment using such a phenomenon is generally performed using a medical electrical stimulation device.
  • the treatment place is limited to the patient's bedside or the like, or the device and its wiring are physically disturbed and the treatment operation becomes complicated. There was a problem. In addition, the patient may feel pain depending on the output of the apparatus. Furthermore, there is a problem that the treatment cost becomes relatively high.
  • an object of the present invention is to provide a wound healing patch that can easily perform wound healing by electricity with high safety and low cost.
  • the wound healing patch of the present invention includes a plurality of electrodes including at least one positive electrode (cathode) or negative electrode (anode) carrying an enzyme that catalyzes an oxidation-reduction reaction, and a conductive material that electrically connects the plurality of electrodes. And a sex member.
  • the plurality of electrodes do not substantially contain water.
  • the wound healing patch of the present invention further includes an outer surface cover for sealing the plurality of electrodes and the conductive member.
  • the plurality of electrodes are preferably provided such that the positive electrode is sandwiched between the negative electrodes on both sides.
  • (A), (b) is a figure which shows the patch for wound healing of 1st embodiment of this invention in the state before use with the finger with a wound site
  • (A) is a perspective view of the patch, and (b) is a cross-sectional view of the wound healing patch of the first embodiment of the present invention along a plane along line I-I shown in (a).
  • (A), (b) is a figure which shows the patch for wound healing of 1st embodiment of this invention in the state which is used with a finger with a wound site
  • (A) is a perspective view of the patch, and (b) is a cross-sectional view of the wound healing patch according to the first embodiment of the present invention taken along a line II-II shown in (a).
  • (A), (b) is a figure which shows the patch for wound healing of 2nd embodiment of this invention in the state before use with the finger with a wound site
  • (A) is a perspective view of the patch, and (b) is a cross-sectional view of the wound healing patch according to the second embodiment of the present invention, taken along the line III-III shown in (a). It is a figure which shows the modification of the patch for wound healing of 2nd embodiment of this invention in the state before use.
  • (A), (b) is a figure which shows the wound healing patch of 3rd embodiment of this invention in the state before use with the eye with a wound site
  • FIGS. 1 shows an in vitro wound healing assay system in which normal human corneal epithelial cells are not cultured, and (b) shows the current density of the current flowing through the channel when the cross-sectional area of the channel is 0.025 mm 2 ( The chart showing the change with time of ⁇ A / cm 2 ) is shown.
  • (A) (i) to (iii) show the results of in vitro wound healing assay, and (b) shows a summary of the results shown in (a).
  • FIG. 1A and 1 (b) show a wound healing patch according to the first embodiment of the present invention in a state before use together with a finger having a wound site.
  • FIG. 1A is a perspective view of the patch
  • FIG. 1B is a cross-sectional view of the wound healing patch according to the first embodiment of the present invention, taken along the line I-I shown in FIG.
  • the figure is shown.
  • 2 (a) and 2 (b) show a wound healing patch according to the first embodiment of the present invention in use, together with a finger having a wound site.
  • FIG. 2 (a) shows the patch in a perspective view
  • FIG. 2 (b) shows a cross-section of the wound healing patch according to the first embodiment of the present invention, taken along the line II-II shown in FIG. 2 (a).
  • the wound healing patch according to the first embodiment of the present invention is of a bandage type mainly used by being applied to a skin wound site.
  • the wound healing patch 60 (hereinafter also referred to as “patch 60”) according to the first embodiment of the present invention includes three positive electrodes (cathodes) 2a and two negative electrodes (anodes) 2b (2b1, 2b2).
  • the conductive member 4x which electrically connects the electrode 2, the positive electrode 2a and the negative electrode 2b1, the conductive member 4y which electrically connects the positive electrode 2a and the negative electrode 2b2, and the three electrodes 2 It includes a conductive layer 5 provided in contact with (2a, 2b).
  • the positive electrode 2a carries an enzyme 3a that catalyzes a reduction reaction
  • the negative electrode 2b (2b1, 2b2) carries an enzyme 3b (3b1, 3b2) that catalyzes an oxidation reaction.
  • the conductive layer 5 includes a substrate for the enzyme 3 (3a, 3b).
  • the conductive layer 5 further contains an electrolyte and water. The conductive layer 5 is in contact with both the positive electrode 2a and the negative electrode 2b (2b1, 2b2).
  • one positive electrode (cathode) 2a and two negative electrodes (anodes) 2b (2b1, 2b2) are aligned in parallel, and the positive electrode 2a Is sandwiched between two negative electrodes 2 (2b1, 2b2) in a direction perpendicular to the extending direction.
  • the user can use the patch 60 by applying the patch 60 to the living tissue 50 around the wound site 1, and in particular, as shown in FIGS. 2 (a) and 2 (b), the patch 60 can be used. It is preferable to use the patch 60 by attaching the electrode 2 so that the positive electrode 2a of the electrode 2 is located at the wound site 1 of the living tissue 50 (finger 51 in FIG. 2).
  • the conductive layer 5 includes a substrate of the enzyme 3 (3a, 3b). Electrons generated by the oxidation reaction by the enzyme 3b (3b1, 3b2) in the negative electrode 2b (2b1, 2b2) are delivered to the positive electrode 2a through the conductive member 4 (4x, 4y), and reduced by the enzyme 3a in the positive electrode 2a. Used for reaction.
  • the electrode 2 (2a, 2b) is in contact with the living tissue 50 via the conductive layer 5, the living tissue 50 is located between the positive electrode 2a and the negative electrode 2b1, and between the positive electrode 2a and the negative electrode 2b2. A current flows through the living tissue 50 portion.
  • epidermal cells of animal cells such as humans have electromotility that migrates from the negative electrode 2b (2b1, 2b2) side to the positive electrode 2a side. Therefore, the migration of the cells occurs due to the current flowing through the wound site 1, the cells gather from the living tissue 50 around the wound site 1 to the wound site 1, and the wound heals.
  • the patch 60 of the first embodiment When the patch 60 of the first embodiment is affixed to the living tissue 50 around the wound site 1, the aforementioned cell migration is promoted around the wound site 1, and the cells move to the living tissue 50 around the wound site 1. Concentrate on wound site 1. By this action, the effect of wound healing can be enhanced.
  • the cells have the property of migrating from the negative electrode 2b (2b1, 2b2) side toward the positive electrode 2a side, it is preferable to position the positive electrode 2a at the wound site 1 when the patch 60 is used to heal a wound.
  • the user uses the patch 60 and the positive electrode 2a among the electrodes 2 is a living body. It can be used by applying it so that it is located at the wound site 1 of the tissue 50 (finger 51 in FIG. 2).
  • the positive electrode 2 a is positioned at the wound site 1
  • the negative electrode 2 b is positioned at two positions sandwiching the wound site 1 in the living tissue 50 around the wound site 1. It becomes possible, and the migration of cells from the living tissue 50 around the wound site 1 toward the wound site 1 can be promoted. Therefore, the effect of wound healing by the patch 60 can be particularly enhanced.
  • a medical electrical stimulation device As a device that is generally used to perform wound healing by electricity, a medical electrical stimulation device can be cited.
  • the treatment place is limited to the patient's bedside, etc.
  • the device and its wiring are physically disturbed and the therapeutic operation becomes complicated.
  • the patch 60 of the first embodiment it is possible to easily perform wound healing by electricity without using a large-scale device that is restricted in terms of treatment place and treatment operation.
  • a patient feels pain when the current density when a current is passed through a living body exceeds a certain value (for example, 500 ⁇ A / cm 2 or more).
  • a certain value for example, 500 ⁇ A / cm 2 or more.
  • the patient may feel pain depending on the output of the device.
  • a current can be passed through the wound site with a current density at which the patient does not feel pain without particularly requiring control or the like. Therefore, it is possible to perform wound healing by electricity with high safety.
  • the patch 60 of the first embodiment Since the patch 60 of the first embodiment generates electricity using a substance that is harmless to the human body such as the enzyme 3 (3a, 3b) or its substrate, there is a need for expensive materials such as metallic electrodes and electrolytes. Low. Therefore, according to the patch 60 of the first embodiment, it is possible to perform wound healing by electricity at a low cost.
  • the patch 60 can be placed under a temperature condition suitable for the enzyme reaction. Therefore, the current can be obtained using the redox reaction of the enzyme 3 (3a, 3b). It is possible to efficiently perform bioelectric power generation that generates electricity. Further, since the patch 60 does not use a metallic electrode or the like, the disposal process can be facilitated and the environmental load can be reduced.
  • the patch 60 of the first embodiment includes the conductive layer 5 provided in contact with the two electrodes 2 (2a, 2b), the patch 60 is attached to the living tissue 50 around the wound site 1.
  • the conductive layer 5 exists between the living tissue 50 and the electrode 2 (2a, 2b). Therefore, it can prevent that the electrode 2 (2a, 2b) contacts the wound site
  • the conductive layer 5 is interposed between the electrodes. An electric current can be passed through the wound site 1 and the effect of wound healing by the patch 60 can be obtained.
  • the electrode 2 (2a, 2b) carrying the enzyme 3 (3a, 3b) is dried by freeze drying or the like. According to this configuration, it is possible to prevent the enzyme 3 from being deactivated between the time when the patch 60 is manufactured and when it is used.
  • the area of the positive electrode 2a in plan view may be determined so as to be smaller than the area of the wound site 1 in plan view. If the area of the positive electrode 2a is made smaller than the area of the wound site 1, all of the current flowing between the positive electrode 2a and the negative electrode 2b can contribute to the action of promoting cell migration in the wound site 1, and the patch 60 The effect of wound healing by can be particularly enhanced.
  • the conductive layer 5 contains an electrolyte, the resistance value of the conductive layer 5 can be reduced and the conductivity can be increased.
  • the patch 60 may further be provided with an inner surface cover (not shown) attached to the side of the two electrodes 2 attached to the living tissue 50.
  • the inner surface cover can protect the surface of the patch 60 attached to the living tissue 50.
  • the patch 60 may further be provided with a member (such as a frame) (not shown) for adjusting the overall shape of the patch 60.
  • the patch 60 including the conductive layer further includes an isolation member (not shown) that separates the electrode 2 (2a, 2b) from the conductive layer 5 in order to keep the electrode 2 (2a, 2b) dry. May be included.
  • This isolation member can be detachably provided.
  • FIG. 3 (a) and 3 (b) show a wound healing patch according to a second embodiment of the present invention in a state before use together with a finger having a wound site.
  • FIG. 3 (a) shows the patch in a perspective view
  • FIG. 3 (b) shows a cross section of the wound healing patch of the second embodiment of the present invention along the plane along line III-III shown in FIG. 3 (a). The figure is shown.
  • the wound healing patch according to the second embodiment of the present invention is of a bandage type that is mainly used by being applied to a wound site on the skin.
  • symbol is attached
  • the wound healing patch 70 (hereinafter also referred to as “patch 70”) of the second embodiment of the present invention includes two electrodes 2 including one positive electrode (cathode) 2a and one negative electrode (anode) 2b, and a positive electrode.
  • a conductive member 4 that electrically connects 2a and the negative electrode 2b, and a conductive layer 5 provided in contact with the two electrodes 2 (2a, 2b).
  • Other elements of the patch 70 are the same as those in the case of the patch 60.
  • the positive electrode 2a is preferably provided so that both sides thereof are sandwiched between the negative electrodes 2b, and the configuration of the electrode of the patch 60 of the first embodiment and the patch 70 of the second embodiment. It is not limited to the configuration of the electrodes. Specifically, in the wound healing patch of the present invention, it is preferable that two negative electrode 2b portions exist on a straight line in an arbitrary direction passing through the positive electrode 2a. According to such a configuration, as described above, the effect of wound healing by the patch 60 can be particularly enhanced.
  • the planar view shape of the positive electrode 2a and the negative electrode 2b (2b1, 2b2) may be determined according to the planar view shape of the wound site 1.
  • FIG. 4 the modification of the patch for wound healing of 2nd embodiment of this invention in the state before use is shown. If the planar view shapes of the positive electrode 2a and the negative electrode 2b are matched with the planar view shape of the wound site 1 (see FIG. 3 and the like), cell migration can be effectively promoted at the entire outer edge of the wound site 1. Therefore, the effect of wound healing by the patch 70 can be particularly enhanced.
  • the positive electrode 2a and the negative electrode 2b (2b1, 2b2) are preferably deformable, such as having flexibility and stretchability.
  • FIGS. 6A and 6B show a wound healing patch according to a third embodiment of the present invention in use, together with an eye having a wound site.
  • FIG. 6A is a perspective view of the patch
  • FIG. 6B is a cross-sectional view of the wound healing patch according to the third embodiment of the present invention taken along the line VV shown in FIG.
  • the wound healing patch according to the third embodiment of the present invention is of a contact lens type that is mainly used by being applied to a wound site of an eye.
  • symbol is attached
  • a patch 80 for wound healing (hereinafter, also referred to as “patch 80”) according to the third embodiment of the present invention includes two electrodes 2 including one positive electrode (cathode) 2a and one negative electrode (anode) 2b, and a positive electrode. 2a and the negative electrode 2b, and the conductive layer 5 which embeds the two electrodes 2 (2a, 2b).
  • the negative electrode 2b is provided around the positive electrode 2a.
  • Other elements of the patch 80 are the same as those of the patch 70.
  • the user uses the patch 80 by applying the patch 80 to the living tissue 50 (the eye 52 in FIG. 6) around the wound site 1. be able to.
  • the electrode 2 (2a, 2b) is embedded in the conductive layer 5
  • the electrode 2 (2a, 2b) is prevented from coming into direct contact with the wound site 1. Damage to cells around the wound site 1 can be reduced.
  • the embedding method is not particularly limited. For example, when a hydrogel is used as the conductive layer 5, a method of solidifying the gel after impregnating the electrode 2 (2a, 2b) with the gel solution, etc. may be mentioned. It is done.
  • the electrode 2 (2a, 2b) can contact the living tissue 50, a current flows through the living tissue 50 portion between the positive electrode 2a and the negative electrode 2b.
  • the patch for wound healing of this invention does not contain the conductive layer 5, the effect of wound healing of this invention can be acquired.
  • Examples of the enzyme 3a that catalyzes the reduction reaction supported on the positive electrode (cathode) 2a include, for example, bilirubin oxidase (BOD), laccase, Cu efflux oxidase (Cueo), ascorbate oxidase, and the like. From the viewpoint of enhancing resistance to pH, chloride ions, etc., bilirubin oxidase (BOD) is preferred.
  • Examples of the enzyme 3b that catalyzes the oxidation reaction supported on the negative electrode (anode) 2b include glucose oxidase, glucose dehydrogenase (Glucose Dehydrogenase, GDH), fructose dehydrogenase (D-Fructose Dehydrogenase, FDH), alcohol oxidase, alcohol dehydrogenase, Examples thereof include lactate oxidase and lactate dehydrogenase.
  • fructose dehydrogenase (FDH) is preferable because it does not require a mediator (coenzyme) and can simplify the enzyme reaction system.
  • the combination of BOD and FDH is preferable because it can exhibit high activity under the condition of pH 5 equivalent to the pH on the outer surface of the living tissue 50.
  • the enzyme 3a that catalyzes the reduction reaction and the enzyme 3b that catalyzes the oxidation reaction may be used singly or in combination of two or more.
  • the voltage stability is increased by serializing a plurality of electrodes 2 carrying the enzyme 3 or by paralleling a plurality of electrodes 2 carrying the enzyme 3. This can also be improved, and a desired current can be stably secured.
  • the electrode 2 carrying the enzyme 3 is dried by freeze-drying or the like.
  • the present invention is not limited to this. If the electrode 2 is substantially free of water, the enzyme 3 is inactivated between the time when the patches 60, 70, 80 are manufactured and used. The effect of preventing this can be obtained. “Substantially free of water” means that the weight ratio of water to the electrode is less than 10%. Incidentally, the ratio is preferably less than 5%, and more preferably less than 2%.
  • the material of the conductive member 4 examples include carbon materials such as carbon nanotube, ketjen black, glassy carbon, graphene, fullerene, carbon fiber, carbon fabric, and carbon aerogel; polyaniline, polyacetylene, polypyrrole, poly (p-phenylene vinylene), Conductive polymers such as polythiophene and poly (p-phenylene sulfide); semiconductors such as silicone, germanium, indium tin oxide (ITO), titanium oxide, copper oxide, silver oxide; gold, platinum, titanium, aluminum, tungsten, copper, Examples thereof include metals such as iron and palladium, and conductive polymers are particularly preferable from the viewpoints of flexibility and biocompatibility.
  • the conductive member 4 may be a circuit formed of a conductive polymer on the surface of the conductive layer 5 using a printing technique.
  • hydrogel used for the conductive layer 5 included in the patch of the present embodiment examples include agar, gelatin, agarose, xanthan gum, gellan gum, sclerotia gum, arabic gum, tragacanth gum, caraya gum, cellulose gum, tamarind gum, guar gum, locust bean gum, Glucomannan, chitosan, carrageenan, quince seed, galactan, mannan, starch, dextrin, curdlan, casein, pectin, collagen, fibrin, peptide, chondroitin sulfate such as sodium chondroitin sulfate, hyaluronic acid (mucopolysaccharide) and hyaluronic acid Natural polymers such as hyaluronates such as sodium, alginates such as alginic acid, sodium alginate, and calcium alginate, and derivatives thereof Gels containing cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxy
  • An interpenetrating network hydrogel refers to a gel in which other network structures are uniformly entangled with the base network structure, resulting in the formation of a plurality of network structures throughout the gel, and a semi-interpenetrating network structure.
  • the hydrogel refers to a gel in which other linear structures are uniformly entangled with a base network structure, and as a result, a plurality of network structures are formed throughout the gel.
  • the network structure and / or the linear structure is formed from a plurality of types of polymers.
  • the (semi) interpenetrating network hydrogel is a double It is called a network gel (DN gel).
  • hydrogels having very high mechanical strength (see WO2003 / 093337).
  • 10 mol% or more of the first monomer component is a charged monomer
  • 60 mol% or more of the second monomer component is electrically neutral.
  • the molar ratio of the amount of the first monomer component to the amount of the second monomer component in the hydrogel is 1: 2 to 1: 100 (preferably 1: 3 to 1:50). More preferably, it is 1: 3 to 1:30), and the degree of crosslinking when polymerizing and crosslinking the second monomer component is greater than the degree of crosslinking when polymerizing and crosslinking the first monomer component. Small points are essential.
  • Examples of the first monomer component include olefins having an acidic group (for example, a carboxyl group, a phosphoric acid group, and a sulfonic acid group) and a basic group (for example, an amino group). Examples include methylpropanesulfonic acid, acrylic acid, methacrylic acid, and salts thereof.
  • Examples of the second monomer component include acrylamide, N-isopropylacrylamide, vinyl pyridine, styrene, methyl methacrylate, fluorine-containing olefin (for example, trifluoroethyl acrylate), hydroxyethyl acrylate, vinyl acetate, and the like.
  • An example of a method for producing a (semi) interpenetrating network structure hydrogel is as follows. First, a first monomer component is polymerized and crosslinked to form a network structure (first network structure) in which a certain amount or more of charged groups (for example, a carboxyl group) are present, and then electrically The second monomer component, which is electrically neutral, is introduced into the first network structure by polymerizing and crosslinking the second monomer component which is neutral.
  • first network structure in which a certain amount or more of charged groups (for example, a carboxyl group) are present
  • the tensile breaking stress of the hydrogel is preferably 1 kPa to 100 MPa, and more preferably 10 kPa to 20 MPa.
  • the mechanical strength of the conductive layer 5 can be increased.
  • the hydrogel is prevented from being destroyed, while maintaining the regularity of the patch, this embodiment Can be kept in close contact with the living tissue 50 around the wound site 1.
  • the “tensile breaking stress” can be measured by measuring the stress at which the hydrogel breaks by a tensile load using a load cell. Examples of the measuring apparatus include a tensile tester 5960 series manufactured by Instron.
  • the pH of the hydrogel used for the conductive layer 5 is preferably 3 to 9, and more preferably 4 to 8. If it is the said range, it can be set as the optimal pH of an enzyme, activity can be improved, and the inflammation by the contact with the conductive layer 5 of the biological tissue 50 can be suppressed.
  • the substrate of enzyme 3 (3a, 3b) can be determined according to enzyme 3 (3a, 3b) used.
  • Water-- Examples of water include ultrapure water.
  • Electrolyte-- The electrolyte is not particularly limited as long as it has an effect of increasing the conductivity of the conductive layer 5, and examples thereof include organic acids and / or inorganic acids and derivatives thereof and salts thereof.
  • examples of the anionic species constituting the electrolyte include amino acid ions (natural amino acid ions, non-natural amino acid ions), chloride ions, citrate ions, lactate ions, succinate ions, phosphate ions, malate ions, pyrrolidone carboxylic acids.
  • Non-natural amino acids include hydroxyproline, cystine, and thyroxine. It is.
  • Examples of the cation species constituting the electrolyte include K + , Na + , Ca 2+ , Mg 2+ and the like.
  • Specific examples of the electrolyte include, for example, sodium salts of amino acids, sodium chloride, calcium chloride, magnesium chloride, sodium citrate, sodium lactate, calcium lactate, sodium succinate, sodium malate, sodium pyrrolidonecarboxylate, zinc sulfocolate, Examples include potassium aluminum sulfate (alum), sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate and the like.
  • sodium citrate, sodium lactate, sodium monohydrogen phosphate, phosphorus Sodium dihydrogen acid and sodium phosphate are preferred.
  • these electrolytes may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the concentration of the electrolyte in the conductive layer 5 is preferably 1 mM or more, and more preferably 50 mM or more. If it is the said range, the resistance of the conductive layer 5 can be reduced (for example, to 3 k ⁇ or less), and the current can be increased.
  • the outer cover 7 is preferably waterproof. If the outer surface cover 7 having a waterproof property is provided, the wound site 1 can be protected, and the evaporation of moisture in the wound site 1 can be prevented. Therefore, the enzyme 3 ( The conditions for the redox reaction according to 3a and 3b) can be ensured, and the service life of the patch can be extended. Examples of the outer cover 7 include a waterproof spray paste, a waterproof tape, and a waterproof bandage.
  • the outer cover 7 preferably has air permeability. If the outer surface cover 7 having air permeability is provided, an enzyme using a substance contained in the atmosphere as a substrate (for example, BOD using oxygen as a substrate for the reduction reaction) can be used for the enzyme 3a supported on the positive electrode 2a. Cost related to the substrate of enzyme 3 can be reduced.
  • an enzyme using a substance contained in the atmosphere as a substrate for example, BOD using oxygen as a substrate for the reduction reaction
  • the material for the inner cover examples include polyethylene, polypropylene, polyethylene terephthalate, plastics such as acrylic resin, polycarbonate, and polyamide, cellophane made of elastomer, rubber, and cellulose, polymer resin, quartz, glass, and the like. Cellophane and plastic are preferable from the viewpoint of safety.
  • the living tissue 50 to which the wound healing patch of the present embodiment can be affixed is mainly composed of keratin such as the face, fingers 51, eyes 52, arms, skin of the body, hair, nails, lips, inner surface of the oral cavity, and the like.
  • the keratin-containing tissue and the like to be used are exemplified, but not limited thereto, any tissue that forms the outer surface of a living body can be used.
  • the patch 60 shown in FIGS. 1 and 2 includes three electrodes 2 including one positive electrode (cathode) 2a and two negative electrodes (anodes) 2b (2b1 and 2b2), and the patch 70 shown in FIGS.
  • the patch 80 shown in FIGS. 5 and 6 includes two electrodes 2 including one positive electrode 2a and one negative electrode 2b.
  • the wound healing patch of the present invention carries an enzyme that catalyzes a redox reaction. It is only necessary to include a plurality of electrodes including at least one positive electrode or negative electrode.
  • the enzyme 3a is supported on the positive electrode 2a and the enzyme 3b is supported on the negative electrode 2b.
  • the negative electrode 2b may carry an enzyme 3b that catalyzes an oxidation reaction.
  • an inorganic catalyst such as platinum, a platinum alloy, gold, or copper, and those obtained by nano-particulate these inorganic catalysts supported on a carbon electrode obtained by solidifying activated carbon can be used.
  • only the positive electrode 2a may carry an enzyme 3a that catalyzes the reduction reaction.
  • an inorganic catalyst such as platinum, a platinum alloy, gold, or copper, and those obtained by nano-particulate these inorganic catalysts supported on a carbon electrode obtained by solidifying activated carbon can be used.
  • Electrode Material a carbon fiber fabric (product number: TCC-3250, manufactured by Toho Tenax) for modifying carbon nanotubes was used as an electrode material.
  • glucose dehydrogenase glucose dehydrogenase (GDH), derived from Microorganism, EC number: 1.1.1.1.47, 250 U / mg, Mw: about 101,000, manufactured by Toyobo Co., Ltd.
  • Fructose dehydrogenase D-fructose dehydrogenase (FDH), derived from Gluconobacter, EC number: 1.1.99.11, 20 U / mg, Mw: about 140000, manufactured by Toyobo Co., Ltd.
  • FDH Fructose dehydrogenase
  • bilirubin oxidase (BOD, derived from Myrothecium, EC number: 1.3.3.5, Mw: about 68000, 2.39 U / mg, manufactured by Amano Enzyme) was used.
  • Carbon nanotubes (product number: C 70 P, manufactured by Bayer MaterialScience) (hereinafter also referred to as CNT) are heated to 400 ° C. over 11 hours using an oven, and then naturally cooled. The CNTs were heat treated. By this heat treatment, defects were generated in the CNT. Distilled water, nitric acid, and sulfuric acid were mixed in a beaker at a volume ratio of 1: 3: 1, and the mixed solution was allowed to cool for several tens of minutes. Then, CNT was added to this acidic mixed solution, and the surface of the CNT was oxidized by ultrasonic treatment for about 30 minutes using an ultrasonic bath.
  • CNT product number: C 70 P, manufactured by Bayer MaterialScience
  • A-3 Enzyme support and freeze-drying of enzyme support electrode A-3-1. Production of negative electrode (anode) A-3-1-1. Preparation of FDH-supported negative electrode A CNT suspension adjusted to 10 mg / mL was purified using a 0.5% Triton X-100 aqueous solution. In order to improve the dispersibility of CNTs, this CNT suspension was sonicated for 5 minutes using an ultrasonic homogenizer. 10 ⁇ L of the CNT suspension was dropped onto a 5 mm ⁇ 5 mm carbon fiber fabric and dried at 70 ° C. for about 5 minutes. This dropping and drying operation was repeated, and a total of 40 to 50 ⁇ L of the CNT suspension was added onto the carbon fiber fabric.
  • a carbon fiber fabric modified with CNTs was impregnated with 50 mM citrate buffer, and washed for 1 hour or more with stirring under reduced pressure. This electrode was immersed in an FDH solution adjusted to 5 mg / mL at 4 ° C. for 8 hours or more to fix the FDH to the electrode.
  • the FDH electrode was immersed in a 50 mM citrate buffer at room temperature for 5 minutes to remove unadsorbed FDH.
  • the FDH electrode was immersed in a 50 mM citrate buffer solution in which 1 M trehalose was dissolved.
  • the FDH electrode was snap frozen by immersing in liquid nitrogen. Finally, it was put into a freeze dryer (product number: ALPHA 2-4 LSC, manufactured by CHRiST (Kubota Corp.)) to prepare a dried FDH electrode.
  • A-3-1-2 Preparation of GDH-supported negative electrode A CNT suspension adjusted to 10 mg / mL was purified using a 0.5% Triton X-100 aqueous solution. In order to improve the dispersibility of CNTs, this CNT suspension was subjected to ultrasonic treatment for 10 minutes using an ultrasonic homogenizer. 12.5 ⁇ L of the CNT suspension was dropped on a 5 mm ⁇ 5 mm carbon fiber fabric and dried at 70 ° C. for about 10 minutes. This dropping and drying operation was repeated, and a total of 50 ⁇ L of the CNT suspension was added onto the carbon fiber fabric. Carbon fiber fabric modified with CNT was impregnated in distilled water and washed for about 1 hour with stirring.
  • This electrode was immersed in a Nile blue solution prepared to 100 ⁇ M in 100 mM phosphate buffer, and stirred at 4 ° C. for 1 hour or more under reduced pressure. Then, Nile blue was electropolymerized on the electrode by performing CV for 10 cycles in the voltage range of ⁇ 0.8 to 1.2 V at a potential sweep rate of 100 mVs ⁇ 1 . After the electropolymerization, the electrode was washed with distilled water for about 10 hours, and impregnated in a glucose dehydrogenase (GDH) solution adjusted to 1 mg / mL in a phosphate buffer solution at 4 ° C. with stirring for 3 hours or more. Was supported on the electrode.
  • GDH glucose dehydrogenase
  • the size of the negative electrode is 1.5 mm in width and 10 mm in length in the case of the type of patch 60 shown in FIGS. 1 and 2, and in the case of the patch 70 shown in FIGS.
  • the inner diameter was 8 mm and the outer diameter was 10 mm.
  • A-3-2 Preparation of positive electrode (cathode)
  • Pre-treated CNTs were added to 1.0% Triton X-100 aqueous solution and ethanol, and 10 mg / mL CNT suspension (water) and 4 mg / mL CNT suspension, respectively. (Ethanol) was prepared.
  • this CNT suspension was subjected to ultrasonic treatment for 10 minutes using an ultrasonic homogenizer. 12.5 ⁇ L of the CNT suspension (water) was dropped on a 5 mm ⁇ 5 mm carbon fiber fabric and dried at 70 ° C. for about 10 minutes.
  • C Production of conductive layer C-1. Production of conductive layer in case of wound healing patch (adhesive plaster type)
  • MES is 500 mM
  • fructose is 500 mM
  • low melting point agarose 317-01182, manufactured by Wako Pure Chemical Industries, Ltd.
  • the thickness of the gel was 0.5 mm.
  • the production of the conductive layer for the GDH-supporting negative electrode was the same except that glucose and ⁇ -NAD + were used instead of fructose.
  • Preparation of wound healing patch (adhesive plaster type) As shown in FIG. 1, a medical tape is placed with its adhesive surface facing up, and a positive electrode, a negative electrode, a conductive member, and a conductive layer are placed on the adhesive surface, and the adhesive bandage type A wound healing patch was prepared.
  • FIGS. 11 (a) and 11 (i) show photographs of a patch for wound healing (adhesive plaster type) of the type of patch 70 shown in FIGS. 3 and 4 produced in (Test 1) “D1.”
  • the photograph of a mode that the patch for wound healing shown to Fig.11 (a) (i) was affixed on the finger to a) (ii) is shown.
  • FIGS. 11B and 11I show photographs of a patch for wound healing (contact lens type) of the type of patch 80 shown in FIGS. 5 and 6 produced in (Test 1) “D2.”
  • FIG. (B) (ii) shows a picture of the wound healing patch shown in FIGS. 11 (b) and 11 (i) attached to a glass bulb.
  • (Test 2) Output Performance Measurement Test 2 was performed using a patch for wound healing (negative electrode: FDH-supported negative electrode) of the type of patch 60 shown in FIGS. 1 and 2 prepared in (Test 1) “E2.”.
  • the prepared patch for wound healing adheresive plaster type
  • FIG. 7A the vertical axis shows the patch current density ( ⁇ A / cm 2 ) (black circle) and the power density ( ⁇ W / cm 2 ) (black triangle), and the horizontal axis shows the cell voltage.
  • the open circuit voltage of the patch was 0.7V, and the maximum power density was 1000 ⁇ W / cm 2 . It has been found that when the conductive layer is 0.5 mm thick, a current of about 80 ⁇ A can flow between the positive electrode and the negative electrode. The magnitude of this current was strong enough to promote cell migration at the wound site.
  • Test 4 In Vitro Wound Healing Assay Test to confirm whether the model system of the wound healing patch of the present invention including the positive electrode and the negative electrode prepared in the above (Test 1) “A.” brings about the effect of wound healing. Went.
  • FIG. 8 (a) shows the in vitro wound healing assay system constructed in (Test 2), and
  • FIG. 8 (b) shows a method for evaluating the tendency of cell migration in the in vitro wound healing assay system shown in FIG. 8 (a). An explanatory diagram is shown.
  • the positive electrode side medium tank was impregnated with the positive electrode and the negative electrode side medium tank was impregnated with the negative electrode, and bioelectric power generation was performed.
  • the displacement in the x direction ( ⁇ x) and the displacement in the y direction ( ⁇ y) were calculated.
  • the average value (A ( ⁇ x)) of displacement ( ⁇ x) in the x direction in each cell was calculated, and the tendency of cell migration was evaluated.
  • a ( ⁇ x) the larger the absolute value
  • FIG. 9 (a) shows an in vitro wound healing assay system in which normal human corneal epithelial cells are not cultured
  • FIG. 9 (b) shows the current flowing through the channel when the channel cross-sectional area is 0.025 mm 2.
  • the chart showing the time-dependent change of the current density ( ⁇ A / cm 2 ) is shown.
  • the cross-sectional area of the channel (microchannel) by the cross section perpendicular to the extending direction is such that when the wound healing patch is applied to the wound site, the current flows in a very thin area between the wound site and the patch. It is necessary to define appropriately considering what happens. Therefore, as shown in FIG.
  • the current density: 300 ⁇ A / cm 2 is small compared to the current density when humans feel pain: 500 ⁇ A / cm 2, and the current density in the model system for wound healing patches is suitable for the treatment of wound sites by electricity. It was a thing. From this result, the cross-sectional area of the channel in the assay system was determined to be about 0.025 mm 2 .
  • an electrode suitable for an in vitro wound healing assay that does not affect cells was prepared as follows.
  • the positive electrode and the negative electrode prepared in the above (Test 1) “A. Production of electrode” were washed with sterilized 50 mM PBS (pH 7.0).
  • the cleaned positive electrode and negative electrode are impregnated with a 5 mM glucose aqueous solution, a 2 wt% agarose aqueous solution, and an aqueous solution containing 5 mM ⁇ -NAD + , and then the gel is cooled and solidified, whereby the cleaned positive electrode and negative electrode are agarose gel. Embedded in (not shown).
  • the open circuit voltage of this model system when using an electrode embedded in the prepared gel was 0.82V. This open circuit voltage was appropriate for the treatment of wound sites with electricity.
  • the in vitro wound healing assay was performed using normal human corneal epithelial cells.
  • 10 (a) (i) to (iii) show the results of the in vitro wound healing assay, and FIG. 10 (b) shows a summary of the results shown in FIG. 10 (a). From the results shown in FIGS.
  • the present invention it is possible to provide a wound healing patch that makes it possible to easily perform wound healing by electricity with high safety and low cost.
  • the wound healing patch of the present invention is particularly suitably used in the beauty / medical field.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Electrotherapy Devices (AREA)
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Abstract

L'invention concerne un timbre favorisant la cicatrisation, comprenant : une pluralité d'électrodes comprenant au moins une cathode ou une anode portant une enzyme qui catalyse une réaction d'oxydo-réduction ; et un élément conducteur pour connecter électriquement la pluralité d'électrodes.
PCT/JP2015/078126 2014-09-26 2015-09-25 Timbre favorisant la cicatrisation Ceased WO2016047811A1 (fr)

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GB2568498A (en) * 2017-11-17 2019-05-22 Sumitomo Chemical Co Materials reducing formation of hypochlorite
CN114945403A (zh) * 2020-01-21 2022-08-26 株式会社离子用具 生物电池治疗器具

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KR102081794B1 (ko) * 2017-11-07 2020-02-26 재단법인 대구경북과학기술원 상처 치유 가속화 장치
JP7272576B2 (ja) * 2018-07-04 2023-05-12 株式会社アドイン研究所 電気施術装置及び電気施術システム
US12239527B2 (en) 2019-03-04 2025-03-04 Tohoku University Method of absorbing or discharging water of ophthalmic medical device and ophthalmic medical device
JP2025096725A (ja) 2022-05-30 2025-06-30 キッコーマン株式会社 経皮通電パッチ

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CN114945403A (zh) * 2020-01-21 2022-08-26 株式会社离子用具 生物电池治疗器具

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