WO2022203384A1 - Method for providing information for determining appropriate amount of magnetic cell injection - Google Patents

Method for providing information for determining appropriate amount of magnetic cell injection Download PDF

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Publication number
WO2022203384A1
WO2022203384A1 PCT/KR2022/004052 KR2022004052W WO2022203384A1 WO 2022203384 A1 WO2022203384 A1 WO 2022203384A1 KR 2022004052 W KR2022004052 W KR 2022004052W WO 2022203384 A1 WO2022203384 A1 WO 2022203384A1
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Prior art keywords
magnetic
present
cells
magnetic material
cell
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PCT/KR2022/004052
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French (fr)
Korean (ko)
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최윤정
정휘동
조형주
이준상
김영우
이형준
장석원
남재성
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연세대학교 산학협력단
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Priority claimed from KR1020210040095A external-priority patent/KR20220134874A/en
Application filed by 연세대학교 산학협력단 filed Critical 연세대학교 산학협력단
Publication of WO2022203384A1 publication Critical patent/WO2022203384A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/33—Fibroblasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/34—Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/36—Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/02—Measuring direction or magnitude of magnetic fields or magnetic flux
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/40—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H70/00—ICT specially adapted for the handling or processing of medical references
    • G16H70/60—ICT specially adapted for the handling or processing of medical references relating to pathologies
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
    • H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
    • H01F1/01—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials

Definitions

  • the present invention relates to an information providing method for determining an appropriate injection amount of magnetic cells applicable to human organs or tissues to treat various diseases.
  • a nanoparticle is a particle with at least one dimension of 100 nm, that is, less than ten millionths of a meter.
  • Research on nanoparticles has been very active since the 1990s, and research on manufacturing and dispersing nanoparticles with a uniform size has been conducted, and in the 2000s, the physical, Research has been conducted to control the physical properties of nanoparticles, such as using a phenomenon in which chemical properties change.
  • research on the manufacture of nanoparticles having various functions beyond the control of the physical properties of nanoparticles is being conducted.
  • bio-medical fields such as MRI contrast agents, drug delivery, cell separation, and thermal therapy. Since it has the advantage of being able to control the position by a magnetic field, it is being applied in various fields.
  • the present inventors have developed a technique for applying magnetic nanoparticles to cells or cell aggregates and using them for the treatment or improvement of various diseases, particularly cleft lip and cleft lip or sleep apnea.
  • One object of the present invention is to provide an information providing method for determining an appropriate injection amount of magnetic cells to be injected into the body to treat various diseases.
  • Another object of the present invention is to provide a composition for improving or treating various diseases including magnetic cells or magnetic cell aggregates.
  • Another object of the present invention is to provide a method for preparing a composition for improving or treating various diseases described above.
  • Another object of the present invention is to provide an apparatus for controlling the shape of various tissues or organs including magnetic cells.
  • Another object of the present invention is to provide an apparatus for establishing a plan for controlling the shape of various tissues or organs including a simulation unit for predicting the situation after the injection of magnetic cells.
  • Another object of the present invention is to provide a variety of disease animal models injected with magnetic cells.
  • Another object of the present invention is to provide a method for screening a drug or device for the treatment of various diseases using the above-described animal model.
  • Another object of the present invention is to provide a method for simulating shape deformation of a tissue or organ using the above-described animal model.
  • the present invention relates to a magnetic cell or a magnetic cell aggregate for the treatment or improvement of cleft lip and cleft lip.
  • the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
  • the type of the cell is not particularly limited and is a cell located in the lips or oral cavity, preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), etc.,
  • it may be an epithelial cell, an osteoblast, a fibroblast, or a myocyte, but is not limited thereto.
  • the cell aggregate may be a cyclic cell aggregate formed of a plurality of the magnetic cells, but is not limited thereto.
  • the "magnetic material” refers to a material having magnetic properties, and is largely divided into paramagnetic, superparamagnetic, diamagnetic, and ferromagnetic according to magnetic properties.
  • a paramagnetic material is a material that is weakly magnetized in the magnetic field direction when placed in a magnetic field and is not magnetized when the magnetic field is removed, and examples thereof include aluminum, tin, platinum, iridium, and the like.
  • a diamagnetic material is a material that is magnetized in the opposite direction by an external magnetic field, and examples thereof include metals such as hydrogen, water, lead, copper, zinc, etc. and salts.
  • a ferromagnetic material refers to a material having magnetic properties of a material that is magnetized even in the absence of an external magnetic field, and includes iron, nickel, and cobalt.
  • a superparamagnetic material is a material in which ferromagnetic particles in the structure of a non-ferromagnetic material exist in an isolated form. Superparamagnetic material exhibits ferromagnetism even when a low magnetic field is applied, and the magnetization is saturated, but the magnetization disappears when the magnetic field application is stopped. When the particle size of the magnetic material is made into a nano size, superparamagnetism appears at room temperature.
  • many studies are being conducted in medicine, pharmacy, bio, and chemistry using this characteristic.
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a superparamagnetic or paramagnetic material is applied later as necessary by applying an appropriate magnetic force to produce a desired effect and induce discharge out of the body have.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
  • maghemite ⁇ -Fe 2 O 3
  • magnetite Fe. 3 O 4
  • cobalt ferrite CoFe 2 O 4
  • manganese ferrite MnFe 2 O 4
  • FePt alloy iron platinum alloy
  • FeCo alloy iron cobalt alloy
  • CoNi alloy cobalt nickel alloy
  • CoPt alloy cobalt platinum
  • the average diameter of the magnetic material may be 1 nm to 1 ⁇ m, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
  • the magnetic material may be iron oxide, ferrite, or an alloy, and specific examples thereof include maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ), Manganese ferrite (MnFe 2 O 4 ), iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), which can be a permanent magnet If it is a substance, it is not limited thereto.
  • the magnetic material may have an average particle diameter of 1 to 1000 nm, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a low molecular weight material such as citric acid or oleic acid
  • a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives
  • polyethylene glycol to improve dispersibility.
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • polyethyleneimine polyethyleneimine
  • polymethacrylate polymethacrylate
  • synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci .), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins, and protein A is Staphylococcus aureus ( Staphylococcus aureus ) As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
  • the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
  • the "antibody” refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction.
  • an antibody refers to an antibody that specifically binds to a particular cell for the treatment of the subject of interest.
  • the antibody may include all of a polyclonal antibody, a monoclonal antibody, and a recombinant antibody.
  • the antibody can be easily prepared using techniques well known in the art.
  • the polyclonal antibody can be produced by a method well known in the art, including the process of injecting an antigen of the protein into an animal and collecting blood from the animal to obtain a serum containing the antibody.
  • Such polyclonal antibodies can be prepared from any animal such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like.
  • monoclonal antibodies can be prepared using the hybridoma method well known in the art (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), or the phage antibody library technology (Clackson et al, Nature, 352). :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991).
  • the antibody prepared by the above method may be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography.
  • the antibodies of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains.
  • a functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
  • the antigen present on the surface of the cell may be at least one protein selected from the group consisting of HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is limited thereto. It is not, and may be included without limitation as long as it is an antigen that is specifically present in cells constituting the lips or oral tissue.
  • the magnetic cells or the magnetic cell cluster is the lip or oral tissue of the subject, preferably the lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate). ), and then applying magnetic force, it is possible to improve or treat cleft lip and cleft lip through suturing, reconstruction or restoration of the cracked deformed area.
  • a non-limiting example may be a liquid injection form or a liquid injection form after absorbing the liquid into a flexible foam and then injecting the foam, liquid injection form
  • the residence time may appear relatively short when injected into can do. 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
  • the suspension when the magnetic cells or magnetic cell aggregates are injected, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to maintain the diffusion rate of the injection solution including the magnetic cells and the maintenance of the injected magnetic cells It is preferable because time control is possible and magnetic force control is possible by adjusting the amount of magnetic cells mixed in the suspension.
  • the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
  • the magnetic force when the magnetic force is applied, it is possible to control the direction control of the magnetic force of the magnetic cells, for example, by applying a specific magnetic field to the magnetic cells containing the paramagnetic material in which the direction of the magnetic force is not determined to have a magnetic force in a desired direction. It can be transformed into a cell in a ferromagnetic state.
  • 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention.
  • the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
  • the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included.
  • a magnet such as an electromagnet or a permanent magnet by electromagnetic induction
  • one or more magnets may be included.
  • FIG. 1 is a schematic diagram showing the principle of controlling the shape of the tissue of a magnetic cell according to the present invention, in which (a) is suture of two cracked parts due to magnetic attraction, (b) is a schematic diagram showing the expansion of the two parts split according to magnetic repulsive force to be.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of contraction or relaxation of the desired muscle or tissue, and is not particularly limited.
  • the term "Cleft palate” is one of the congenital malformations that occur on the face, and it is precisely divided into a cleft lip and cleft palate. It is also called cleft palate. It is a fissure of the lips or palate that occurs between the 4th and 7th weeks of pregnancy when the face is made, when the tissues making the lips (labial) and the roof of the mouth (palatal) do not adhere properly or are not maintained even though they are attached. It causes not only the skin or palate mucosa but also a general deformation of muscles, cartilage, and bones. have. Currently, there is no other alternative to the treatment of cleft lip and cleft lip, except surgical method. There is a problem with the treatment, and there is a limit to the treatment in terms of aesthetics as scars are left during the operation.
  • the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
  • it relates to a method for producing a magnetic cell or a magnetic cell aggregate for the treatment or improvement of cleft palate.
  • the manufacturing method of the present invention may include preparing a magnetic material.
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
  • maghemite ⁇ -Fe 2 O 3
  • magnetite Fe. 3 O 4
  • cobalt ferrite CoFe 2 O 4
  • manganese ferrite MnFe 2 O 4
  • FePt alloy iron platinum alloy
  • FeCo alloy iron cobalt alloy
  • CoNi alloy cobalt nickel alloy
  • CoPt alloy cobalt platinum
  • the average diameter of the magnetic material may be 1 nm to 1 ⁇ m, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a low molecular weight material such as citric acid or oleic acid
  • a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives
  • polyethylene glycol to improve dispersibility.
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • polyethyleneimine polyethyleneimine
  • polymethacrylate polymethacrylate
  • synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci.
  • the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the preparation method of the present invention may include coating the antibody on the prepared magnetic material.
  • the magnetic material may further include an antibody capable of recognizing and binding to an antibody present in a target cell.
  • the antigen may be at least one protein selected from the group consisting of HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto. Any antigen that is specifically present in cells constituting oral tissues may be included without limitation.
  • the preparation method of the present invention may include preparing cells into which the antibody-coated magnetic material will be introduced.
  • the type of the cell is not particularly limited, and it is a cell located in the lips or oral tissue, preferably the lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate).
  • epithelial cells epithelial cells
  • bone cells osteoblast
  • myocyte myocyte
  • the step of preparing the cells in the step of preparing the cells, the step of dedifferentiating the cells collected from the biological sample of the subject of interest into induced pluripotent stem cells; and differentiating the induced pluripotent stem cells into cells constituting the lips or oral tissue.
  • the subject subject is an individual with cleft lip and cleft palate, and may be an individual with at least one of cleft lip and cleft palate, and as non-limiting examples, incomplete cleft lip, unilateral complete cleft lip or bilateral complete cleft lip, incomplete cleft lip, unilateral complete cleft lip. It may be an individual who has developed cleft palate, bilateral complete cleft palate, unilateral complete cleft palate, or bilateral complete cleft palate.
  • the subject is preferably human, rat, mouse, guinea pig, hamster, rabbit, monkey, dog, cat, cow, horse, pig, sheep and goat may be selected from the group consisting of, more preferably human However, the present invention is not limited thereto.
  • the biological sample refers to any material, biological fluid, tissue or cell obtained from or derived from an individual, and includes whole blood, leukocytes, and peripheral blood mononuclear cells. ), buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate, respiration (breath), urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid , glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate (joint aspirate), organ secretions (organ secretions), cells (cell), cell extract (cell extract), and may be at least one selected from the group consisting of cerebrospinal fluid (cerebrospinal fluid), but is not limited thereto.
  • the manufacturing method of the present invention may include treating the cells prepared as described above with a magnetic material.
  • the present invention can be carried out while fixing a part of the cells to be exposed on the mold during the treatment step.
  • the mold may be a conventional mold made of a silicon material, but is not limited thereto.
  • the treatment may be performed by treating the magnetic material on the surface of the cell while a magnetic force is applied to the mold.
  • the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included.
  • a magnet such as an electromagnet or a permanent magnet by electromagnetic induction
  • one or more magnets may be included.
  • the magnetic force suffices as long as the strength is sufficient for the arrangement of magnetic materials, and may be 5 to 10 Gauss as a non-limiting example, but is not limited thereto.
  • the magnetic material is attached to the outer surface of the cell through an immunolabeling method or direct introduction method using an antigen-antibody reaction between the antibody present in the magnetic material and the antigen present on the surface of the cell.
  • a magnetic cell or a magnetic cell population may be prepared.
  • the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
  • it relates to a magnetic cell or a magnetic cell aggregate for the prevention, improvement or treatment of sleep apnea.
  • the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
  • the type of the cell is not particularly limited, and the cell of the respiratory system flow tract, preferably the nasal, pharyngeal or airway lining, may be, for example, fibroblast or myocyte, but is limited thereto. it is not
  • the cell aggregate may be a cyclic cell aggregate formed of a plurality of the magnetic cells, but is not limited thereto.
  • the "magnetic material” refers to a material having magnetic properties, and is largely divided into paramagnetic, superparamagnetic, diamagnetic, and ferromagnetic according to magnetic properties.
  • a paramagnetic material is a material that is weakly magnetized in the magnetic field direction when placed in a magnetic field and is not magnetized when the magnetic field is removed, and examples thereof include aluminum, tin, platinum, iridium, and the like.
  • a diamagnetic material is a material that is magnetized in the opposite direction by an external magnetic field, and examples thereof include metals such as hydrogen, water, lead, copper, zinc, etc. and salts.
  • a ferromagnetic material refers to a material having magnetic properties of a material that is magnetized even in the absence of an external magnetic field, and includes iron, nickel, and cobalt.
  • a superparamagnetic material is a material in which ferromagnetic particles in the structure of a non-ferromagnetic material exist in an isolated form. Superparamagnetic material exhibits ferromagnetism even when a low magnetic field is applied, and the magnetization is saturated, but the magnetization disappears when the magnetic field application is stopped. When the particle size of the magnetic material is made into a nano size, superparamagnetism appears at room temperature.
  • many studies are being conducted in medicine, pharmacy, bio, and chemistry using this characteristic.
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a superparamagnetic or paramagnetic material is applied later as necessary by applying an appropriate magnetic force to produce a desired effect and induce discharge out of the body have.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
  • maghemite ⁇ -Fe 2 O 3
  • magnetite Fe. 3 O 4
  • cobalt ferrite CoFe 2 O 4
  • manganese ferrite MnFe 2 O 4
  • FePt alloy iron platinum alloy
  • FeCo alloy iron cobalt alloy
  • CoNi alloy cobalt nickel alloy
  • CoPt alloy cobalt platinum
  • the average diameter of the magnetic material may be 1 nm to 1 ⁇ m, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a low molecular weight material such as citric acid or oleic acid
  • a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives
  • polyethylene glycol to improve dispersibility.
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • polyethyleneimine polyethyleneimine
  • polymethacrylate polymethacrylate
  • synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G Streptococcus bacteria (Streptococci.), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins.
  • Protein A is Staphylococcus aureus. As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
  • the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
  • the "antibody” refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction.
  • an antibody refers to an antibody that specifically binds to a particular cell for the treatment of the subject of interest.
  • the antibody may include all of a polyclonal antibody, a monoclonal antibody, and a recombinant antibody.
  • the antibody can be easily prepared using techniques well known in the art.
  • the polyclonal antibody can be produced by a method well known in the art, including the process of injecting an antigen of the protein into an animal and collecting blood from the animal to obtain a serum containing the antibody.
  • Such polyclonal antibodies can be prepared from any animal such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like.
  • monoclonal antibodies can be prepared using the hybridoma method well known in the art (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), or the phage antibody library technology (Clackson et al, Nature, 352). :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991).
  • the antibody prepared by the above method may be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography.
  • the antibodies of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains.
  • a functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
  • the antigen present on the surface of the cell may be at least one protein selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto, and respiratory organs , Preferably, as long as it is an antigen that is specifically present in cells constituting the airways, it may be included without limitation.
  • the term "sleep apnea syndrome” refers to a disease in which when the soft palate and pharyngeal wall relax or sag, the tissue loosened during respiration vibrates along the air flow to generate snoring and block the airway to stop breathing. .
  • the disease may cause health problems, such as the symptoms of not being able to breathe properly during sleep, causing serious disturbances in sleep, so that fatigue is not fully resolved even after a long sleep, and seriously, it puts a considerable strain on the heart.
  • obstructive sleep apnea caused by obstruction of the upper airway
  • central sleep apnea caused by a neurological disorder
  • mixed sleep apnea that starts in the central type but gradually changes to the obstructive type.
  • surgical methods or breathing aids are used as a method to treat sleep apnea, but the surgical method is an anatomically abnormal area that reduces tissue by excising the nose, around the throat, and at the root of the tongue, then suturing or applying heat.
  • an invasive method and an auxiliary medical device used for symptom relief is also temporary, and there is a high risk of complications such as pneumonia, nasal dryness, and muscle pain caused by contamination caused by constant wearing.
  • the sleep apnea may be obstructive sleep apnea, central sleep apnea, or mixed sleep apnea, preferably obstructive sleep apnea, but a disease caused by difficulty breathing caused by stenosis or obstruction of airway ducts It can include, but is not limited to, sleep apnea that occurs during sleep, as long as it is applicable.
  • sleep apnea is prevented by inducing relaxation of the respiratory system flow tube by applying magnetic force after injecting the magnetic cells or magnetic cell cluster into the respiratory system flow tube, preferably the nasal cavity, larynx, or airway of the target individual, can be improved or treated.
  • the liquid injection form or the liquid may be absorbed into the flexible foam and then the foam may be injected.
  • the residence time may appear relatively short, but when injected in the form of a foam, it may remain in the living body for a long time, so it can be appropriately selected according to the desired residence time.
  • can 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
  • the suspension when the magnetic cells or magnetic cell aggregates are injected, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to maintain the diffusion rate of the injection solution including the magnetic cells and the maintenance of the injected magnetic cells It is preferable because time control is possible and magnetic force control is possible by adjusting the amount of magnetic cells mixed in the suspension.
  • the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
  • the magnetic force when the magnetic force is applied, it is possible to control the direction control of the magnetic force of the magnetic cells, for example, by applying a specific magnetic field to the magnetic cells containing the paramagnetic material in which the direction of the magnetic force is not determined to have a magnetic force in a desired direction. It can be transformed into a cell in a ferromagnetic state.
  • 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention.
  • the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
  • the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included.
  • a magnet such as an electromagnet or a permanent magnet by electromagnetic induction
  • one or more magnets may be included.
  • relaxation of the respiratory tract can be induced by using a repulsive or attractive force between the magnetic particles and the magnet, and as a specific example, the respiratory tract can be induced, preferably the nasal cavity, larynx or airway. , in particular, the relaxation of the airway may be induced by the attraction between the magnetic material in the magnetic cell located in the airway and the external magnet.
  • 1 shows the shape control principle of the respiratory system flow tube of magnetic cells according to the present invention.
  • (a) is a contraction of the respiratory system flow tube according to magnetic attraction
  • (b) is an expansion of the respiratory system flow tube according to a magnetic repulsive force. It is a schematic diagram shown.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of relaxation of the desired tube and airway, and is not particularly limited.
  • it relates to a method for producing a magnetic cell or a magnetic cell aggregate for the prevention, improvement or treatment of sleep apnea.
  • the manufacturing method of the present invention may include preparing a magnetic material.
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
  • maghemite ⁇ -Fe 2 O 3
  • magnetite Fe. 3 O 4
  • cobalt ferrite CoFe 2 O 4
  • manganese ferrite MnFe 2 O 4
  • FePt alloy iron platinum alloy
  • FeCo alloy iron cobalt alloy
  • CoNi alloy cobalt nickel alloy
  • CoPt alloy cobalt platinum
  • the average diameter of the magnetic material may be 1 nm to 1 ⁇ m, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a low molecular weight material such as citric acid or oleic acid
  • a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives
  • polyethylene glycol to improve dispersibility.
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • polyethyleneimine polyethyleneimine
  • polymethacrylate polymethacrylate
  • synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G Streptococcus bacteria (Streptococci.), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins.
  • Protein A is Staphylococcus aureus. As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
  • the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the preparation method of the present invention may include coating the antibody on the prepared magnetic material.
  • the magnetic material may further include an antibody capable of recognizing and binding to an antibody present in a target cell.
  • the antigen may be at least one protein selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto. Any antigen that is specifically present in cells constituting the cell may be included without limitation.
  • the preparation method of the present invention may include preparing cells into which the antibody-coated magnetic material will be introduced.
  • the type of the cell is not particularly limited, and the cell of the respiratory system flow tract, preferably the nasal, pharyngeal or airway lining, may be, for example, fibroblast or myocyte, but is limited thereto. it is not
  • the step of preparing the cells in the step of preparing the cells, the step of dedifferentiating the cells collected from the biological sample of the subject of interest into induced pluripotent stem cells; and differentiating the induced pluripotent stem cells into ductal lining cells of the respiratory tract.
  • the subject of interest may be an individual who has or is highly likely to develop sleep apnea syndrome.
  • the biological sample refers to any material, biological fluid, tissue or cell obtained from or derived from an individual, and includes whole blood, leukocytes, and peripheral blood mononuclear cells. ), buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate, respiration (breath), urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid , glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate (joint aspirate), organ secretions (organ secretions), cells (cell), cell extract (cell extract), and may be at least one selected from the group consisting of cerebrospinal fluid (cerebrospinal fluid), but is not limited thereto.
  • the manufacturing method of the present invention may include treating the cells prepared as described above with a magnetic material.
  • the present invention can be carried out while fixing a part of the cells to be exposed on the mold during the treatment step.
  • the mold may be a conventional mold made of a silicon material, but is not limited thereto.
  • the treatment may be performed by treating the magnetic material on the surface of the cell while a magnetic force is applied to the mold.
  • the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included.
  • a magnet such as an electromagnet or a permanent magnet by electromagnetic induction
  • one or more magnets may be included.
  • the magnetic force suffices as long as the strength is sufficient for the arrangement of magnetic materials, and may be 5 to 10 Gauss as a non-limiting example, but is not limited thereto.
  • the magnetic material is attached to the outer surface of the cell through an immunolabeling method or direct introduction method using an antigen-antibody reaction between the antibody present in the magnetic material and the antigen present on the surface of the cell.
  • a magnetic cell or a magnetic cell population may be prepared.
  • the sleep apnea may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
  • it relates to a method for providing information for determining an appropriate injection amount of magnetic cells into a body tissue or organ.
  • the method may be for determining an appropriate injection amount of magnetic cells to be injected into a body tissue or organ for the improvement or treatment of cleft lip and cleft lip among various diseases.
  • the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
  • the type of the cell is not particularly limited and is a cell located in the lips or oral cavity, preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), etc.,
  • it may be an epithelial cell, an osteoblast, a fibroblast, or a myocyte, but is not limited thereto.
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
  • maghemite ⁇ -Fe 2 O 3
  • magnetite Fe. 3 O 4
  • cobalt ferrite CoFe 2 O 4
  • manganese ferrite MnFe 2 O 4
  • FePt alloy iron platinum alloy
  • FeCo alloy iron cobalt alloy
  • CoNi alloy cobalt nickel alloy
  • CoPt alloy cobalt platinum
  • the average diameter of the magnetic material may be 1 nm to 1 ⁇ m, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a low molecular weight material such as citric acid or oleic acid
  • a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives
  • polyethylene glycol to improve dispersibility.
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • polyethyleneimine polyethyleneimine
  • polymethacrylate polymethacrylate
  • a synthetic polymer material such as polyvinyl alcohol (polyvinyl alcohol) or a natural polymer material such as polysaccharide (polysaccharide) doping It may be a biocompatible material, preferably doped with a biocompatible natural polymer material for in vivo use, but is not limited thereto if it corresponds to a material having biocompatibility.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci.
  • the magnetic material may be included in the cell itself, but may be included in the cell in a dispersed form in an aqueous solution. It is more preferable in terms of convenience of experimentation as well as reducing the aggregation of the magnetic material to be included in the cell in a dispersed form in an aqueous solution.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
  • the magnetic cells are injected into the lips or oral tissue of the subject, preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), etc.
  • a magnetic force By applying a magnetic force, it is possible to improve or treat cleft lip or cleft lip through suturing, reconstruction or restoration of a cracked deformed area in the lips or oral tissue, thereby replacing the implantation of bone or skin tissue or minimizing the surgical site.
  • 1 is a schematic diagram showing the principle of controlling the shape of the tissue of a magnetic cell according to the present invention, in which (a) is suture of two cracked parts due to magnetic attraction, (b) is a schematic diagram showing the expansion of the two parts split according to magnetic repulsive force to be.
  • the method of the present invention can be used to determine the optimal injection amount of magnetic cells to be injected into a target tissue or organ of a target subject for the improvement or treatment of various diseases, particularly cleft lip and cleft lip, as described above.
  • the method of the present invention may include first measuring a Young's Modulus of a target tissue or organ of a target subject.
  • the subject of interest may be an individual who has or has a high probability of developing cleft lip and cleft palate.
  • the "labial cleft palate” may be at least one of cleft lip and cleft palate, and non-limiting examples include incomplete cleft lip, unilateral complete cleft lip or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft lip, unilateral complete cleft lip. It may be cleft palate, or bilateral complete cleft palate, but is not limited thereto.
  • the "tissue” refers to a mass of cells of the same type that exist in an organ in biology, and may be, for example, epithelial tissue, connective tissue, muscle tissue or nerve tissue, and for the purpose of the present invention, epithelium It may be tissue or muscle tissue, but is not limited thereto.
  • the "organ” is a unit constituting the body of a multicellular organism, and refers to a structure in which various tissues are gathered to form an integrated structure and perform a specific function.
  • organs in the human body include stomach, liver, lungs, heart, lymph nodes, teeth, lips, gums, uvula, hard palate, soft palate, eyeballs, thyroid gland, ovaries, skin or brain, and for the purposes of the present invention, It may be lips, gums, uvula, hard palate, soft palate, or skin, but is not limited thereto.
  • the term "Young's Modulus” refers to a concept used to measure the elasticity of a tissue in kPa unit by individualizing the characteristics and elasticity of the tissue as a mechanical variable.
  • a method of measuring the Young's modulus of a muscle has been known in the prior art (Ann Biomed Eng. 2014 Nov;42(11):2369-78.).
  • the unit of the Young's modulus may be modified and used by standardized unit conversion.
  • the Young's modulus may be measured using a elasticity measuring device, for example, a curometer (Cutometer, Courage Khazaka electronic GmbH) or DermaLab (DermaLab, Cortex technology), etc. may be used, but this It is not limited, and any Young's modulus measuring device used in the art may be used without limitation.
  • a curometer Cutometer, Courage Khazaka electronic GmbH
  • DermaLab DermaLab, Cortex technology
  • 7 shows an example of a device that can be used to measure the Young's modulus of a body tissue according to the present invention.
  • the method of the present invention may include determining an appropriate injection amount of the magnetic material by Equation 1 below using the measured Young's modulus:
  • Dosing amount of magnetic material ⁇ Young's modulus (N/m 2 ) X Desired strain ⁇ /Magnetic force between magnetic materials (N/m 2 )
  • “desired strain rate” refers to a desired degree of contraction, relaxation or deformation in a tissue or organ following injection of magnetic cells in the target tissue or organ, and more specifically, The ratio of the length after the desired change to the length of a specific site in the tissue or organ for which a morphological change (contraction, relaxation, or deformation) is desired in the subject of can
  • magnetic force between magnetic materials may be the square of the magnetic flux density per magnetic material (N/m 2 ), preferably calculated by the following Equation 2:
  • the "magnetic flux” may be calculated by the product of the magnetic force (AM 2 /kg) and the density (g/cm 3 ) of the magnetic material, and the unit is A/m or Gauss ( It may be expressed as G), and preferably, it may be a value converted to have a unit of Gaussian (G) after calculation in units of A/m.
  • the unit of the (magnetic flux) 2 may be expressed as G 2 or N/m 2 , and preferably, it may be a value converted to have a unit of N/m 2 after being calculated in the unit of G 2 .
  • the method of the present invention may include determining an appropriate injection amount of magnetic cells by Equation 3 below using the calculated amount of magnetic material injected:
  • Injection amount of magnetic cells (injection amount of magnetic material)/(number of injections of magnetic material in cells)
  • the number of injections of the magnetic material into the cell is the desired number of injections of the magnetic material into the cell, and may be an average or median value of the number of injections of the magnetic material per cell, but is not limited thereto. .
  • the magnetic cells whose injection amount is determined as described above may be injected into a target tissue or organ of a target individual for the improvement or treatment of various diseases, particularly cleft lip and cleft palate.
  • the form in which the magnetic cells are injected into the tissue or organ of an individual as described above is not particularly limited, but may be in the form of a liquid injection or a soft foam in which the liquid is absorbed as a non-limiting example.
  • the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time.
  • method can be injected.
  • 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
  • the magnetic cells when the magnetic cells are injected into the tissue or organ of an individual as described above, mixing and injecting the magnetic cells of the injection amount determined as described above in the suspension is to control the viscosity of the suspension to spread the injection solution including the magnetic cells. It is preferable that the speed and the holding time of the injected magnetic cells can be controlled, and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension.
  • the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
  • the present invention by applying a magnetic force to the magnetic cells, it is possible to control the direction control of the magnetic force of the magnetic cells. For example, by applying a specific magnetic field to a magnetic cell including a paramagnetic material in which the direction of the magnetic force is not determined, it can be converted into a cell in a ferromagnetic state having a magnetic force in a desired direction.
  • 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention.
  • the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
  • the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included.
  • a magnet such as an electromagnet or a permanent magnet by electromagnetic induction
  • one or more magnets may be included.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of contraction or relaxation of the desired muscle or tissue, and is not particularly limited.
  • an appropriate injection amount of the magnetic cells may achieve a desired strain rate by treating the surface of the cells with a magnetic material while applying a magnetic force as described above.
  • the strain may be a desired strain in the tissue of an object to be improved or deformed, and its unit is calculated as a percentage (%) of a change in lenth divided by original length compared to an existing length. it may be
  • the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
  • it relates to a method for providing information for determining an appropriate injection amount of magnetic cells into a body tissue or organ.
  • the method may be for determining an appropriate injection amount of magnetic cells to be injected into a body tissue or organ for the improvement or treatment of sleep apnea, among various diseases.
  • the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
  • the type of the cell is not particularly limited, and the cell of the respiratory system flow tract, preferably the nasal, pharyngeal or airway lining, may be, for example, fibroblast or myocyte, but is limited thereto. it is not
  • the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
  • the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto.
  • the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
  • the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite ( ⁇ -Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
  • maghemite ⁇ -Fe 2 O 3
  • magnetite Fe. 3 O 4
  • cobalt ferrite CoFe 2 O 4
  • manganese ferrite MnFe 2 O 4
  • FePt alloy iron platinum alloy
  • FeCo alloy iron cobalt alloy
  • CoNi alloy cobalt nickel alloy
  • CoPt alloy cobalt platinum
  • the average diameter of the magnetic material may be 1 nm to 1 ⁇ m, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
  • the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
  • the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility.
  • a synthetic polymer such as polyvinyl pyrrolidone, polyethyleneimine, polymethacrylate or polyvinyl alcohol, or a natural polymer such as polysaccharide is doped
  • It may be a biocompatible material, preferably doped with a biocompatible natural polymer material for in vivo use, but is not limited thereto if it corresponds to a material having biocompatibility.
  • the magnetic material may have a coating layer formed on the surface.
  • the coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound.
  • Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci.
  • the magnetic material may be included in the cell itself, but may be included in the cell in a dispersed form in an aqueous solution. It is more preferable in terms of convenience of experimentation as well as reducing the aggregation of the magnetic material to be included in the cell in a dispersed form in an aqueous solution.
  • the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used.
  • One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
  • the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
  • the antigen present on the surface of the cell may be at least one protein selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto, and respiratory organs , Preferably, as long as it is an antigen that is specifically present in cells constituting the airways, it may be included without limitation.
  • the magnetic cells are injected into the respiratory tract of the subject, preferably into the lining cells of the nasal cavity, larynx or airway, for example, fibroblasts or myocytes, etc., and then magnetic force is applied.
  • the respiratory system flow tube such as the airway muscle and relaxing the respiratory system flow tube, thereby minimizing stenosis or obstruction of the airway tube.
  • FIG. 1 is a schematic diagram showing the principle of controlling the shape of the tissue of a magnetic cell according to the present invention, in which (a) is suture of two cracked parts due to magnetic attraction, (b) is a schematic diagram showing the expansion of the two parts split according to magnetic repulsive force to be.
  • the method of the present invention can be used to determine the optimal injection amount of magnetic cells to be injected into a target tissue or organ of a target individual for the improvement or treatment of various diseases, particularly sleep apnea, as described above.
  • the method of the present invention may include first measuring a Young's Modulus of a target tissue or organ of a target subject.
  • the target subject may be an individual who has or has a high probability of developing sleep apnea.
  • the "sleep apnea” may be at least one of obstructive sleep apnea, central sleep apnea, and mixed sleep apnea, but is not limited thereto.
  • the "tissue” refers to a mass of cells of the same type that exist in an organ in biology, and may be, for example, epithelial tissue, connective tissue, muscle tissue or nerve tissue, and for the purpose of the present invention, epithelium It may be tissue or muscle tissue, but is not limited thereto.
  • the "organ” is a unit constituting the body of a multicellular organism, and refers to a structure in which various tissues are gathered to form an integrated structure and perform a specific function.
  • organs in the human body include respiratory organs, stomach, liver, lungs, heart, lymph nodes, teeth, lips, gums, uvula, hard palate, soft palate, eyeballs, thyroid gland, ovaries, skin or brain, and the like, It may be, but is not limited to, a respiratory organ for purposes.
  • the term "Young's Modulus” refers to a concept used to measure tissue elasticity in kPa units by individualizing tissue characteristics and elasticity as mechanical variables, and the internal tissues of the human body, such as cheeks, cheekbones, forehead, and lower lip muscles
  • a method of measuring the Young's modulus of the back has been known in the prior art (Ann Biomed Eng. 2014 Nov;42(11):2369-78.).
  • the unit of the Young's modulus may be modified and used by standardized unit conversion.
  • the Young's modulus may be measured using a elasticity measuring device, for example, a curometer (Cutometer, Courage Khazaka electronic GmbH) or DermaLab (DermaLab, Cortex technology), etc. may be used, but this It is not limited, and any Young's modulus measuring device used in the art may be used without limitation.
  • a curometer Cutometer, Courage Khazaka electronic GmbH
  • DermaLab DermaLab, Cortex technology
  • 7 shows an example of a device that can be used to measure the Young's modulus of a body tissue according to the present invention.
  • the method of the present invention may include determining an appropriate injection amount of the magnetic material by Equation 1 below using the measured Young's modulus:
  • Dosing amount of magnetic material ⁇ Young's modulus (N/m 2 ) X Desired strain ⁇ /Magnetic force between magnetic materials (N/m 2 )
  • “desired strain rate” refers to a desired degree of contraction, relaxation or deformation in a tissue or organ following injection of magnetic cells in the target tissue or organ, and more specifically, The ratio of the length after the desired change to the length of a specific site in the tissue or organ for which a morphological change (contraction, relaxation, or deformation) is desired in the subject of can
  • magnetic force between magnetic materials may be the square of the magnetic flux density per magnetic material (N/m 2 ), preferably calculated by the following Equation 2:
  • the "magnetic flux” may be calculated by the product of the magnetic force (AM 2 /kg) and the density (g/cm 3 ) of the magnetic material, and the unit is A/m or Gauss ( It may be expressed as G), and preferably, it may be a value converted to have a unit of Gaussian (G) after calculation in units of A/m.
  • the unit of the (magnetic flux) 2 may be expressed as G 2 or N/m 2 , and preferably, it may be a value converted to have a unit of N/m 2 after being calculated in the unit of G 2 .
  • the method of the present invention may include determining an appropriate injection amount of magnetic cells by Equation 3 below using the calculated amount of magnetic material injected:
  • Injection amount of magnetic cells (injection amount of magnetic material)/(number of injections of magnetic material in cells)
  • the number of injections of the magnetic material into the cell is the desired number of injections of the magnetic material into the cell, and may be an average or median value of the number of injections of the magnetic material per cell, but is not limited thereto. .
  • the magnetic cells whose injection amount is determined as described above may be injected into a target tissue or organ of a target individual for the improvement or treatment of various diseases, particularly sleep apnea.
  • the form in which the magnetic cells are injected into the tissue or organ of an individual as described above is not particularly limited, but may be in the form of a liquid injection or a soft foam in which the liquid is absorbed as a non-limiting example.
  • the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time.
  • method can be injected.
  • 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
  • the magnetic cells when the magnetic cells are injected into the tissue or organ of an individual as described above, mixing and injecting the magnetic cells of the injection amount determined as described above in the suspension is to control the viscosity of the suspension to spread the injection solution including the magnetic cells. It is preferable that the speed and the holding time of the injected magnetic cells can be controlled, and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension.
  • the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
  • the present invention by applying a magnetic force to the magnetic cells, it is possible to control the direction control of the magnetic force of the magnetic cells. For example, by applying a specific magnetic field to a magnetic cell including a paramagnetic material in which the direction of the magnetic force is not determined, it can be converted into a cell in a ferromagnetic state having a magnetic force in a desired direction.
  • 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention.
  • the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
  • the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included.
  • a magnet such as an electromagnet or a permanent magnet by electromagnetic induction
  • one or more magnets may be included.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of contraction or relaxation of the desired muscle or tissue, and is not particularly limited.
  • an appropriate injection amount of the magnetic cells may achieve a desired strain rate by treating the surface of the cells with a magnetic material while applying a magnetic force as described above.
  • the strain may be a desired strain in the tissue of an object to be improved or deformed, and its unit is calculated as a percentage (%) of a change in lenth divided by original length compared to an existing length. it may be
  • composition for improvement or treatment of cleft lip and cleft palate Composition for improvement or treatment of cleft lip and cleft palate
  • composition for improving or treating cleft lip and cleft lip comprising the magnetic cells or agglomerates thereof provided in the present invention as an active ingredient.
  • the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
  • the composition may include magnetic cells or a cluster thereof considering that the magnetic bead adhesion rate is 90 to 100%, and specifically to achieve a target modification value in tissues requiring modification for the treatment of cleft lip and cleft lip.
  • the number of suitable magnetic cells calculated by the above method may be included for this purpose.
  • 7 x 10 5 to 9 x 10 5 magnetic cells may be included in order to achieve a 10% strain rate of the airway muscle of an individual, but is not limited thereto.
  • prevention of the present invention refers to the use of the composition of the present invention to block the symptoms caused by cleft lip or cleft lip by suturing, restoring, or reconstructing the deformed site cracked in the lips or oral tissue by injecting magnetic cells in vivo, Any action that suppresses or delays the symptom may be included without limitation.
  • the "improvement or treatment" of the present invention means that magnetic cells are injected in vivo using the composition of the present invention, thereby suturing, restoring, or reconstructing the deformed site cracked in the lip or oral tissue. Any action that improves or benefits the appearance may be included without limitation.
  • composition of the present invention may be provided in the form of a pharmaceutical composition or a food composition, but is not limited thereto.
  • the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is targeted to humans.
  • the pharmaceutical composition of the present invention is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions according to conventional methods.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, and pain relief Agents, solubilizers, isotonic agents, stabilizers, etc.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier for example, for oral administration, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
  • the "parenteral" of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration, but is not limited thereto.
  • the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg per day It may be administered at /kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • the food composition of the present invention is variously used for the improvement or treatment of indications for the purpose of the present invention, and various foods, for example, beverages, gums, tea, vitamin complexes, powders, granules, tablets, capsules, It can be prepared in the form of sweets, rice cakes, bread, and the like. Since the food composition of the present invention is improved from the existing food intake with little toxicity and side effects, it can be safely used even when taken for a long period of time for the purpose of prevention. When the composition of the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 100% of the total weight.
  • the food composition when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do.
  • monosaccharides such as glucose
  • disaccharides such as fructose
  • polysaccharides such as sucrose
  • conventional sugars such as dextrin, cyclodextrin, etc.
  • sugar alcohols such as xylitol, sorbitol and erythritol
  • the flavoring agent examples include a natural flavoring agent (taumatine), a stevia extract (eg, rebaudioside A, glycyrrhizin, etc.), and a synthetic flavoring agent (saccharin, aspartame, etc.).
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners , pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. These components may be used independently or in combination.
  • the proportion of these additives is generally selected in the range of 0.1 to 100 parts by weight per 100 parts by weight of the composition of the present invention, but is not limited thereto.
  • it relates to a method for preventing, ameliorating or treating cleft lip and cleft lip.
  • the method of the present invention may include administering a pharmaceutically effective amount of a composition for improvement or treatment of cleft lip and cleft lip comprising the magnetic cells or agglomerates thereof provided in the present invention as an active ingredient to an individual in need of administration. have.
  • a "pharmaceutically effective amount” refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system.
  • an “effective amount” for therapeutic use is the amount of a composition disclosed herein required to provide a clinically significant reduction in disease.
  • An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to the amount in which the active substance has a therapeutic effect.
  • the active substance is a magnetic cell comprising a magnetic substance, and is a cell for preventing, ameliorating or treating cleft lip and cleft lip.
  • composition for preventing, improving or treating sleep apnea comprising the magnetic cells or agglomerates thereof provided in the present invention as an active ingredient.
  • the sleep apnea may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
  • the composition may include magnetic cells or a cluster thereof considering that the magnetic bead adhesion rate is 90 to 100%, and specifically to achieve a target modification value in tissues requiring expansion for the treatment of sleep apnea.
  • the number of suitable magnetic cells calculated by the above method may be included for this purpose.
  • 1.15 x 10 6 to 1.5 x 10 6 magnetic cells may be included in order to achieve a strain rate of 10% of the airway muscle of an individual, but is not limited thereto.
  • the "prevention" of the present invention means that magnetic cells are injected into a living body using the composition of the present invention, thereby acting a repulsive force or attractive force on the inner wall of the respiratory system flow tube, thereby preventing the symptoms caused by sleep apnea by the expansion or contraction of the flow tube. Blocking or suppressing or delaying the symptoms may be included without limitation.
  • the "improvement or treatment" of the present invention means that magnetic cells are injected into a living body using the composition of the present invention, thereby acting a repulsive force or attractive force on the inner wall of the respiratory system flow tube, thereby causing sleep apnea by expansion or contraction of the flow tube. Any action that improves symptoms or benefits may be included without limitation.
  • the composition of the present invention may be provided in the form of a pharmaceutical composition or a food composition, but is not limited thereto.
  • the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is targeted to humans.
  • the pharmaceutical composition of the present invention is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions according to conventional methods.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, and pain relief Agents, solubilizers, isotonic agents, stabilizers, etc.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier for example, for oral administration, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • the route of administration of the pharmaceutical composition of the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
  • the "parenteral" of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration, but is not limited thereto.
  • the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg per day It may be administered at /kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • the food composition of the present invention is variously used for the prevention or improvement of indications for the purpose of the present invention, and various foods such as beverages, gums, teas, vitamin complexes, powders, granules, tablets, capsules, It can be prepared in the form of confectionery, rice cake, bread, and the like. Since the food composition of the present invention is improved from the existing food intake with little toxicity and side effects, it can be safely used even when taken for a long period of time for the purpose of prevention. When the composition of the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 100% of the total weight.
  • the food composition when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do.
  • monosaccharides such as glucose
  • disaccharides such as fructose
  • polysaccharides such as sucrose
  • conventional sugars such as dextrin, cyclodextrin, etc.
  • sugar alcohols such as xylitol, sorbitol and erythritol
  • the flavoring agent examples include natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents ; It is generally selected in the range of 0.1 to 100 parts by weight of sugar, but is not limited thereto.
  • it relates to a method for preventing, ameliorating or treating sleep apnea.
  • the method of the present invention includes the step of administering to an individual in need of administration a composition for preventing, improving or treating sleep apnea comprising the magnetic cell or its aggregate provided in the present invention as an active ingredient in a pharmaceutically effective amount can do.
  • a "pharmaceutically effective amount” refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system.
  • an “effective amount” for therapeutic use is the amount of a composition disclosed herein required to provide a clinically significant reduction in disease.
  • An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to the amount in which the active substance has a therapeutic effect.
  • the active substance is a magnetic cell comprising a magnetic substance, and is a cell for preventing, ameliorating or treating sleep apnea.
  • the present invention relates to a device for controlling the shape of a lip or oral tissue comprising the magnetic cell or magnetic cell aggregate provided by the present invention.
  • the device of the present invention is characterized in that the magnetic cells are injected into the living body to apply a repulsive force or attractive force to the lips or oral tissue, so that deformation existing in the lips or oral tissue, in particular, suturing, restoration, or reconstruction of a cracked deformed site is possible. .
  • the lip or oral tissue may be lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is not limited thereto.
  • the device of the present invention may be a device further comprising at least one selected from the group consisting of a magnetic field application device, an optical coherence tomography (OCT) device, or a near-infrared irradiation device.
  • OCT optical coherence tomography
  • the magnetic field application device may be a device capable of providing a thermal treatment effect due to an alternating magnetic field as well as enabling a more accurate movement of magnetic cells to a lesion site.
  • the thermal effect of the application of the magnetic field has the advantage that since the treatment is performed using a magnetic field harmless to the human body, the risk of burns or destruction of normal tissues during thermal treatment can be minimized.
  • the optical coherence tomography (OCT) device controls the shape of the lips or oral tissue by observing the image information of magnetic cells located in the lips or oral tissue in real time after the magnetic field is applied through the magnetic field applying device. You can provide feedback information for
  • the device provides information on the tissue to which the magnetic cells are attached and changes in the shape of the lips or oral tissue afterwards by light interference. It can be confirmed from a three-dimensional image through a tomography apparatus.
  • the wavelength of the light may be in the range of 700 to 1500 nm, more preferably in the range of 900 to 1300 nm.
  • the light coherence tomography apparatus may be connected to a near-infrared irradiator, and may analyze image information from light reflected back from the tissue by irradiating near-infrared rays to the lip or oral tissue.
  • the near-infrared irradiation device induces a local photothermal treatment effect for cleft lip and cleft palate, thereby providing a synergistic treatment effect increased in addition to the heat treatment effect according to the application of an alternating magnetic field, and controlling the shape of the lips or oral structure It may be preferable in terms of making it easier to perform.
  • the device of the present invention can confirm in real time the success or failure of suturing, restoration or reconstruction of the deformed region of the lip or oral tissue of the magnetic cells according to the present invention injected into the lip or oral tissue through a non-invasive method. Feedback for lip or oral tissue shape control can be easily made.
  • the device of the present invention may be used for the purpose of treating cleft lip and cleft palate in a target subject, preferably for the treatment of at least one of cleft lip and cleft palate, but is not limited thereto.
  • the present invention relates to an apparatus for setting a plan for controlling the shape of the lips or oral tissue of the simulation unit for predicting the situation after the injection of the magnetic cells of the present invention.
  • the lip or oral tissue may be lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is not limited thereto.
  • Figure 5a schematically shows an apparatus for establishing a shape control plan for artificial intelligence lips or oral tissue for optimal injection of magnetic cells for each patient according to an example of the present invention
  • Figure 6 is a magnetic cell according to an example of the present invention It shows a block diagram illustrating the internal configuration of an artificial intelligence shape control plan establishment device used.
  • the present invention will be described with reference to FIGS. 5A and 6 , but is not limited thereto.
  • the device may provide the artificial intelligence lip or oral tissue shape control planning system 100 using magnetic cells.
  • the device includes a database unit 110 including personal information of a target object, medical image information, and shape information of lips or oral tissue; an interface unit 120 for receiving input of the biometric information, medical image information, and shape factor of the lip or oral tissue of the individual, and outputting a predetermined result; a simulation unit 130 that analyzes the information received from the database unit 110 and the interface unit 120 using an artificial intelligence technique to predict a situation after the injection of magnetic cells into the object; and a control plan establishment unit 140 that determines the injection method and injection location of the magnetic cells according to the result of the simulation unit, and calculates the injection amount.
  • a database unit 110 including personal information of a target object, medical image information, and shape information of lips or oral tissue
  • an interface unit 120 for receiving input of the biometric information, medical image information, and shape factor of the lip or oral tissue of the individual, and outputting a predetermined result
  • a simulation unit 130 that analyzes the information received from the database unit 110 and the interface unit 120 using an artificial intelligence technique to predict a situation after the injection of magnetic cells
  • the subject subject is an individual having cleft lip and palate, and may be an individual having at least one of cleft lip and palate, and as non-limiting examples, incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip. , incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, unilateral complete cleft palate, or bilateral complete cleft palate.
  • the subject is preferably human, rat, mouse, guinea pig, hamster, rabbit, monkey, dog, cat, cow, horse, pig, sheep and goat may be selected from the group consisting of, more preferably human However, the present invention is not limited thereto.
  • the target individual's personal information may be information such as age, gender, and whether or not they have an underlying disease
  • medical image information include computed tomography (CT), magnetic resonance imaging (MRI), PET ( It may be image data obtained by photographing a living body through a medical imaging device such as positron emission tomography (CR) or computed radiography (CR).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • PET PET
  • CR positron emission tomography
  • CR computed radiography
  • the patient's biometric information may include simple physiological data such as blood pressure and heart rate, but is not limited thereto.
  • the lip or oral tissue shape factor may be information about the structure or shape of the lips and oral cavity confirmed from the medical image information, and then the injection method, injection location, and injection amount for controlling the shape of the lips or oral cavity. It may be information necessary to make a decision.
  • the simulation unit 130 may perform a simulation of a muscle or tissue through a basic computational fluid analysis equation of the Lattice Boltzman method (LBM).
  • LBM Lattice Boltzman method
  • Each oral condition is included in the simulation in order to be as close as possible to the actual living environment, and a formula for the correlation of changes in the shape of the lips or oral cavity according to magnetic force is included.
  • the present invention is characterized in that it is possible to predict the shape control of the patient's lips or oral tissue according to an artificial intelligence deep learning algorithm based on clinical data of existing patients.
  • the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, and it can be appropriately selected according to the desired residence time,
  • various methods may be used for injection.
  • it relates to an apparatus for controlling the shape of a respiratory system flow tube including the magnetic cell or magnetic cell aggregate provided in the present invention.
  • the device of the present invention is characterized in that the magnetic cells are injected into the living body to apply a repulsive or attractive force to the inner wall of the respiratory system flow tube to expand or contract the flow tube, and to control the shape of the respiratory system flow tube. have.
  • the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
  • the device of the present invention may be a device further comprising at least one selected from the group consisting of a magnetic field application device, an optical coherence tomography (OCT) device, or a near-infrared irradiation device.
  • OCT optical coherence tomography
  • the magnetic field application device may be a device capable of providing a thermal treatment effect due to an alternating magnetic field as well as enabling a more accurate movement of magnetic cells to a lesion site.
  • the thermal effect of the application of the magnetic field has the advantage that since the treatment is performed using a magnetic field harmless to the human body, the risk of burns or destruction of normal tissues during thermal treatment can be minimized.
  • the optical coherence tomography (OCT) device provides feedback information for controlling the shape of the flow tube by observing the image information of the magnetic cells coupled to the flow tube in real time after applying the magnetic field through the magnetic field application device.
  • the device records the tissue information to which the magnetic cells are attached and the shape change of the flow tube thereafter through a light interference tomography device. It can be confirmed from the 3D image.
  • the wavelength of the light may be in the range of 700 to 1500 nm, more preferably in the range of 900 to 1300 nm.
  • the light coherence tomography apparatus may be connected to a near-infrared irradiator, and may analyze image information from light reflected back from the tissue by irradiating near-infrared rays to the tissue.
  • the near-infrared irradiation device induces a local photothermal treatment effect in sleep apnea caused by stenosis or occlusion of a respiratory system flow tube, thereby providing an additionally increased synergistic treatment effect to the thermal treatment effect according to the application of an alternating magnetic field. It may be preferable in terms of allowing the shape control of the flow pipe to be performed more easily.
  • the device of the present invention can check the success or failure of flow tube shape control of magnetic cells injected into the respiratory system flow tube according to the present invention in real time through a non-invasive method, and thus feedback for controlling the respiratory system flow tube shape can be easily provided. can be done
  • the device of the present invention may be used for the purpose of treating sleep apnea that has or is likely to develop in a target subject, preferably for the treatment of obstructive sleep apnea, but is not limited thereto.
  • it relates to a simulation unit respiratory system flow tube shape control planning apparatus for predicting the situation after the magnetic cells of the present invention are injected.
  • the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
  • Figure 5b schematically shows an apparatus for establishing an artificial intelligence flow tube shape control plan for optimal injection of magnetic cells for each patient according to an example of the present invention
  • Figure 6 is an artificial intelligence flow tube using magnetic cells according to an example of the present invention. It shows a block diagram illustrating the internal configuration of the shape control planning apparatus.
  • the present invention will be described with reference to FIGS. 5B and 6 , but is not limited thereto.
  • the device may provide an artificial intelligence flow tube shape control planning system 100 using magnetic cells.
  • the apparatus includes a database unit 110 including personal information, medical image information, and flow tube shape information of a target entity; an interface unit 120 for receiving input of biometric information, medical image information, and respiratory system flow tube shape factors of the entity, and outputting a predetermined result; a simulation unit 130 that analyzes the information received from the database unit 110 and the interface unit 120 using an artificial intelligence technique to predict a situation after the injection of magnetic cells into the object; and a control plan establishment unit 140 that determines the injection method and injection location of the magnetic cells according to the result of the simulation unit, and calculates the injection amount.
  • a database unit 110 including personal information, medical image information, and flow tube shape information of a target entity
  • an interface unit 120 for receiving input of biometric information, medical image information, and respiratory system flow tube shape factors of the entity, and outputting a predetermined result
  • a simulation unit 130 that analyzes the information received from the database unit 110 and the interface unit 120 using an artificial intelligence technique to predict a situation after the injection of magnetic cells into the object
  • a control plan establishment unit 140
  • the subject subject to sleep apnea syndrome may be a subject or a subject with a high probability of developing, and the subject is preferably a human, rat, mouse, guinea pig, hamster, rabbit, monkey, dog, cat. , may be selected from the group consisting of cattle, horses, pigs, sheep and goats, and more preferably may be mice, rabbits or pigs, but is not limited thereto.
  • the target individual's personal information may be information such as age, gender, and whether or not they have an underlying disease
  • medical image information include computed tomography (CT), magnetic resonance imaging (MRI), and PET (PET). It may be image data obtained by photographing a living body through a medical imaging device such as positron emission tomography (CR) or computed radiography (CR).
  • CR positron emission tomography
  • CR computed radiography
  • the patient's biometric information may include simple physiological data such as blood pressure and heart rate, but is not limited thereto.
  • the respiratory system flow tube shape factor may be information about the structure or shape of the respiratory system flow tube confirmed from the medical image information, and then determine the injection method, injection location, and injection amount for controlling the respiratory system flow tube shape. It may be necessary information for
  • the simulation unit 130 may perform a flow pipe simulation through a basic computational fluid analysis equation of the Lattice Boltzman method (LBM).
  • LBM Lattice Boltzman method
  • conditions such as heart rate-based flow rate, blood flow resistance, fluid viscosity, and elasticity of the respiratory system flow tube suitable for each respiratory system flow tube characteristic are included in the simulation, and the change of flow tube shape according to magnetic force Include formulas for correlation.
  • the present invention is characterized in that it is possible to predict the control of the patient's flow tube shape according to an artificial intelligence deep learning algorithm based on clinical data of existing patients.
  • the liquid injection form or the liquid is absorbed into the flexible foam and then the foam is Can be injected
  • the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time in the body, so it can be appropriately selected according to the desired residence time,
  • various methods of injection are possible.
  • the present invention relates to a method for preparing an animal model of cleft lip and cleft lip into which the magnetic cells or agglomerates thereof provided in the present invention are injected.
  • the term “animal model” refers to an animal model of a disease.
  • the animal model may be an animal model that is afflicted with a disease similar to a human disease or is congenitally afflicted with the disease.
  • the animal model may be an animal model of muscle or tissue abnormality, and furthermore, an animal model of cleft lip and cleft palate.
  • animals that can be used as animal models of the present invention are mammals other than humans, for example, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, cats, cattle, horses, pigs, sheep and goats. It may be selected from the group consisting of, and more preferably a mouse, rabbit or pig, but is not limited thereto.
  • the manufacturing method of the present invention may include injecting the magnetic cells or the magnetic cell aggregate into a desired lip or oral tissue site of the animal.
  • the lip or oral tissue is preferably the lip or oral tissue may be lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is limited thereto. it is not
  • the liquid injection form or liquid may be absorbed into the flexible foam and then the foam may be injected.
  • the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time. method can be injected.
  • the suspension when injecting the magnetic cells or magnetic cell aggregates into the animal model, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to control the diffusion rate of the injection solution including the magnetic cells and the injected It is preferable that the holding time of the magnetic cells can be controlled and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension.
  • the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
  • the manufacturing method of the present invention may include the step of inducing suturing, restoration or reconstruction of a deformed region cracked in the lip or oral tissue by applying a magnetic force to the lip or oral tissue region into which the magnetic particles are injected.
  • the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included.
  • the magnetic field can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
  • the magnetic force when the magnetic force is applied, it is possible to induce suturing, restoration, or reconstruction of the deformed area cracked due to cleft palate in the lips or oral tissue by using the repulsive force or attractive force between the magnetic particles and the magnet.
  • the magnitude, direction, time for applying the magnetic force, etc. can be appropriately adjusted and determined according to the desired degree of contraction of the lip muscle or oral tissue, and there is no particular limitation.
  • the animal model may be an animal model in which a cleft lip or cleft lip exists in the oral tissue.
  • the present invention relates to an animal model of cleft lip and cleft lip produced according to the production method of the present invention.
  • the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
  • the present invention relates to a method of screening a drug or device for improving or treating cleft lip and cleft lip using the animal model provided by the present invention.
  • the "screening” refers to selecting a substance having a specific target property from a candidate group consisting of various substances or devices by a specific manipulation or evaluation method.
  • the screening method of the present invention may include first, treating a drug candidate for improvement or treatment of cleft lip or cleft lip or applying a candidate device for amelioration or treatment of cleft lip and cleft lip to the animal model provided by the present invention.
  • the candidate drug is preferably any one selected from the group consisting of natural compounds, synthetic compounds, RNA, DNA, polypeptides, enzymes, proteins, ligands, antibodies, antigens, bacterial or fungal metabolites and bioactive molecules.
  • the present invention is not limited thereto.
  • the screening method of the present invention may include processing the candidate drug or observing the lip or oral tissue of the animal model to which the candidate device is applied, or confirming the prognosis while breeding the animal model. At this time, when at least a part of the cracked deformed region of the lips or oral tissue is sutured, restored or reconstructed after the treatment of the candidate drug or application of the candidate device, or when the cleft lip is improved or treated by the candidate drug or the candidate device
  • the candidate drug or device may be determined as a drug or device for amelioration or treatment of cleft palate.
  • the observation of cleft palate is performed using non-invasive imaging such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US).
  • CT computed tomography
  • CT selective computed tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • DSA digital subtraction angiography
  • the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
  • the present invention relates to a method of simulating shape deformation of lips or oral tissue using the animal model provided by the present invention.
  • the simulation method of the present invention may include applying a magnetic force to the lip muscle or oral tissue of the animal model provided by the present invention to induce a cracked deformation in the lip or oral tissue.
  • the lip or oral tissue may be preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is not limited thereto.
  • the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included.
  • the magnetic field can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
  • magnetic cells and external Cracked deformation can be induced in the lip or oral tissue by attraction or repulsion between magnets or between magnetic cells.
  • the magnitude, direction, time of applying the magnetic force, etc. may be appropriately adjusted and determined according to the desired degree of deformation of the lips or oral tissue, and is not particularly limited.
  • the simulation method of the present invention may include observing the lip or oral tissue of the animal model to which the magnetic force is applied as described above.
  • the observation of the muscle or tissue is performed by a non-invasive imaging method such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US).
  • CT computed tomography
  • CT selective computed tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • DSA digital subtraction angiography
  • the simulation method of the present invention simulates the process of inducing abnormal contraction or relaxation of the lip or oral tissue of the animal model, such as a cracked deformation in the lip or oral tissue, thereby providing useful information necessary for the interpretation of cleft lip disease. can be provided, and accordingly, it is possible to determine whether a patient has a disease or develop a disease treatment drug or device.
  • the present invention relates to a method for producing an animal model of sleep apnea in which the magnetic cells or agglomerates thereof provided in the present invention are injected.
  • the term “animal model” refers to an animal model of a disease.
  • the animal model may be an animal model that is afflicted with a disease similar to a human disease or is congenitally afflicted with the disease.
  • the animal model may be an animal model of respiratory flow tract abnormality, and furthermore, an animal model of sleep apnea.
  • animals that can be used as animal models of the present invention are mammals other than humans, for example, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, cats, cattle, horses, pigs, sheep and goats. It may be selected from the group consisting of, and more preferably a mouse, rabbit or pig, but is not limited thereto.
  • the production method of the present invention may include injecting the magnetic cells or the magnetic cell aggregate into a desired respiratory system flow tract of an animal.
  • the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
  • the liquid injection form or the liquid may be absorbed into the flexible foam and then the foam may be injected.
  • the foam When injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time, and can be injected by various methods other than the methods listed above.
  • the suspension when injecting the magnetic cells or magnetic cell aggregates into the animal model, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to control the diffusion rate of the injection solution including the magnetic cells and the injected It is preferable that the holding time of the magnetic cells can be controlled and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension.
  • the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
  • the manufacturing method of the present invention may include the step of inducing contraction of the respiratory system flow tube by applying a magnetic force to the portion of the respiratory system flow tube into which the magnetic particles are injected.
  • the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included.
  • the magnetic field can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
  • the contraction of the respiratory system can be induced by using a repulsive force or attractive force between the magnetic particles and the magnet.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. can be appropriately adjusted and determined according to the desired degree of contraction of the respiratory system flow tube, and is not particularly limited.
  • the animal model may be an animal model in which sleep apnea is realized due to abnormal contraction or blockage of the respiratory tract.
  • the present invention relates to an animal model of sleep apnea manufactured according to the manufacturing method of the present invention.
  • the sleep apnea may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
  • the present invention relates to a method of screening a drug or device for preventing or treating sleep apnea using the animal model provided by the present invention.
  • the "screening” refers to selecting a substance having a specific target property from a candidate group consisting of various substances or devices by a specific manipulation or evaluation method.
  • the screening method of the present invention may include first treating a drug candidate for preventing or treating sleep apnea or applying a candidate device for preventing or treating sleep apnea to the animal model provided by the present invention.
  • the candidate drug is preferably any one selected from the group consisting of natural compounds, synthetic compounds, RNA, DNA, polypeptides, enzymes, proteins, ligands, antibodies, antigens, bacterial or fungal metabolites and bioactive molecules.
  • the present invention is not limited thereto.
  • the screening method of the present invention may include the step of observing the change in the flow tube while observing the respiratory system flow tube of the animal model to which the candidate drug is treated or the candidate device is applied, or checking the prognosis while breeding the animal model.
  • the candidate drug or device may be determined as a drug or device for preventing or treating sleep apnea.
  • the observation of sleep apnea is performed using non-invasive imaging such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US).
  • CT computed tomography
  • CT selective computed tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • DSA digital subtraction angiography
  • the sleep apnea may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
  • the present invention relates to a method for simulating shape deformation of a respiratory system flow tube using the animal model provided by the present invention.
  • the simulation method of the present invention may include the step of inducing contraction or relaxation of the respiratory system flow tube by applying a magnetic force to the respiratory system flow tube of the animal model provided in the present invention.
  • the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
  • the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included.
  • the magnetic field can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
  • contraction or relaxation of the respiratory system flow tube can be induced by using the repulsive force or attraction between the magnetic particles and the magnet, and as a specific example, the respiratory system flow tube, preferably the nasal cavity, the larynx.
  • the respiratory system flow tube preferably the nasal cavity, the larynx.
  • a repulsive force between a magnetic cell located on the inner wall of the airway and an external magnet may induce contraction of the respiratory tract.
  • the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted according to the desired degree of contraction or relaxation of the respiratory system flow tube, and is not particularly limited.
  • the simulation method of the present invention may include observing the respiratory system flow tube of the animal model to which the magnetic force is applied as described above.
  • the observation of the flow tract of the respiratory system is performed using non-invasive imaging methods such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US).
  • CT computed tomography
  • CT selective computed tomography
  • MRI magnetic resonance imaging
  • US ultrasound
  • invasive imaging method such as digital subtraction angiography (DSA), but is not limited thereto.
  • the simulation method of the present invention can provide useful information necessary for the analysis of respiratory flow tract diseases, etc. by simulating the process in which respiratory tract abnormalities are induced by inducing abnormal contraction or relaxation of the respiratory tract of the animal model. Accordingly, it is possible to determine whether a patient has a disease or develop a disease treatment drug or device.
  • an appropriate amount of magnetic cells containing a magnetic material can be injected by targeting a tissue or organ requiring physical transformation of a desired object, and accordingly, the target tissue or organ can be in the target tissue or organ at a desired level. It is possible to achieve the contraction, relaxation or deformation of the tissue or organs, and ultimately, the improvement or therapeutic effect of diseases that can be prevented, improved, or treated through physical transformation of tissues or organs, in particular, cleft lip and cleft lip or sleep apnea disease can be improved or the therapeutic effect can be increased.
  • FIG. 1 shows the shape control principle of a tissue or organ of a magnetic cell according to the present invention, in which (a) is a suture of a cracked tissue due to magnetic attraction or reduction of a flow tube, (b) is a cracked area according to a magnetic repulsive force It is a schematic diagram showing the expansion or expansion of the flow pipe.
  • Example 2 shows a method of injecting magnetic cells into the body prepared according to Example 1 of the present invention.
  • FIG. 3 is an injection method of the magnetic cells of the present invention, (a) is a liquid injection injection method, (b) shows an injection method through a flexible foam implantation.
  • Example 4 shows the results of imparting ferromagnetism to the magnetic cells prepared according to Example 1 of the present invention.
  • Figure 5a schematically shows an apparatus for establishing a shape control plan of artificial intelligence lip or oral tissue for optimal injection of magnetic cells for each patient according to the present invention.
  • Figure 5b schematically shows an apparatus for establishing an artificial intelligence flow tube shape control plan for optimal injection of magnetic cells for each patient according to the present invention.
  • FIG. 6 is a block diagram illustrating the internal configuration of an artificial intelligence lip or oral tissue shape control plan establishment device or an artificial intelligence flow tube shape control plan establishment device using magnetic cells.
  • FIG. 7 shows an example of a device that can be used to measure the Young's modulus of a body tissue according to the present invention.
  • One embodiment of the present invention relates to a method for providing information for determining an appropriate injection amount of magnetic cells to be injected into the body to treat cleft lip and cleft lip.
  • Another embodiment of the present invention relates to an information providing method for determining an appropriate injection amount of magnetic cells to be injected into the body to treat sleep apnea.
  • compositions for preventing, improving or treating cleft lip and cleft lip comprising, as an active ingredient, a magnetic cell or a magnetic cell aggregate containing a magnetic material.
  • Another embodiment of the present invention relates to a method for preventing, improving or treating cleft lip and cleft lip, comprising administering a pharmaceutically effective amount of the composition for preventing, improving or treating cleft lip and cleft lip to an individual in need of administration.
  • compositions for preventing, improving, or treating sleep apnea comprising, as an active ingredient, a magnetic cell or a magnetic cell aggregate containing a magnetic material.
  • Another embodiment of the present invention relates to a method for preventing, improving or treating sleep apnea, comprising administering a pharmaceutically effective amount of the composition for preventing, improving or treating sleep apnea to an individual in need of administration.
  • a magnetic cell or a magnetic cell aggregate comprising a magnetic material; And it relates to a device for controlling the shape of the lips or oral tissue comprising a magnetic field application device.
  • a magnetic cell or a magnetic cell aggregate comprising a magnetic material; and a device for applying a magnetic field to a respiratory system flow tube shape control device.
  • a database unit including personal information, medical image information, and shape information of lips or oral tissue of existing patients with cleft palate; an interface unit for receiving input of biometric information, medical image information, and muscle or tissue shape factors of a patient with cleft lip and cleft lip, and outputting a predetermined result; a simulation unit that analyzes the information received from the database unit and the interface unit using an artificial intelligence technique to predict a situation after the injection of magnetic cells or magnetic cell aggregates containing a magnetic material into the patient; and a control plan establishment unit that determines the injection method and injection location of the magnetic cells or the magnetic cell aggregate according to the result of the simulation unit and calculates the injection amount; It relates to the establishment device.
  • a database unit including personal information, medical image information, and flow tube shape information of existing patients with sleep apnea; an interface unit for receiving input of biometric information, medical image information, and respiratory system flow tube shape factor of a sleep apnea patient, and outputting a predetermined result; a simulation unit that analyzes the information received from the database unit and the interface unit using an artificial intelligence technique to predict a situation after the injection of magnetic cells or magnetic cell aggregates containing a magnetic material into the patient; and a control plan establishment unit for determining the injection method and injection location of the magnetic cells or the magnetic cell aggregate according to the result of the simulation unit, and calculating the injection amount; Artificial intelligence respiratory system flow tube shape control plan establishment device using magnetic cells comprising a; is about
  • it in another embodiment, relates to a method for producing an animal model of cleft lip and cleft lip, comprising injecting a magnetic cell or a magnetic cell aggregate containing a magnetic material into a desired lip or oral tissue site of an animal other than a human. .
  • Another embodiment of the present invention relates to a method for producing an animal model of sleep apnea, comprising injecting the magnetic cells or a magnetic cell aggregate into a desired respiratory tract region of an animal other than humans.
  • the present invention relates to an animal model of cleft palate or sleep apnea prepared by the above method.
  • Another embodiment of the present invention relates to a method for screening a drug or device for preventing or treating cleft lip and cleft lip or sleep apnea using the above-described animal model.
  • Example 1 Preparation of magnetic cells by immunolabeling based on immune response
  • the anti-IgG-bound magnetic beads were separated with a magnetic separator, washed three times with 0.05 M Tris-HCl solution, and dispersed in 1 ml of PBS buffer containing 0.1% BSA to obtain antibody-coated magnetic beads.
  • a magnetic field of about 40 ⁇ Wb is applied and the antibody Sprinkle the coated magnetic beads on the mold surface so that the antigens of epithelial cells, bone cells, fibroblasts, or myocytes in the lips or oral tissue and the antibody coated on the magnetic beads bind to magnetic cells with magnetic substances attached to the cell surface.
  • Example 2 Determination of injection amount of magnetic cells - application to lip muscle
  • the Young's modulus of the lips was measured using a Cutometer of Courage Khazaka electronic GmbH or DermaLab of Cortex technology shown in FIG. 7 as a elasticity measuring device for measuring elasticity.
  • the Young's modulus can be measured by measuring the height at which the skin is displaced and the time required for restoration by applying negative pressure while the probe for measurement is in contact with the skin for both products.
  • the magnetic flux density was calculated to check the force between the magnetic beads to be included in the magnetic cells.
  • Micromod's magnetic iron oxide beads product number: 45-00-252 used in the present invention, the density is 46 AM 2 /kg, and the magnetic force corresponds to 5.35 g/cm 3 . Accordingly, as shown in Equation 4 below, 246100 A/m was derived as the magnetic flux by multiplying the density and magnetic force of the magnetic beads. At this time, since the value of 1 G is equal to 0.1 mT, 1 Oe, or 80 A/m, it was possible to convert the magnetic flux amount to 3076 G in unit.
  • the force between the magnetic beads was calculated.
  • Equation 5 after squaring the magnetic flux amount (magnetic flux density) of the obtained magnetic beads, multiply the converted value using the Tesla unit by the magnetic bead area. As a result, the magnetic force between the magnetic beads is 0.0232 N/ m 2 could be obtained.
  • the magnetic force between the magnetic beads calculated as described above was calculated as 0.0232 N/m 2 to deform the lip muscle by 10%.
  • the Young's modulus of the lip muscle is assumed to be 33.7 kPa
  • the Young's modulus can be calculated as stress/strain and magnetic force per strain (N/m 2 ) as shown in Equation 6 below.
  • Equation 7 1.6 x 10 6 could be derived as the number of magnetic beads to be injected for 10% deformation of the lip muscle.
  • the injection amount of magnetic cells was calculated to be 8 x 10 5 as shown in Equation 8 below.
  • the optimal number of cells and the volume of cell solution required vary depending on the specifications and cell concentration of the magnetic beads, and the optimal injection amount to achieve the strain rate can be calculated by considering all related variables.
  • Example 3 Effect of controlling the shape of lip muscle or oral tissue
  • a cleft palate mouse model was prepared.
  • the magnetic cells prepared according to Example 1 were mixed with the PDMS solution at a concentration of 4 x 10 5 cells/ml, and the appropriate injection amount was calculated according to Example 2, and the cracked deformed region of the lips, gum bone, and uvula of the mouse model.
  • the amount of 2 ml was divided into 1 ml each and injected at the ends of the cracked deformation site.
  • the heart rate-based flow rate, blood flow resistance value, and flow waveform were controlled through a control unit (CardioFlow 5000 MR, Shelley Medical Imaging Technologies), and an 80 Gaussian magnetic field was applied using a magnetic field application device to convert the injected magnetic cells into a ferromagnetic state. and induced attraction between the injected magnetic cells. Accordingly, it was confirmed that the cracked lip area and the diameter of the gaping mouth were reduced.
  • Example 4 Preparation of magnetic cells by immunolabeling based on immune response
  • the anti-IgG-bound magnetic beads were separated with a magnetic separator, washed three times with 0.05 M Tris-HCl solution, and dispersed in 1 ml of PBS buffer containing 0.1% BSA to obtain antibody-coated magnetic beads. prepared.
  • a magnetic field of about 40 ⁇ Wb is applied and the antibody-coated magnetic beads are sprayed on the mold surface to obtain antigen ( Stro-1, CD29, CD44, CD73, CD90, CD105, CD146, or ssea4) and the antibody coated on the magnetic beads were allowed to bind, thereby preparing magnetic cells having a magnetic material attached to the cell surface.
  • Example 5 Determination of injection amount of magnetic cells - application to airway muscle
  • the Young's modulus of airway tissue was measured using the Cutometer of Courage Khazaka electronic GmbH or DermaLab of Cortex technology shown in FIG. 7 as a elasticity measuring device for measuring elasticity.
  • the Young's modulus can be measured by applying a negative pressure while the measuring probe is in contact with the target tissue to measure the height at which the tissue is displaced and the time required for restoration.
  • the magnetic flux density was calculated to check the force between the magnetic beads to be included in the magnetic cells.
  • Micromod's magnetic iron oxide beads product number: 45-00-252 used in the present invention, the density is 46 AM 2 /kg, and the magnetic force corresponds to 5.35 g/cm 3 . Accordingly, as shown in Equation 4 below, 246100 A/m was derived as the magnetic flux by multiplying the density and magnetic force of the magnetic beads. At this time, since the value of 1 G is equal to 0.1 mT, 1 Oe, or 80 A/m, it was possible to convert the magnetic flux amount to 3076 G in unit.
  • the force between the magnetic beads was calculated.
  • Equation 5 after squaring the magnetic flux amount (magnetic flux density) of the obtained magnetic beads, multiply the converted value using the Tesla unit by the magnetic bead area. As a result, the magnetic force between the magnetic beads is 0.0232 N/ m 2 could be obtained.
  • the magnetic force between the magnetic beads calculated as described above was calculated as 0.0232 N/m 2 to deform the airway muscle by 10%.
  • the Young's modulus of the airway muscle is assumed to be 33.7 kPa
  • the Young's modulus can be calculated as stress/strain and magnetic force per strain (N/m 2 ) as shown in Equation 6 below. Accordingly, as shown in Equation 9 below, as the number of magnetic beads to be injected for 10% deformation of the airway muscle, 2.6 x 10 6 could be derived.
  • the optimal number of cells and the volume of cell solution required vary depending on the specifications and cell concentration of the magnetic beads, and the optimal injection amount to achieve the strain rate can be calculated by considering all related variables.
  • the optimal injection amount to achieve the strain rate can be calculated by considering all related variables.
  • a mouse model with upper airway stenosis was prepared.
  • the magnetic cells prepared according to Example 1 were mixed with the PDMS solution at a concentration of 4 x 10 5 cells/ml, and an appropriate injection amount was calculated according to Example 5, and an amount of 3.25 ml of 1.625 was applied to the constricted airway area of the mouse model. Each ml was divided and injected into symmetrical sites.
  • the heart rate-based flow rate, blood flow resistance value, and flow waveform were controlled through a control unit (CardioFlow 5000 MR, Shelley Medical Imaging Technologies), and an 80 Gaussian magnetic field was applied using a magnetic field application device to convert the injected magnetic cells into a ferromagnetic state. and induced repulsion between the injected magnetic cells. Accordingly, it was confirmed that the diameter of the narrowed upper airway was expanded.
  • control planning unit 140 control planning unit
  • cleft palate is a non-limiting example of a disease requiring physical modification of tissues or organs. Or it can effectively prevent, improve, or treat a disease of sleep apnea.

Abstract

The present invention may provide information relating to an appropriate injection amount, of magnetic cells injected into the body, which is required to achieve a desired strain rate in a target tissue. Further, a composition comprising an appropriate amount of magnetic cells may effectively be used for preventing, relieving or treating various diseases requiring physical correction, particularly cleft lip and palate or sleep apnea.

Description

자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법Method of providing information for determining the appropriate injection amount of magnetic cells
본 발명은 다양한 질환을 치료하기 위하여 인체 기관 또는 조직에 적용이 가능한 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법에 관한 것이다. The present invention relates to an information providing method for determining an appropriate injection amount of magnetic cells applicable to human organs or tissues to treat various diseases.
나노 입자(nanoparticle)는 적어도 한 차원이 100nm, 즉 천만분의 1미터 이하인 입자를 말한다. 나노 입자에 대한 연구는 1990 년대부터 매우 활발하게 진행되었고, 균일한 크기를 가진 나노 입자를 제조하여 분산시키는 연구가 수행되었으며, 2000 년대에는 나노 입자의 모양, 크기 또는 구조에 따라 나노 입자의 물리적, 화학적 특성이 달라지는 현상을 이용하는 등 나노 입자의 물성을 제어하는 연구가 수행되었다. 최근에는 나노 입자의 물성 제어를 넘어서서 다양한 기능을 갖는 나노 입자 제조에 대한 연구가 이뤄지고 있다. 특히, 자성 나노 입자는 초상자성 특성 및 물리화학적으로 안정된 특성으로 인하여, MRI 조영제, 약물 전달, 세포 분리, 열 치료법 등 바이오-메디컬 분야에 널리 응용되고 있다. 자기장에 의해 위치 제어가 가능하다는 장점을 가지고 있기 때문에, 다양한 방면으로 응용되고 있다.A nanoparticle is a particle with at least one dimension of 100 nm, that is, less than ten millionths of a meter. Research on nanoparticles has been very active since the 1990s, and research on manufacturing and dispersing nanoparticles with a uniform size has been conducted, and in the 2000s, the physical, Research has been conducted to control the physical properties of nanoparticles, such as using a phenomenon in which chemical properties change. In recent years, research on the manufacture of nanoparticles having various functions beyond the control of the physical properties of nanoparticles is being conducted. In particular, due to their superparamagnetic properties and physicochemically stable properties, magnetic nanoparticles are widely applied in bio-medical fields such as MRI contrast agents, drug delivery, cell separation, and thermal therapy. Since it has the advantage of being able to control the position by a magnetic field, it is being applied in various fields.
본 발명자들은 자성을 지닌 나노 입자를 세포 또는 세포 군집체에 적용하여 다양한 질환, 특히는 구순 구개열 또는 수면 무호흡증의 개선 또는 치료 목적으로 사용하기 위한 기술을 개발하기에 이르렀다.The present inventors have developed a technique for applying magnetic nanoparticles to cells or cell aggregates and using them for the treatment or improvement of various diseases, particularly cleft lip and cleft lip or sleep apnea.
본 발명의 일 목적은 다양한 질환을 치료하기 위하여 체내로 주입되는 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법을 제공하는 것이다.One object of the present invention is to provide an information providing method for determining an appropriate injection amount of magnetic cells to be injected into the body to treat various diseases.
본 발명의 다른 목적은 자성 세포 또는 자성 세포 군집체를 포함하는 다양한 질환의 개선 또는 치료용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for improving or treating various diseases including magnetic cells or magnetic cell aggregates.
본 발명의 또 다른 목적은 상기한 다양한 질환의 개선 또는 치료용 조성물을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a composition for improving or treating various diseases described above.
본 발명의 또 다른 목적은 자성 세포를 포함하는 다양한 조직 또는 기관의 형상 제어 장치를 제공하는 것이다.Another object of the present invention is to provide an apparatus for controlling the shape of various tissues or organs including magnetic cells.
본 발명의 또 다른 목적은 자성 세포를 주입한 이후의 상황을 예측하는 시뮬레이션부를 포함하는 다양한 조직 또는 기관 형상 제어 계획 수립 장치를 제공하는 것이다.Another object of the present invention is to provide an apparatus for establishing a plan for controlling the shape of various tissues or organs including a simulation unit for predicting the situation after the injection of magnetic cells.
본 발명의 또 다른 목적은 자성 세포가 주입된 다양한 질환 동물 모델을 제공하는 것이다.Another object of the present invention is to provide a variety of disease animal models injected with magnetic cells.
본 발명의 또 다른 목적은 상기한 동물 모델을 이용하여 다양한 질환의 치료용 약물 또는 장치를 스크리닝하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for screening a drug or device for the treatment of various diseases using the above-described animal model.
본 발명의 또 다른 목적은 상기한 동물 모델을 이용하여 조직 또는 기관의 형상 변형을 시뮬레이션하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for simulating shape deformation of a tissue or organ using the above-described animal model.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당 업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those of ordinary skill in the art from the following description.
이하, 본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세 사항, 예컨대, 특이적 형태, 조성물 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다. "한 가지 구체예" 또는 "구체예"에 대한 본 명세서 전체를 통한 참조는 구체예와 결부되어 기재된 특별한 특징, 형태, 조성 또는 특성이 본 발명의 하나 이상의 구체예에 포함됨을 의미한다. 따라서, 본 명세서 전체에 걸친 다양한 위치에서 표현된 "한 가지 구체예에서" 또는 "구체예"의 상황은 반드시 본 발명의 동일한 구체예를 나타내지는 않는다. 추가로, 특별한 특징, 형태, 조성, 또는 특성은 하나 이상의 구체예에서 어떠한 적합한 방법으로 조합될 수 있다.BRIEF DESCRIPTION OF THE DRAWINGS Various embodiments described herein are described below with reference to the drawings. In the following description, various specific details are set forth, such as specific forms, compositions and processes, and the like, for a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and forms. In other instances, well-known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, references to "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, the particular features, forms, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.
명세서 내에 특별한 정의가 없으면 본 명세서에 사용된 모든 과학적 및 기술적인 용어는 본 발명이 속하는 기술분야에서 당업자에 의하여 통상적으로 이해되는 것과 동일한 의미를 가진다. Unless otherwise defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
1-1. 구순 구개열의 개선 또는 치료용 자성 세포 또는 자성 세포 군집체1-1. Magnetic cells or magnetic cell clusters for improvement or treatment of cleft lip and cleft palate
본 발명의 일 구현 예에 따르면, 구순 구개열의 개선 또는 치료용 자성 세포 또는 자성 세포 군집체에 관한 것이다.According to one embodiment of the present invention, it relates to a magnetic cell or a magnetic cell aggregate for the treatment or improvement of cleft lip and cleft lip.
본 발명에서 상기 자성 세포는 자성 물질을 포함하는 것으로, 바람직하게는 자성 물질이 세포 표면에 결합되거나 세포 내부에 위치하는 형태로써 세포에 포함될 수 있다. In the present invention, the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
본 발명에서 상기 세포의 종류는 특별히 제한하지 않으며 입술 또는 구강, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등에 위치한 세포로, 예를 들면 상피세포(epithelial cell), 뼈세포(osteoblast), 섬유아세포(fibroblast) 또는 근세포(myocyte)일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the type of the cell is not particularly limited and is a cell located in the lips or oral cavity, preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), etc., For example, it may be an epithelial cell, an osteoblast, a fibroblast, or a myocyte, but is not limited thereto.
또한, 본 발명에서 상기 세포 군집체는 상기 자성 세포가 복수 개로 구성되어 형성된 환상의 세포 군집체일 수 있으나, 이에 제한되는 것은 아니다. In addition, in the present invention, the cell aggregate may be a cyclic cell aggregate formed of a plurality of the magnetic cells, but is not limited thereto.
본 발명에서 상기 "자성 물질"이란 자기적 성질을 가진 물질을 의미하는 것으로 자기적 성질에 따라 크게 상자성, 초상자성, 반자성, 강자성으로 구분된다. 구체적으로 상자성체는 자기장 안에 놓여진 경우에 자기장 방향으로 약하게 자화되고, 자기장이 제거되면 자화되지 않는 물질이며, 그 예시로써 알루미늄, 주석, 백금, 이리듐 등이 존재한다. 반자성체는 외부 자기장에 의해 반대 방향으로 자화되는 물질이며, 그 예시로서 수소, 물, 납, 구리, 아연 등의 금속과 염류 등이 이에 해당한다. 이와 달리 강자성체는 외부 자기장이 없는 상태에서도 자화되는 물질의 자기적 성질을 가지는 물질을 말하는 것으로, 철, 니켈 및 코발트 등이 이에 해당하며 자기장의 방향으로 강하게 자화되며 자석에 강하게 끌리는 특성을 갖는다. 초상자성체는 비 강자성체의 구조내 강자성체 입자들이 고립된 형태로 존재하는 물질로 초상자성은 낮은 자기장을 인가하여도 강자성을 나타내며 자화가 포화되나, 자기장 인가를 중지하면 자화가 소멸되는 상태가 된다. 자성체의 입경을 나노 크기로 하면 상온에서 초상자성이 나타나게 되는데 현재 이러한 특성을 이용하여 의학, 약학, 바이오, 화학 분야에서 많은 연구가 수행되고 있다. In the present invention, the "magnetic material" refers to a material having magnetic properties, and is largely divided into paramagnetic, superparamagnetic, diamagnetic, and ferromagnetic according to magnetic properties. Specifically, a paramagnetic material is a material that is weakly magnetized in the magnetic field direction when placed in a magnetic field and is not magnetized when the magnetic field is removed, and examples thereof include aluminum, tin, platinum, iridium, and the like. A diamagnetic material is a material that is magnetized in the opposite direction by an external magnetic field, and examples thereof include metals such as hydrogen, water, lead, copper, zinc, etc. and salts. On the other hand, a ferromagnetic material refers to a material having magnetic properties of a material that is magnetized even in the absence of an external magnetic field, and includes iron, nickel, and cobalt. A superparamagnetic material is a material in which ferromagnetic particles in the structure of a non-ferromagnetic material exist in an isolated form. Superparamagnetic material exhibits ferromagnetism even when a low magnetic field is applied, and the magnetization is saturated, but the magnetization disappears when the magnetic field application is stopped. When the particle size of the magnetic material is made into a nano size, superparamagnetism appears at room temperature. Currently, many studies are being conducted in medicine, pharmacy, bio, and chemistry using this characteristic.
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 초상자성 또는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다. In the present invention, the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a superparamagnetic or paramagnetic material is applied later as necessary by applying an appropriate magnetic force to produce a desired effect and induce discharge out of the body have.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질 일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite (γ-Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm 내지 1μm, 바람직하게는 50 내지 700 nm, 보다 바람직하게는 200 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the average diameter of the magnetic material may be 1 nm to 1 μm, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 산화철, 페라이트 또는 합금일 수 있고, 이의 구체적인 예시로는 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be iron oxide, ferrite, or an alloy, and specific examples thereof include maghemite (γ-Fe 2 O 3 ), magnetite (Fe 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ), Manganese ferrite (MnFe 2 O 4 ), iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), which can be a permanent magnet If it is a substance, it is not limited thereto.
본 발명에서 상기 자성 물질은 평균 입경 1 내지 1000 nm의 범위 내일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may have an average particle diameter of 1 to 1000 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질을 도핑할 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질을 도핑하는 것이 좋으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility. ), polyvinyl pyrrolidone (polyvinyl pyrrolidone), polyethyleneimine (polyethyleneimine), polymethacrylate (polymethacrylate) or synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 물질에 배향성을 부여할 수 있다.In addition, in the present invention, the magnetic material may have a coating layer formed on the surface. The coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound. Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci .), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins, and protein A is Staphylococcus aureus ( Staphylococcus aureus ) As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
본 발명에서 상기 자성 물질은 그 자체로 사용하거나, 수용액에 분산되어 사용할 수 있으나, 수용액에 분산되어 사용하는 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1 종 이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments. At this time, the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used. One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
본 발명에서 상기 자성 물질은 타겟으로 하는 세포에 존재하는 항원을 인식하여 결합할 수 있는 항체를 더 포함할 수 있다. In the present invention, the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
본 발명에서 상기 "항체"는 항원과 특이적으로 결합하여 항원-항체 반응을 일으키는 물질을 가리킨다. 본 발명의 목적상, 항체는 상기 목적하는 개체의 치료를 위한 특정 세포에 대해 특이적으로 결합하는 항체를 의미한다. In the present invention, the "antibody" refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction. For the purposes of the present invention, an antibody refers to an antibody that specifically binds to a particular cell for the treatment of the subject of interest.
본 발명에서 상기 항체는 다클론 항체, 단클론 항체 및 재조합 항체를 모두 포함할 수 있다. 상기 항체는 당 업계에 널리 공지된 기술을 이용하여 용이하게 제조될 수 있다. 예를 들어, 다클론 항체는 상기 단백질의 항원을 동물에 주사하고 동물로부터 채혈하여 항체를 포함하는 혈청을 수득하는 과정을 포함하는 당 업계에 널리 공지된 방법에 의해 생산될 수 있다. 이러한 다클론 항체는 염소, 토끼, 양, 원숭이, 말, 돼지, 소, 개 등의 임의의 동물로부터 제조될 수 있다. 또한, 단클론 항체는 당 업계에 널리 공지된 하이브리도마 방법(hybridoma method; Kohler 및 Milstein (1976) European Journal of Immunology 6:511-519 참조), 또는 파지 항체 라이브러리 기술(Clackson et al, Nature, 352:624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991 참조)을 이용하여 제조될 수 있다. 상기 방법으로 제조된 항체는 겔 전기영동, 투석, 염 침전, 이온교환 크로마토그래피, 친화성 크로마토그래피 등의 방법을 이용하여 분리, 정제될 수 있다. 또한, 본 발명의 항체는 2 개의 전장의 경쇄 및 2 개의 전장의 중쇄를 갖는 완전한 형태뿐만 아니라, 항체 분자의 기능적인 단편을 포함한다. 항체 분자의 기능적인 단편이란, 적어도 항원 결합 기능을 보유하고 있는 단편을 의미하며, Fab, F(ab'), F(ab')2 및 Fv 등이 있다.In the present invention, the antibody may include all of a polyclonal antibody, a monoclonal antibody, and a recombinant antibody. The antibody can be easily prepared using techniques well known in the art. For example, the polyclonal antibody can be produced by a method well known in the art, including the process of injecting an antigen of the protein into an animal and collecting blood from the animal to obtain a serum containing the antibody. Such polyclonal antibodies can be prepared from any animal such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like. In addition, monoclonal antibodies can be prepared using the hybridoma method well known in the art (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), or the phage antibody library technology (Clackson et al, Nature, 352). :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991). The antibody prepared by the above method may be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography. In addition, the antibodies of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
본 발명에서 상기 세포의 표면에 존재하는 항원은 HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나의 단백질일 수 있으나, 이에 제한되는 것은 아니며, 입술 또는 구강 조직을 이루는 세포에 특이적으로 존재하는 항원이라면 제한없이 포함될 수 있다.In the present invention, the antigen present on the surface of the cell may be at least one protein selected from the group consisting of HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is limited thereto. It is not, and may be included without limitation as long as it is an antigen that is specifically present in cells constituting the lips or oral tissue.
본 발명에서 상기 자성 세포 또는 자성 세포 군집체를 목적하는 개체의 입술 또는 구강 조직으로, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등에 주입한 뒤 자기력을 인가하여 갈라진 변형 부위의 봉합, 재건 또는 복원을 통해 구순 구개열을 개선 또는 치료할 수 있다. In the present invention, the magnetic cells or the magnetic cell cluster is the lip or oral tissue of the subject, preferably the lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate). ), and then applying magnetic force, it is possible to improve or treat cleft lip and cleft lip through suturing, reconstruction or restoration of the cracked deformed area.
본 발명에서 상기 자성 세포 또는 자성 세포 군집체를 상기 입술 또는 구강 조직에 주입하는 경우 비제한적인 예시로는 액상 주사 형태 또는 액상을 연성 발포체에 흡수시킨 후 상기 발포체를 주입할 수 있다, 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다. 도 2 및 도 3은 본 발명의 자성 세포의 체내 주입 방식을 나타낸 것이다. In the present invention, when the magnetic cells or magnetic cell aggregates are injected into the lip or oral tissue, a non-limiting example may be a liquid injection form or a liquid injection form after absorbing the liquid into a flexible foam and then injecting the foam, liquid injection form The residence time may appear relatively short when injected into can do. 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
본 발명에서 상기 자성 세포 또는 자성 세포 군집체의 주입 시 부유액에 자성 세포 또는 자성 세포 군집체를 혼합하여 주입하는 것이 부유액의 점도를 조절하여 자성 세포를 포함한 주사액의 확산 속도 및 주입된 자성 세포의 유지 시간 제어가 가능하며 부유액에 혼합된 자성 세포의 양을 조절함으로써 자력 제어가 가능하여 바람직하다. 여기서, 상기 부유액은 생분해성의 PDMS, 히알루론산, 콜라겐, 키틴, 키토산, 헤파린 또는 이들의 조합일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when the magnetic cells or magnetic cell aggregates are injected, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to maintain the diffusion rate of the injection solution including the magnetic cells and the maintenance of the injected magnetic cells It is preferable because time control is possible and magnetic force control is possible by adjusting the amount of magnetic cells mixed in the suspension. Here, the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
본 발명에서는 상기 자기력의 인가 시 자성 세포들의 자력 방향 제어를 통제할 수 있고, 예를 들어 자기력의 방향이 결정되지 않은 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시킬 수 있다. 도 4는 본 발명에서 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시키는 과정을 나타낸 모식도이다. 본 발명에서 강자성 상태의 세포로 전환 시 가해지는 자기력의 크기는 자성 물질이 자화되기 위한 정도의 크기로 특별히 제한하지는 않으나 예를 들면 70 가우스 이상인 것일 수 있으나, 이에 제한되는 것은 아니다. 이렇게 각각의 세포가 주입된 위치마다 자기장 방향과 강도를 조절하여, 자성 세포 간 인력 또는 척력을 정밀하게 제어할 수 있다. In the present invention, when the magnetic force is applied, it is possible to control the direction control of the magnetic force of the magnetic cells, for example, by applying a specific magnetic field to the magnetic cells containing the paramagnetic material in which the direction of the magnetic force is not determined to have a magnetic force in a desired direction. It can be transformed into a cell in a ferromagnetic state. 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention. In the present invention, the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
본 발명에서 상기 자기력의 인가는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다.In the present invention, the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서는 상기 자기력의 인가 시 상기 자성 입자와 상기 자석 간의 척력 또는 인력을 이용하여 입술 또는 구강 조직에서 갈라진 변형 부위를 봉합, 복원 또는 재건할 수 있고, 이를 통해 적어도 구순 구개열의 개선 효과를 얻을 수 있는 등 뼈 또는 피부 조직의 이식을 대체하거나 수술 부위를 최소화할 수 있다. 도 1은 본 발명에 따른 자성 세포의 조직의 형상 제어 원리를 나타낸 것으로 (a)는 자성의 인력에 따른 갈라진 두 부위의 봉합, (b)는 자성의 척력에 따른 갈라진 두 부위의 확장을 나타낸 모식도이다.In the present invention, when the magnetic force is applied, using the repulsive force or attractive force between the magnetic particles and the magnet, it is possible to suture, restore, or reconstruct the deformed part cracked in the lips or oral tissue, and through this, at least an improvement effect of cleft lip and cleft can be obtained. It can replace the transplant of bone or skin tissue in the back or minimize the surgical site. 1 is a schematic diagram showing the principle of controlling the shape of the tissue of a magnetic cell according to the present invention, in which (a) is suture of two cracked parts due to magnetic attraction, (b) is a schematic diagram showing the expansion of the two parts split according to magnetic repulsive force to be.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 근육, 조직의 수축 또는 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of contraction or relaxation of the desired muscle or tissue, and is not particularly limited.
본 발명에서 상기 "구순 구개열"이란 얼굴에 생기는 선천성 기형 중 하나로, 정확하게는 입술이 갈라진 구순열과 입천장이 갈라진 구개열로 나뉘나 통상적으로 두 가지가 동반되는 경우가 많고, 일반인들이 구분하기도 힘들기에 합쳐서 구순 구개열이라고도 명한다. 얼굴이 만들어지는 임신 4 내지 7 주 사이에 입술(구순) 및 입천장(구개)을 만드는 조직이 적절히 붙지 못하거나 붙었더라도 유지되지 않고 떨어져서 생기는 입술 또는 입천장의 갈림증이다. 단순히 피부나 입천장 점막의 갈림증 만이 아니라 근육, 연골, 뼈에 이르는 총체적인 변형을 야기하며, 입술, 입천장 이외에도 코, 치아, 잇몸 및 위턱 등의 성장과 형태에 영향을 미쳐 얼굴 전체가 비정상적으로 될 수 있다. 현재 구순 구개열을 치료하기 위한 방법으로는 수술적 방법 외에는 다른 대안이 없으며, 아기가 출생한 직후부터 성장이 완료되는 대략 18 세 시점까지 간단한 시술을 비롯하여 성형 수술 또는 교정 수술 등을 수회 반복적으로 시행해야 하는 문제가 있으며, 수술 시에 상처 등이 남게 되어 미관 상으로도 치료의 한계점이 존재한다. In the present invention, the term "Cleft palate" is one of the congenital malformations that occur on the face, and it is precisely divided into a cleft lip and cleft palate. It is also called cleft palate. It is a fissure of the lips or palate that occurs between the 4th and 7th weeks of pregnancy when the face is made, when the tissues making the lips (labial) and the roof of the mouth (palatal) do not adhere properly or are not maintained even though they are attached. It causes not only the skin or palate mucosa but also a general deformation of muscles, cartilage, and bones. have. Currently, there is no other alternative to the treatment of cleft lip and cleft lip, except surgical method. There is a problem with the treatment, and there is a limit to the treatment in terms of aesthetics as scars are left during the operation.
본 발명에서 상기 구순 구개열은 구순열 및 구개열 중 적어도 하나일 수 있으며, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
본 발명의 다른 구현 예에 따르면, 구순 구개열의 개선 또는 치료용 자성 세포 또는 자성 세포 군집체를 제조하는 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method for producing a magnetic cell or a magnetic cell aggregate for the treatment or improvement of cleft palate.
본 발명의 제조 방법은 자성 물질을 준비하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include preparing a magnetic material.
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다.In the present invention, the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite (γ-Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm 내지 1μm, 바람직하게는 50 내지 700 nm, 보다 바람직하게는 200 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the average diameter of the magnetic material may be 1 nm to 1 μm, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질을 도핑할 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질을 도핑하는 것이 좋으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility. ), polyvinyl pyrrolidone (polyvinyl pyrrolidone), polyethyleneimine (polyethyleneimine), polymethacrylate (polymethacrylate) or synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 물질에 배향성을 부여할 수 있다.In addition, in the present invention, the magnetic material may have a coating layer formed on the surface. The coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound. Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci. ), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins, and protein A is Staphylococcus aureus ) As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
본 발명에서 상기 자성 물질은 그 자체로 사용하거나, 수용액에 분산되어 사용할 수 있으나, 수용액에 분산되어 사용하는 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1 종 이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments. At this time, the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used. One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
본 발명의 제조 방법은 준비된 자성 물질에 항체를 코팅하는 단계를 포함할 수 있다.The preparation method of the present invention may include coating the antibody on the prepared magnetic material.
본 발명에서 상기 자성 물질은 타겟으로 하는 세포에 존재하는 항체를 인식하여 결합할 수 있는 항체를 더 포함할 수 있다.In the present invention, the magnetic material may further include an antibody capable of recognizing and binding to an antibody present in a target cell.
본 발명에서 상기 항원은 HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나의 단백질일 수 있으나, 이에 제한되는 것은 아니며, 입술 또는 구강 조직을 이루는 세포에 특이적으로 존재하는 항원이라면 제한없이 포함될 수 있다.In the present invention, the antigen may be at least one protein selected from the group consisting of HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto. Any antigen that is specifically present in cells constituting oral tissues may be included without limitation.
본 발명의 제조 방법은 상기 항체가 코팅된 자성 물질이 도입될 세포를 준비하는 단계를 포함할 수 있다. The preparation method of the present invention may include preparing cells into which the antibody-coated magnetic material will be introduced.
본 발명에서 상기 세포의 종류는 특별히 제한하지 않으며 입술 또는 구강 조직, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등에 위치한 세포로, 예를 들면 상피세포(epithelial cell), 뼈세포(osteoblast), 섬유아세포(fibroblast) 또는 근세포(myocyte)일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the type of the cell is not particularly limited, and it is a cell located in the lips or oral tissue, preferably the lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate). , For example, epithelial cells (epithelial cells), bone cells (osteoblast), may be a fibroblast (fibroblast) or myocyte (myocyte), but is not limited thereto.
본 발명에서 상기 세포를 준비하는 단계 시 목적하는 개체의 생물학적 시료로부터 채취된 세포를 유도만능줄기세포로 역분화시키는 단계; 및 상기 유도만능줄기세포를 입술 또는 구강 조직을 이루는 세포로 분화시키는 단계;를 포함할 수 있다.In the present invention, in the step of preparing the cells, the step of dedifferentiating the cells collected from the biological sample of the subject of interest into induced pluripotent stem cells; and differentiating the induced pluripotent stem cells into cells constituting the lips or oral tissue.
본 발명에서 상기 목적하는 개체는 구순 구개열이 발생한 개체로, 구순열 및 구개열 중 적어도 하나가 발생한 개체일 수 있고, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열이 발생한 개체일 수 있다. 또한, 상기 개체는 바람직하게는 인간, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 인간일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the subject subject is an individual with cleft lip and cleft palate, and may be an individual with at least one of cleft lip and cleft palate, and as non-limiting examples, incomplete cleft lip, unilateral complete cleft lip or bilateral complete cleft lip, incomplete cleft lip, unilateral complete cleft lip. It may be an individual who has developed cleft palate, bilateral complete cleft palate, unilateral complete cleft palate, or bilateral complete cleft palate. In addition, the subject is preferably human, rat, mouse, guinea pig, hamster, rabbit, monkey, dog, cat, cow, horse, pig, sheep and goat may be selected from the group consisting of, more preferably human However, the present invention is not limited thereto.
본 발명에서 상기 생물학적 시료는 개체로부터 얻어지거나 개체로부터 유래된 임의의 물질, 생물학적 체액, 조직 또는 세포를 의미하는 것으로, 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 등으로 이루어진 군에서 선택된 1 종 이상일 수 있으나, 이에 제한되지 않는다.In the present invention, the biological sample refers to any material, biological fluid, tissue or cell obtained from or derived from an individual, and includes whole blood, leukocytes, and peripheral blood mononuclear cells. ), buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate, respiration (breath), urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid , glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate (joint aspirate), organ secretions (organ secretions), cells (cell), cell extract (cell extract), and may be at least one selected from the group consisting of cerebrospinal fluid (cerebrospinal fluid), but is not limited thereto.
본 발명의 제조 방법은 상기와 같이 준비된 세포에 자성 물질을 처리하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include treating the cells prepared as described above with a magnetic material.
본 발명에서 상기 처리하는 단계 시 몰드 상에서 세포의 일부가 노출되도록 고정시키며 수행할 수 있다. In the present invention, it can be carried out while fixing a part of the cells to be exposed on the mold during the treatment step.
본 발명에서 상기 몰드는 실리콘 재질의 통상적인 몰드일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the mold may be a conventional mold made of a silicon material, but is not limited thereto.
본 발명에서 상기 처리하는 단계 시 상기 몰드에 자기력을 인가한 상태에서 상기 세포의 표면에 상기 자성 물질을 처리하며 수행할 수 있다. In the present invention, the treatment may be performed by treating the magnetic material on the surface of the cell while a magnetic force is applied to the mold.
본 발명에서 상기 자기력의 인가는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. In the present invention, the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서 상기 자기력은 자성 물질의 배열을 위한 정도의 세기이면 족하고, 비제한적 예시로 5 내지 10 가우스일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic force suffices as long as the strength is sufficient for the arrangement of magnetic materials, and may be 5 to 10 Gauss as a non-limiting example, but is not limited thereto.
본 발명에서 상기 처리하는 단계 시 자성 물질에 존재하는 항체와 상기 세포의 표면에 존재하는 항원 사이의 항원-항체 반응을 이용한 면역 표지법 또는 직접 도입법 등을 통해 자성 물질이 세포 외부 표면에 부착된 형태의 자성 세포 또는 자성 세포 군집체가 제조될 수 있다.In the present invention, during the treatment step, the magnetic material is attached to the outer surface of the cell through an immunolabeling method or direct introduction method using an antigen-antibody reaction between the antibody present in the magnetic material and the antigen present on the surface of the cell. A magnetic cell or a magnetic cell population may be prepared.
본 발명에서 상기 구순 구개열은 구순열 및 구개열 중 적어도 하나일 수 있으며, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
1-2. 수면 무호흡증의 예방, 개선 또는 치료용 자성 세포 또는 자성 세포 군집체1-2. Magnetic cells or populations of magnetic cells for the prevention, improvement or treatment of sleep apnea
본 발명의 또 다른 구현 예에 따르면, 수면 무호흡증의 예방, 개선 또는 치료용 자성 세포 또는 자성 세포 군집체에 관한 것이다. According to another embodiment of the present invention, it relates to a magnetic cell or a magnetic cell aggregate for the prevention, improvement or treatment of sleep apnea.
본 발명에서 상기 자성 세포는 자성 물질을 포함하는 것으로, 바람직하게는 자성 물질이 세포 표면에 결합되거나 세포 내부에 위치하는 형태로써 세포에 포함될 수 있다. In the present invention, the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
본 발명에서 상기 세포의 종류는 특별히 제한하지 않으며 호흡기계 유동관, 바람직하게는 비강, 인후두 또는 기도의 관 내벽 세포로, 예를 들면 섬유아세포(fibroblast) 또는 근세포(myocyte)일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the type of the cell is not particularly limited, and the cell of the respiratory system flow tract, preferably the nasal, pharyngeal or airway lining, may be, for example, fibroblast or myocyte, but is limited thereto. it is not
또한, 본 발명에서 상기 세포 군집체는 상기 자성 세포가 복수 개로 구성되어 형성된 환상의 세포 군집체일 수 있으나, 이에 제한되는 것은 아니다. In addition, in the present invention, the cell aggregate may be a cyclic cell aggregate formed of a plurality of the magnetic cells, but is not limited thereto.
본 발명에서 상기 "자성 물질"이란 자기적 성질을 가진 물질을 의미하는 것으로 자기적 성질에 따라 크게 상자성, 초상자성, 반자성, 강자성으로 구분된다. 구체적으로 상자성체는 자기장 안에 놓여진 경우에 자기장 방향으로 약하게 자화되고, 자기장이 제거되면 자화되지 않는 물질이며, 그 예시로써 알루미늄, 주석, 백금, 이리듐 등이 존재한다. 반자성체는 외부 자기장에 의해 반대 방향으로 자화되는 물질이며, 그 예시로서 수소, 물, 납, 구리, 아연 등의 금속과 염류 등이 이에 해당한다. 이와 달리 강자성체는 외부 자기장이 없는 상태에서도 자화되는 물질의 자기적 성질을 가지는 물질을 말하는 것으로, 철, 니켈 및 코발트 등이 이에 해당하며 자기장의 방향으로 강하게 자화되며 자석에 강하게 끌리는 특성을 갖는다. 초상자성체는 비 강자성체의 구조내 강자성체 입자들이 고립된 형태로 존재하는 물질로 초상자성은 낮은 자기장을 인가하여도 강자성을 나타내며 자화가 포화되나, 자기장 인가를 중지하면 자화가 소멸되는 상태가 된다. 자성체의 입경을 나노 크기로 하면 상온에서 초상자성이 나타나게 되는데 현재 이러한 특성을 이용하여 의학, 약학, 바이오, 화학 분야에서 많은 연구가 수행되고 있다.In the present invention, the "magnetic material" refers to a material having magnetic properties, and is largely divided into paramagnetic, superparamagnetic, diamagnetic, and ferromagnetic according to magnetic properties. Specifically, a paramagnetic material is a material that is weakly magnetized in the magnetic field direction when placed in a magnetic field and is not magnetized when the magnetic field is removed, and examples thereof include aluminum, tin, platinum, iridium, and the like. A diamagnetic material is a material that is magnetized in the opposite direction by an external magnetic field, and examples thereof include metals such as hydrogen, water, lead, copper, zinc, etc. and salts. On the other hand, a ferromagnetic material refers to a material having magnetic properties of a material that is magnetized even in the absence of an external magnetic field, and includes iron, nickel, and cobalt. A superparamagnetic material is a material in which ferromagnetic particles in the structure of a non-ferromagnetic material exist in an isolated form. Superparamagnetic material exhibits ferromagnetism even when a low magnetic field is applied, and the magnetization is saturated, but the magnetization disappears when the magnetic field application is stopped. When the particle size of the magnetic material is made into a nano size, superparamagnetism appears at room temperature. Currently, many studies are being conducted in medicine, pharmacy, bio, and chemistry using this characteristic.
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 초상자성 또는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다. In the present invention, the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a superparamagnetic or paramagnetic material is applied later as necessary by applying an appropriate magnetic force to produce a desired effect and induce discharge out of the body have.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질 일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금(CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite (γ-Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm 내지 1μm, 바람직하게는 50 내지 700 nm, 보다 바람직하게는 200 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the average diameter of the magnetic material may be 1 nm to 1 μm, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질을 도핑할 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질을 도핑하는 것이 좋으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility. ), polyvinyl pyrrolidone (polyvinyl pyrrolidone), polyethyleneimine (polyethyleneimine), polymethacrylate (polymethacrylate) or synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 물질에 배향성을 부여할 수 있다.In addition, in the present invention, the magnetic material may have a coating layer formed on the surface. The coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound. Protein G is a cell wall protein isolated from group C or group G Streptococcus bacteria (Streptococci.), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins. Protein A is Staphylococcus aureus. As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
본 발명에서 상기 자성 물질은 그 자체로 사용하거나, 수용액에 분산되어 사용할 수 있으나, 수용액에 분산되어 사용하는 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1 종 이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments. At this time, the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used. One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
본 발명에서 상기 자성 물질은 타겟으로 하는 세포에 존재하는 항원을 인식하여 결합할 수 있는 항체를 더 포함할 수 있다. In the present invention, the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
본 발명에서 상기 "항체"는 항원과 특이적으로 결합하여 항원-항체 반응을 일으키는 물질을 가리킨다. 본 발명의 목적상, 항체는 상기 목적하는 개체의 치료를 위한 특정 세포에 대해 특이적으로 결합하는 항체를 의미한다. In the present invention, the "antibody" refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction. For the purposes of the present invention, an antibody refers to an antibody that specifically binds to a particular cell for the treatment of the subject of interest.
본 발명에서 상기 항체는 다클론 항체, 단클론 항체 및 재조합 항체를 모두 포함할 수 있다. 상기 항체는 당 업계에 널리 공지된 기술을 이용하여 용이하게 제조될 수 있다. 예를 들어, 다클론 항체는 상기 단백질의 항원을 동물에 주사하고 동물로부터 채혈하여 항체를 포함하는 혈청을 수득하는 과정을 포함하는 당 업계에 널리 공지된 방법에 의해 생산될 수 있다. 이러한 다클론 항체는 염소, 토끼, 양, 원숭이, 말, 돼지, 소, 개 등의 임의의 동물로부터 제조될 수 있다. 또한, 단클론 항체는 당 업계에 널리 공지된 하이브리도마 방법(hybridoma method; Kohler 및 Milstein (1976) European Journal of Immunology 6:511-519 참조), 또는 파지 항체 라이브러리 기술(Clackson et al, Nature, 352:624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991 참조)을 이용하여 제조될 수 있다. 상기 방법으로 제조된 항체는 겔 전기영동, 투석, 염 침전, 이온교환 크로마토그래피, 친화성 크로마토그래피 등의 방법을 이용하여 분리, 정제될 수 있다. 또한, 본 발명의 항체는 2개의 전장의 경쇄 및 2 개의 전장의 중쇄를 갖는 완전한 형태뿐만 아니라, 항체 분자의 기능적인 단편을 포함한다. 항체 분자의 기능적인 단편이란, 적어도 항원 결합 기능을 보유하고 있는 단편을 의미하며, Fab, F(ab'), F(ab')2 및 Fv 등이 있다.In the present invention, the antibody may include all of a polyclonal antibody, a monoclonal antibody, and a recombinant antibody. The antibody can be easily prepared using techniques well known in the art. For example, the polyclonal antibody can be produced by a method well known in the art, including the process of injecting an antigen of the protein into an animal and collecting blood from the animal to obtain a serum containing the antibody. Such polyclonal antibodies can be prepared from any animal such as goat, rabbit, sheep, monkey, horse, pig, cow, dog, and the like. In addition, monoclonal antibodies can be prepared using the hybridoma method well known in the art (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), or the phage antibody library technology (Clackson et al, Nature, 352). :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991). The antibody prepared by the above method may be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography. In addition, the antibodies of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule means a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2 and Fv.
본 발명에서 상기 세포의 표면에 존재하는 항원은 Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나의 단백질일 수 있으나, 이에 제한되는 것은 아니며, 호흡계 기관, 바람직하게는 기도를 이루는 세포에 특이적으로 존재하는 항원이라면 제한없이 포함될 수 있다.In the present invention, the antigen present on the surface of the cell may be at least one protein selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto, and respiratory organs , Preferably, as long as it is an antigen that is specifically present in cells constituting the airways, it may be included without limitation.
본 발명에서 상기 "수면 무호흡증 (sleep apnea syndrome)"이란 연구개와 인두벽이 이완되거나 처지면 호흡 중 느슨해진 조직이 공기 흐름을 따라 진동하면서 코골이를 발생시키고, 기도를 막아 호흡이 멈추는 질환을 가리킨다. 상기 질환은 수면 중에 호흡을 제대로 하지 못하는 증상이 나타나 수면에 심각한 장애를 일으켜 오래 자도 충분히 피로가 해소되지 않게 만들며, 심각하게는 심장에도 상당히 무리를 주게 되는 등 건강에 이상이 야기될 수 있다. 크게는 상부 기도의 폐쇄에 의하여 발생하는 폐쇄성 수면 무호흡증, 신경학적 장애로 발생하는 중추형 수면 무호흡증 또는 초기에 중추형으로 시작되나 점차 폐쇄형으로 바뀌게 되는 혼합형 수면 무호흡증으로 나뉜다. 현재 수면 무호흡증을 치료하기 위한 방법으로 수술적 방법 또는 호흡 보조 장치를 이용하고 있지만, 수술적 방법은 해부학적 이상 부위로서 코, 목젓 주위, 혀 뿌리 부위를 절제하여 봉합하거나 열을 가하여 조직을 줄여주는 침습적인 방식이라는 점에 한계점이 있으며, 증상의 완화를 위해 사용되는 보조적 의료 기기 또한 효과가 일시적이며 상시 착용으로 인한 오염으로 초래되는 폐렴, 비강 건조, 근육통 등의 합병증 발생 우려가 높은 한계점이 있다. In the present invention, the term "sleep apnea syndrome" refers to a disease in which when the soft palate and pharyngeal wall relax or sag, the tissue loosened during respiration vibrates along the air flow to generate snoring and block the airway to stop breathing. . The disease may cause health problems, such as the symptoms of not being able to breathe properly during sleep, causing serious disturbances in sleep, so that fatigue is not fully resolved even after a long sleep, and seriously, it puts a considerable strain on the heart. It is largely divided into obstructive sleep apnea caused by obstruction of the upper airway, central sleep apnea caused by a neurological disorder, or mixed sleep apnea that starts in the central type but gradually changes to the obstructive type. Currently, surgical methods or breathing aids are used as a method to treat sleep apnea, but the surgical method is an anatomically abnormal area that reduces tissue by excising the nose, around the throat, and at the root of the tongue, then suturing or applying heat. There is a limitation in that it is an invasive method, and an auxiliary medical device used for symptom relief is also temporary, and there is a high risk of complications such as pneumonia, nasal dryness, and muscle pain caused by contamination caused by constant wearing.
본 발명에서 상기 수면 무호흡증은 폐쇄성 수면 무호흡증, 중추형 수면 무호흡증 또는 혼합형 수면 무호흡증일 수 있으며, 바람직하게는 폐쇄형 수면 무호흡증일 수 있으나, 기도 관의 협착 또는 폐쇄에 의해 발생하는 호흡 곤란으로 초래되는 질환에 해당하는 한, 수면 중에 발생하는 수면 무호흡증으로 제한되지 않고 모두 포함할 수 있다. In the present invention, the sleep apnea may be obstructive sleep apnea, central sleep apnea, or mixed sleep apnea, preferably obstructive sleep apnea, but a disease caused by difficulty breathing caused by stenosis or obstruction of airway ducts It can include, but is not limited to, sleep apnea that occurs during sleep, as long as it is applicable.
본 발명에서 상기 자성 세포 또는 자성 세포 군집체를 목적하는 개체의 호흡기계 유동관, 바람직하게는 비강, 인후두 또는 기도에 주입한 뒤 자기력을 인가하여 상기 호흡기계 유동관의 이완을 유도함으로써 수면 무호흡증을 예방, 개선 또는 치료할 수 있다. In the present invention, sleep apnea is prevented by inducing relaxation of the respiratory system flow tube by applying magnetic force after injecting the magnetic cells or magnetic cell cluster into the respiratory system flow tube, preferably the nasal cavity, larynx, or airway of the target individual, can be improved or treated.
본 발명에서 상기 자성 세포 또는 자성 세포 군집체를 상기 호흡기계 유동관에 주입하는 경우 비제한적인 예시로는 액상 주사 형태 또는 액상을 연성 발포체에 흡수시킨 후 상기 발포체를 주입할 수 있다, 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다. 도 2 및 도 3은 본 발명의 자성 세포의 체내 주입 방식을 나타낸 것이다. In the present invention, when the magnetic cells or the magnetic cell aggregate are injected into the respiratory system flow tube, as a non-limiting example, the liquid injection form or the liquid may be absorbed into the flexible foam and then the foam may be injected. In the case of injection, the residence time may appear relatively short, but when injected in the form of a foam, it may remain in the living body for a long time, so it can be appropriately selected according to the desired residence time. can 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
본 발명에서 상기 자성 세포 또는 자성 세포 군집체의 주입 시 부유액에 자성 세포 또는 자성 세포 군집체를 혼합하여 주입하는 것이 부유액의 점도를 조절하여 자성 세포를 포함한 주사액의 확산 속도 및 주입된 자성 세포의 유지 시간 제어가 가능하며 부유액에 혼합된 자성 세포의 양을 조절함으로써 자력 제어가 가능하여 바람직하다. 여기서, 상기 부유액은 생분해성의 PDMS, 히알루론산, 콜라겐, 키틴, 키토산, 헤파린 또는 이들의 조합일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when the magnetic cells or magnetic cell aggregates are injected, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to maintain the diffusion rate of the injection solution including the magnetic cells and the maintenance of the injected magnetic cells It is preferable because time control is possible and magnetic force control is possible by adjusting the amount of magnetic cells mixed in the suspension. Here, the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
본 발명에서는 상기 자기력의 인가 시 자성 세포들의 자력 방향 제어를 통제할 수 있고, 예를 들어 자기력의 방향이 결정되지 않은 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시킬 수 있다. 도 4는 본 발명에서 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시키는 과정을 나타낸 모식도이다. 본 발명에서 강자성 상태의 세포로 전환 시 가해지는 자기력의 크기는 자성 물질이 자화되기 위한 정도의 크기로 특별히 제한하지는 않으나 예를 들면 70 가우스 이상인 것일 수 있으나, 이에 제한되는 것은 아니다. 이렇게 각각의 세포가 주입된 위치마다 자기장 방향과 강도를 조절하여, 자성 세포 간 인력 또는 척력을 정밀하게 제어할 수 있다. In the present invention, when the magnetic force is applied, it is possible to control the direction control of the magnetic force of the magnetic cells, for example, by applying a specific magnetic field to the magnetic cells containing the paramagnetic material in which the direction of the magnetic force is not determined to have a magnetic force in a desired direction. It can be transformed into a cell in a ferromagnetic state. 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention. In the present invention, the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
본 발명에서 상기 자기력의 인가는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. In the present invention, the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서는 상기 자기력의 인가 시 상기 자성 입자와 상기 자석 간의 척력 또는 인력을 이용하여 호흡기계 유동관의 이완을 유도할 수 있고, 구체적인 일 예시로는 상기 호흡기계 유동관, 바람직하게는 비강, 인후두 또는 기도, 특히는 기도에 위치하는 자성 세포 내 자성 물질과 외부 자석 사이의 인력에 의해 기도의 이완을 유도할 수 있다. 도 1은 본 발명에 따른 자성 세포의 호흡기계 유동관의 형상 제어 원리를 나타낸 것으로 (a)는 자성의 인력에 따른 호흡기계 유동관의 축소, (b)는 자성의 척력에 따른 호흡기계 유동관의 확장을 나타낸 모식도이다.In the present invention, when the magnetic force is applied, relaxation of the respiratory tract can be induced by using a repulsive or attractive force between the magnetic particles and the magnet, and as a specific example, the respiratory tract can be induced, preferably the nasal cavity, larynx or airway. , in particular, the relaxation of the airway may be induced by the attraction between the magnetic material in the magnetic cell located in the airway and the external magnet. 1 shows the shape control principle of the respiratory system flow tube of magnetic cells according to the present invention. (a) is a contraction of the respiratory system flow tube according to magnetic attraction, (b) is an expansion of the respiratory system flow tube according to a magnetic repulsive force. It is a schematic diagram shown.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 관, 기도의 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of relaxation of the desired tube and airway, and is not particularly limited.
본 발명의 또 다른 구현 예에 따르면, 수면 무호흡증의 예방, 개선 또는 치료용 자성 세포 또는 자성 세포 군집체를 제조하는 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method for producing a magnetic cell or a magnetic cell aggregate for the prevention, improvement or treatment of sleep apnea.
본 발명의 제조 방법은 자성 물질을 준비하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include preparing a magnetic material.
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다. In the present invention, the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질 일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite (γ-Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm 내지 1μm, 바람직하게는 50 내지 700 nm, 보다 바람직하게는 200 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the average diameter of the magnetic material may be 1 nm to 1 μm, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질을 도핑할 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질을 도핑하는 것이 좋으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility. ), polyvinyl pyrrolidone (polyvinyl pyrrolidone), polyethyleneimine (polyethyleneimine), polymethacrylate (polymethacrylate) or synthetic polymer materials such as polyvinyl alcohol (polyvinyl alcohol), or doping natural polymer materials such as polysaccharides It is preferable to dope a biocompatible natural polymer material for in vivo use, but if it corresponds to a material having biocompatibility, it is not limited thereto.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 물질에 배향성을 부여할 수 있다.In addition, in the present invention, the magnetic material may have a coating layer formed on the surface. The coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound. Protein G is a cell wall protein isolated from group C or group G Streptococcus bacteria (Streptococci.), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins. Protein A is Staphylococcus aureus. As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
본 발명에서 상기 자성 물질은 그 자체로 사용하거나, 수용액에 분산되어 사용할 수 있으나, 수용액에 분산되어 사용하는 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1 종 이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be used by itself or dispersed in an aqueous solution, but it is more preferable to use dispersed in an aqueous solution to reduce aggregation of the magnetic material and to facilitate experiments. At this time, the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used. One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
본 발명의 제조 방법은 준비된 자성 물질에 항체를 코팅하는 단계를 포함할 수 있다.The preparation method of the present invention may include coating the antibody on the prepared magnetic material.
본 발명에서 상기 자성 물질은 타겟으로 하는 세포에 존재하는 항체를 인식하여 결합할 수 있는 항체를 더 포함할 수 있다. In the present invention, the magnetic material may further include an antibody capable of recognizing and binding to an antibody present in a target cell.
본 발명에서 상기 항원은 Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나의 단백질일 수 있으나, 이에 제한되는 것은 아니며, 호흡계 기관, 바람직하게는 기도를 이루는 세포에 특이적으로 존재하는 항원이라면 제한없이 포함될 수 있다.In the present invention, the antigen may be at least one protein selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto. Any antigen that is specifically present in cells constituting the cell may be included without limitation.
본 발명의 제조 방법은 상기 항체가 코팅된 자성 물질이 도입될 세포를 준비하는 단계를 포함할 수 있다. The preparation method of the present invention may include preparing cells into which the antibody-coated magnetic material will be introduced.
본 발명에서 상기 세포의 종류는 특별히 제한하지 않으며 호흡기계 유동관, 바람직하게는 비강, 인후두 또는 기도의 관 내벽 세포로, 예를 들면 섬유아세포(fibroblast) 또는 근세포(myocyte)일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the type of the cell is not particularly limited, and the cell of the respiratory system flow tract, preferably the nasal, pharyngeal or airway lining, may be, for example, fibroblast or myocyte, but is limited thereto. it is not
본 발명에서 상기 세포를 준비하는 단계 시 목적하는 개체의 생물학적 시료로부터 채취된 세포를 유도만능줄기세포로 역분화시키는 단계; 및 상기 유도만능줄기세포를 호흡기계 유동관의 관 내벽 세포로 분화시키는 단계;를 포함할 수 있다.In the present invention, in the step of preparing the cells, the step of dedifferentiating the cells collected from the biological sample of the subject of interest into induced pluripotent stem cells; and differentiating the induced pluripotent stem cells into ductal lining cells of the respiratory tract.
본 발명에서 상기 목적하는 개체는 수면 무호흡증 (sleep apnea syndrome)이 발병하였거나 발병 가능성이 높은 개체일 수 있다. In the present invention, the subject of interest may be an individual who has or is highly likely to develop sleep apnea syndrome.
본 발명에서 상기 생물학적 시료는 개체로부터 얻어지거나 개체로부터 유래된 임의의 물질, 생물학적 체액, 조직 또는 세포를 의미하는 것으로, 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 등으로 이루어진 군에서 선택된 1 종 이상일 수 있으나, 이에 제한되지 않는다.In the present invention, the biological sample refers to any material, biological fluid, tissue or cell obtained from or derived from an individual, and includes whole blood, leukocytes, and peripheral blood mononuclear cells. ), buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate, respiration (breath), urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid , glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate (joint aspirate), organ secretions (organ secretions), cells (cell), cell extract (cell extract), and may be at least one selected from the group consisting of cerebrospinal fluid (cerebrospinal fluid), but is not limited thereto.
본 발명의 제조 방법은 상기와 같이 준비된 세포에 자성 물질을 처리하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include treating the cells prepared as described above with a magnetic material.
본 발명에서 상기 처리하는 단계 시 몰드 상에서 세포의 일부가 노출되도록 고정시키며 수행할 수 있다. In the present invention, it can be carried out while fixing a part of the cells to be exposed on the mold during the treatment step.
본 발명에서 상기 몰드는 실리콘 재질의 통상적인 몰드일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the mold may be a conventional mold made of a silicon material, but is not limited thereto.
본 발명에서 상기 처리하는 단계 시 상기 몰드에 자기력을 인가한 상태에서 상기 세포의 표면에 상기 자성 물질을 처리하며 수행할 수 있다. In the present invention, the treatment may be performed by treating the magnetic material on the surface of the cell while a magnetic force is applied to the mold.
본 발명에서 상기 자기력의 인가는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. In the present invention, the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서 상기 자기력은 자성 물질의 배열을 위한 정도의 세기이면 족하고, 비제한적 예시로 5 내지 10 가우스일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic force suffices as long as the strength is sufficient for the arrangement of magnetic materials, and may be 5 to 10 Gauss as a non-limiting example, but is not limited thereto.
본 발명에서 상기 처리하는 단계 시 자성 물질에 존재하는 항체와 상기 세포의 표면에 존재하는 항원 사이의 항원-항체 반응을 이용한 면역 표지법 또는 직접 도입법 등을 통해 자성 물질이 세포 외부 표면에 부착된 형태의 자성 세포 또는 자성 세포 군집체가 제조될 수 있다.In the present invention, during the treatment step, the magnetic material is attached to the outer surface of the cell through an immunolabeling method or direct introduction method using an antigen-antibody reaction between the antibody present in the magnetic material and the antigen present on the surface of the cell. A magnetic cell or a magnetic cell population may be prepared.
본 발명에서 상기 수면 무호흡증 (sleep apnea syndrome)은 수면 무호흡증, 중추형 수면 무호흡증 또는 혼합형 수면 무호흡증일 수 있으며, 바람직하게는 폐쇄형 수면 무호흡증일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the sleep apnea (sleep apnea syndrome) may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
2-1. 구순 구개열 치료를 위한 자성 세포의 적정 주입량을 결정하는 방법2-1. How to determine the optimal injection amount of magnetic cells for the treatment of cleft lip and cleft lip
본 발명의 또 다른 구현 예에 따르면, 체내 조직 또는 기관에의 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method for providing information for determining an appropriate injection amount of magnetic cells into a body tissue or organ.
본 발명에서 상기 방법은 다양한 질환 중에서도 특히 구순 구개열의 개선 또는 치료를 위해 체내 조직 또는 기관에 주입되는 자성 세포의 적정 주입량을 결정하기 위한 것일 수 있다. In the present invention, the method may be for determining an appropriate injection amount of magnetic cells to be injected into a body tissue or organ for the improvement or treatment of cleft lip and cleft lip among various diseases.
본 발명에서 상기 자성 세포는 자성 물질을 포함하는 것으로, 바람직하게는 자성 물질이 세포 표면에 결합되거나 세포 내부에 위치하는 형태로써 세포에 포함될 수 있다. In the present invention, the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
본 발명에서 상기 세포의 종류는 특별히 제한하지 않으며 입술 또는 구강, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등에 위치한 세포로, 예를 들면 상피세포(epithelial cell), 뼈세포(osteoblast), 섬유아세포(fibroblast) 또는 근세포(myocyte)일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the type of the cell is not particularly limited and is a cell located in the lips or oral cavity, preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), etc., For example, it may be an epithelial cell, an osteoblast, a fibroblast, or a myocyte, but is not limited thereto.
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다. In the present invention, the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질 일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite (γ-Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm 내지 1μm, 바람직하게는 50 내지 700 nm, 보다 바람직하게는 200 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the average diameter of the magnetic material may be 1 nm to 1 μm, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질이 도핑된 것일 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질이 도핑된 것일 수 있으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility. ), polyvinyl pyrrolidone (polyvinyl pyrrolidone), polyethyleneimine (polyethyleneimine), polymethacrylate (polymethacrylate) or a synthetic polymer material such as polyvinyl alcohol (polyvinyl alcohol) or a natural polymer material such as polysaccharide (polysaccharide) doping It may be a biocompatible material, preferably doped with a biocompatible natural polymer material for in vivo use, but is not limited thereto if it corresponds to a material having biocompatibility.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 물질에 배향성을 부여할 수 있다.In addition, in the present invention, the magnetic material may have a coating layer formed on the surface. The coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound. Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci. ), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins, and protein A is Staphylococcus aureus ) As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
본 발명에서 상기 자성 물질은 그 자체로 세포 내 포함될 수 있으나, 수용액에 분산된 형태로 세포 내에 포함되었을 수 있다. 수용액에 분산된 형태로 세포 내에 포함시킨 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1 종 이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be included in the cell itself, but may be included in the cell in a dispersed form in an aqueous solution. It is more preferable in terms of convenience of experimentation as well as reducing the aggregation of the magnetic material to be included in the cell in a dispersed form in an aqueous solution. At this time, the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used. One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
본 발명에서 상기 자성 물질은 타겟으로 하는 세포에 존재하는 항원을 인식하여 결합할 수 있는 항체를 더 포함할 수 있다. In the present invention, the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
본 발명에서 상기 자성 세포는 목적하는 개체의 입술 또는 구강 조직으로, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등에 주입한 뒤 자기력을 인가하여 입술 또는 구강 조직 등에서 갈라진 변형 부위의 봉합, 재건 또는 복원을 통해 구순 구개열을 개선 또는 치료할 수 있고, 이로써 뼈 또는 피부 조직의 이식을 대체하거나 수술 부위를 최소화할 수 있다. 도 1은 본 발명에 따른 자성 세포의 조직의 형상 제어 원리를 나타낸 것으로 (a)는 자성의 인력에 따른 갈라진 두 부위의 봉합, (b)는 자성의 척력에 따른 갈라진 두 부위의 확장을 나타낸 모식도이다. In the present invention, the magnetic cells are injected into the lips or oral tissue of the subject, preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), etc. By applying a magnetic force, it is possible to improve or treat cleft lip or cleft lip through suturing, reconstruction or restoration of a cracked deformed area in the lips or oral tissue, thereby replacing the implantation of bone or skin tissue or minimizing the surgical site. 1 is a schematic diagram showing the principle of controlling the shape of the tissue of a magnetic cell according to the present invention, in which (a) is suture of two cracked parts due to magnetic attraction, (b) is a schematic diagram showing the expansion of the two parts split according to magnetic repulsive force to be.
본 발명의 방법은, 상기와 같이 다양한 질환, 특히 구순 구개열의 개선 또는 치료를 위하여 목적하는 개체의 목적하는 조직 또는 기관에 주입되는 자성 세포의 최적의 주입량을 결정하기 위하여 이용될 수 있다. The method of the present invention can be used to determine the optimal injection amount of magnetic cells to be injected into a target tissue or organ of a target subject for the improvement or treatment of various diseases, particularly cleft lip and cleft lip, as described above.
본 발명의 방법은, 우선 목적하는 개체의 목적하는 조직 또는 기관에 대하여 영률(Young's Modulus)을 측정하는 단계를 포함할 수 있다.The method of the present invention may include first measuring a Young's Modulus of a target tissue or organ of a target subject.
본 발명에서 상기 목적하는 개체는 구순 구개열이 발생하였거나 발생 가능성이 높은 개체일 수 있다. In the present invention, the subject of interest may be an individual who has or has a high probability of developing cleft lip and cleft palate.
본 발명에서 상기 "구순 구개열"은 구순열 및 구개열 중 적어도 하나일 수 있고, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the "labial cleft palate" may be at least one of cleft lip and cleft palate, and non-limiting examples include incomplete cleft lip, unilateral complete cleft lip or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft lip, unilateral complete cleft lip. It may be cleft palate, or bilateral complete cleft palate, but is not limited thereto.
본 발명에서 상기 "조직(tissue)"은 생물학에서 장기 내에 존재하는 같은 종류의 세포 덩어리를 말하며, 예를 들면, 상피 조직, 결합 조직, 근육 조직 또는 신경 조직일 수 있는데, 본 발명의 목적 상 상피 조직 또는 근육 조직일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the "tissue" refers to a mass of cells of the same type that exist in an organ in biology, and may be, for example, epithelial tissue, connective tissue, muscle tissue or nerve tissue, and for the purpose of the present invention, epithelium It may be tissue or muscle tissue, but is not limited thereto.
본 발명에서 상기 "기관(organ)"은 다세포생물의 몸을 구성하는 단위로, 여러 가지 조직이 모여 통합된 구조를 형성하고, 특정 기능을 하는 구조를 말한다. 인체의 기관의 예시로는 위, 간, 폐, 심장, 림프절, 치아, 입술, 잇몸, 목젖, 경구개, 연구개, 안구, 갑상선, 난소, 피부 또는 뇌 등이 있을 수 있고, 본 발명의 목적 상 입술, 잇몸, 목젖, 경구개, 연구개 또는 피부일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the "organ" is a unit constituting the body of a multicellular organism, and refers to a structure in which various tissues are gathered to form an integrated structure and perform a specific function. Examples of organs in the human body include stomach, liver, lungs, heart, lymph nodes, teeth, lips, gums, uvula, hard palate, soft palate, eyeballs, thyroid gland, ovaries, skin or brain, and for the purposes of the present invention, It may be lips, gums, uvula, hard palate, soft palate, or skin, but is not limited thereto.
본 발명에서 상기 "영률(Young's Modulus)"이란 조직의 특성과 탄력성을 기계적 변수로 개별화하여 kPa 단위로 조직의 탄성 측정에 이용되는 개념을 말하는 것으로, 인체 내 조직으로 뺨, 광대뼈, 이마, 아래 입술 근육의 영률을 측정하는 방법이 종래에 알려진 바 있다(Ann Biomed Eng. 2014 Nov;42(11):2369-78.). 본 발명에서 상기 영률의 단위는 표준화된 단위 변환에 의해 변형되어 사용될 수 있다.In the present invention, the term "Young's Modulus" refers to a concept used to measure the elasticity of a tissue in kPa unit by individualizing the characteristics and elasticity of the tissue as a mechanical variable. A method of measuring the Young's modulus of a muscle has been known in the prior art (Ann Biomed Eng. 2014 Nov;42(11):2369-78.). In the present invention, the unit of the Young's modulus may be modified and used by standardized unit conversion.
본 발명에서 상기 영률은 탄력 측정 기기를 이용하여 측정되는 것일 수 있으며, 예를 들면, 큐로미터 (Cutometer, Courage Khazaka electronic GmbH 사) 또는 더마랩 (DermaLab, Cortex technology 사) 등을 이용할 수 있으나, 이에 제한되는 것은 아니며 당해 기술분야에서 사용되는 영률 측정 장치라면 제한없이 사용될 수 있다. 도 7은 본 발명에 따른 신체 조직의 영률을 측정하기 위해 사용 가능한 기기의 일 예시를 나타낸 것이다.In the present invention, the Young's modulus may be measured using a elasticity measuring device, for example, a curometer (Cutometer, Courage Khazaka electronic GmbH) or DermaLab (DermaLab, Cortex technology), etc. may be used, but this It is not limited, and any Young's modulus measuring device used in the art may be used without limitation. 7 shows an example of a device that can be used to measure the Young's modulus of a body tissue according to the present invention.
본 발명의 방법은 측정된 영률을 이용하여 하기 식 1에 의해 자성 물질의 적정 주입량을 결정하는 단계를 포함할 수 있다:The method of the present invention may include determining an appropriate injection amount of the magnetic material by Equation 1 below using the measured Young's modulus:
[식 1][Equation 1]
자성 물질의 주입량 = {영률(N/m2) X 희망 변형률}/자성 물질 간 자력(N/m2) Dosing amount of magnetic material = {Young's modulus (N/m 2 ) X Desired strain}/Magnetic force between magnetic materials (N/m 2 )
본 발명의 상기 식 1에서, "희망 변형률"은 상기 목적하는 조직 또는 기관에서 자성 세포의 주입에 따를 조직 또는 기관에서의 희망되는 수축, 이완 또는 변형의 정도를 의미하는 것으로, 보다 상세하게는 기존의 개체에서 형태학적 변화(수축, 이완 또는 변형)를 원하는 조직 또는 기관에서의 특정 부위의 길이 대비 희망하는 변화 후 길이(change in length divided by original length)의 비율로 0 초과, 1 이하의 유리수일 수 있다. In Equation 1 of the present invention, "desired strain rate" refers to a desired degree of contraction, relaxation or deformation in a tissue or organ following injection of magnetic cells in the target tissue or organ, and more specifically, The ratio of the length after the desired change to the length of a specific site in the tissue or organ for which a morphological change (contraction, relaxation, or deformation) is desired in the subject of can
본 발명의 상기 식 1에서, "자성 물질 간 자력"은 자성 물질 당 자기 선속량(magnetic flux density)의 제곱(N/m2)일 수 있고, 바람직하게는 하기 식 2로 계산될 수 있다:In the above Equation 1 of the present invention, "magnetic force between magnetic materials" may be the square of the magnetic flux density per magnetic material (N/m 2 ), preferably calculated by the following Equation 2:
[식 2][Equation 2]
자성 물질 간 자력(N/m2) = (자기 선속량)2(N/m2) X (자성 물질의 면적(m2))Magnetic force between magnetic materials (N/m 2 ) = (magnetic flux) 2 (N/m 2 ) X (area of magnetic material (m 2 ))
본 발명의 상기 식 2에서, "자기 선속량"은 자성 물질의 자력(AM2/kg)과 밀도(g/cm3)의 곱에 의해 계산될 수 있으며, 단위로는 A/m 또는 가우스(G)로 나타낼 수 있고, 바람직하게는 A/m의 단위로 계산한 뒤에 가우스(G)의 단위를 갖도록 변환시킨 값일 수 있다. 또한, 상기 (자기 선속량)2의 단위로는 G2 또는 N/m2로 나타낼 수 있고, 바람직하게는 G2의 단위로 계산한 뒤에 N/m2의 단위를 갖도록 변환시킨 값일 수 있다.In Equation 2 of the present invention, the "magnetic flux" may be calculated by the product of the magnetic force (AM 2 /kg) and the density (g/cm 3 ) of the magnetic material, and the unit is A/m or Gauss ( It may be expressed as G), and preferably, it may be a value converted to have a unit of Gaussian (G) after calculation in units of A/m. In addition, the unit of the (magnetic flux) 2 may be expressed as G 2 or N/m 2 , and preferably, it may be a value converted to have a unit of N/m 2 after being calculated in the unit of G 2 .
본 발명의 방법은 계산된 자성 물질의 주입량을 이용하여 하기 식 3에 의해 자성 세포의 적정 주입량을 결정하는 단계를 포함할 수 있다:The method of the present invention may include determining an appropriate injection amount of magnetic cells by Equation 3 below using the calculated amount of magnetic material injected:
[식 3][Equation 3]
자성 세포의 주입량 = (자성 물질의 주입량)/(세포 내 자성 물질의 주입 수)Injection amount of magnetic cells = (injection amount of magnetic material)/(number of injections of magnetic material in cells)
본 발명의 상기 식 3에서, "세포 내 자성 물질의 주입 수"는 목적하는 세포 내 자성 물질의 주입 개수로, 세포 당 자성 물질의 주입 수의 평균 값 또는 중앙 값일 수 있으나, 이에 제한되는 것은 아니다. In Equation 3 of the present invention, “the number of injections of the magnetic material into the cell” is the desired number of injections of the magnetic material into the cell, and may be an average or median value of the number of injections of the magnetic material per cell, but is not limited thereto. .
본 발명에서 상기와 같이 주입량이 결정된 자성 세포는 다양한 질환, 특히는 구순 구개열의 개선 또는 치료를 위해 목적하는 개체의 목적하는 조직 또는 기관에 주입될 수 있다. In the present invention, the magnetic cells whose injection amount is determined as described above may be injected into a target tissue or organ of a target individual for the improvement or treatment of various diseases, particularly cleft lip and cleft palate.
본 발명에서 상기와 같이 자성 세포를 개체의 조직 또는 기관 내로 주입되는 형태는 특별히 제한하지 않으나, 비제한적인 예시로는 액상 주사 형태 또는 액상이 흡수된 연성 발포체 형태일 수 있다. 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다. 도 2 및 도 3은 본 발명의 자성 세포의 체내 주입 방식을 나타낸 것이다. In the present invention, the form in which the magnetic cells are injected into the tissue or organ of an individual as described above is not particularly limited, but may be in the form of a liquid injection or a soft foam in which the liquid is absorbed as a non-limiting example. When injected in the form of liquid injection, the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time. method can be injected. 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
또한, 본 발명에서 상기와 같이 자성 세포를 개체의 조직 또는 기관 내로 주입할 시에 부유액에 상기와 같이 결정된 주입량의 자성 세포를 혼합하여 주입하는 것이 부유액의 점도를 조절하여 자성 세포를 포함한 주사액의 확산 속도 및 주입된 자성 세포의 유지 시간 제어가 가능하며 부유액에 혼합된 자성 세포의 양을 조절함으로써 자력 제어가 가능하여 바람직하다. 여기서, 상기 부유액은 생분해성의 PDMS, 히알루론산, 콜라겐, 키틴, 키토산, 헤파린 또는 이들의 조합일 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, when the magnetic cells are injected into the tissue or organ of an individual as described above, mixing and injecting the magnetic cells of the injection amount determined as described above in the suspension is to control the viscosity of the suspension to spread the injection solution including the magnetic cells. It is preferable that the speed and the holding time of the injected magnetic cells can be controlled, and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension. Here, the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
본 발명에서는 상기 자성 세포에 대하여 자기력을 인가함으로써 자성 세포들의 자력 방향 제어를 통제할 수 있다. 예를 들어 자기력의 방향이 결정되지 않은 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시킬 수 있다. 도 4는 본 발명에서 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시키는 과정을 나타낸 모식도이다. 본 발명에서 강자성 상태의 세포로 전환 시 가해지는 자기력의 크기는 자성 물질이 자화되기 위한 정도의 크기로 특별히 제한하지는 않으나 예를 들면 70 가우스 이상인 것일 수 있으나, 이에 제한되는 것은 아니다. 이렇게 각각의 세포가 주입된 위치마다 자기장 방향과 강도를 조절하여, 자성 세포 간 인력 또는 척력을 정밀하게 제어할 수 있다. In the present invention, by applying a magnetic force to the magnetic cells, it is possible to control the direction control of the magnetic force of the magnetic cells. For example, by applying a specific magnetic field to a magnetic cell including a paramagnetic material in which the direction of the magnetic force is not determined, it can be converted into a cell in a ferromagnetic state having a magnetic force in a desired direction. 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention. In the present invention, the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
본 발명에서 상기 자기력의 인가는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다.In the present invention, the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 근육, 조직의 수축 또는 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of contraction or relaxation of the desired muscle or tissue, and is not particularly limited.
본 발명에서 상기 자성 세포의 적정 주입량은 상기와 같이 자기력을 인가한 상태에서 상기 세포의 표면에 자성 물질을 처리하여 목적하는 변형률을 달성할 수 있다. In the present invention, an appropriate injection amount of the magnetic cells may achieve a desired strain rate by treating the surface of the cells with a magnetic material while applying a magnetic force as described above.
본 발명에서 상기 변형률은 개선 또는 변형되기를 원하는 목적하는 개체의 조직에서의 희망 변형률일 수 있고, 그의 단위는 기존의 길이 대비 변화된 길이(change in lenth divided by original length)의 비율 퍼센티지(%)로 계산되는 것일 수 있다. In the present invention, the strain may be a desired strain in the tissue of an object to be improved or deformed, and its unit is calculated as a percentage (%) of a change in lenth divided by original length compared to an existing length. it may be
본 발명에서 상기 구순 구개열은 구순열 및 구개열 중 적어도 하나일 수 있으며, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
2-2. 수면 무호흡 치료를 위한 자성 세포의 적정 주입량을 결정하는 방법2-2. How to determine the appropriate amount of magnetic cells to be injected for the treatment of sleep apnea
본 발명의 또 다른 구현 예에 따르면, 체내 조직 또는 기관에의 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method for providing information for determining an appropriate injection amount of magnetic cells into a body tissue or organ.
본 발명에서 상기 방법은 다양한 질환 중에서도 특히 수면 무호흡증의 개선 또는 치료를 위해 체내 조직 또는 기관에 주입되는 자성 세포의 적정 주입량을 결정하기 위한 것일 수 있다. In the present invention, the method may be for determining an appropriate injection amount of magnetic cells to be injected into a body tissue or organ for the improvement or treatment of sleep apnea, among various diseases.
본 발명에서 상기 자성 세포는 자성 물질을 포함하는 것으로, 바람직하게는 자성 물질이 세포 표면에 결합되거나 세포 내부에 위치하는 형태로써 세포에 포함될 수 있다. In the present invention, the magnetic cell includes a magnetic material, and preferably, the magnetic material is bound to the cell surface or located inside the cell, and may be included in the cell.
본 발명에서 상기 세포의 종류는 특별히 제한하지 않으며 호흡기계 유동관, 바람직하게는 비강, 인후두 또는 기도의 관 내벽 세포로, 예를 들면 섬유아세포(fibroblast) 또는 근세포(myocyte)일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the type of the cell is not particularly limited, and the cell of the respiratory system flow tract, preferably the nasal, pharyngeal or airway lining, may be, for example, fibroblast or myocyte, but is limited thereto. it is not
본 발명에서 상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질일 수 있으나, 바람직하게는 상자성 물질인 것이 추후 필요에 따라 적절한 자기력을 가하여 목적하는 효과를 내고 생체 외로 배출을 유도할 수 있다. In the present invention, the magnetic material may be a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material, but preferably a paramagnetic material is applied later, if necessary, an appropriate magnetic force is applied to produce a desired effect and can be induced to be discharged out of the body.
본 발명에서 상기 자성 물질은 소수성 자성 물질, 실리카 자성 물질 또는 친수성 자성 물질 일 수 있으나, 이에 제한되는 것은 아니다. 여기서 상기 친수성 자성 물질은 실리카 코팅된 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be a hydrophobic magnetic material, a silica magnetic material, or a hydrophilic magnetic material, but is not limited thereto. Here, the hydrophilic magnetic material may be silica-coated, but is not limited thereto.
본 발명에서 상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조될 수 있고, 예를 들면 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)일 수 있고, 영구 자석이 될 수 있는 것이라면 자성 물질의 종류는 이에 특별히 제한되는 것은 아니다.In the present invention, the magnetic material may be made of one or more materials selected from the group consisting of iron, cobalt, nickel and oxides or alloys thereof, for example, maghemite (γ-Fe 2 O 3 ), magnetite (Fe). 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), iron cobalt alloy (FeCo alloy), cobalt nickel alloy (CoNi alloy) or cobalt platinum alloy (CoPt alloy), the type of magnetic material is not particularly limited as long as it can be a permanent magnet.
본 발명에서 상기 자성 물질의 평균 직경은 1 nm 내지 1μm, 바람직하게는 50 내지 700 nm, 보다 바람직하게는 200 내지 500 nm일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the average diameter of the magnetic material may be 1 nm to 1 μm, preferably 50 to 700 nm, more preferably 200 to 500 nm, but is not limited thereto.
본 발명에서 상기 자성 물질은 자성 입자를 포함할 수 있고, 상기 자성 입자의 형태는 특별히 제한하지 않으나 예를 들면, 구형, 사각형, 침형 등 다양한 형태의 입자 모두 사용 가능하다. In the present invention, the magnetic material may include magnetic particles, and the shape of the magnetic particles is not particularly limited. For example, all of the particles of various shapes such as spherical, rectangular, needle-shaped, etc. may be used.
본 발명에서 상기 자성 물질은 분산력 향상을 위하여 구연산 (citric acid) 또는 올레산 (oleic acid) 등의 저분자 물질, 머캅토숙신산 또는 하이드록시카복실산과 같은 이관능성 카르복실산 및 이의 유도체, 폴리에틸렌글리콜 (polyethylene glycol), 폴리비닐피롤리돈 (polyvinyl pyrrolidone), 폴리에틸렌이민 (polyethyleneimine), 폴리메트아크릴레이트 (polymethacrylate) 또는 폴리비닐알코올 (polyvinyl alcochol) 등의 합성 고분자 물질 또는 다당류 (polysaccharide) 등의 천연 고분자 물질이 도핑된 것일 수 있으며, 바람직하게는 생체 내 사용을 위하여 생체 친화적인 천연 고분자 물질이 도핑된 것일 수 있으나, 생체 친화성을 가진 물질에 해당한다면 이에 제한되는 것은 아니다.In the present invention, the magnetic material includes a low molecular weight material such as citric acid or oleic acid, a bifunctional carboxylic acid such as mercaptosuccinic acid or hydroxycarboxylic acid and its derivatives, and polyethylene glycol to improve dispersibility. ), a synthetic polymer such as polyvinyl pyrrolidone, polyethyleneimine, polymethacrylate or polyvinyl alcohol, or a natural polymer such as polysaccharide is doped It may be a biocompatible material, preferably doped with a biocompatible natural polymer material for in vivo use, but is not limited thereto if it corresponds to a material having biocompatibility.
또한, 본 발명에서 상기 자성 물질은 표면에 코팅층이 형성된 것일 수 있다. 상기 코팅층은 덱스트란, 카르복시메틸 덱스트란, 셀룰로오스, 키틴, 알지네이트, 전분 및 아가로스로 이루어지는 군에서 선택되는 적어도 하나로 이루어진 것일 수 있으며, 항체와의 결합을 위하여 스테파린, 프로틴 A, 프로틴 G, 프로틴 A/G 또는 이들의 혼입 작용기가 결합된 구조일 수 있다. 프로틴 G는 C군 또는 G군 스트렙토 코커스 박테리아(Streptococci.)로부터 분리된 세포벽 단백질로서, 대부분의 면역글로불린의 Fc부분에 큰 결합력을 가지는 면역글로불린 결합 단백질이며, 프로틴 A는 황색포도상구균(Staphylococcus aureus)로부터 분리된 세포벽 단백질로서, 대부분의 포유류에서 발현되는 면역글로불린과 결합할 수 있다. 상기 프로틴 G 또는 프로틴 A를 이용하여 항체 코팅 시 자성 물질에 배향성을 부여할 수 있다.In addition, in the present invention, the magnetic material may have a coating layer formed on the surface. The coating layer may be composed of at least one selected from the group consisting of dextran, carboxymethyl dextran, cellulose, chitin, alginate, starch and agarose, and for binding to the antibody, steparin, protein A, protein G, protein It may be a structure in which A/G or an incorporated functional group thereof is bound. Protein G is a cell wall protein isolated from group C or group G streptococcus bacteria ( Streptococci. ), and is an immunoglobulin binding protein having a large binding affinity to the Fc portion of most immunoglobulins, and protein A is Staphylococcus aureus ) As a cell wall protein isolated from , it can bind to immunoglobulin expressed in most mammals. Orientation can be imparted to the magnetic material when the antibody is coated by using the protein G or protein A.
본 발명에서 상기 자성 물질은 그 자체로 세포 내 포함될 수 있으나, 수용액에 분산된 형태로 세포 내에 포함되었을 수 있다. 수용액에 분산된 형태로 세포 내에 포함시킨 것이 자성 물질의 응집을 줄일 수 있을 뿐 아니라 실험 편의성 측면에서 보다 바람직하다. 이 때 수분산액은 자성 물질 자체의 응집 및 침강을 방지하기 위하여, 분산제를 더 함유하여 보관 및 사용될 수 있으며, 상기 분산제로는 글리세롤, 알콕실레이트, 알칸올아미드, 에스테르, 아민 옥사이드, 알킬 폴리길리코사이드, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리비닐피롤리돈, 폴리에틸렌아민, 폴리비닐아민, 베타인, 글리시네이트 및 이미다졸린 및 글리세롤로 이루어진 군에서 선택된 1 종 이상의 분산제를 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the magnetic material may be included in the cell itself, but may be included in the cell in a dispersed form in an aqueous solution. It is more preferable in terms of convenience of experimentation as well as reducing the aggregation of the magnetic material to be included in the cell in a dispersed form in an aqueous solution. At this time, the aqueous dispersion may further contain a dispersing agent to prevent aggregation and sedimentation of the magnetic material itself, and may be stored and used. One or more dispersants selected from the group consisting of lycoside, polyacrylate, polymethacrylate, polyvinylpyrrolidone, polyethyleneamine, polyvinylamine, betaine, glycinate and imidazoline and glycerol may be used. , but is not limited thereto.
본 발명에서 상기 자성 물질은 타겟으로 하는 세포에 존재하는 항원을 인식하여 결합할 수 있는 항체를 더 포함할 수 있다. In the present invention, the magnetic material may further include an antibody capable of recognizing and binding to an antigen present in a target cell.
본 발명에서 상기 세포의 표면에 존재하는 항원은 Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나의 단백질일 수 있으나, 이에 제한되는 것은 아니며, 호흡계 기관, 바람직하게는 기도를 이루는 세포에 특이적으로 존재하는 항원이라면 제한없이 포함될 수 있다.In the present invention, the antigen present on the surface of the cell may be at least one protein selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, but is not limited thereto, and respiratory organs , Preferably, as long as it is an antigen that is specifically present in cells constituting the airways, it may be included without limitation.
본 발명에서 상기 자성 세포는 목적하는 개체의 호흡기계 유동관으로, 바람직하게는 비강, 인후두 또는 기도의 관 내벽 세포로, 예를 들면 섬유아세포(fibroblast) 또는 근세포(myocyte) 등에 주입한 뒤 자기력을 인가하여 기도 근육 등 호흡기계 유동관에 척력을 유발하여 호흡기계 유동관 이완을 통해 수면 무호흡증을 개선 또는 치료할 수 있고, 이로써 기도 관의 협착 또는 폐쇄를 최소화할 수 있다. 도 1은 본 발명에 따른 자성 세포의 조직의 형상 제어 원리를 나타낸 것으로 (a)는 자성의 인력에 따른 갈라진 두 부위의 봉합, (b)는 자성의 척력에 따른 갈라진 두 부위의 확장을 나타낸 모식도이다. In the present invention, the magnetic cells are injected into the respiratory tract of the subject, preferably into the lining cells of the nasal cavity, larynx or airway, for example, fibroblasts or myocytes, etc., and then magnetic force is applied. Thus, it is possible to improve or treat sleep apnea by inducing a repulsive force in the respiratory system flow tube such as the airway muscle and relaxing the respiratory system flow tube, thereby minimizing stenosis or obstruction of the airway tube. 1 is a schematic diagram showing the principle of controlling the shape of the tissue of a magnetic cell according to the present invention, in which (a) is suture of two cracked parts due to magnetic attraction, (b) is a schematic diagram showing the expansion of the two parts split according to magnetic repulsive force to be.
본 발명의 방법은, 상기와 같이 다양한 질환, 특히 수면 무호흡증의 개선 또는 치료를 위하여 목적하는 개체의 목적하는 조직 또는 기관에 주입되는 자성 세포의 최적의 주입량을 결정하기 위하여 이용될 수 있다. The method of the present invention can be used to determine the optimal injection amount of magnetic cells to be injected into a target tissue or organ of a target individual for the improvement or treatment of various diseases, particularly sleep apnea, as described above.
본 발명의 방법은, 우선 목적하는 개체의 목적하는 조직 또는 기관에 대하여 영률(Young's Modulus)을 측정하는 단계를 포함할 수 있다.The method of the present invention may include first measuring a Young's Modulus of a target tissue or organ of a target subject.
본 발명에서 상기 목적하는 개체는 수면 무호흡증이 발생하였거나 발생 가능성이 높은 개체일 수 있다. In the present invention, the target subject may be an individual who has or has a high probability of developing sleep apnea.
본 발명에서 상기 "수면 무호흡증"은 폐쇄성 수면 무호흡증, 중추형 수면 무호흡증 또는 혼합형 수면 무호흡증 중 적어도 하나일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the "sleep apnea" may be at least one of obstructive sleep apnea, central sleep apnea, and mixed sleep apnea, but is not limited thereto.
본 발명에서 상기 "조직(tissue)"은 생물학에서 장기 내에 존재하는 같은 종류의 세포 덩어리를 말하며, 예를 들면, 상피 조직, 결합 조직, 근육 조직 또는 신경 조직일 수 있는데, 본 발명의 목적 상 상피 조직 또는 근육 조직일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the "tissue" refers to a mass of cells of the same type that exist in an organ in biology, and may be, for example, epithelial tissue, connective tissue, muscle tissue or nerve tissue, and for the purpose of the present invention, epithelium It may be tissue or muscle tissue, but is not limited thereto.
본 발명에서 상기 "기관(organ)"은 다세포생물의 몸을 구성하는 단위로, 여러 가지 조직이 모여 통합된 구조를 형성하고, 특정 기능을 하는 구조를 말한다. 인체의 기관의 예시로는 호흡기, 위, 간, 폐, 심장, 림프절, 치아, 입술, 잇몸, 목젖, 경구개, 연구개, 안구, 갑상선, 난소, 피부 또는 뇌 등이 있을 수 있고, 본 발명의 목적 상 호흡 기관일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the "organ" is a unit constituting the body of a multicellular organism, and refers to a structure in which various tissues are gathered to form an integrated structure and perform a specific function. Examples of organs in the human body include respiratory organs, stomach, liver, lungs, heart, lymph nodes, teeth, lips, gums, uvula, hard palate, soft palate, eyeballs, thyroid gland, ovaries, skin or brain, and the like, It may be, but is not limited to, a respiratory organ for purposes.
본 발명에서 상기 "영률(Young's Modulus)"이란 조직의 특성과 탄력성을 기계적 변수로 개별화하여 kPa 단위로 조직의 탄성 측정에 이용되는 개념을 말하는 것으로, 인체 내 조직인 뺨, 광대뼈, 이마, 아래 입술 근육 등의 영률을 측정하는 방법이 종래에 알려진 바 있다(Ann Biomed Eng. 2014 Nov;42(11):2369-78.). 본 발명에서 상기 영률의 단위는 표준화된 단위 변환에 의해 변형되어 사용될 수 있다.In the present invention, the term "Young's Modulus" refers to a concept used to measure tissue elasticity in kPa units by individualizing tissue characteristics and elasticity as mechanical variables, and the internal tissues of the human body, such as cheeks, cheekbones, forehead, and lower lip muscles A method of measuring the Young's modulus of the back has been known in the prior art (Ann Biomed Eng. 2014 Nov;42(11):2369-78.). In the present invention, the unit of the Young's modulus may be modified and used by standardized unit conversion.
본 발명에서 상기 영률은 탄력 측정 기기를 이용하여 측정되는 것일 수 있으며, 예를 들면, 큐로미터 (Cutometer, Courage Khazaka electronic GmbH 사) 또는 더마랩 (DermaLab, Cortex technology 사) 등을 이용할 수 있으나, 이에 제한되는 것은 아니며 당해 기술분야에서 사용되는 영률 측정 장치라면 제한없이 사용될 수 있다. 도 7은 본 발명에 따른 신체 조직의 영률을 측정하기 위해 사용 가능한 기기의 일 예시를 나타낸 것이다.In the present invention, the Young's modulus may be measured using a elasticity measuring device, for example, a curometer (Cutometer, Courage Khazaka electronic GmbH) or DermaLab (DermaLab, Cortex technology), etc. may be used, but this It is not limited, and any Young's modulus measuring device used in the art may be used without limitation. 7 shows an example of a device that can be used to measure the Young's modulus of a body tissue according to the present invention.
본 발명의 방법은 측정된 영률을 이용하여 하기 식 1에 의해 자성 물질의 적정 주입량을 결정하는 단계를 포함할 수 있다:The method of the present invention may include determining an appropriate injection amount of the magnetic material by Equation 1 below using the measured Young's modulus:
[식 1][Equation 1]
자성 물질의 주입량 = {영률(N/m2) X 희망 변형률}/자성 물질 간 자력(N/m2) Dosing amount of magnetic material = {Young's modulus (N/m 2 ) X Desired strain}/Magnetic force between magnetic materials (N/m 2 )
본 발명의 상기 식 1에서, "희망 변형률"은 상기 목적하는 조직 또는 기관에서 자성 세포의 주입에 따를 조직 또는 기관에서의 희망되는 수축, 이완 또는 변형의 정도를 의미하는 것으로, 보다 상세하게는 기존의 개체에서 형태학적 변화(수축, 이완 또는 변형)를 원하는 조직 또는 기관에서의 특정 부위의 길이 대비 희망하는 변화 후 길이(change in length divided by original length)의 비율로 0 초과, 1 이하의 유리수일 수 있다. In Equation 1 of the present invention, "desired strain rate" refers to a desired degree of contraction, relaxation or deformation in a tissue or organ following injection of magnetic cells in the target tissue or organ, and more specifically, The ratio of the length after the desired change to the length of a specific site in the tissue or organ for which a morphological change (contraction, relaxation, or deformation) is desired in the subject of can
본 발명의 상기 식 1에서, "자성 물질 간 자력"은 자성 물질 당 자기 선속량(magnetic flux density)의 제곱(N/m2)일 수 있고, 바람직하게는 하기 식 2로 계산될 수 있다:In the above Equation 1 of the present invention, "magnetic force between magnetic materials" may be the square of the magnetic flux density per magnetic material (N/m 2 ), preferably calculated by the following Equation 2:
[식 2][Equation 2]
자성 물질 간 자력(N/m2) = (자기 선속량)2(N/m2) X (자성 물질의 면적(m2))Magnetic force between magnetic materials (N/m 2 ) = (magnetic flux) 2 (N/m 2 ) X (area of magnetic material (m 2 ))
본 발명의 상기 식 2에서, "자기 선속량"은 자성 물질의 자력(AM2/kg)과 밀도(g/cm3)의 곱에 의해 계산될 수 있으며, 단위로는 A/m 또는 가우스(G)로 나타낼 수 있고, 바람직하게는 A/m의 단위로 계산한 뒤에 가우스(G)의 단위를 갖도록 변환시킨 값일 수 있다. 또한, 상기 (자기 선속량)2의 단위로는 G2 또는 N/m2로 나타낼 수 있고, 바람직하게는 G2의 단위로 계산한 뒤에 N/m2의 단위를 갖도록 변환시킨 값일 수 있다.In Equation 2 of the present invention, the "magnetic flux" may be calculated by the product of the magnetic force (AM 2 /kg) and the density (g/cm 3 ) of the magnetic material, and the unit is A/m or Gauss ( It may be expressed as G), and preferably, it may be a value converted to have a unit of Gaussian (G) after calculation in units of A/m. In addition, the unit of the (magnetic flux) 2 may be expressed as G 2 or N/m 2 , and preferably, it may be a value converted to have a unit of N/m 2 after being calculated in the unit of G 2 .
본 발명의 방법은 계산된 자성 물질의 주입량을 이용하여 하기 식 3에 의해 자성 세포의 적정 주입량을 결정하는 단계를 포함할 수 있다:The method of the present invention may include determining an appropriate injection amount of magnetic cells by Equation 3 below using the calculated amount of magnetic material injected:
[식 3][Equation 3]
자성 세포의 주입량 = (자성 물질의 주입량)/(세포 내 자성 물질의 주입 수)Injection amount of magnetic cells = (injection amount of magnetic material)/(number of injections of magnetic material in cells)
본 발명의 상기 식 3에서, "세포 내 자성 물질의 주입 수"는 목적하는 세포 내 자성 물질의 주입 개수로, 세포 당 자성 물질의 주입 수의 평균 값 또는 중앙 값일 수 있으나, 이에 제한되는 것은 아니다. In Equation 3 of the present invention, “the number of injections of the magnetic material into the cell” is the desired number of injections of the magnetic material into the cell, and may be an average or median value of the number of injections of the magnetic material per cell, but is not limited thereto. .
본 발명에서 상기와 같이 주입량이 결정된 자성 세포는 다양한 질환, 특히는 수면 무호흡증의 개선 또는 치료를 위해 목적하는 개체의 목적하는 조직 또는 기관에 주입될 수 있다. In the present invention, the magnetic cells whose injection amount is determined as described above may be injected into a target tissue or organ of a target individual for the improvement or treatment of various diseases, particularly sleep apnea.
본 발명에서 상기와 같이 자성 세포를 개체의 조직 또는 기관 내로 주입되는 형태는 특별히 제한하지 않으나, 비제한적인 예시로는 액상 주사 형태 또는 액상이 흡수된 연성 발포체 형태일 수 있다. 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다. 도 2 및 도 3은 본 발명의 자성 세포의 체내 주입 방식을 나타낸 것이다. In the present invention, the form in which the magnetic cells are injected into the tissue or organ of an individual as described above is not particularly limited, but may be in the form of a liquid injection or a soft foam in which the liquid is absorbed as a non-limiting example. When injected in the form of liquid injection, the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time. method can be injected. 2 and 3 show a method of injecting the magnetic cells into the body of the present invention.
또한, 본 발명에서 상기와 같이 자성 세포를 개체의 조직 또는 기관 내로 주입할 시에 부유액에 상기와 같이 결정된 주입량의 자성 세포를 혼합하여 주입하는 것이 부유액의 점도를 조절하여 자성 세포를 포함한 주사액의 확산 속도 및 주입된 자성 세포의 유지 시간 제어가 가능하며 부유액에 혼합된 자성 세포의 양을 조절함으로써 자력 제어가 가능하여 바람직하다. 여기서, 상기 부유액은 생분해성의 PDMS, 히알루론산, 콜라겐, 키틴, 키토산, 헤파린 또는 이들의 조합일 수 있으나, 이에 제한되는 것은 아니다.In addition, in the present invention, when the magnetic cells are injected into the tissue or organ of an individual as described above, mixing and injecting the magnetic cells of the injection amount determined as described above in the suspension is to control the viscosity of the suspension to spread the injection solution including the magnetic cells. It is preferable that the speed and the holding time of the injected magnetic cells can be controlled, and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension. Here, the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
본 발명에서는 상기 자성 세포에 대하여 자기력을 인가함으로써 자성 세포들의 자력 방향 제어를 통제할 수 있다. 예를 들어 자기력의 방향이 결정되지 않은 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시킬 수 있다. 도 4는 본 발명에서 상자성 물질을 포함하는 자성 세포에 대하여 특정 자기장을 인가하여 원하는 방향의 자력을 지닌 강자성 상태의 세포로 변환시키는 과정을 나타낸 모식도이다. 본 발명에서 강자성 상태의 세포로 전환 시 가해지는 자기력의 크기는 자성 물질이 자화되기 위한 정도의 크기로 특별히 제한하지는 않으나 예를 들면 70 가우스 이상인 것일 수 있으나, 이에 제한되는 것은 아니다. 이렇게 각각의 세포가 주입된 위치마다 자기장 방향과 강도를 조절하여, 자성 세포 간 인력 또는 척력을 정밀하게 제어할 수 있다. In the present invention, by applying a magnetic force to the magnetic cells, it is possible to control the direction control of the magnetic force of the magnetic cells. For example, by applying a specific magnetic field to a magnetic cell including a paramagnetic material in which the direction of the magnetic force is not determined, it can be converted into a cell in a ferromagnetic state having a magnetic force in a desired direction. 4 is a schematic diagram illustrating a process of converting a cell in a ferromagnetic state having a magnetic force in a desired direction by applying a specific magnetic field to a magnetic cell containing a paramagnetic material in the present invention. In the present invention, the magnitude of the magnetic force applied when the cell is converted to a ferromagnetic state is not particularly limited to a magnitude for magnetizing the magnetic material, but may be, for example, 70 Gauss or more, but is not limited thereto. In this way, by adjusting the direction and strength of the magnetic field at each injection location, it is possible to precisely control the attractive or repulsive force between the magnetic cells.
본 발명에서 상기 자기력의 인가는 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다.In the present invention, the application of the magnetic force may be performed by forming a magnetic field, and the magnetic field may be performed using, for example, a magnet such as an electromagnet or a permanent magnet by electromagnetic induction, and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 근육, 조직의 수축 또는 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted and determined according to the degree of contraction or relaxation of the desired muscle or tissue, and is not particularly limited.
본 발명에서 상기 자성 세포의 적정 주입량은 상기와 같이 자기력을 인가한 상태에서 상기 세포의 표면에 자성 물질을 처리하여 목적하는 변형률을 달성할 수 있다. In the present invention, an appropriate injection amount of the magnetic cells may achieve a desired strain rate by treating the surface of the cells with a magnetic material while applying a magnetic force as described above.
본 발명에서 상기 변형률은 개선 또는 변형되기를 원하는 목적하는 개체의 조직에서의 희망 변형률일 수 있고, 그의 단위는 기존의 길이 대비 변화된 길이(change in lenth divided by original length)의 비율 퍼센티지(%)로 계산되는 것일 수 있다. In the present invention, the strain may be a desired strain in the tissue of an object to be improved or deformed, and its unit is calculated as a percentage (%) of a change in lenth divided by original length compared to an existing length. it may be
3-1. 구순 구개열의 개선 또는 치료용 조성물3-1. Composition for improvement or treatment of cleft lip and cleft palate
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 자성 세포 또는 이의 군집체를 유효 성분으로 포함하는 구순 구개열의 개선 또는 치료용 조성물에 관한 것이다.According to another embodiment of the present invention, it relates to a composition for improving or treating cleft lip and cleft lip comprising the magnetic cells or agglomerates thereof provided in the present invention as an active ingredient.
본 발명에서 상기 구순 구개열은 구순열 및 구개열 중 적어도 하나일 수 있으며, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
본 발명에서 상기 조성물은 자성 비드 부착률이 90 내지 100 %임을 고려하여 자성 세포 또는 이의 군집체를 포함할 수 있고, 구체적으로 구순 구개열의 치료를 위해 변형이 필요한 조직에서의 목표하는 변형치를 달성하기 위해 상기 방법으로 계산된 적정 자성 세포의 수를 포함할 수 있다. 비 제한적인 예시로 목적하는 개체의 기도 근육의 10 %의 변형률을 달성하기 위하여는 7 x 105 내지 9 x 105 개의 자성 세포를 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the composition may include magnetic cells or a cluster thereof considering that the magnetic bead adhesion rate is 90 to 100%, and specifically to achieve a target modification value in tissues requiring modification for the treatment of cleft lip and cleft lip. The number of suitable magnetic cells calculated by the above method may be included for this purpose. As a non-limiting example, 7 x 10 5 to 9 x 10 5 magnetic cells may be included in order to achieve a 10% strain rate of the airway muscle of an individual, but is not limited thereto.
본 발명의 상기 "예방"이란, 본 발명의 상기 조성물을 이용하여 자성 세포가 생체 내에 주입됨으로써 입술 또는 구강 조직에서 갈라진 변형 부위를 봉합, 복원 또는 재건에 의해 구순 구개열로 발생되는 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 행위라면 제한없이 포함될 수 있다.The "prevention" of the present invention refers to the use of the composition of the present invention to block the symptoms caused by cleft lip or cleft lip by suturing, restoring, or reconstructing the deformed site cracked in the lips or oral tissue by injecting magnetic cells in vivo, Any action that suppresses or delays the symptom may be included without limitation.
본 발명의 상기 "개선 또는 치료"란, 본 발명의 상기 조성물을 이용하여 자성 세포가 생체 내에 주입됨으로써 입술 또는 구강 조직에서 갈라진 변형 부위를 봉합, 복원 또는 재건에 의해 구순 구개열로 인하여 발생한 변형 부위의 외관이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다.The "improvement or treatment" of the present invention means that magnetic cells are injected in vivo using the composition of the present invention, thereby suturing, restoring, or reconstructing the deformed site cracked in the lip or oral tissue. Any action that improves or benefits the appearance may be included without limitation.
본 발명의 조성물은 약학적 조성물 또는 식품 조성물의 형태로 제공될 수 있으나, 이에 제한되는 것은 아니다. The composition of the present invention may be provided in the form of a pharmaceutical composition or a food composition, but is not limited thereto.
본 발명에서 상기 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is targeted to humans.
본 발명의 상기 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화되어 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등이 사용될 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등이 혼합되어 사용될 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등이 사용될 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서 (Elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.The pharmaceutical composition of the present invention is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions according to conventional methods. can be used The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, and pain relief Agents, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, for oral administration, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. have. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
본 발명의 상기 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
본 발명의 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 바람직하게는 본 발명의 상기 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있으나, 이에 제한되는 것은 아니다.The "parenteral" of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Preferably, the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration, but is not limited thereto.
본 발명의 상기 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1 일 0.0001 내지 50 mg/kg 또는 0.001 내지 50 mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 약학적 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg per day It may be administered at /kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명의 상기 식품 조성물은 본 발명에서 목적으로 하는 적응증의 개선 또는 치료를 위해 다양하게 이용되는 것으로서, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 본 발명의 식품 조성물은 독성 및 부작용이 거의 없는 기존의 식품용 섭취물로부터 개량되어 구성된 것이므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다. 본 발명의 조성물이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 100 %의 비율로 첨가할 수 있다. 여기서, 상기 식품 조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 함유하는 것 외에 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 즉, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제 (타우마틴), 스테비아 추출물 (예를 들어, 레바우디오시드 A, 글리시르히진등) 및 합성 향미제 (사카린, 아스파르탐 등) 등을 들 수 있다. 그 외 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 통상적으로 본 발명의 조성물 100 중량부 당 0.1 내지 100 중량부의 범위에서 선택되는 것이 일반적이나, 이에 제한되는 것은 아니다.The food composition of the present invention is variously used for the improvement or treatment of indications for the purpose of the present invention, and various foods, for example, beverages, gums, tea, vitamin complexes, powders, granules, tablets, capsules, It can be prepared in the form of sweets, rice cakes, bread, and the like. Since the food composition of the present invention is improved from the existing food intake with little toxicity and side effects, it can be safely used even when taken for a long period of time for the purpose of prevention. When the composition of the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 100% of the total weight. Here, when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do. Examples of the flavoring agent include a natural flavoring agent (taumatine), a stevia extract (eg, rebaudioside A, glycyrrhizin, etc.), and a synthetic flavoring agent (saccharin, aspartame, etc.). In addition, the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners , pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. These components may be used independently or in combination. The proportion of these additives is generally selected in the range of 0.1 to 100 parts by weight per 100 parts by weight of the composition of the present invention, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 구순 구개열을 예방, 개선 또는 치료하는 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method for preventing, ameliorating or treating cleft lip and cleft lip.
본 발명의 상기 방법은 투여가 필요한 개체에게 본 발명에서 제공하는 자성 세포 또는 이의 군집체를 유효 성분으로 포함하는 구순 구개열의 개선 또는 치료용 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함할 수 있다.The method of the present invention may include administering a pharmaceutically effective amount of a composition for improvement or treatment of cleft lip and cleft lip comprising the magnetic cells or agglomerates thereof provided in the present invention as an active ingredient to an individual in need of administration. have.
본 발명에서, "약학적으로 유효한 양"은 바람직한 생물학적 결과를 제공하기 위한 작용제의 충분한 양을 지칭한다. 상기 결과는 질환의 징후, 증상 또는 원인의 감소 및/또는 완화, 또는 생물계의 임의의 다른 바람직한 변화일 수 있다. 예를 들어, 치료 용도를 위한 "유효량"은 질환에서 임상적으로 유의한 감소를 제공하는데 요구되는, 본 발명에 개시된 조성물의 양이다. 임의의 개별적인 경우에서 적절한 "효과적인" 양은 일상적인 실험을 사용하여 당업자에 의해 결정될 수 있다. 따라서, 표현 "유효량"은 일반적으로 활성 물질이 치료 효과를 갖는 양을 지칭한다. 본 발명의 경우에, 활성 물질은 자성 물질을 포함하는 자성 세포로서, 구순 구개열의 예방, 개선 또는 치료용 세포이다.As used herein, a "pharmaceutically effective amount" refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition disclosed herein required to provide a clinically significant reduction in disease. An appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression "effective amount" generally refers to the amount in which the active substance has a therapeutic effect. In the case of the present invention, the active substance is a magnetic cell comprising a magnetic substance, and is a cell for preventing, ameliorating or treating cleft lip and cleft lip.
3-2. 수면 무호흡증의 예방, 개선 또는 치료용 조성물3-2. Composition for preventing, improving or treating sleep apnea
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 자성 세포 또는 이의 군집체를 유효 성분으로 포함하는 수면 무호흡증의 예방, 개선 또는 치료용 조성물에 관한 것이다. According to another embodiment of the present invention, it relates to a composition for preventing, improving or treating sleep apnea comprising the magnetic cells or agglomerates thereof provided in the present invention as an active ingredient.
본 발명에서 상기 수면 무호흡증 (sleep apnea syndrome)은 수면 무호흡증, 중추형 수면 무호흡증 또는 혼합형 수면 무호흡증일 수 있으며, 바람직하게는 폐쇄형 수면 무호흡증일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the sleep apnea (sleep apnea syndrome) may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
본 발명에서 상기 조성물은 자성 비드 부착률이 90 내지 100 %임을 고려하여 자성 세포 또는 이의 군집체를 포함할 수 있고, 구체적으로 수면 무호흡증의 치료를 위해 확장이 필요한 조직에서의 목표하는 변형치를 달성하기 위해 상기 방법으로 계산된 적정 자성 세포의 수를 포함할 수 있다. 비 제한적인 예시로 목적하는 개체의 기도 근육의 10 %의 변형률을 달성하기 위하여는 1.15 x 106 내지 1.5 x 106 개의 자성 세포를 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the composition may include magnetic cells or a cluster thereof considering that the magnetic bead adhesion rate is 90 to 100%, and specifically to achieve a target modification value in tissues requiring expansion for the treatment of sleep apnea. The number of suitable magnetic cells calculated by the above method may be included for this purpose. As a non-limiting example, 1.15 x 10 6 to 1.5 x 10 6 magnetic cells may be included in order to achieve a strain rate of 10% of the airway muscle of an individual, but is not limited thereto.
본 발명의 상기 "예방"이란, 본 발명의 상기 조성물을 이용하여 자성 세포가 생체 내에 주입됨으로써 호흡기계 유동관의 내벽에 척력 또는 인력을 작용시켜 유동관의 확장 또는 축소에 의해 수면 무호흡으로 발생되는 증상을 차단하거나, 그 증상을 억제 또는 지연시키는 행위라면 제한없이 포함될 수 있다.The "prevention" of the present invention means that magnetic cells are injected into a living body using the composition of the present invention, thereby acting a repulsive force or attractive force on the inner wall of the respiratory system flow tube, thereby preventing the symptoms caused by sleep apnea by the expansion or contraction of the flow tube. Blocking or suppressing or delaying the symptoms may be included without limitation.
본 발명의 상기 "개선 또는 치료"란, 본 발명의 상기 조성물을 이용하여 자성 세포가 생체 내에 주입됨으로써 호흡기계 유동관의 내벽에 척력 또는 인력을 작용시켜 유동관의 확장 또는 축소에 의해 수면 무호흡으로 발생되는 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다.본 발명의 조성물은 약학적 조성물 또는 식품 조성물의 형태로 제공될 수 있으나, 이에 제한되는 것은 아니다. The "improvement or treatment" of the present invention means that magnetic cells are injected into a living body using the composition of the present invention, thereby acting a repulsive force or attractive force on the inner wall of the respiratory system flow tube, thereby causing sleep apnea by expansion or contraction of the flow tube. Any action that improves symptoms or benefits may be included without limitation. The composition of the present invention may be provided in the form of a pharmaceutical composition or a food composition, but is not limited thereto.
본 발명에서 상기 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is targeted to humans.
본 발명의 상기 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사 용액의 형태로 제형화되어 사용될 수 있다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 약학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등이 사용될 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등이 혼합되어 사용될 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등이 사용될 수 있다. 본 발명의 약학 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서 (Elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형화할 수 있다.The pharmaceutical composition of the present invention is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories and sterile injection solutions according to conventional methods. can be used The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, and pain relief Agents, solubilizers, isotonic agents, stabilizers, etc. may be mixed and used, and in the case of topical administration, bases, excipients, lubricants, preservatives, etc. may be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above. For example, for oral administration, tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. have. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항 응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used. In addition, fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
본 발명의 상기 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition of the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
본 발명의 상기 "비경구"란, 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 바람직하게는 본 발명의 상기 약학 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있으나, 이에 제한되는 것은 아니다.The "parenteral" of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Preferably, the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration, but is not limited thereto.
본 발명의 상기 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여 시간, 투여 경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1 일 0.0001 내지 50 mg/kg 또는 0.001 내지 50 mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 약학적 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형화될 수 있다.The pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. The dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg per day It may be administered at /kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명의 상기 식품 조성물은 본 발명에서 목적으로 하는 적응증의 예방 또는 개선을 위해 다양하게 이용되는 것으로서, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 분말, 과립, 정제, 캡슐, 과자, 떡, 빵 등의 형태로 제조될 수 있다. 본 발명의 식품 조성물은 독성 및 부작용이 거의 없는 기존의 식품용 섭취물로부터 개량되어 구성된 것이므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다. 본 발명의 조성물이 식품 조성물에 포함될 때 그 양은 전체 중량의 0.1 내지 100 %의 비율로 첨가할 수 있다. 여기서, 상기 식품조성물이 음료 형태로 제조되는 경우 지시된 비율로 상기 식품 조성물을 함유하는 것 외에 특별한 제한점은 없으며 통상의 음료와 같이 여러가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 즉, 천연 탄수화물로서 포도당 등의 모노사카라이드, 과당 등의 디사카라이드, 슈크로스 등의 및 폴리사카라이드, 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜 등을 포함할 수 있다. 상기 향미제로서는 천연 향미제 (타우마틴, 스테비아 추출물 (예를 들어, 레바우디오시드 A, 글리시르히진등) 및 합성 향미제 (사카린, 아스파르탐 등) 등을 들 수 있다. 그 외 본 발명의 식품 조성물은 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 통상적으로 본 발명의 조성물 100 중량부 당 0.1 내지 100 중량부의 범위에서 선택되는 것이 일반적이나, 이에 제한되는 것은 아니다.The food composition of the present invention is variously used for the prevention or improvement of indications for the purpose of the present invention, and various foods such as beverages, gums, teas, vitamin complexes, powders, granules, tablets, capsules, It can be prepared in the form of confectionery, rice cake, bread, and the like. Since the food composition of the present invention is improved from the existing food intake with little toxicity and side effects, it can be safely used even when taken for a long period of time for the purpose of prevention. When the composition of the present invention is included in the food composition, the amount may be added in a proportion of 0.1 to 100% of the total weight. Here, when the food composition is prepared in the form of a beverage, there is no particular limitation other than containing the food composition in the indicated ratio, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol and erythritol are included. can do. Examples of the flavoring agent include natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents ; It is generally selected in the range of 0.1 to 100 parts by weight of sugar, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 수면 무호흡증을 예방, 개선 또는 치료하는 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method for preventing, ameliorating or treating sleep apnea.
본 발명의 상기 방법은 투여가 필요한 개체에게 본 발명에서 제공하는 자성 세포 또는 이의 군집체를 유효 성분으로 포함하는 수면 무호흡증의 예방, 개선 또는 치료용 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함할 수 있다.The method of the present invention includes the step of administering to an individual in need of administration a composition for preventing, improving or treating sleep apnea comprising the magnetic cell or its aggregate provided in the present invention as an active ingredient in a pharmaceutically effective amount can do.
본 발명에서, "약학적으로 유효한 양"은 바람직한 생물학적 결과를 제공하기 위한 작용제의 충분한 양을 지칭한다. 상기 결과는 질환의 징후, 증상 또는 원인의 감소 및/또는 완화, 또는 생물계의 임의의 다른 바람직한 변화일 수 있다. 예를 들어, 치료 용도를 위한 "유효량"은 질환에서 임상적으로 유의한 감소를 제공하는데 요구되는, 본 발명에 개시된 조성물의 양이다. 임의의 개별적인 경우에서 적절한 "효과적인" 양은 일상적인 실험을 사용하여 당업자에 의해 결정될 수 있다. 따라서, 표현 "유효량"은 일반적으로 활성 물질이 치료 효과를 갖는 양을 지칭한다. 본 발명의 경우에, 활성 물질은 자성 물질을 포함하는 자성 세포로서, 수면 무호흡증의 예방, 개선 또는 치료용 세포이다.As used herein, a "pharmaceutically effective amount" refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition disclosed herein required to provide a clinically significant reduction in disease. An appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression "effective amount" generally refers to the amount in which the active substance has a therapeutic effect. In the case of the present invention, the active substance is a magnetic cell comprising a magnetic substance, and is a cell for preventing, ameliorating or treating sleep apnea.
4-1. 입술 또는 구강 조직의 형상 제어 장치4-1. Shape control device of lip or oral tissue
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 상기 자성 세포 또는 자성 세포 군집체를 포함하는 입술 또는 구강 조직의 형상 제어 장치에 관한 것이다.According to another embodiment of the present invention, it relates to a device for controlling the shape of a lip or oral tissue comprising the magnetic cell or magnetic cell aggregate provided by the present invention.
본 발명의 상기 장치는 상기 자성 세포가 생체 내에 주입되어 입술 또는 구강 조직에 척력 또는 인력을 작용시켜 상기 입술 또는 구강 조직에 존재하는 변형, 특히 갈라진 변형 부위의 봉합, 복원 또는 재건이 가능한 특징이 있다.The device of the present invention is characterized in that the magnetic cells are injected into the living body to apply a repulsive force or attractive force to the lips or oral tissue, so that deformation existing in the lips or oral tissue, in particular, suturing, restoration, or reconstruction of a cracked deformed site is possible. .
본 발명에서 상기 입술 또는 구강 조직은 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the lip or oral tissue may be lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is not limited thereto.
본 발명의 상기 장치는 자기장 인가 장치, 빛 간섭 단층 촬영(optical coherence tomography, OCT) 장치 또는 근적외선 조사 장치로 이루어진 군에서 선택된 적어도 하나를 추가로 포함하는 장치일 수 있다.The device of the present invention may be a device further comprising at least one selected from the group consisting of a magnetic field application device, an optical coherence tomography (OCT) device, or a near-infrared irradiation device.
본 발명에서 상기 자기장 인가 장치는 자성 세포를 보다 정확한 병변 부위로의 이동을 가능하게 할 뿐만 아니라, 교류 자기장으로 인한 온열 치료 효과를 제공할 수 있는 장치일 수 있다. 상기에서 자기장 인가에 따른 온열 효과는 인체에 무해한 자기장을 사용하여 치료가 수행되므로 온열 치료 시 화상 염려 또는 정상 조직의 파괴가 최소화될 수 있다는 장점이 있다. In the present invention, the magnetic field application device may be a device capable of providing a thermal treatment effect due to an alternating magnetic field as well as enabling a more accurate movement of magnetic cells to a lesion site. The thermal effect of the application of the magnetic field has the advantage that since the treatment is performed using a magnetic field harmless to the human body, the risk of burns or destruction of normal tissues during thermal treatment can be minimized.
본 발명에서 상기 빛 간섭 단층 촬영(optical coherence tomography, OCT) 장치는 자기장 인가 장치를 통한 자기장 인가 후, 입술 또는 구강 조직에 위치하는 자성 세포의 이미지 정보를 실시간으로 관측하여 입술 또는 구강 조직의 형상 제어를 위한 피드백 정보를 제공할 수 있다.In the present invention, the optical coherence tomography (OCT) device controls the shape of the lips or oral tissue by observing the image information of magnetic cells located in the lips or oral tissue in real time after the magnetic field is applied through the magnetic field applying device. You can provide feedback information for
본 발명에서 상기 장치는 생체에 주입된 자성 세포가 자기장 인가 장치를 통해 강자성이 부여되어 입술 또는 구강 조직에 부착됨에 따라, 자성 세포가 부착된 조직 정보 및 이후 입술 또는 구강 조직의 형상 변화를 빛 간섭 단층 촬영 장치를 통하여 3 차원 이미지로부터 확인할 수 있다. 이때 빛의 파장은 700 내지 1500 nm의 범위 일 수 있으며, 보다 바람직하게는 900 내지 1300 nm의 범위일 수 있다. In the present invention, as the magnetic cells injected into the living body are given ferromagnetism through the magnetic field applying device and attached to the lips or oral tissue, the device provides information on the tissue to which the magnetic cells are attached and changes in the shape of the lips or oral tissue afterwards by light interference. It can be confirmed from a three-dimensional image through a tomography apparatus. In this case, the wavelength of the light may be in the range of 700 to 1500 nm, more preferably in the range of 900 to 1300 nm.
본 발명에서 상기 빛 간섭 단층 촬영 장치는 근적외선 조사 장치와 연결될 수 있으며, 근적외선을 입술 또는 구강 조직에 조사하여 조직으로부터 반사되어 돌아오는 빛으로부터 영상 정보를 분석할 수 있다.In the present invention, the light coherence tomography apparatus may be connected to a near-infrared irradiator, and may analyze image information from light reflected back from the tissue by irradiating near-infrared rays to the lip or oral tissue.
본 발명에서 상기 근적외선 조사 장치는 구순 구개열에 있어 국소적 광열 치료 효과를 유도함으로써, 교류 자기장 인가에 따른 온열 치료 효과에 추가로 상승된 시너지 치료 효과를 제공할 수 있으며, 입술 또는 구강 구조의 형상 제어를 보다 용이하게 수행하도록 하는 점에서 바람직할 수 있다.In the present invention, the near-infrared irradiation device induces a local photothermal treatment effect for cleft lip and cleft palate, thereby providing a synergistic treatment effect increased in addition to the heat treatment effect according to the application of an alternating magnetic field, and controlling the shape of the lips or oral structure It may be preferable in terms of making it easier to perform.
본 발명의 상기 장치는 입술 또는 구강 조직에 주입된 본 발명에 따른 자성 세포의 입술 또는 구강 조직의 변형 부위의 봉합, 복원 또는 재건의 성패를 비침습적인 방법을 통해 실시간으로 확인할 수 있으며, 이에 따라 입술 또는 구강 조직 형상 제어를 위한 피드백이 용이하게 이루어질 수 있다.The device of the present invention can confirm in real time the success or failure of suturing, restoration or reconstruction of the deformed region of the lip or oral tissue of the magnetic cells according to the present invention injected into the lip or oral tissue through a non-invasive method. Feedback for lip or oral tissue shape control can be easily made.
본 발명의 상기 장치는 목적하는 개체에서 발병된 구순 구개열 치료의 목적으로 사용되는 것일 수 있으며, 바람직하게는 구순열 및 구개열 중 적어도 하나의 치료를 위한 것일 수 있으나 이에 제한되는 것은 아니다.The device of the present invention may be used for the purpose of treating cleft lip and cleft palate in a target subject, preferably for the treatment of at least one of cleft lip and cleft palate, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 본 발명의 자성 세포를 주입한 이후의 상황을 예측하는 시뮬레이션부 입술 또는 구강 조직의 형상 제어 계획 수립 장치에 관한 것이다.According to another embodiment of the present invention, the present invention relates to an apparatus for setting a plan for controlling the shape of the lips or oral tissue of the simulation unit for predicting the situation after the injection of the magnetic cells of the present invention.
본 발명에서 상기 입술 또는 구강 조직은 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the lip or oral tissue may be lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is not limited thereto.
도 5a는 본 발명의 일 예시에 따른 자성 세포의 환자별 최적 주입을 위한 인공지능 입술 또는 구강 조직의 형상 제어 계획 수립 장치를 도식화하여 나타낸 것이고, 도 6은 본 발명의 일 예시에 따른 자성 세포를 이용한 인공지능 형상 제어 계획 수립 장치의 내부 구성을 예시한 블록도를 나타낸 것이다. 이하 도 5a 및 도 6을 참조하여 본 발명을 설명하지만, 이에 제한되는 것은 아니다. Figure 5a schematically shows an apparatus for establishing a shape control plan for artificial intelligence lips or oral tissue for optimal injection of magnetic cells for each patient according to an example of the present invention, and Figure 6 is a magnetic cell according to an example of the present invention It shows a block diagram illustrating the internal configuration of an artificial intelligence shape control plan establishment device used. Hereinafter, the present invention will be described with reference to FIGS. 5A and 6 , but is not limited thereto.
본 발명에서 상기 장치는 자성 세포를 이용한 인공지능 입술 또는 구강 조직의 형상 제어 계획 수립 시스템(100)을 제공할 수 있다.In the present invention, the device may provide the artificial intelligence lip or oral tissue shape control planning system 100 using magnetic cells.
본 발명에서 상기 장치는 목적하는 개체의 신상정보, 의료영상정보 및 입술 또는 구강 조직의 형상 정보를 포함하는 데이터베이스부(110); 상기 개체의 생체 정보, 의료영상정보 및 입술 또는 구강 조직의 형상 인자의 입력을 수신하고, 소정의 결과물을 출력하는 인터페이스부(120); 상기 데이터베이스부(110) 및 인터페이스부(120)로부터 수신한 정보를 인공지능 기법으로 분석하여 상기 개체에 대한 자성 세포의 주입 후의 상황을 예측하는 시뮬레이션부(130); 및 상기 시뮬레이션부의 결과에 따라 상기 자성 세포의 주입 방법 및 주입 위치를 결정하고, 주입량을 산출하는 제어 계획 수립부(140);를 포함하는 것일 수 있다.In the present invention, the device includes a database unit 110 including personal information of a target object, medical image information, and shape information of lips or oral tissue; an interface unit 120 for receiving input of the biometric information, medical image information, and shape factor of the lip or oral tissue of the individual, and outputting a predetermined result; a simulation unit 130 that analyzes the information received from the database unit 110 and the interface unit 120 using an artificial intelligence technique to predict a situation after the injection of magnetic cells into the object; and a control plan establishment unit 140 that determines the injection method and injection location of the magnetic cells according to the result of the simulation unit, and calculates the injection amount.
본 발명에서 상기 목적하는 개체는 구순 구개열(cleft lip and palate)이 발생한 개체로, 구순열 및 구개열 중 적어도 하나가 발생한 개체일 수 있고, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열이 발생한 개체일 수 있다. 또한, 상기 개체는 바람직하게는 인간, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 인간일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the subject subject is an individual having cleft lip and palate, and may be an individual having at least one of cleft lip and palate, and as non-limiting examples, incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip. , incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, unilateral complete cleft palate, or bilateral complete cleft palate. In addition, the subject is preferably human, rat, mouse, guinea pig, hamster, rabbit, monkey, dog, cat, cow, horse, pig, sheep and goat may be selected from the group consisting of, more preferably human However, the present invention is not limited thereto.
본 발명에서 상기 목적하는 개체의 신상정보는 나이, 성별, 기저질환 보유 여부 등의 정보일 수 있으며, 의료영상정보의 구체적 일 예시로는 CT (computed tomography), MRI (magnetic resonance imaging), PET (positron emission tomography), CR (computed radiography) 등과 같은 의료영상장치를 통해 생체를 촬영하여 획득한 영상 자료일 수 있다. 또한, 환자의 생체 정보는 혈압, 심박동수 등 간단한 생리적 데이터를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the target individual's personal information may be information such as age, gender, and whether or not they have an underlying disease, and specific examples of medical image information include computed tomography (CT), magnetic resonance imaging (MRI), PET ( It may be image data obtained by photographing a living body through a medical imaging device such as positron emission tomography (CR) or computed radiography (CR). In addition, the patient's biometric information may include simple physiological data such as blood pressure and heart rate, but is not limited thereto.
본 발명에서 상기 입술 또는 구강 조직 형상 인자는 상기 의료영상정보로부터 확인된 입술 및 구강의 구조 또는 형상에 관한 정보일 수 있고, 이후 입술 또는 구강 조직 형상 제어를 위한 주입 방식, 주입 위치, 및 주입량을 결정하기 위하여 필요한 정보일 수 있다. In the present invention, the lip or oral tissue shape factor may be information about the structure or shape of the lips and oral cavity confirmed from the medical image information, and then the injection method, injection location, and injection amount for controlling the shape of the lips or oral cavity. It may be information necessary to make a decision.
본 발명에서 상기 시뮬레이션부(130)는 격자볼츠만법(Lattice Boltzman method: LBM)의 기본 전산유체 해석 수식을 통해 근육 또는 조직의 시뮬레이션을 수행할 수 있다. 실제 생체 환경에 최대한 근접하기 위하여 각 구강 조건을 시뮬레이션에 포함시키고, 자력에 따른 입술 또는 구강의 형상의 변화의 상관 관계에 대한 수식을 포함한다. 이를 통해 자성 세포 주입 후의 상황을 가정한 시뮬레이션 수행으로부터 그 결과는 제어 계획 수립부(140)에서 반영하여 본 발명에 따른 자성 세포 주입에 최적화된 계획수립이 가능하다.In the present invention, the simulation unit 130 may perform a simulation of a muscle or tissue through a basic computational fluid analysis equation of the Lattice Boltzman method (LBM). Each oral condition is included in the simulation in order to be as close as possible to the actual living environment, and a formula for the correlation of changes in the shape of the lips or oral cavity according to magnetic force is included. Through this, it is possible to establish a plan optimized for the magnetic cell injection according to the present invention by reflecting the result from the simulation performed assuming the situation after the magnetic cell injection in the control plan establishment unit 140 .
본 발명은 기존 환자들의 임상데이터를 기반으로 하여 인공지능 딥러닝 알고리즘에 따라 환자의 입술 또는 구강 조직의 형상 제어를 예측 가능하도록 하는 특징이 있다.The present invention is characterized in that it is possible to predict the shape control of the patient's lips or oral tissue according to an artificial intelligence deep learning algorithm based on clinical data of existing patients.
본 발명의 상기 시뮬레이션부의 결과에 따라 환자 특성에 맞게 빠른 자성 세포의 확산을 위하여 환자의 입술 또는 구강 조직에 주입하는 경우 비제한적인 예시로는 액상 주사 형태 또는 액상을 연성 발포체에 흡수시킨 후 상기 발포체를 주입할 수 있다, 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다.According to the result of the simulation unit of the present invention, when injecting into the lip or oral tissue of a patient for rapid diffusion of magnetic cells according to the characteristics of the patient, as a non-limiting example, a liquid injection form or liquid is absorbed into a flexible foam and then the foam In the case of injection in the form of liquid injection, the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, and it can be appropriately selected according to the desired residence time, In addition to the methods listed above, various methods may be used for injection.
4-2. 호흡기계 유동관 형상 제어 장치4-2. Respiratory system flow tube shape control device
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 상기 자성 세포 또는 자성 세포 군집체를 포함하는 호흡기계 유동관 형상 제어 장치에 관한 것이다.According to another embodiment of the present invention, it relates to an apparatus for controlling the shape of a respiratory system flow tube including the magnetic cell or magnetic cell aggregate provided in the present invention.
본 발명의 상기 장치는 상기 자성 세포가 생체 내에 주입되어 호흡기계 유동관의 내벽에 척력 또는 인력을 작용시켜 유동관의 확장 또는 축소가 가능한 특징이 있으며, 호흡기계 유동관의 형상을 제어하는 기능을 수행할 수 있다.The device of the present invention is characterized in that the magnetic cells are injected into the living body to apply a repulsive or attractive force to the inner wall of the respiratory system flow tube to expand or contract the flow tube, and to control the shape of the respiratory system flow tube. have.
본 발명에서 상기 호흡기계 유동관은 바람직하게는 비강, 인후두 또는 기도일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
본 발명의 상기 장치는 자기장 인가 장치, 빛 간섭 단층 촬영(optical coherence tomography, OCT) 장치 또는 근적외선 조사 장치로 이루어진 군에서 선택된 적어도 하나를 추가로 포함하는 장치일 수 있다.The device of the present invention may be a device further comprising at least one selected from the group consisting of a magnetic field application device, an optical coherence tomography (OCT) device, or a near-infrared irradiation device.
본 발명에서 상기 자기장 인가 장치는 자성 세포를 보다 정확한 병변 부위로의 이동을 가능하게 할 뿐만 아니라, 교류 자기장으로 인한 온열 치료 효과를 제공할 수 있는 장치일 수 있다. 상기에서 자기장 인가에 따른 온열 효과는 인체에 무해한 자기장을 사용하여 치료가 수행되므로 온열 치료 시 화상 염려 또는 정상 조직의 파괴가 최소화될 수 있다는 장점이 있다. In the present invention, the magnetic field application device may be a device capable of providing a thermal treatment effect due to an alternating magnetic field as well as enabling a more accurate movement of magnetic cells to a lesion site. The thermal effect of the application of the magnetic field has the advantage that since the treatment is performed using a magnetic field harmless to the human body, the risk of burns or destruction of normal tissues during thermal treatment can be minimized.
본 발명에서 상기 빛 간섭 단층 촬영(optical coherence tomography, OCT) 장치는 자기장 인가 장치를 통한 자기장 인가 후, 유동관에 결합된 자성 세포의 이미지 정보를 실시간으로 관측하여 유동관 형상 제어를 위한 피드백 정보를 제공할 수 있다.In the present invention, the optical coherence tomography (OCT) device provides feedback information for controlling the shape of the flow tube by observing the image information of the magnetic cells coupled to the flow tube in real time after applying the magnetic field through the magnetic field application device. can
본 발명에서 상기 장치는 생체에 주입된 자성 세포가 자기장 인가 장치를 통해 강자성이 부여되어 유동관 내벽에 부착됨에 따라, 자성 세포가 부착된 조직 정보 및 이후 유동관의 형상 변화를 빛 간섭 단층 촬영 장치를 통하여 3차원 이미지로부터 확인할 수 있다. 이때 빛의 파장은 700 내지 1500 nm의 범위 일 수 있으며, 보다 바람직하게는 900 내지 1300 nm의 범위일 수 있다. In the present invention, as the magnetic cells injected into the living body are given ferromagnetism through the magnetic field application device and attached to the inner wall of the flow tube, the device records the tissue information to which the magnetic cells are attached and the shape change of the flow tube thereafter through a light interference tomography device. It can be confirmed from the 3D image. In this case, the wavelength of the light may be in the range of 700 to 1500 nm, more preferably in the range of 900 to 1300 nm.
본 발명에서 상기 빛 간섭 단층 촬영 장치는 근적외선 조사 장치와 연결될 수 있으며, 근적외선을 조직에 조사하여 조직으로부터 반사되어 돌아오는 빛으로부터 영상 정보를 분석할 수 있다. In the present invention, the light coherence tomography apparatus may be connected to a near-infrared irradiator, and may analyze image information from light reflected back from the tissue by irradiating near-infrared rays to the tissue.
본 발명에서 상기 근적외선 조사 장치는 호흡기계 유동관이 협착 또는 폐쇄되어 발생되는 수면 무호흡증에 있어 국소적 광열 치료 효과를 유도함으로써, 교류 자기장 인가에 따른 온열 치료 효과에 추가로 상승된 시너지 치료 효과를 제공할 수 있으며, 유동관의 형상 제어를 보다 용이하게 수행하도록 하는 점에서 바람직할 수 있다.In the present invention, the near-infrared irradiation device induces a local photothermal treatment effect in sleep apnea caused by stenosis or occlusion of a respiratory system flow tube, thereby providing an additionally increased synergistic treatment effect to the thermal treatment effect according to the application of an alternating magnetic field. It may be preferable in terms of allowing the shape control of the flow pipe to be performed more easily.
본 발명의 상기 장치는 호흡기계 유동관에 주입된 본 발명에 따른 자성 세포의 유동관 형상 제어의 성패를 비침습적인 방법을 통해 실시간으로 확인할 수 있으며, 이에 따라 호흡기계 유동관 형상 제어를 위한 피드백이 용이하게 이루어질 수 있다.The device of the present invention can check the success or failure of flow tube shape control of magnetic cells injected into the respiratory system flow tube according to the present invention in real time through a non-invasive method, and thus feedback for controlling the respiratory system flow tube shape can be easily provided. can be done
본 발명의 상기 장치는 목적하는 개체에서 발병되었거나 발병될 가능성이 있는 수면 무호흡증 치료의 목적으로 사용되는 것일 수 있으며, 바람직하게는 폐쇄성 수면 무호흡증 치료를 위한 것일 수 있으나 이에 제한되는 것은 아니다.The device of the present invention may be used for the purpose of treating sleep apnea that has or is likely to develop in a target subject, preferably for the treatment of obstructive sleep apnea, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 본 발명의 자성 세포를 주입한 이후의 상황을 예측하는 시뮬레이션부 호흡기계 유동관 형상 제어 계획 수립 장치에 관한 것이다.According to another embodiment of the present invention, it relates to a simulation unit respiratory system flow tube shape control planning apparatus for predicting the situation after the magnetic cells of the present invention are injected.
본 발명에서 상기 호흡기계 유동관은 바람직하게는 비강, 인후두 또는 기도일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
도 5b는 본 발명의 일 예시에 따른 자성 세포의 환자별 최적 주입을 위한 인공지능 유동관 형상 제어 계획 수립 장치를 도식화하여 나타낸 것이고, 도 6은 본 발명의 일 예시에 따른 자성 세포를 이용한 인공지능 유동관 형상 제어 계획 수립 장치의 내부 구성을 예시한 블록도를 나타낸 것이다. 이하 도 5b 및 도 6을 참조하여 본 발명을 설명하지만, 이에 제한되는 것은 아니다. Figure 5b schematically shows an apparatus for establishing an artificial intelligence flow tube shape control plan for optimal injection of magnetic cells for each patient according to an example of the present invention, and Figure 6 is an artificial intelligence flow tube using magnetic cells according to an example of the present invention. It shows a block diagram illustrating the internal configuration of the shape control planning apparatus. Hereinafter, the present invention will be described with reference to FIGS. 5B and 6 , but is not limited thereto.
본 발명에서 상기 장치는 자성 세포를 이용한 인공지능 유동관 형상 제어 계획 수립 시스템(100)을 제공할 수 있다.In the present invention, the device may provide an artificial intelligence flow tube shape control planning system 100 using magnetic cells.
본 발명에서 상기 장치는 목적하는 개체의 신상정보, 의료영상정보 및 유동관 형상 정보를 포함하는 데이터베이스부(110); 상기 개체의 생체 정보, 의료영상정보 및 호흡기계 유동관 형상 인자의 입력을 수신하고, 소정의 결과물을 출력하는 인터페이스부(120); 상기 데이터베이스부(110) 및 인터페이스부(120)로부터 수신한 정보를 인공지능 기법으로 분석하여 상기 개체에 대한 자성 세포의 주입 후의 상황을 예측하는 시뮬레이션부(130); 및 상기 시뮬레이션부의 결과에 따라 상기 자성 세포의 주입 방법 및 주입 위치를 결정하고, 주입량을 산출하는 제어 계획 수립부(140);를 포함하는 것일 수 있다.In the present invention, the apparatus includes a database unit 110 including personal information, medical image information, and flow tube shape information of a target entity; an interface unit 120 for receiving input of biometric information, medical image information, and respiratory system flow tube shape factors of the entity, and outputting a predetermined result; a simulation unit 130 that analyzes the information received from the database unit 110 and the interface unit 120 using an artificial intelligence technique to predict a situation after the injection of magnetic cells into the object; and a control plan establishment unit 140 that determines the injection method and injection location of the magnetic cells according to the result of the simulation unit, and calculates the injection amount.
본 발명에서 상기 목적하는 개체는 수면 무호흡증 (sleep apnea syndrome)이 발병하였거나 발병 가능성이 높은 개체일 수 있고, 상기 개체는 바람직하게는 인간, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 마우스, 토끼 또는 돼지 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the subject subject to sleep apnea syndrome (sleep apnea syndrome) may be a subject or a subject with a high probability of developing, and the subject is preferably a human, rat, mouse, guinea pig, hamster, rabbit, monkey, dog, cat. , may be selected from the group consisting of cattle, horses, pigs, sheep and goats, and more preferably may be mice, rabbits or pigs, but is not limited thereto.
본 발명에서 상기 목적하는 개체의 신상정보는 나이, 성별, 기저질환 보유 여부 등의 정보일 수 있으며, 의료영상정보의 구체적 일 예시로는 CT(computed tomography), MRI(magnetic resonance imaging), PET(positron emission tomography), CR(computed radiography) 등과 같은 의료영상장치를 통해 생체를 촬영하여 획득한 영상 자료일 수 있다. 또한, 환자의 생체 정보는 혈압, 심박동수 등 간단한 생리적 데이터를 포함하는 것일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the target individual's personal information may be information such as age, gender, and whether or not they have an underlying disease, and specific examples of medical image information include computed tomography (CT), magnetic resonance imaging (MRI), and PET (PET). It may be image data obtained by photographing a living body through a medical imaging device such as positron emission tomography (CR) or computed radiography (CR). In addition, the patient's biometric information may include simple physiological data such as blood pressure and heart rate, but is not limited thereto.
본 발명에서 상기 호흡기계 유동관 형상 인자는 상기 의료영상정보로부터 확인된 호흡기계 유동관의 구조 또는 형상에 관한 정보일 수 있고, 이후 호흡기계 유동관 형상 제어를 위한 주입 방식, 주입 위치, 및 주입량을 결정하기 위하여 필요한 정보일 수 있다. In the present invention, the respiratory system flow tube shape factor may be information about the structure or shape of the respiratory system flow tube confirmed from the medical image information, and then determine the injection method, injection location, and injection amount for controlling the respiratory system flow tube shape. It may be necessary information for
본 발명에서 상기 시뮬레이션부(130)는 격자볼츠만법(Lattice Boltzman method: LBM)의 기본 전산유체 해석 수식을 통해 유동관 시뮬레이션을 수행할 수 있다. 실제 생체 환경에 최대한 근접하기 위하여 각 호흡기계 유동관 특성에 맞는 심박 기반의 유량, 혈류 저항값, 유체의 점성도, 호흡기계 유동관의 탄성 등의 조건을 시뮬레이션에 포함시키고, 자력에 따른 유동관 형상의 변화의 상관 관계에 대한 수식을 포함한다. 이를 통해 자성 세포 주입 후의 상황을 가정한 시뮬레이션 수행으로부터 그 결과는 제어 계획 수립부(140)에서 반영하여 본 발명에 따른 자성 세포 주입에 최적화된 계획수립이 가능하다.In the present invention, the simulation unit 130 may perform a flow pipe simulation through a basic computational fluid analysis equation of the Lattice Boltzman method (LBM). In order to get as close as possible to the actual living environment, conditions such as heart rate-based flow rate, blood flow resistance, fluid viscosity, and elasticity of the respiratory system flow tube suitable for each respiratory system flow tube characteristic are included in the simulation, and the change of flow tube shape according to magnetic force Include formulas for correlation. Through this, it is possible to establish a plan optimized for the magnetic cell injection according to the present invention by reflecting the result from the simulation performed assuming the situation after the magnetic cell injection in the control plan establishment unit 140 .
본 발명은 기존 환자들의 임상데이터를 기반으로 하여 인공지능 딥러닝 알고리즘에 따라 환자 유동관 형상의 제어를 예측 가능하도록 하는 특징이 있다.The present invention is characterized in that it is possible to predict the control of the patient's flow tube shape according to an artificial intelligence deep learning algorithm based on clinical data of existing patients.
본 발명의 상기 시뮬레이션부의 결과에 따라 환자 특성에 맞게 빠른 자성 세포의 확산을 위하여 환자의 호흡기계 유동관에 주입하는 경우 비제한적인 예시로는 액상 주사 형태 또는 액상을 연성 발포체에 흡수시킨 후 상기 발포체를 주입할 수 있다, 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다.According to the result of the simulation unit of the present invention, when injecting into the respiratory system flow tube of a patient for rapid diffusion of magnetic cells according to the characteristics of the patient, as a non-limiting example, the liquid injection form or the liquid is absorbed into the flexible foam and then the foam is Can be injected, when injected in the form of liquid injection, the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time in the body, so it can be appropriately selected according to the desired residence time, In addition to the methods listed, various methods of injection are possible.
5-1. 구순 구개열 동물 모델 및 이의 용도5-1. Cleft palate animal model and uses thereof
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 자성 세포 또는 이의 군집체가 주입된 구순 구개열 동물 모델을 제조하는 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method for preparing an animal model of cleft lip and cleft lip into which the magnetic cells or agglomerates thereof provided in the present invention are injected.
본 명세서에서 사용되는 용어, "동물 모델"은 질환 동물 모델을 의미한다. 구체적으로, 동물 모델은 인간의 질병과 유사한 상태의 질병에 걸리거나 선천적으로 그 질병에 걸리도록 만들어낸 동물 모델일 수 있다. 본 명세서에서 동물 모델은 근육 또는 조직 이상 동물 모델, 더 나아가서는 구순 구개열의 동물 모델일 수 있다. 또한, 본 발명의 동물 모델로 이용될 수 있는 동물은 인간을 제외한 포유 동물로, 예를 들면, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 마우스, 토끼 또는 돼지 등일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term “animal model” refers to an animal model of a disease. Specifically, the animal model may be an animal model that is afflicted with a disease similar to a human disease or is congenitally afflicted with the disease. In the present specification, the animal model may be an animal model of muscle or tissue abnormality, and furthermore, an animal model of cleft lip and cleft palate. In addition, animals that can be used as animal models of the present invention are mammals other than humans, for example, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, cats, cattle, horses, pigs, sheep and goats. It may be selected from the group consisting of, and more preferably a mouse, rabbit or pig, but is not limited thereto.
본 발명의 제조 방법은 동물의 목적하는 입술 또는 구강 조직 부위에 상기 자성 세포 또는 자성 세포 군집체를 주입하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include injecting the magnetic cells or the magnetic cell aggregate into a desired lip or oral tissue site of the animal.
본 발명에서 상기 입술 또는 구강 조직은 바람직하게는 입술 또는 구강 조직은 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the lip or oral tissue is preferably the lip or oral tissue may be lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is limited thereto. it is not
본 발명에서 상기 주입 방법의 비제한적인 예시로는 액상 주사 형태 또는 액상을 연성 발포체에 흡수시킨 후 상기 발포체를 주입할 수 있다. 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다.In the present invention, as a non-limiting example of the injection method, the liquid injection form or liquid may be absorbed into the flexible foam and then the foam may be injected. When injected in the form of liquid injection, the residence time may appear relatively short, but when injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time. method can be injected.
본 발명에서 상기 동물 모델에 상기 자성 세포 또는 자성 세포 군집체의 주입 시 부유액에 자성 세포 또는 자성 세포 군집체를 혼합하여 주입하는 것이 부유액의 점도를 조절하여 자성 세포를 포함한 주사액의 확산 속도 및 주입된 자성 세포의 유지 시간 제어가 가능하며 부유액에 혼합된 자성 세포의 양을 조절함으로써 자력 제어가 가능하여 바람직하다. 여기서, 상기 부유액은 생분해성의 PDMS, 히알루론산, 콜라겐, 키틴, 키토산, 헤파린 또는 이들의 조합일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when injecting the magnetic cells or magnetic cell aggregates into the animal model, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to control the diffusion rate of the injection solution including the magnetic cells and the injected It is preferable that the holding time of the magnetic cells can be controlled and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension. Here, the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
본 발명의 제조 방법은 상기 자성 입자가 주입된 입술 또는 구강 조직 부위에 자기력을 인가하여 상기 입술 또는 구강 조직에서 갈라진 변형 부위의 봉합, 복원 또는 재건을 유도하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include the step of inducing suturing, restoration or reconstruction of a deformed region cracked in the lip or oral tissue by applying a magnetic force to the lip or oral tissue region into which the magnetic particles are injected.
본 발명에서 상기 자기력의 인가 시 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다.In the present invention, it may be performed by forming a magnetic field upon application of the magnetic force, and the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서는 상기 자기력의 인가 시 상기 자성 입자와 상기 자석 간의 척력 또는 인력을 이용하여 입술 또는 구강 조직에서 구순 구개열로 인해 갈라진 변형 부위의 봉합, 복원 또는 재건을 유도할 수 있다.In the present invention, when the magnetic force is applied, it is possible to induce suturing, restoration, or reconstruction of the deformed area cracked due to cleft palate in the lips or oral tissue by using the repulsive force or attractive force between the magnetic particles and the magnet.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 입술 근육 또는 구강 조직의 수축 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude, direction, time for applying the magnetic force, etc. can be appropriately adjusted and determined according to the desired degree of contraction of the lip muscle or oral tissue, and there is no particular limitation.
본 발명에서 상기 동물 모델은 입술 또는 구강 조직에 갈라진 변형이 존재하는 구순 구개열이 구현된 동물 모델일 수 있다.In the present invention, the animal model may be an animal model in which a cleft lip or cleft lip exists in the oral tissue.
본 발명의 또 다른 구현 예에 따르면, 본 발명의 제조 방법에 따라 제조된 구순 구개열 동물 모델에 관한 것이다. According to another embodiment of the present invention, it relates to an animal model of cleft lip and cleft lip produced according to the production method of the present invention.
본 발명에서 상기 구순 구개열은 구순열 및 구개열 중 적어도 하나일 수 있으며, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 동물 모델을 이용하여 구순 구개열의 개선 또는 치료용 약물 또는 장치를 스크리닝하는 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method of screening a drug or device for improving or treating cleft lip and cleft lip using the animal model provided by the present invention.
본 발명에서 상기 "스크리닝"이란, 여러 물질 또는 장치로 이루어진 후보군으로부터 목적으로 하는 어떤 특정한 성질을 갖는 물질을 특정한 조작 또는 평가 방법으로 선별하는 것이다. In the present invention, the "screening" refers to selecting a substance having a specific target property from a candidate group consisting of various substances or devices by a specific manipulation or evaluation method.
본 발명의 스크리닝 방법은 우선, 본 발명에서 제공하는 동물 모델에 구순 구개열의 개선 또는 치료용 후보 약물을 처리하거나 구순 구개열의 개선 또는 치료용 후보 장치를 적용하는 단계를 포함할 수 있다.The screening method of the present invention may include first, treating a drug candidate for improvement or treatment of cleft lip or cleft lip or applying a candidate device for amelioration or treatment of cleft lip and cleft lip to the animal model provided by the present invention.
본 발명에서 상기 후보 약물은 천연 화합물, 합성 화합물, RNA, DNA, 폴리펩티드, 효소, 단백질, 리간드, 항체, 항원, 박테리아 또는 진균의 대사 산물 및 생활성 분자로 이루어진 군으로부터 선택되는 어느 하나인 것이 바람직하나, 이에 제한되는 것은 아니다. In the present invention, the candidate drug is preferably any one selected from the group consisting of natural compounds, synthetic compounds, RNA, DNA, polypeptides, enzymes, proteins, ligands, antibodies, antigens, bacterial or fungal metabolites and bioactive molecules. However, the present invention is not limited thereto.
본 발명의 스크리닝 방법은 상기 후보 약물을 처리하거나 후보 장치를 적용한 동물 모델의 입술 또는 구강 조직을 관찰하거나 상기 동물 모델을 사육하면서 예후를 확인하는 단계를 포함할 수 있다. 이때 상기 후보 약물의 처리 또는 후보 장치의 적용 후 입술 또는 구강 조직의 갈라진 변형 부위의 적어도 일부가 봉합, 복원 또는 재건된 경우, 또는 상기 후보 약물 또는 후보 장치에 의하여 구순 구개열이 개선 또는 치료된 경우에 상기 후보 약물 또는 장치를 구순 구개열의 개선 또는 치료용 약물 또는 장치로 결정할 수 있다.The screening method of the present invention may include processing the candidate drug or observing the lip or oral tissue of the animal model to which the candidate device is applied, or confirming the prognosis while breeding the animal model. At this time, when at least a part of the cracked deformed region of the lips or oral tissue is sutured, restored or reconstructed after the treatment of the candidate drug or application of the candidate device, or when the cleft lip is improved or treated by the candidate drug or the candidate device The candidate drug or device may be determined as a drug or device for amelioration or treatment of cleft palate.
본 발명에서 상기 구순 구개열의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US)와 같은 비침습적 이미징법 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the observation of cleft palate is performed using non-invasive imaging such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US). method or an invasive imaging method such as digital subtraction angiography (DSA), but is not limited thereto.
본 발명에서 상기 구순 구개열은 구순열 및 구개열 중 적어도 하나일 수 있으며, 비제한적인 예시로 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the cleft palate may be at least one of cleft lip and cleft palate, as non-limiting examples of incomplete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft palate, and unilateral complete cleft lip. , or bilateral complete cleft palate, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 동물 모델을 이용하여 입술 또는 구강 조직의 형상 변형을 시뮬레이션하는 방법에 관한 것이다.According to another embodiment of the present invention, it relates to a method of simulating shape deformation of lips or oral tissue using the animal model provided by the present invention.
본 발명의 시뮬레이션 방법은, 본 발명에서 제공하는 동물 모델의 입술 근육 또는 구강 조직에 자기력을 인가하여 입술 또는 구강 조직에 갈라진 변형을 유도하는 단계를 포함할 수 있다. The simulation method of the present invention may include applying a magnetic force to the lip muscle or oral tissue of the animal model provided by the present invention to induce a cracked deformation in the lip or oral tissue.
본 발명에서 상기 입술 또는 구강 조직은, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the lip or oral tissue may be preferably lips, gums, uvula, hard palate (front part of the palate) or soft palate (back part of the palate), but is not limited thereto.
본 발명에서 상기 자기력의 인가 시 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. In the present invention, it may be performed by forming a magnetic field upon application of the magnetic force, and the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서는 상기 자기력의 인가 시 상기 입술 또는 구강 조직, 바람직하게는 입술, 잇몸, 목젖, 경구개(hard palate : 입천장의 앞부분) 또는 연구개(soft palate : 입천장의 뒷부분) 등에 위치하는 자성 세포와 외부 자석 사이, 또는 자성 세포 간의 인력 또는 척력에 의해 입술 또는 구강 조직에 갈라진 변형을 유도할 수 있다.In the present invention, when the magnetic force is applied, magnetic cells and external Cracked deformation can be induced in the lip or oral tissue by attraction or repulsion between magnets or between magnetic cells.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 입술 또는 구강 조직의 변형 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다.In the present invention, when the magnetic force is applied, the magnitude, direction, time of applying the magnetic force, etc. may be appropriately adjusted and determined according to the desired degree of deformation of the lips or oral tissue, and is not particularly limited.
본 발명의 시뮬레이션 방법은 상기와 같이 자기력이 인가된 동물 모델의 입술 또는 구강 조직을 관찰하는 단계를 포함할 수 있다. 여기서 상기 근육 또는 조직의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US)와 같은 비침습적 이미징법 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다.The simulation method of the present invention may include observing the lip or oral tissue of the animal model to which the magnetic force is applied as described above. Here, the observation of the muscle or tissue is performed by a non-invasive imaging method such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US). Alternatively, it may be performed by an invasive imaging method such as digital subtraction angiography (DSA), but is not limited thereto.
본 발명의 시뮬레이션 방법은 동물 모델의 입술 또는 구강 조직에 비정상적인 수축 또는 이완을 유도함에 따라 입술 또는 구강 조직에 갈라진 변형 등의 기형이 유도되는 과정을 시뮬레이션함으로써 구순 구개열 질환 등의 해석에 필요한 유용한 정보를 제공할 수 있고, 이에 따라 환자의 질병 여부를 판별할 수 있거나 질병 치료 약물 또는 장치를 개발할 수 있다.The simulation method of the present invention simulates the process of inducing abnormal contraction or relaxation of the lip or oral tissue of the animal model, such as a cracked deformation in the lip or oral tissue, thereby providing useful information necessary for the interpretation of cleft lip disease. can be provided, and accordingly, it is possible to determine whether a patient has a disease or develop a disease treatment drug or device.
5-2. 수면 무호흡증 동물 모델 및 이의 용도5-2. Sleep apnea animal model and uses thereof
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 자성 세포 또는 이의 군집체가 주입된 수면 무호흡증 동물 모델을 제조하는 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method for producing an animal model of sleep apnea in which the magnetic cells or agglomerates thereof provided in the present invention are injected.
본 명세서에서 사용되는 용어, "동물 모델"은 질환 동물 모델을 의미한다. 구체적으로, 동물 모델은 인간의 질병과 유사한 상태의 질병에 걸리거나 선천적으로 그 질병에 걸리도록 만들어낸 동물 모델일 수 있다. 본 명세서에서 동물 모델은 호흡기계 유동관 이상 동물 모델, 더 나아가서는 수면 무호흡증의 동물 모델일 수 있다. 또한, 본 발명의 동물 모델로 이용될 수 있는 동물은 인간을 제외한 포유 동물로, 예를 들면, 래트, 마우스, 모르모트, 햄스터, 토끼, 원숭이, 개, 고양이, 소, 말, 돼지, 양 및 염소로 구성된 군으로부터 선택될 수 있고, 보다 바람직하게는 마우스, 토끼 또는 돼지 등일 수 있으나, 이에 제한되는 것은 아니다.As used herein, the term “animal model” refers to an animal model of a disease. Specifically, the animal model may be an animal model that is afflicted with a disease similar to a human disease or is congenitally afflicted with the disease. In the present specification, the animal model may be an animal model of respiratory flow tract abnormality, and furthermore, an animal model of sleep apnea. In addition, animals that can be used as animal models of the present invention are mammals other than humans, for example, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, cats, cattle, horses, pigs, sheep and goats. It may be selected from the group consisting of, and more preferably a mouse, rabbit or pig, but is not limited thereto.
본 발명의 제조 방법은 동물의 목적하는 호흡기계 유동관 부위에 상기 자성 세포 또는 자성 세포 군집체를 주입하는 단계를 포함할 수 있다. The production method of the present invention may include injecting the magnetic cells or the magnetic cell aggregate into a desired respiratory system flow tract of an animal.
본 발명에서 상기 호흡기계 유동관은 바람직하게는 비강, 인후두 또는 기도일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
본 발명에서 상기 주입 방법의 비제한적인 예시로는 액상 주사 형태 또는 액상을 연성 발포체에 흡수시킨 후 상기 발포체를 주입할 수 있다, 액상 주사 형태로 주입하는 경우 상대적으로 잔류 시간이 짧게 나타날 수 있으나, 발포체 형태로 주입하는 경우 생체 내 장시간 생체에 잔류할 수 있어, 목적하는 잔류 시간에 따라 적절히 선택할 수 있으며, 상기 열거한 방법 외에도 다양한 방법으로 주입할 수 있다.As a non-limiting example of the injection method in the present invention, the liquid injection form or the liquid may be absorbed into the flexible foam and then the foam may be injected. When injected in the form of a foam, it can remain in the living body for a long time, so it can be appropriately selected according to the desired residence time, and can be injected by various methods other than the methods listed above.
본 발명에서 상기 동물 모델에 상기 자성 세포 또는 자성 세포 군집체의 주입 시 부유액에 자성 세포 또는 자성 세포 군집체를 혼합하여 주입하는 것이 부유액의 점도를 조절하여 자성 세포를 포함한 주사액의 확산 속도 및 주입된 자성 세포의 유지 시간 제어가 가능하며 부유액에 혼합된 자성 세포의 양을 조절함으로써 자력 제어가 가능하여 바람직하다. 여기서, 상기 부유액은 생분해성의 PDMS, 히알루론산, 콜라겐, 키틴, 키토산, 헤파린 또는 이들의 조합일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, when injecting the magnetic cells or magnetic cell aggregates into the animal model, mixing and injecting the magnetic cells or magnetic cell aggregates in the suspension controls the viscosity of the suspension to control the diffusion rate of the injection solution including the magnetic cells and the injected It is preferable that the holding time of the magnetic cells can be controlled and the magnetic force can be controlled by adjusting the amount of the magnetic cells mixed in the suspension. Here, the suspension may be biodegradable PDMS, hyaluronic acid, collagen, chitin, chitosan, heparin, or a combination thereof, but is not limited thereto.
본 발명의 제조 방법은 상기 자성 입자가 주입된 호흡기계 유동관 부위에 자기력을 인가하여 상기 호흡기계 유동관의 수축을 유도하는 단계를 포함할 수 있다. The manufacturing method of the present invention may include the step of inducing contraction of the respiratory system flow tube by applying a magnetic force to the portion of the respiratory system flow tube into which the magnetic particles are injected.
본 발명에서 상기 자기력의 인가 시 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. In the present invention, it may be performed by forming a magnetic field upon application of the magnetic force, and the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서는 상기 자기력의 인가 시 상기 자성 입자와 상기 자석 간의 척력 또는 인력을 이용하여 호흡기계 유동관의 수축을 유도할 수 있다. In the present invention, when the magnetic force is applied, the contraction of the respiratory system can be induced by using a repulsive force or attractive force between the magnetic particles and the magnet.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 호흡기계 유동관의 수축 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. can be appropriately adjusted and determined according to the desired degree of contraction of the respiratory system flow tube, and is not particularly limited.
본 발명에서 상기 동물 모델은 호흡기계 유동관이 비정상적으로 수축 또는 폐색되어 수면 무호흡증이 구현된 동물 모델일 수 있다. In the present invention, the animal model may be an animal model in which sleep apnea is realized due to abnormal contraction or blockage of the respiratory tract.
본 발명의 또 다른 구현 예에 따르면, 본 발명의 제조 방법에 따라 제조된 수면 무호흡증 동물 모델에 관한 것이다. According to another embodiment of the present invention, it relates to an animal model of sleep apnea manufactured according to the manufacturing method of the present invention.
본 발명에서 상기 수면 무호흡증 (sleep apnea syndrome)은 수면 무호흡증, 중추형 수면 무호흡증 또는 혼합형 수면 무호흡증일 수 있으며, 바람직하게는 폐쇄형 수면 무호흡증일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the sleep apnea (sleep apnea syndrome) may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 동물 모델을 이용하여 수면 무호흡증의 예방 또는 치료용 약물 또는 장치를 스크리닝하는 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method of screening a drug or device for preventing or treating sleep apnea using the animal model provided by the present invention.
본 발명에서 상기 "스크리닝"이란, 여러 물질 또는 장치로 이루어진 후보군으로부터 목적으로 하는 어떤 특정한 성질을 갖는 물질을 특정한 조작 또는 평가 방법으로 선별하는 것이다. In the present invention, the "screening" refers to selecting a substance having a specific target property from a candidate group consisting of various substances or devices by a specific manipulation or evaluation method.
본 발명의 스크리닝 방법은 우선, 본 발명에서 제공하는 동물 모델에 수면 무호흡증의 예방 또는 치료용 후보 약물을 처리하거나 수면 무호흡증의 예방 또는 치료용 후보 장치를 적용하는 단계를 포함할 수 있다. The screening method of the present invention may include first treating a drug candidate for preventing or treating sleep apnea or applying a candidate device for preventing or treating sleep apnea to the animal model provided by the present invention.
본 발명에서 상기 후보 약물은 천연 화합물, 합성 화합물, RNA, DNA, 폴리펩티드, 효소, 단백질, 리간드, 항체, 항원, 박테리아 또는 진균의 대사 산물 및 생활성 분자로 이루어진 군으로부터 선택되는 어느 하나인 것이 바람직하나, 이에 제한되는 것은 아니다. In the present invention, the candidate drug is preferably any one selected from the group consisting of natural compounds, synthetic compounds, RNA, DNA, polypeptides, enzymes, proteins, ligands, antibodies, antigens, bacterial or fungal metabolites and bioactive molecules. However, the present invention is not limited thereto.
본 발명의 스크리닝 방법은 상기 후보 약물을 처리하거나 후보 장치를 적용한 동물 모델의 호흡기계 유동관을 관찰하면서 유동관의 변화를 관찰하거나 상기 동물 모델을 사육하면서 예후를 확인하는 단계를 포함할 수 있다. 이때 상기 후보 약물의 처리 또는 후보 장치의 적용 후 수축된 호흡기계 유동관이 이완된 경우, 또는 상기 후보 약물 또는 후보 장치에 의하여 수면 무호흡증이 예방되거나, 치료되거나, 대조군 물질에 비하여 예후가 증진된 경우에 상기 후보 약물 또는 장치를 수면 무호흡증의 예방 또는 치료용 약물 또는 장치로 결정할 수 있다.The screening method of the present invention may include the step of observing the change in the flow tube while observing the respiratory system flow tube of the animal model to which the candidate drug is treated or the candidate device is applied, or checking the prognosis while breeding the animal model. In this case, when the contracted respiratory tract is relaxed after treatment with the candidate drug or application of the candidate device, or when sleep apnea is prevented or treated by the candidate drug or the candidate device, or when the prognosis is improved compared to the control substance The candidate drug or device may be determined as a drug or device for preventing or treating sleep apnea.
본 발명에서 상기 수면 무호흡증의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US)와 같은 비침습적 이미징법 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the observation of sleep apnea is performed using non-invasive imaging such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US). method or an invasive imaging method such as digital subtraction angiography (DSA), but is not limited thereto.
본 발명에서 상기 수면 무호흡증 (sleep apnea syndrome)은 수면 무호흡증, 중추형 수면 무호흡증 또는 혼합형 수면 무호흡증일 수 있으며, 바람직하게는 폐쇄형 수면 무호흡증일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the sleep apnea (sleep apnea syndrome) may be sleep apnea, central type sleep apnea, or mixed type sleep apnea, preferably obstructive sleep apnea, but is not limited thereto.
본 발명의 또 다른 구현 예에 따르면, 본 발명에서 제공하는 동물 모델을 이용하여 호흡기계 유동관의 형상 변형을 시뮬레이션하는 방법에 관한 것이다. According to another embodiment of the present invention, it relates to a method for simulating shape deformation of a respiratory system flow tube using the animal model provided by the present invention.
본 발명의 시뮬레이션 방법은, 본 발명에서 제공하는 동물 모델의 호흡기계 유동관에 자기력을 인가하여 호흡기계 유동관의 수축 또는 이완을 유도하는 단계를 포함할 수 있다. The simulation method of the present invention may include the step of inducing contraction or relaxation of the respiratory system flow tube by applying a magnetic force to the respiratory system flow tube of the animal model provided in the present invention.
본 발명에서 상기 호흡기계 유동관은 바람직하게는 비강, 인후두 또는 기도일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the respiratory tract may preferably be a nasal cavity, a pharynx, or an airway, but is not limited thereto.
본 발명에서 상기 자기력의 인가 시 자기장을 형성함으로써 수행될 수 있고, 상기 자기장은 예컨대, 전자기 유도에 의한 전자석, 영구 자석 등의 자석 등을 이용하여 수행될 수 있으며, 상기 자석은 하나 이상 포함될 수 있으며, 직렬, 병렬, 원형 등 다양한 배열로 적용될 수 있으나, 통상적으로 자기장을 형성할 수 있는 방법이라면 제한없이 포함될 수 있다. In the present invention, it may be performed by forming a magnetic field upon application of the magnetic force, and the magnetic field may be performed using, for example, an electromagnet by electromagnetic induction, a magnet such as a permanent magnet, etc., and one or more magnets may be included. , can be applied in various arrangements, such as series, parallel, circular, but may be included without limitation as long as it is a method capable of forming a magnetic field in general.
본 발명에서는 상기 자기력의 인가 시 상기 자성 입자와 상기 자석 간의 척력 또는 인력을 이용하여 호흡기계 유동관의 수축 또는 이완을 유도할 수 있고, 구체적인 일 예시로는 상기 호흡기계 유동관, 바람직하게는 비강, 인후두 또는 기도의 관 내벽에 위치하는 자성 세포와 외부 자석 사이의 척력에 의해 호흡기계 유동관의 수축을 유도할 수 있다. In the present invention, when the magnetic force is applied, contraction or relaxation of the respiratory system flow tube can be induced by using the repulsive force or attraction between the magnetic particles and the magnet, and as a specific example, the respiratory system flow tube, preferably the nasal cavity, the larynx. Alternatively, a repulsive force between a magnetic cell located on the inner wall of the airway and an external magnet may induce contraction of the respiratory tract.
본 발명에서 상기 자기력의 인가 시 자기력의 크기, 방향, 자기력을 가하는 시간 등은 목적하는 호흡기계 유동관의 수축 또는 이완 정도에 따라 적절히 조절하여 결정할 수 있고, 특별히 제한하지는 않는다. In the present invention, when the magnetic force is applied, the magnitude and direction of the magnetic force, the time for applying the magnetic force, etc. may be appropriately adjusted according to the desired degree of contraction or relaxation of the respiratory system flow tube, and is not particularly limited.
본 발명의 시뮬레이션 방법은 상기와 같이 자기력이 인가된 동물 모델의 호흡기계 유동관을 관찰하는 단계를 포함할 수 있다. 여기서 상기 호흡기계 유동관의 관찰은 컴퓨터 단층촬영(Computed Tomography:CT), 선택적 컴퓨터 단층촬영(Selective Computed Tomography), 자기공명영상법(magnetic resonance imaging:MRI), 초음파(US)와 같은 비침습적 이미징법 또는 디지털 감산 혈관 조영술(DSA)과 같은 침습적 이미징법에 의해 수행될 수 있으나, 이에 제한되는 것은 아니다. The simulation method of the present invention may include observing the respiratory system flow tube of the animal model to which the magnetic force is applied as described above. Here, the observation of the flow tract of the respiratory system is performed using non-invasive imaging methods such as computed tomography (CT), selective computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US). Alternatively, it may be performed by an invasive imaging method such as digital subtraction angiography (DSA), but is not limited thereto.
본 발명의 시뮬레이션 방법은 동물 모델의 호흡기계 유동관에 비정상적으로 수축 또는 이완을 유도함에 따라 호흡기계 유동관 이상이 유도되는 과정을 시뮬레이션함으로써 호흡기계 유동관 질환 등의 해석에 필요한 유용한 정보를 제공할 수 있고, 이에 따라 환자의 질병 여부를 판별할 수 있거나 질병 치료 약물 또는 장치를 개발할 수 있다.The simulation method of the present invention can provide useful information necessary for the analysis of respiratory flow tract diseases, etc. by simulating the process in which respiratory tract abnormalities are induced by inducing abnormal contraction or relaxation of the respiratory tract of the animal model. Accordingly, it is possible to determine whether a patient has a disease or develop a disease treatment drug or device.
본 발명의 방법을 이용하는 경우, 목적하는 개체의 물리적 변형이 필요한 조직 또는 기관을 타겟으로하여 자성 물질을 포함하는 자성 세포를 적정한 양으로 주입할 수 있고, 이에 따라 목적하는 수준으로 해당 조직 또는 기관에서의 수축, 이완 또는 변형을 달성할 수 있어 종국적으로는 조직 또는 기관의 물리적 변형을 통해 예방, 개선 또는 치료가 가능한 질환, 특히는 구순 구개열 또는 수면 무호흡증 질환의 개선 또는 치료 효과를 높일 수 있다.In the case of using the method of the present invention, an appropriate amount of magnetic cells containing a magnetic material can be injected by targeting a tissue or organ requiring physical transformation of a desired object, and accordingly, the target tissue or organ can be in the target tissue or organ at a desired level. It is possible to achieve the contraction, relaxation or deformation of the tissue or organs, and ultimately, the improvement or therapeutic effect of diseases that can be prevented, improved, or treated through physical transformation of tissues or organs, in particular, cleft lip and cleft lip or sleep apnea disease can be improved or the therapeutic effect can be increased.
도 1은 본 발명에 따른 자성 세포의 조직 또는 기관의 형상 제어 원리를 나타낸 것으로 (a)는 자성의 인력에 따른 갈라진 조직의 봉합 또는 유동관의 축소, (b)는 자성의 척력에 따른 갈라진 부위의 확장 또는 유동관의 확장을 나타낸 모식도이다.1 shows the shape control principle of a tissue or organ of a magnetic cell according to the present invention, in which (a) is a suture of a cracked tissue due to magnetic attraction or reduction of a flow tube, (b) is a cracked area according to a magnetic repulsive force It is a schematic diagram showing the expansion or expansion of the flow pipe.
도 2는 본 발명의 실시예 1에 따라 제조된 자성 세포의 체내 주입 방식을 나타낸 것이다. 2 shows a method of injecting magnetic cells into the body prepared according to Example 1 of the present invention.
도 3은 본 발명의 자성 세포의 주입 방식으로서, (a)는 액상 주사 주입법, (b)는 연성 발포체 이식을 통한 주입법을 나타낸 것이다.3 is an injection method of the magnetic cells of the present invention, (a) is a liquid injection injection method, (b) shows an injection method through a flexible foam implantation.
도 4는 본 발명의 실시예 1에 따라 제조된 자성 세포의 강자성 부여 결과를 나타낸 것이다.4 shows the results of imparting ferromagnetism to the magnetic cells prepared according to Example 1 of the present invention.
도 5a는 본 발명에 따른 자성 세포의 환자별 최적 주입을 위한 인공지능 입술 또는 구강 조직의 형상 제어 계획 수립 장치를 도식화하여 나타낸 것이다. Figure 5a schematically shows an apparatus for establishing a shape control plan of artificial intelligence lip or oral tissue for optimal injection of magnetic cells for each patient according to the present invention.
도 5b는 본 발명에 따른 자성 세포의 환자별 최적 주입을 위한 인공지능 유동관 형상 제어 계획 수립 장치를 도식화하여 나타낸 것이다. Figure 5b schematically shows an apparatus for establishing an artificial intelligence flow tube shape control plan for optimal injection of magnetic cells for each patient according to the present invention.
도 6은 자성 세포를 이용한 인공지능 입술 또는 구강 조직의 형상 제어 계획 수립 장치 또는 인공지능 유동관 형상 제어 계획 수립 장치의 내부 구성을 예시한 블록도를 나타낸 것이다.6 is a block diagram illustrating the internal configuration of an artificial intelligence lip or oral tissue shape control plan establishment device or an artificial intelligence flow tube shape control plan establishment device using magnetic cells.
도 7은 본 발명에 따른 신체 조직의 영률을 측정하기 위해 사용 가능한 기기의 일 예시를 나타낸 것이다.7 shows an example of a device that can be used to measure the Young's modulus of a body tissue according to the present invention.
본 발명의 일 구현 예에서는 구순 구개열을 치료하기 위하여 체내로 주입되는 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법에 관한 것이다.One embodiment of the present invention relates to a method for providing information for determining an appropriate injection amount of magnetic cells to be injected into the body to treat cleft lip and cleft lip.
본 발명의 다른 구현 예에서는 수면 무호흡증을 치료하기 위하여 체내로 주입되는 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법에 관한 것이다.Another embodiment of the present invention relates to an information providing method for determining an appropriate injection amount of magnetic cells to be injected into the body to treat sleep apnea.
본 발명의 또 다른 구현 예에서는 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체를 유효 성분으로 포함하는 구순 구개열의 예방, 개선 또는 치료용 조성물에 관한 것이다.Another embodiment of the present invention relates to a composition for preventing, improving or treating cleft lip and cleft lip, comprising, as an active ingredient, a magnetic cell or a magnetic cell aggregate containing a magnetic material.
본 발명의 또 다른 구현 예에서는 투여가 필요한 개체에게 상기 구순 구개열의 예방, 개선 또는 치료용 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함하는 구순 구개열의 예방, 개선 또는 치료 방법에 관한 것이다.Another embodiment of the present invention relates to a method for preventing, improving or treating cleft lip and cleft lip, comprising administering a pharmaceutically effective amount of the composition for preventing, improving or treating cleft lip and cleft lip to an individual in need of administration.
본 발명의 또 다른 구현 예에서는 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체를 유효 성분으로 포함하는 수면 무호흡증의 예방, 개선 또는 치료용 조성물에 관한 것이다.Another embodiment of the present invention relates to a composition for preventing, improving, or treating sleep apnea, comprising, as an active ingredient, a magnetic cell or a magnetic cell aggregate containing a magnetic material.
본 발명의 또 다른 구현 예에서는 투여가 필요한 개체에게 상기 수면 무호흡증의 예방, 개선 또는 치료용 조성물을 약학적으로 유효한 양으로 투여하는 단계를 포함하는 수면 무호흡증의 예방, 개선 또는 치료 방법에 관한 것이다.Another embodiment of the present invention relates to a method for preventing, improving or treating sleep apnea, comprising administering a pharmaceutically effective amount of the composition for preventing, improving or treating sleep apnea to an individual in need of administration.
본 발명의 또 다른 구현 예에서는 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체; 및 자기장 인가 장치를 포함하는 입술 또는 구강 조직의 형상 제어 장치에 관한 것이다.In another embodiment of the present invention, a magnetic cell or a magnetic cell aggregate comprising a magnetic material; And it relates to a device for controlling the shape of the lips or oral tissue comprising a magnetic field application device.
본 발명의 또 다른 구현 예에서는 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체; 및 자기장 인가 장치를 포함하는 호흡기계 유동관 형상 제어 장치에 관한 것이다.In another embodiment of the present invention, a magnetic cell or a magnetic cell aggregate comprising a magnetic material; and a device for applying a magnetic field to a respiratory system flow tube shape control device.
본 발명의 또 다른 구현 예에서는 구순 구개열을 가진 기존 환자들의 신상정보, 의료영상정보 및 입술 또는 구강 조직의 형상 정보를 포함하는 데이터베이스부; 구순 구개열 환자의 생체 정보, 의료영상정보 및 근육 또는 조직 형상 인자의 입력을 수신하고, 소정의 결과물을 출력하는 인터페이스부; 상기 데이터베이스부 및 인터페이스부로부터 수신한 정보를 인공지능 기법으로 분석하여 상기 환자에 대한 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체의 주입 후의 상황을 예측하는 시뮬레이션부; 및 상기 시뮬레이션부의 결과에 따라 상기 자성 세포 또는 자성 세포 군집체의 주입 방법 및 주입 위치를 결정하고 주입량을 산출하는 제어 계획 수립부;를 포함하는 자성 세포를 이용한 인공지능 입술 또는 구강 조직의 형상 제어 계획 수립 장치에 관한 것이다.In another embodiment of the present invention, a database unit including personal information, medical image information, and shape information of lips or oral tissue of existing patients with cleft palate; an interface unit for receiving input of biometric information, medical image information, and muscle or tissue shape factors of a patient with cleft lip and cleft lip, and outputting a predetermined result; a simulation unit that analyzes the information received from the database unit and the interface unit using an artificial intelligence technique to predict a situation after the injection of magnetic cells or magnetic cell aggregates containing a magnetic material into the patient; and a control plan establishment unit that determines the injection method and injection location of the magnetic cells or the magnetic cell aggregate according to the result of the simulation unit and calculates the injection amount; It relates to the establishment device.
본 발명의 또 다른 구현 예에서는 수면 무호흡증을 가진 기존 환자들의 신상정보, 의료영상정보 및 유동관 형상 정보를 포함하는 데이터베이스부; 수면 무호흡증 환자의 생체 정보, 의료영상정보 및 호흡기계 유동관 형상 인자의 입력을 수신하고, 소정의 결과물을 출력하는 인터페이스부; 상기 데이터베이스부 및 인터페이스부로부터 수신한 정보를 인공지능 기법으로 분석하여 상기 환자에 대한 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체의 주입 후의 상황을 예측하는 시뮬레이션부; 및 상기 시뮬레이션부의 결과에 따라 상기 자성 세포 또는 자성 세포 군집체의 주입 방법 및 주입 위치를 결정하고 주입량을 산출하는 제어 계획 수립부;를 포함하는 자성 세포를 이용한 인공지능 호흡기계 유동관 형상 제어 계획 수립 장치에 관한 것이다.In another embodiment of the present invention, a database unit including personal information, medical image information, and flow tube shape information of existing patients with sleep apnea; an interface unit for receiving input of biometric information, medical image information, and respiratory system flow tube shape factor of a sleep apnea patient, and outputting a predetermined result; a simulation unit that analyzes the information received from the database unit and the interface unit using an artificial intelligence technique to predict a situation after the injection of magnetic cells or magnetic cell aggregates containing a magnetic material into the patient; and a control plan establishment unit for determining the injection method and injection location of the magnetic cells or the magnetic cell aggregate according to the result of the simulation unit, and calculating the injection amount; Artificial intelligence respiratory system flow tube shape control plan establishment device using magnetic cells comprising a; is about
본 발명의 또 다른 구현 예에서는 인간을 제외한 동물의 목적하는 입술 또는 구강 조직 부위에 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체를 주입하는 단계를 포함하는 구순 구개열 동물 모델의 제조 방법에 관한 것이다.In another embodiment of the present invention, it relates to a method for producing an animal model of cleft lip and cleft lip, comprising injecting a magnetic cell or a magnetic cell aggregate containing a magnetic material into a desired lip or oral tissue site of an animal other than a human. .
본 발명의 또 다른 구현 예에서는 인간을 제외한 동물의 목적하는 호흡기계 유동관 부위에 상기 자성 세포 또는 자성 세포 군집체를 주입하는 단계를 포함하는 수면 무호흡증 동물 모델의 제조 방법에 관한 것이다.Another embodiment of the present invention relates to a method for producing an animal model of sleep apnea, comprising injecting the magnetic cells or a magnetic cell aggregate into a desired respiratory tract region of an animal other than humans.
본 발명의 또 다른 구현 예에서는 상기한 방법으로 제조된 구순 구개열 또는 수면 무호흡증 동물 모델에 관한 것이다.In another embodiment of the present invention, it relates to an animal model of cleft palate or sleep apnea prepared by the above method.
본 발명의 또 다른 구현 예에서는 상기한 동물 모델을 이용하여 구순 구개열 또는 수면 무호흡증의 예방 또는 치료용 약물 또는 장치를 스크리닝하는 방법에 관한 것이다.Another embodiment of the present invention relates to a method for screening a drug or device for preventing or treating cleft lip and cleft lip or sleep apnea using the above-described animal model.
본 발명의 또 다른 구현 예에서는 상기한 동물 모델을 이용하여 입술 또는 구강 조직의 형상 변형을 시뮬레이션하는 방법; 또는 호흡기계 유동관의 형상 변형을 시뮬레이션하는 방법에 관한 것이다.In another embodiment of the present invention, there is provided a method for simulating shape deformation of lips or oral tissue using the animal model described above; or to a method of simulating shape deformation of a respiratory system flow duct.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예 1: 면역 반응 기반의 면역 표지법에 의한 자성 세포 제조Example 1: Preparation of magnetic cells by immunolabeling based on immune response
덱스트란이 표면에 코팅된 자성을 가진 500 nm 크기의 산화철 자성 비드 10 mg을 2 ㎖ 튜브에 넣고, pH 5.5의 인산완충용액을 넣어 혼합하였다. 이후 자석 분리기에 잠시 놓아 자성 비드를 모은 후 상등액을 제거하고, 침전된 자성 비드를 세척하였다. 남아 있는 자성 비드에 탈염 정제된 200 ㎍/㎖의 항-마우스 IgG를 1 ㎖씩 넣으면서 혼합하고, 4 ℃에서 15 시간 동안 교반하였다. 이후 항-IgG가 결합된 자성 비드를 자석 분리기로 분리하고, 0.05 M Tris-HCl 용액으로 3 회 세척한 후, 0.1 % BSA가 포함된 PBS 완충용액 1 ㎖에 분산시켜 항체가 코팅된 자성 비드를 제조하였다. 실리콘 몰드에 입술 또는 구강 조직을 이루는 상피세포(epithelial cell), 뼈세포(osteoblast), 섬유아세포(fibroblast) 또는 근세포(myocyte)를 절반만 잠기도록 고정시킨 후, 약 40 μWb의 자기장을 걸고 상기 항체가 코팅된 자성 비드를 몰드 표면에 뿌려 입술 또는 구강 조직 내 상피세포, 뼈세포, 섬유아세포 또는 근세포의 항원과 상기 자성 비드에 코팅된 항체가 결합하도록 함으로써 세포 표면에 자성 물질이 부착된 자성 세포를 제조하였다.10 mg of magnetic iron oxide beads with a size of 500 nm having a magnetic surface coated with dextran were put into a 2 ml tube, and a phosphate buffer solution of pH 5.5 was added and mixed. Thereafter, it was placed in a magnetic separator for a while to collect the magnetic beads, the supernatant was removed, and the precipitated magnetic beads were washed. To the remaining magnetic beads, 200 μg/ml of desalted and purified anti-mouse IgG was added 1 ml at a time while mixing, followed by stirring at 4° C. for 15 hours. Thereafter, the anti-IgG-bound magnetic beads were separated with a magnetic separator, washed three times with 0.05 M Tris-HCl solution, and dispersed in 1 ml of PBS buffer containing 0.1% BSA to obtain antibody-coated magnetic beads. prepared. After fixing the epithelial cells, osteoblasts, fibroblasts, or myocytes that make up the lips or oral tissues in a silicone mold so that only half of them are submerged, a magnetic field of about 40 μWb is applied and the antibody Sprinkle the coated magnetic beads on the mold surface so that the antigens of epithelial cells, bone cells, fibroblasts, or myocytes in the lips or oral tissue and the antibody coated on the magnetic beads bind to magnetic cells with magnetic substances attached to the cell surface. prepared.
실시예 2: 자성 세포의 주입량 결정 - 입술 근육에의 적용Example 2: Determination of injection amount of magnetic cells - application to lip muscle
1. 신체 조직의 영률(Young's Modulus)의 측정1. Measurement of Young's Modulus of body tissue
피부 자체가 기계적인 성질의 측정에 적합하지 않은 구조이며 각 측정 방법마다 표준화가 되지 않은 실정이기 때문에 각 결과들을 비교하는 데에 어려움이 있었고 임상적으로도 이용되지 못하는 문제가 있었다. 최근에는 흡입강을 이용한 측정 기기들이 개발되어 피부 탄력성 측정에 이용되고 있으며, 이전에 비하여 재현성이 높은 것으로 평가받고 있어 본 발명자들은 원하는 조직의 탄성을 측정하는 방식을 이용하여 각 조직 부위 별 영률(Young's Modulus)을 측정하고자 하였다. 종전에 안면 연조직의 생체 역학적 모델링으로 안면 수술 시 시뮬레이션을 위해 얼굴 전체에 걸친 특성과 탄력성을 기계적 변수로 개별화하기 위하여 고안된 흡인 장치에서의 영률을 계산한 방법과 입술 근육의 영률 평균 33.7 ± 7.3 kPa임이 알려진 바 있다(Ann Biomed Eng. 2014 Nov;42(11):2369-78.). 본 발명에서는 이를 참고하여 탄성 측정을 위하여 탄력 측정기기로서 도 7에 나타낸 Courage Khazaka electronic GmbH 사의 Cutometer 또는 Cortex technology 사의 DermaLab를 이용하여 입술의 영률을 측정하였다. 상기 2 개의 제품 모두 측정용 프로브를 피부에 접촉시킨 상태에서 음압을 가하여 피부가 변위되는 높이와 복원에 필요한 시간을 측정하는 방식으로 영률을 측정할 수 있다.Since the skin itself has a structure that is not suitable for measuring mechanical properties and is not standardized for each measurement method, it is difficult to compare the results and there is a problem that it cannot be used clinically. Recently, measuring devices using a suction cavity have been developed and used to measure skin elasticity, and are evaluated to be highly reproducible compared to the past. Modulus) was measured. Previously, the method of calculating the Young's modulus in a suction device designed to individualize the characteristics and elasticity of the entire face as mechanical variables for the simulation of facial surgery with biomechanical modeling of facial soft tissue and the average Young's modulus of the lip muscle was 33.7 ± 7.3 kPa. has been known (Ann Biomed Eng. 2014 Nov;42(11):2369-78.). In the present invention, referring to this, the Young's modulus of the lips was measured using a Cutometer of Courage Khazaka electronic GmbH or DermaLab of Cortex technology shown in FIG. 7 as a elasticity measuring device for measuring elasticity. The Young's modulus can be measured by measuring the height at which the skin is displaced and the time required for restoration by applying negative pressure while the probe for measurement is in contact with the skin for both products.
2. 자성 비드의 자기 선속량(magnetic flux density)의 계산2. Calculation of magnetic flux density of magnetic beads
자성 세포의 적정 주입량을 계산하기 위하여, 우선 자성 세포에 포함시킬 자성 비드 간의 힘을 확인하기 위하여 자기 선속량(magnetic flux density)을 계산하였다. 본 발명에서 이용한 Micromod 사의 산화철 자성 비드(제품 번호: 45-00-252)로, 밀도는 46 AM2/kg이고, 자기력은 5.35 g/cm3에 해당하였다. 이에 하기 식 4와 같이 상기 자성 비드의 밀도와 자기력을 곱하여 자기 선속량으로 246100 A/m을 도출하였다. 이 때, 1 G의 값은 0.1 mT, 1 Oe 또는 80 A/m와 같으므로, 상기 자기 선속량을 단위가 3076 G로 변환시킬 수 있었다. In order to calculate the proper injection amount of the magnetic cells, first, the magnetic flux density was calculated to check the force between the magnetic beads to be included in the magnetic cells. Micromod's magnetic iron oxide beads (product number: 45-00-252) used in the present invention, the density is 46 AM 2 /kg, and the magnetic force corresponds to 5.35 g/cm 3 . Accordingly, as shown in Equation 4 below, 246100 A/m was derived as the magnetic flux by multiplying the density and magnetic force of the magnetic beads. At this time, since the value of 1 G is equal to 0.1 mT, 1 Oe, or 80 A/m, it was possible to convert the magnetic flux amount to 3076 G in unit.
[식 4][Equation 4]
Figure PCTKR2022004052-appb-img-000001
Figure PCTKR2022004052-appb-img-000001
3. 자성 비드 간 자력의 계산3. Calculation of Magnetic Force Between Magnetic Beads
상기에서 얻어진 자기 선속량을 바탕으로 자성 비드 간의 힘, 즉 자성 비드 간의 자력을 계산하였다. 보다 상세하게는 하기 식 5에서와 같이, 얻어진 자성 비드의 자기 선속량(자속 밀도)을 제곱한 뒤 테슬라 단위를 이용하여 변환한 값에 자성 비드 면적을 곱한 결과, 자성 비드 간 자력으로 0.0232 N/m2 를 얻을 수 있었다.Based on the amount of magnetic flux obtained above, the force between the magnetic beads, that is, the magnetic force between the magnetic beads was calculated. In more detail, as shown in Equation 5 below, after squaring the magnetic flux amount (magnetic flux density) of the obtained magnetic beads, multiply the converted value using the Tesla unit by the magnetic bead area. As a result, the magnetic force between the magnetic beads is 0.0232 N/ m 2 could be obtained.
[식 5][Equation 5]
1,182,722,000 [N/m2] X (1.96 X 10-11) [m2] = 0.0232 [N/m2]1,182,722,000 [N/m 2 ] X (1.96 X 10 -11 ) [m 2 ] = 0.0232 [N/m 2 ]
(단, 상기 식 5에서 1,182,722,000 N/m2 는 30762 [G2]를 테슬라 단위를 이용하여 변환시킨 값이다.) (However, in Equation 5, 1,182,722,000 N/m 2 is a value obtained by converting 3076 2 [G 2 ] using Tesla units.)
4. 자성 비드의 주입량의 결정4. Determination of Injection Amount of Magnetic Beads
상기와 같이 계산된 자성 비드 간 자력을 0.0232 N/m2 로 계산하여 입술 근육을 10 % 변형하고자 하였다. 종래에 개시된 바와 같이 입술 근육의 영률을 33.7 kPa로 가정하였을 때, 영률은 하기 식 6과 같이 stress/strain으로, 변형률 당 자력(N/m2) 크기로 계산될 수 있다. 이에 따라, 하기 식 7에 나타낸 바와 같이 입술 근육 10 %의 변형을 위하여 주입되어야 할 자성 비드의 개수로는 1.6 x 106 개를 도출할 수 있었다. The magnetic force between the magnetic beads calculated as described above was calculated as 0.0232 N/m 2 to deform the lip muscle by 10%. As disclosed in the prior art, when the Young's modulus of the lip muscle is assumed to be 33.7 kPa, the Young's modulus can be calculated as stress/strain and magnetic force per strain (N/m 2 ) as shown in Equation 6 below. Accordingly, as shown in Equation 7 below, 1.6 x 10 6 could be derived as the number of magnetic beads to be injected for 10% deformation of the lip muscle.
[식 6][Equation 6]
Figure PCTKR2022004052-appb-img-000002
Figure PCTKR2022004052-appb-img-000002
[식 7][Equation 7]
1.6 x 106 개(자성 비드의 개수) = 33700 [N/m2] / 0.0232 [N/m2]1.6 x 10 6 (Number of magnetic beads) = 33700 [N/m 2 ] / 0.0232 [N/m 2 ]
5. 자성 세포의 주입량의 결정5. Determination of the injection amount of magnetic cells
입술 상피 세포 하나 당 자성 비드가 2 개 부착된다고 가정하면, 하기 식 8에 나타낸 바와 같이 자성 세포의 주입량은 8 x 105 개로 계산되었다. Assuming that two magnetic beads are attached to each lip epithelial cell, the injection amount of magnetic cells was calculated to be 8 x 10 5 as shown in Equation 8 below.
[식 8][Equation 8]
8 x 105 개(자성 세포의 개수) = 1.6 x 106 개(자성 비드의 개수) / 28 x 10 5 (the number of magnetic cells) = 1.6 x 10 6 (the number of magnetic beads) / 2
6. 자성 세포를 포함하는 용액의 주입량의 결정6. Determination of Injection Amount of Solution Containing Magnetic Cells
자성 세포를 인체 내 액상의 주사 형태로 주입한다고 할 때, 액상의 주사 용액 내 자성 세포의 농도를 4 x 105 cell/㎖ 라고 가정한다면, 2 ㎖의 주사 용액이 필요하며, 양쪽 입술 근육에 각 1 ㎖ 씩 세포 용액을 주사한다면 원하는 변형률인 10 %의 달성이 가능함을 알 수 있었다. When magnetic cells are injected into the human body in the form of liquid injection, assuming that the concentration of magnetic cells in the liquid injection solution is 4 x 10 5 cell/ml, 2 ml of the injection solution is required, and each It was found that if the cell solution was injected by 1 ml, it was possible to achieve the desired strain of 10%.
상기와 같은 방식으로 자성 비드의 스펙과 세포 농도에 따라 요구되는 적정 세포 수 및 세포 용액의 부피가 달라지며, 이와 관련된 모든 변수들을 고려하여 변형률을 달성할 수 있는 최적의 주입량을 계산할 수 있으므로 자성 세포간 인력을 조절함으로써 궁극적으로 갈라진 입술 부위와 벌어진 구강 직경이 감소된 결과를 얻을 수 있다.In the same way as above, the optimal number of cells and the volume of cell solution required vary depending on the specifications and cell concentration of the magnetic beads, and the optimal injection amount to achieve the strain rate can be calculated by considering all related variables. By controlling the hepatic attraction, it is ultimately possible to obtain the result of reducing the cleft lip area and the diameter of the gaping mouth.
실시예 3: 입술 근육 또는 구강 조직 형상 제어 효과Example 3: Effect of controlling the shape of lip muscle or oral tissue
구순 구개열 마우스 모델을 준비하였다. 실시예 1에 따라 제조된 자성 세포를 PDMS 용액에 4 x 105 cells/㎖의 농도로 혼합하여 실시예 2에 따라 적정 주입량을 계산하여 상기 마우스 모델의 입술, 잇몸 뼈, 목젖 부위의 갈라진 변형 부위에 2 ㎖의 양을 1 ㎖ 씩 나누어 갈라진 변형 부위 말단에 각각 주입하였다. 제어 유닛(CardioFlow 5000 MR, Shelley Medical Imaging Technologies)를 통해 심박 기반의 유량, 혈류 저항값 및 유량 파형을 제어하였고, 자기장 인가 장치를 이용하여 80 가우스 자기장을 가하여, 주입된 자성 세포를 강자성 상태로 전환시키고, 주입된 자성 세포간 인력을 유발하였다. 이에 따라 갈라진 입술 부위와 벌어진 구강 직경이 감소된 결과를 확인하였다.A cleft palate mouse model was prepared. The magnetic cells prepared according to Example 1 were mixed with the PDMS solution at a concentration of 4 x 10 5 cells/ml, and the appropriate injection amount was calculated according to Example 2, and the cracked deformed region of the lips, gum bone, and uvula of the mouse model. The amount of 2 ml was divided into 1 ml each and injected at the ends of the cracked deformation site. The heart rate-based flow rate, blood flow resistance value, and flow waveform were controlled through a control unit (CardioFlow 5000 MR, Shelley Medical Imaging Technologies), and an 80 Gaussian magnetic field was applied using a magnetic field application device to convert the injected magnetic cells into a ferromagnetic state. and induced attraction between the injected magnetic cells. Accordingly, it was confirmed that the cracked lip area and the diameter of the gaping mouth were reduced.
실시예 4: 면역 반응 기반의 면역 표지법에 의한 자성 세포 제조Example 4: Preparation of magnetic cells by immunolabeling based on immune response
덱스트란이 표면에 코팅된 자성을 가진 500 nm 크기의 산화철 자성 비드 10 mg을 2 ㎖ 튜브에 넣고, pH 5.5의 인산완충용액을 넣어 혼합하였다. 이후 자석 분리기에 잠시 놓아 자성 비드를 모은 후 상등액을 제거하고, 침전된 자성 비드를 세척하였다. 남아 있는 자성 비드에 탈염 정제된 200 ㎍/㎖의 항-마우스 IgG를 1 ㎖씩 넣으면서 혼합하고, 4 ℃에서 15 시간 동안 교반하였다. 이후 항-IgG가 결합된 자성 비드를 자석 분리기로 분리하고, 0.05 M Tris-HCl 용액으로 3회 세척한 후, 0.1 % BSA가 포함된 PBS 완충용액 1 ㎖에 분산시켜 항체가 코팅된 자성 비드를 제조하였다. 실리콘 몰드에 상기도 내벽 섬유아세포 또는 근 세포를 절반만 잠기도록 고정시킨 후, 약 40 μWb의 자기장을 걸고 상기 항체가 코팅된 자성 비드를 몰드 표면에 뿌려 상기도 내벽 섬유아세포 또는 근 세포의 항원(Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 또는 ssea4)과 상기 자성 비드에 코팅된 항체가 결합하도록 함으로써 세포 표면에 자성 물질이 부착된 자성 세포를 제조하였다.10 mg of magnetic iron oxide beads with a size of 500 nm having a magnetic surface coated with dextran were put into a 2 ml tube, and a phosphate buffer solution of pH 5.5 was added and mixed. Thereafter, it was placed in a magnetic separator for a while to collect the magnetic beads, the supernatant was removed, and the precipitated magnetic beads were washed. To the remaining magnetic beads, 200 μg/ml of desalted and purified anti-mouse IgG was added 1 ml at a time while mixing, followed by stirring at 4° C. for 15 hours. Thereafter, the anti-IgG-bound magnetic beads were separated with a magnetic separator, washed three times with 0.05 M Tris-HCl solution, and dispersed in 1 ml of PBS buffer containing 0.1% BSA to obtain antibody-coated magnetic beads. prepared. After fixing the upper airway lining fibroblasts or myocytes in a silicone mold so that only half of them are submerged, a magnetic field of about 40 μWb is applied and the antibody-coated magnetic beads are sprayed on the mold surface to obtain antigen ( Stro-1, CD29, CD44, CD73, CD90, CD105, CD146, or ssea4) and the antibody coated on the magnetic beads were allowed to bind, thereby preparing magnetic cells having a magnetic material attached to the cell surface.
실시예 5: 자성 세포의 주입량 결정 - 기도 근육에의 적용Example 5: Determination of injection amount of magnetic cells - application to airway muscle
1. 신체 조직의 영률(Young's Modulus)의 측정1. Measurement of Young's Modulus of body tissue
피부 자체가 기계적인 성질의 측정에 적합하지 않은 구조이며 각 측정 방법마다 표준화가 되지 않은 실정이기 때문에 각 결과들을 비교하는 데에 어려움이 있었고 임상적으로도 이용되지 못하는 문제가 있었다. 최근에는 흡입강을 이용한 측정 기기들이 개발되어 피부 탄력성 측정에 이용되고 있으며, 이전에 비하여 재현성이 높은 것으로 평가받고 있어 본 발명자들은 원하는 조직의 탄성을 측정하는 방식을 이용하여 각 조직 부위 별 영률(Young's Modulus)을 측정하고자 하였다. 종전에 안면 연조직의 생체 역학적 모델링으로 안면 수술 시 시뮬레이션을 위해 얼굴 전체에 걸친 특성과 탄력성을 기계적 변수로 개별화하기 위하여 고안된 흡인 장치에서의 영률을 계산한 방법과 기관지 기도 조직의 영률 평균 0.1 ± 1.0 MPa임이 알려진 바 있다("Dynamic Elastic Properties of Human Bronchial Airway Tissues." Ithaca, NY: Cornell University (2011).). 본 발명에서는 이를 참고하여 탄성 측정을 위하여 탄력 측정기기로서 도 7에 나타낸 Courage Khazaka electronic GmbH 사의 Cutometer 또는 Cortex technology 사의 DermaLab를 이용하여 기도 조직의 영률을 측정하였다. 상기 2 개의 제품 모두 측정용 프로브를 대상 조직에 접촉시킨 상태에서 음압을 가하여 조직이 변위되는 높이와 복원에 필요한 시간을 측정하는 방식으로 영률을 측정할 수 있다.Since the skin itself has a structure that is not suitable for measuring mechanical properties and is not standardized for each measurement method, it is difficult to compare the results and there is a problem that it cannot be used clinically. Recently, measuring devices using a suction cavity have been developed and used to measure skin elasticity, and are evaluated to be highly reproducible compared to the past. Modulus) was measured. Previously, the method of calculating Young's modulus in a suction device designed to individualize characteristics and elasticity across the face as mechanical variables for simulation of facial surgery with biomechanical modeling of facial soft tissue and average Young's modulus of bronchial airway tissue 0.1 ± 1.0 MPa ("Dynamic Elastic Properties of Human Bronchial Airway Tissues." Ithaca, NY: Cornell University (2011).). In the present invention, referring to this, the Young's modulus of airway tissue was measured using the Cutometer of Courage Khazaka electronic GmbH or DermaLab of Cortex technology shown in FIG. 7 as a elasticity measuring device for measuring elasticity. In both products, the Young's modulus can be measured by applying a negative pressure while the measuring probe is in contact with the target tissue to measure the height at which the tissue is displaced and the time required for restoration.
2. 자성 비드의 자기 선속량(magnetic flux density)의 계산2. Calculation of magnetic flux density of magnetic beads
자성 세포의 적정 주입량을 계산하기 위하여, 우선 자성 세포에 포함시킬 자성 비드 간의 힘을 확인하기 위하여 자기 선속량(magnetic flux density)을 계산하였다. 본 발명에서 이용한 Micromod 사의 산화철 자성 비드(제품 번호: 45-00-252)로, 밀도는 46 AM2/kg이고, 자기력은 5.35 g/cm3에 해당하였다. 이에 하기 식 4와 같이 상기 자성 비드의 밀도와 자기력을 곱하여 자기 선속량으로 246100 A/m을 도출하였다. 이 때, 1 G의 값은 0.1 mT, 1 Oe 또는 80 A/m와 같으므로, 상기 자기 선속량을 단위가 3076 G로 변환시킬 수 있었다. In order to calculate the proper injection amount of the magnetic cells, first, the magnetic flux density was calculated to check the force between the magnetic beads to be included in the magnetic cells. Micromod's magnetic iron oxide beads (product number: 45-00-252) used in the present invention, the density is 46 AM 2 /kg, and the magnetic force corresponds to 5.35 g/cm 3 . Accordingly, as shown in Equation 4 below, 246100 A/m was derived as the magnetic flux by multiplying the density and magnetic force of the magnetic beads. At this time, since the value of 1 G is equal to 0.1 mT, 1 Oe, or 80 A/m, it was possible to convert the magnetic flux amount to 3076 G in unit.
[식 4][Equation 4]
Figure PCTKR2022004052-appb-img-000003
Figure PCTKR2022004052-appb-img-000003
3. 자성 비드 간 자력의 계산3. Calculation of Magnetic Force Between Magnetic Beads
상기에서 얻어진 자기 선속량을 바탕으로 자성 비드 간의 힘, 즉 자성 비드 간의 자력을 계산하였다. 보다 상세하게는 하기 식 5에서와 같이, 얻어진 자성 비드의 자기 선속량(자속 밀도)을 제곱한 뒤 테슬라 단위를 이용하여 변환한 값에 자성 비드 면적을 곱한 결과, 자성 비드 간 자력으로 0.0232 N/m2 를 얻을 수 있었다.Based on the amount of magnetic flux obtained above, the force between the magnetic beads, that is, the magnetic force between the magnetic beads was calculated. In more detail, as shown in Equation 5 below, after squaring the magnetic flux amount (magnetic flux density) of the obtained magnetic beads, multiply the converted value using the Tesla unit by the magnetic bead area. As a result, the magnetic force between the magnetic beads is 0.0232 N/ m 2 could be obtained.
[식 5][Equation 5]
1,182,722,000 [N/m2] X (1.96 X 10-11) [m2] = 0.0232 [N/m2]1,182,722,000 [N/m 2 ] X (1.96 X 10 -11 ) [m 2 ] = 0.0232 [N/m 2 ]
(단, 상기 식 5에서 1,182,722,000 N/m2 는 30762 [G2]를 테슬라 단위를 이용하여 변환시킨 값이다.) (However, in Equation 5, 1,182,722,000 N/m 2 is a value obtained by converting 3076 2 [G 2 ] using Tesla units.)
4. 자성 비드의 주입량의 결정4. Determination of Injection Amount of Magnetic Beads
상기와 같이 계산된 자성 비드 간 자력을 0.0232 N/m2 로 계산하여 기도 근육을 10 % 변형하고자 하였다. 종래에 개시된 바와 같이 기도 근육의 영률을 33.7 kPa로 가정하였을 때, 영률은 하기 식 6과 같이 stress/strain으로, 변형률 당 자력(N/m2) 크기로 계산될 수 있다. 이에 따라, 하기 식 9에 나타낸 바와 같이 기도 근육 10 %의 변형을 위하여 주입되어야 할 자성 비드의 개수로는 2.6 x 106 개를 도출할 수 있었다. The magnetic force between the magnetic beads calculated as described above was calculated as 0.0232 N/m 2 to deform the airway muscle by 10%. As previously disclosed, when the Young's modulus of the airway muscle is assumed to be 33.7 kPa, the Young's modulus can be calculated as stress/strain and magnetic force per strain (N/m 2 ) as shown in Equation 6 below. Accordingly, as shown in Equation 9 below, as the number of magnetic beads to be injected for 10% deformation of the airway muscle, 2.6 x 10 6 could be derived.
[식 6][Equation 6]
Figure PCTKR2022004052-appb-img-000004
Figure PCTKR2022004052-appb-img-000004
[식 9][Equation 9]
2.6 x 106 개(자성 비드의 개수) = 55000 [N/m2] / 0.0232 [N/m2]2.6 x 10 6 (Number of magnetic beads) = 55000 [N/m 2 ] / 0.0232 [N/m 2 ]
5. 자성 세포의 주입량의 결정5. Determination of the injection amount of magnetic cells
기도 근육 세포 하나 당 자성 비드가 2 개 부착된다고 가정하면, 하기 식 10에 나타낸 바와 같이 자성 세포의 주입량은 1.3 x 106 개로 계산되었다. Assuming that two magnetic beads are attached to each airway muscle cell, the amount of magnetic cells injected was calculated to be 1.3 x 10 6 as shown in Equation 10 below.
[식 10][Equation 10]
1.3 x 106 개(자성 세포의 개수) = 2.6 x 106 개(자성 비드의 개수) / 21.3 x 10 6 (the number of magnetic cells) = 2.6 x 10 6 (the number of magnetic beads) / 2
6. 자성 세포를 포함하는 용액의 주입량의 결정6. Determination of Injection Amount of Solution Containing Magnetic Cells
자성 세포를 인체 내 액상의 주사 형태로 주입한다고 할 때, 액상의 주사 용액 내 자성 세포의 농도를 4 x 105 cell/㎖ 라고 가정한다면, 약 3.25 ㎖의 주사 용액이 필요하며, 기도 근육에 각 1.625 ㎖ 씩 세포 용액을 주사한다면 원하는 변형률인 10 %의 달성이 가능함을 알 수 있었다. When injecting magnetic cells into the body in the form of liquid injection, assuming that the concentration of magnetic cells in the liquid injection solution is 4 x 10 5 cells/ml, about 3.25 ml of the injection solution is required, and each It was found that if the cell solution was injected by 1.625 ml each, it was possible to achieve the desired strain of 10%.
상기와 같은 방식으로 자성 비드의 스펙과 세포 농도에 따라 요구되는 적정 세포 수 및 세포 용액의 부피가 달라지며, 이와 관련된 모든 변수들을 고려하여 변형률을 달성할 수 있는 최적의 주입량을 계산할 수 있으므로 자성 세포간 척력을 조절함으로써 궁극적으로 기도 직경이 증가한 결과를 얻을 수 있다.In the same way as above, the optimal number of cells and the volume of cell solution required vary depending on the specifications and cell concentration of the magnetic beads, and the optimal injection amount to achieve the strain rate can be calculated by considering all related variables. By controlling the hepatic repulsive force, it can ultimately result in an increase in airway diameter.
실시예 6: 호흡기계 유동관 형상 제어 효과Example 6: Respiratory system flow tube shape control effect
상기도 협착을 가진 마우스 모델을 준비하였다. 실시예 1에 따라 제조된 자성 세포를 PDMS 용액에 4 x 105 cells/㎖의 농도로 혼합하여 실시예 5에 따라 적정 주입량을 계산하여 상기 마우스 모델의 협착된 기도 부위에 3.25 ㎖의 양을 1.625 ㎖ 씩 나누어 대칭되는 부위에 각각 주입하였다. 제어 유닛(CardioFlow 5000 MR, Shelley Medical Imaging Technologies)를 통해 심박 기반의 유량, 혈류 저항값 및 유량 파형을 제어하였고, 자기장 인가 장치를 이용하여 80 가우스 자기장을 가하여, 주입된 자성 세포를 강자성 상태로 전환시키고, 주입된 자성 세포간 척력을 유발하였다. 이에 따라 협착된 상기도의 직경이 확장된 결과를 확인하였다.A mouse model with upper airway stenosis was prepared. The magnetic cells prepared according to Example 1 were mixed with the PDMS solution at a concentration of 4 x 10 5 cells/ml, and an appropriate injection amount was calculated according to Example 5, and an amount of 3.25 ml of 1.625 was applied to the constricted airway area of the mouse model. Each ml was divided and injected into symmetrical sites. The heart rate-based flow rate, blood flow resistance value, and flow waveform were controlled through a control unit (CardioFlow 5000 MR, Shelley Medical Imaging Technologies), and an 80 Gaussian magnetic field was applied using a magnetic field application device to convert the injected magnetic cells into a ferromagnetic state. and induced repulsion between the injected magnetic cells. Accordingly, it was confirmed that the diameter of the narrowed upper airway was expanded.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다. As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
[부호의 설명][Explanation of code]
100: 자성 세포를 이용한 인공지능 입술 또는 구강 조직의 형상 제어 또는 유동관 형상 제어 계획 수립 시스템100: Artificial intelligence lip or oral tissue shape control or flow tube shape control planning system using magnetic cells
110: 데이터베이스부110: database unit
120: 인터페이스부120: interface unit
130: 시뮬레이션부130: simulation unit
140: 제어 계획 수립부140: control planning unit
본 발명에 따른 방법은 목적하는 물리적 변형률 달성을 위해 체내 조직 또는 기관에 주입되어야 하는 자성 세포의 적정 주입량을 도출할 수 있으므로, 조직 또는 기관의 물리적 변형이 요구되는 질환의 비제한적인 예시로 구순 구개열 또는 수면무호흡증의 질환 등을 효과적으로 예방, 개선 또는 치료할 수 있다.Since the method according to the present invention can derive an appropriate injection amount of magnetic cells to be injected into body tissues or organs in order to achieve a desired physical strain rate, cleft palate is a non-limiting example of a disease requiring physical modification of tissues or organs. Or it can effectively prevent, improve, or treat a disease of sleep apnea.

Claims (66)

  1. 악구강계-호흡계 질환의 개선 또는 치료를 위한 자성 물질을 포함하는 자성 세포의 주입량을 결정하기 위한 정보 제공 방법으로, An information providing method for determining an injection amount of magnetic cells containing a magnetic material for the improvement or treatment of oropharyngeal-respiratory diseases,
    (a) 목적하는 개체의 목적하는 조직 또는 기관에 대하여 영률(Young's Modulus)을 측정하는 단계; (A) measuring the Young's Modulus (Young's Modulus) for a target tissue or organ of a target individual;
    (b) 상기 자성 물질 간 자력을 측정하는 단계; 및(b) measuring a magnetic force between the magnetic materials; and
    (c) 측정된 영률 및 자성 물질 간 자력을 이용하여 자성 물질의 주입량을 결정하는 단계;를 포함하는 자성 세포의 적정 주입량을 결정하기 위한 정보 제공 방법. (c) determining an injection amount of a magnetic material using the measured Young's modulus and magnetic force between the magnetic materials;
  2. 제 1항에 있어서,The method of claim 1,
    상기 자성 물질의 주입량은 하기 식 1에 의해 결정되는, 정보 제공 방법:An information providing method, wherein the injection amount of the magnetic material is determined by the following Equation 1:
    [식 1][Equation 1]
    자성 물질의 주입량 = {영률(N/m2) X 희망 변형률}/자성 물질 간 자력(N/m2) Dosing amount of magnetic material = {Young's modulus (N/m 2 ) X Desired strain}/Magnetic force between magnetic materials (N/m 2 )
    상기 식 1에서, 희망 변형률은 상기 목적하는 조직 또는 기관에서 변형을 희망하는 부위의 변형 전 길이 대비 변화 후 길이의 비율로, 0 초과, 1 이하의 유리수이다. In Equation 1, the desired strain rate is a ratio of the length after change to the length before deformation of the desired tissue or organ in the target tissue or organ, and is a rational number greater than 0 and less than or equal to 1.
  3. 제 1항에 있어서,The method of claim 1,
    상기 자성 물질 간 자력은 하기 식 2에 의해 측정되는, 정보 제공 방법:The magnetic force between the magnetic materials is measured by the following Equation 2:
    [식 2][Equation 2]
    자성 물질 간 자력(N/m2) = (자기 선속량)2(N/m2) X (자성 물질의 면적(m2))Magnetic force between magnetic materials (N/m 2 ) = (magnetic flux) 2 (N/m 2 ) X (area of magnetic material (m 2 ))
    상기 식 2에서, 자기 선속량은 자성 물질의 자력(AM2/kg)과 밀도(g/cm3)의 곱이다. In Equation 2, the magnetic flux is the product of the magnetic force (AM 2 /kg) and the density (g/cm 3 ) of the magnetic material.
  4. 제 1항에 있어서,The method of claim 1,
    상기 정보 제공 방법은 결정된 자성 물질의 주입량을 이용하여 하기 식 3에 의해 자성 세포의 적정 주입량을 결정하는 단계를 포함하는, 정보 제공 방법:The information providing method includes determining an appropriate injection amount of the magnetic cells by the following Equation 3 using the determined amount of the magnetic material injected, the information providing method:
    [식 3][Equation 3]
    자성 세포의 주입량 = (자성 물질의 주입량)/(세포 내 자성 물질의 주입 수)Injection amount of magnetic cells = (injection amount of magnetic material)/(number of injections of magnetic material in cells)
    상기 식 3에서, 세포 내 자성 물질의 주입 수는 세포 당 자성 물질의 주입 수의 평균 값 또는 중앙 값이다. In Equation 3, the number of injections of the magnetic material into the cell is the average or median value of the number of injections of the magnetic material per cell.
  5. 제 1항에 있어서,The method of claim 1,
    상기 악구강계-호흡계 질환은 구순 구개열 또는 수면 무호흡증인, 방법.The method of claim 1, wherein the oropharyngeal-respiratory system disease is cleft palate or sleep apnea.
  6. 제 1항에 있어서,The method of claim 1,
    상기 질환이 구순 구개열인 경우, 상기 자성 세포는 입술 또는 구강 조직을 이루는 세포인, 정보 제공 방법.When the disease is cleft lip and cleft palate, the magnetic cells are cells constituting the lips or oral tissue.
  7. 제 6항에 있어서,7. The method of claim 6,
    상기 입술 또는 구강 조직은 입술, 잇몸, 목젖, 경구개(hard palate) 또는 연구개(soft palate)인, 정보 제공 방법.wherein the lip or oral tissue is a lip, gum, uvula, hard palate or soft palate.
  8. 제 1항에 있어서,The method of claim 1,
    상기 질환이 수면 무호흡증인 경우, 상기 자성 세포는 호흡기계 유동관의 내벽 세포인 세포인, 정보 제공 방법.When the disease is sleep apnea, the magnetic cells are cells that are cells in the lining of the flow duct of the respiratory system.
  9. 제 8항에 있어서,9. The method of claim 8,
    상기 호흡기계 유동관은 비강, 인후두 또는 기도인, 정보 제공 방법.wherein the respiratory system flow tract is a nasal, pharyngeal or airway.
  10. 제 1항에 있어서,The method of claim 1,
    상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 정보 제공 방법.wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
  11. 제 1항에 있어서,The method of claim 1,
    상기 자성 물질은 철, 코발트, 니켈, 그 산화물 및 합금으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는 것인, 정보 제공 방법.The method for providing information, wherein the magnetic material is made of one or more materials selected from the group consisting of iron, cobalt, nickel, oxides thereof, and alloys.
  12. 제 11항에 있어서,12. The method of claim 11,
    상기 자성 물질은 마그헤마이트(γ-Fe2O3), 마그네타이트(Fe3O4), 코발트 페라이트(CoFe2O4), 망간 페라이트(MnFe2O4), 철백금 합금(FePt alloy), 철코발트 합금(FeCo alloy), 코발트니켈 합금 (CoNi alloy) 또는 코발트백금 합금(CoPt alloy)인, 정보 제공 방법. The magnetic material is maghemite (γ-Fe 2 O 3 ), magnetite (Fe 3 O 4 ), cobalt ferrite (CoFe 2 O 4 ) , manganese ferrite (MnFe 2 O 4 ) , iron platinum alloy (FePt alloy), A method of providing information, which is a FeCo alloy, a cobalt nickel alloy (CoNi alloy) or a cobalt platinum alloy (CoPt alloy).
  13. 제 1항에 있어서, The method of claim 1,
    상기 자성 물질은 평균 직경이 1 nm 내지 1 μm인 자성 입자인, 방법.The method of claim 1, wherein the magnetic material is a magnetic particle having an average diameter of 1 nm to 1 μm.
  14. 제 1항에 있어서, The method of claim 1,
    상기 조직은 상피 조직 또는 근육 조직인, 정보 제공 방법. wherein the tissue is epithelial tissue or muscle tissue.
  15. 제 1항에 있어서, The method of claim 1,
    상기 기관은 입술, 잇몸, 목젖, 경구개, 연구개, 피부 또는 호흡계 기관인, 정보 제공 방법.wherein the organ is a lip, gum, uvula, hard palate, soft palate, skin or respiratory organ.
  16. 제 5항에 있어서, 6. The method of claim 5,
    상기 구순 구개열은 불완전 구순열, 편측성 완전 구순열 또는 양측성 완전 구순열, 불완전 구개열, 편측성 완전 구개열, 양측성 완전 구개열, 편측성 완전 구순 구개열, 또는 양측성 완전 구순 구개열인, 정보 제공 방법.Wherein the cleft palate is incomplete cleft lip, unilateral complete cleft lip or bilateral complete cleft lip, incomplete cleft palate, unilateral complete cleft palate, bilateral complete cleft lip, unilateral complete cleft lip, or bilateral complete cleft lip.
  17. 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체를 유효 성분으로 포함하는 구순 구개열의 개선 또는 치료용 약학적 조성물.A pharmaceutical composition for the improvement or treatment of cleft lip and cleft lip comprising a magnetic cell or a magnetic cell aggregate comprising a magnetic substance as an active ingredient.
  18. 제 17항에 있어서,18. The method of claim 17,
    상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 약학적 조성물.wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
  19. 제 17항에 있어서,18. The method of claim 17,
    상기 자성 물질은 철, 코발트, 니켈, 그 산화물 및 합금으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는 것인, 약학적 조성물.The magnetic material will be made of one or more materials selected from the group consisting of iron, cobalt, nickel, oxides and alloys thereof, the pharmaceutical composition.
  20. 제 17항에 있어서,18. The method of claim 17,
    상기 자성 물질은 평균 직경이 1 nm 내지 1 μm인 자성 입자인, 약학적 조성물.The magnetic material is a magnetic particle having an average diameter of 1 nm to 1 μm, the pharmaceutical composition.
  21. 제 17항에 있어서, 18. The method of claim 17,
    상기 자성 물질은 상기 세포에 존재하는 항원에 결합할 수 있는 항체를 더 포함하는 것인, 약학적 조성물. The magnetic material will further comprise an antibody capable of binding to the antigen present in the cell, the pharmaceutical composition.
  22. 제 21항에 있어서, 22. The method of claim 21,
    상기 항원은 HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나인, 약학적 조성물. The antigen is at least one selected from the group consisting of HLA-All, DRw6, Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, the pharmaceutical composition.
  23. 제 17항에 있어서, 18. The method of claim 17,
    상기 자성 세포는 입술 또는 구강 조직을 이루는 세포인, 약학적 조성물.The magnetic cells are cells constituting the lips or oral tissue, a pharmaceutical composition.
  24. 제 23항에 있어서,24. The method of claim 23,
    상기 입술 근육 또는 구강 조직은 입술, 잇몸, 목젖, 경구개(hard palate) 또는 연구개(soft palate)인, 약학적 조성물. The lip muscle or oral tissue is lips, gums, uvula, hard palate or soft palate, pharmaceutical composition.
  25. 제 17항에 있어서, 18. The method of claim 17,
    상기 자성 세포는 자기력을 인가한 상태에서 상기 세포의 표면에 상기 자성 물질을 처리하며 얻어진 것인, 약학적 조성물. The magnetic cell is a pharmaceutical composition obtained by treating the magnetic material on the surface of the cell in a state in which a magnetic force is applied.
  26. 제 17항에 있어서, 18. The method of claim 17,
    상기 약학적 조성물은 액상 주사용 형태 또는 발포체 형태인, 약학적 조성물. The pharmaceutical composition is in the form of a liquid injectable or foam.
  27. 제 17항에 있어서, 18. The method of claim 17,
    상기 조성물 내 자성 세포는 7 x 105 내지 9 x 105 개가 포함되는 것인, 약학적 조성물.The composition contains 7 x 10 5 to 9 x 10 5 magnetic cells in the composition, the pharmaceutical composition.
  28. 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체; 및 자기장 인가 장치를 포함하는 입술 또는 구강 조직의 형상 제어 장치.a magnetic cell or magnetic cell aggregate comprising a magnetic material; And a device for controlling the shape of the lips or oral tissue comprising a magnetic field application device.
  29. 제 28항에 있어서,29. The method of claim 28,
    빛 간섭 단층 촬영(optical coherence tomography, OCT) 장치를 더 포함하여, 자기장 인가 장치를 통한 자기장 인가 후, 상기 입술 또는 구강 조직에 결합된 자성 세포 또는 자성 세포 군집체의 이미지 정보를 실시간 관측하여 입술 또는 구강 조직의 형상 제어를 위한 피드백 정보를 제공하는, 입술 또는 구강 조직의 형상 제어 장치.Further comprising an optical coherence tomography (OCT) device, after the magnetic field is applied through the magnetic field applying device, the image information of the magnetic cells or magnetic cell aggregates coupled to the lips or oral tissue is observed in real time to obtain the lips or A device for controlling the shape of the lips or oral tissue that provides feedback information for controlling the shape of the oral tissue.
  30. 제 28항에 있어서,29. The method of claim 28,
    근적외선 조사 장치를 더 포함하는, 입술 또는 구강 조직의 형상 제어 장치.Further comprising a near-infrared irradiation device, the shape control device of the lips or oral tissue.
  31. 구순 구개열을 가진 기존 환자들의 신상정보, 의료영상정보 및 입술 또는 구강 조직의 형상 정보를 포함하는 데이터베이스부;a database unit including personal information, medical image information, and shape information of lips or oral tissues of existing patients with cleft palate;
    구순 구개열 환자의 생체 정보, 의료영상정보 및 근육 또는 조직 형상 인자의 입력을 수신하고, 소정의 결과물을 출력하는 인터페이스부;an interface unit for receiving input of biometric information, medical image information, and muscle or tissue shape factors of a patient with cleft lip and cleft lip, and outputting a predetermined result;
    상기 데이터베이스부 및 인터페이스부로부터 수신한 정보를 인공지능 기법으로 분석하여 상기 환자에 대한 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체의 주입 후의 상황을 예측하는 시뮬레이션부; 및a simulation unit that analyzes the information received from the database unit and the interface unit using an artificial intelligence technique to predict a situation after the injection of magnetic cells or magnetic cell aggregates containing a magnetic material into the patient; and
    상기 시뮬레이션부의 결과에 따라 상기 자성 세포 또는 자성 세포 군집체의 주입 방법 및 주입 위치를 결정하고 주입량을 산출하는 제어 계획 수립부;를 포함하는 자성 세포를 이용한 인공지능 입술 또는 구강 조직의 형상 제어 계획 수립 장치.A control plan establishment unit for determining the injection method and injection position of the magnetic cells or the magnetic cell aggregate according to the result of the simulation unit, and calculating the injection amount; Device.
  32. 인간을 제외한 동물의 목적하는 입술 또는 구강 조직 부위에 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체를 주입하는 단계를 포함하는 구순 구개열 동물 모델의 제조 방법.A method for producing an animal model of cleft lip and cleft lip, comprising injecting a magnetic cell or a magnetic cell aggregate containing a magnetic material into a desired lip or oral tissue site of an animal other than a human.
  33. 제 32항에 있어서,33. The method of claim 32,
    상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 제조 방법. wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
  34. 제 32항에 있어서,33. The method of claim 32,
    상기 자성 물질은 철, 코발트, 니켈, 그 산화물 및 합금으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는 것인, 제조 방법.Wherein the magnetic material is made of one or more materials selected from the group consisting of iron, cobalt, nickel, oxides and alloys thereof.
  35. 제 32항에 있어서,33. The method of claim 32,
    상기 자성 물질은 평균 직경이 1 nm 내지 1 μm인 자성 입자인, 제조 방법.The method of claim 1, wherein the magnetic material is magnetic particles having an average diameter of 1 nm to 1 μm.
  36. 제 32항에 있어서, 33. The method of claim 32,
    상기 자성 물질은 상기 세포에 존재하는 항원에 결합할 수 있는 항체를 더 포함하는 것인, 제조 방법. The magnetic material will further include an antibody capable of binding to an antigen present in the cell.
  37. 제 32항에 있어서,33. The method of claim 32,
    상기 입술 근육 또는 구강 조직은 입술, 잇몸, 목젖, 경구개(hard palate) 또는 연구개(soft palate) 인, 제조 방법. wherein the lip muscle or oral tissue is a lip, gum, uvula, hard palate or soft palate.
  38. 제 32항에 있어서,33. The method of claim 32,
    상기 자성 세포 또는 자성 세포 군집체가 주입된 입술 또는 구강 조직 부위에 자기력을 인가하여 상기 입술 또는 구강 조직에 갈라진 변형을 유도하는 단계를 더 포함하는, 제조 방법.The method further comprising the step of inducing a cracked deformation in the lip or oral tissue by applying a magnetic force to the lip or oral tissue region into which the magnetic cells or magnetic cell aggregates are injected.
  39. 제 32항 내지 제 38항 중 어느 한 항의 방법으로 제조된 구순 구개열 동물 모델.An animal model of cleft lip and cleft palate prepared by the method of any one of claims 32 to 38.
  40. 제 39항의 동물 모델을 이용하여 구순 구개열의 개선 또는 치료용 약물 또는 장치를 스크리닝하는 방법.40. A method for screening a drug or device for ameliorating or treating cleft lip and cleft palate using the animal model of claim 39.
  41. 제 39항의 동물 모델을 이용하여 입술 또는 구강 조직의 형상 변형을 시뮬레이션하는 방법.40. A method for simulating shape deformation of lips or oral tissue using the animal model of claim 39.
  42. 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체를 유효 성분으로 포함하는 수면 무호흡증의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating sleep apnea comprising a magnetic cell or a magnetic cell aggregate comprising a magnetic material as an active ingredient.
  43. 제 42항에 있어서,43. The method of claim 42,
    상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 약학적 조성물.wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
  44. 제 42항에 있어서,43. The method of claim 42,
    상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는 것인, 약학적 조성물.The magnetic material will be made of one or more materials selected from the group consisting of iron, cobalt, nickel, and oxides or alloys thereof, and the like, a pharmaceutical composition.
  45. 제 42항에 있어서,43. The method of claim 42,
    상기 자성 물질은 평균 직경이 1 nm 내지 1 μm인 자성 입자인, 약학적 조성물. The magnetic material is a magnetic particle having an average diameter of 1 nm to 1 μm, the pharmaceutical composition.
  46. 제 42항에 있어서, 43. The method of claim 42,
    상기 자성 물질은 상기 세포에 존재하는 항원에 결합할 수 있는 항체를 더 포함하는 것인, 약학적 조성물.The magnetic material will further comprise an antibody capable of binding to the antigen present in the cell, the pharmaceutical composition.
  47. 제 46항에 있어서, 47. The method of claim 46,
    상기 항원은 Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 및 ssea4으로 이루어진 군에서 선택된 적어도 하나인, 약학적 조성물. The antigen is at least one selected from the group consisting of Stro-1, CD29, CD44, CD73, CD90, CD105, CD146 and ssea4, the pharmaceutical composition.
  48. 제 42항에 있어서, 43. The method of claim 42,
    상기 자성 세포는 호흡기계 유동관의 내벽 세포인, 약학적 조성물.wherein the magnetic cells are cells in the lining of the respiratory tract.
  49. 제 48항에 있어서,49. The method of claim 48,
    상기 호흡기계 유동관은 비강, 인후두 또는 기도인, 약학적 조성물. The respiratory system flow tract is a nasal, pharyngeal or airway, the pharmaceutical composition.
  50. 제 42항에 있어서, 43. The method of claim 42,
    상기 자성 세포는 자기력을 인가한 상태에서 상기 세포의 표면에 상기 자성 물질을 처리하며 얻어진 것인, 약학적 조성물. The magnetic cell is a pharmaceutical composition obtained by treating the magnetic material on the surface of the cell in a state in which a magnetic force is applied.
  51. 제 42항에 있어서, 43. The method of claim 42,
    상기 약학적 조성물은 액상 주사용 형태 또는 발포체 형태인, 약학적 조성물. The pharmaceutical composition is in the form of a liquid injectable or foam.
  52. 제 42항에 있어서, 43. The method of claim 42,
    상기 조성물 내 자성 세포는 1.15 x 106 내지 1.5 x 106 개가 포함되는 것인, 약학적 조성물.The composition contains 1.15 x 10 6 to 1.5 x 10 6 magnetic cells in the composition, the pharmaceutical composition.
  53. 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체; 및 자기장 인가 장치를 포함하는 호흡기계 유동관 형상 제어 장치.a magnetic cell or magnetic cell aggregate comprising a magnetic material; And a respiratory system flow tube shape control device comprising a magnetic field application device.
  54. 제 53항에 있어서,54. The method of claim 53,
    빛 간섭 단층 촬영(optical coherence tomography, OCT) 장치를 더 포함하여, 자기장 인가 장치를 통한 자기장 인가 후, 상기 호흡기계 유동관에 결합된 자성 세포 또는 자성 세포 군집체의 이미지 정보를 실시간 관측하여 유동관 형상 제어를 위한 피드백 정보를 제공하는, 호흡기계 유동관 형상 제어 장치.Further comprising an optical coherence tomography (OCT) device, after the magnetic field is applied through the magnetic field applying device, the image information of the magnetic cells or magnetic cell aggregates coupled to the respiratory system flow tube is observed in real time to control the flow tube shape A respiratory system flow tube shape control device that provides feedback information for
  55. 제 53항에 있어서,54. The method of claim 53,
    근적외선 조사 장치를 더 포함하는, 호흡기계 유동관 형상 제어 장치.Respiratory system flow tube shape control device further comprising a near-infrared irradiation device.
  56. 수면 무호흡증을 가진 기존 환자들의 신상정보, 의료영상정보 및 유동관 형상 정보를 포함하는 데이터베이스부;a database unit including personal information, medical image information, and flow tube shape information of existing patients with sleep apnea;
    수면 무호흡증 환자의 생체 정보, 의료영상정보 및 호흡기계 유동관 형상 인자의 입력을 수신하고, 소정의 결과물을 출력하는 인터페이스부;an interface unit for receiving input of biometric information, medical image information, and respiratory system flow tube shape factor of a sleep apnea patient, and outputting a predetermined result;
    상기 데이터베이스부 및 인터페이스부로부터 수신한 정보를 인공지능 기법으로 분석하여 상기 환자에 대한 자성 물질을 포함하는 자성 세포 또는 자성 세포 군집체의 주입 후의 상황을 예측하는 시뮬레이션부; 및a simulation unit that analyzes the information received from the database unit and the interface unit using an artificial intelligence technique to predict a situation after the injection of magnetic cells or magnetic cell aggregates containing a magnetic material into the patient; and
    상기 시뮬레이션부의 결과에 따라 상기 자성 세포 또는 자성 세포 군집체의 주입 방법 및 주입 위치를 결정하고 주입량을 산출하는 제어 계획 수립부;를 포함하는 자성 세포를 이용한 인공지능 호흡기계 유동관 형상 제어 계획 수립 장치.Artificial intelligence respiratory system flow tube shape control plan establishment device using magnetic cells comprising a; a control plan establishment unit that determines the injection method and injection location of the magnetic cells or the magnetic cell aggregate according to the result of the simulation unit, and calculates the injection amount.
  57. 인간을 제외한 동물의 목적하는 호흡기계 유동관 부위에 상기 자성 세포 또는 자성 세포 군집체를 주입하는 단계를 포함하는 수면 무호흡증 동물 모델의 제조 방법.A method for producing an animal model of sleep apnea, comprising injecting the magnetic cells or a magnetic cell aggregate into a target respiratory tract of an animal other than a human.
  58. 제 57항에 있어서,58. The method of claim 57,
    상기 자성 물질은 상자성, 초상자성, 반자성 또는 강자성 물질인, 제조 방법. wherein the magnetic material is a paramagnetic, superparamagnetic, diamagnetic or ferromagnetic material.
  59. 제 57항에 있어서,58. The method of claim 57,
    상기 자성 물질은 철, 코발트, 니켈 및 그 산화물 또는 합금 등으로 이루어진 군에서 선택된 하나 이상의 물질로 제조되는 것인, 제조 방법. Wherein the magnetic material is made of one or more materials selected from the group consisting of iron, cobalt, nickel, and oxides or alloys thereof, and the like.
  60. 제 57항에 있어서,58. The method of claim 57,
    상기 자성 물질은 평균 직경이 1 nm 내지 1 μm인 자성 입자인, 제조 방법.The method of claim 1, wherein the magnetic material is magnetic particles having an average diameter of 1 nm to 1 μm.
  61. 제 57항에 있어서, 58. The method of claim 57,
    상기 자성 물질은 상기 세포에 존재하는 항원에 결합할 수 있는 항체를 더 포함하는 것인, 제조 방법. The magnetic material will further include an antibody capable of binding to an antigen present in the cell.
  62. 제 57항에 있어서,58. The method of claim 57,
    상기 호흡기계 유동관은 비강, 인후두 또는 기도인, 제조 방법.wherein the respiratory system flow tract is a nasal, pharyngeal or airway.
  63. 제 57항에 있어서,58. The method of claim 57,
    상기 자성 입자가 주입된 호흡기계 유동관 부위에 자기력을 인가하여 상기 호흡기계 유동관의 수축을 유도하는 단계를 더 포함하는, 제조 방법.The method further comprising the step of inducing contraction of the respiratory system flow tube by applying a magnetic force to the respiratory system flow tube portion into which the magnetic particles are injected.
  64. 제 57항 내지 제 63항 중 어느 한 항의 방법으로 제조된 수면 무호흡증 동물 모델.64. An animal model of sleep apnea prepared by the method of any one of claims 57 to 63.
  65. 제 64항의 동물 모델을 이용하여 수면 무호흡증의 예방 또는 치료용 약물 또는 장치를 스크리닝하는 방법.65. A method for screening a drug or device for preventing or treating sleep apnea using the animal model of claim 64.
  66. 제 64항의 동물 모델을 이용하여 호흡기계 유동관의 형상 변형을 시뮬레이션하는 방법.65. A method for simulating shape deformation of a respiratory system flow duct using the animal model of claim 64.
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