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WO2018008779A1 - Procédé d'orientation de la direction de croissance de dendrites neuronales - Google Patents

Procédé d'orientation de la direction de croissance de dendrites neuronales Download PDF

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Publication number
WO2018008779A1
WO2018008779A1 PCT/KR2016/007383 KR2016007383W WO2018008779A1 WO 2018008779 A1 WO2018008779 A1 WO 2018008779A1 KR 2016007383 W KR2016007383 W KR 2016007383W WO 2018008779 A1 WO2018008779 A1 WO 2018008779A1
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Prior art keywords
cell
magnetic
growth
magnetic nanoparticles
magnetic field
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Ceased
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PCT/KR2016/007383
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English (en)
Korean (ko)
Inventor
최정우
조현열
이상율
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Sogang University Research Foundation
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Sogang University Research Foundation
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Priority to PCT/KR2016/007383 priority Critical patent/WO2018008779A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves

Definitions

  • the present invention was made by task number 2013K1A4A3055268 under the auspices of the Ministry of Science, ICT and Future Planning of Korea.
  • the research project name is “Overseas Research Institute Promotion Project”, the research project title is “Sogang-Harvard Disease Biophysical Research Center” Cooperation teams, research period is from 2014.09.01 ⁇ 2015.08.31.
  • the present invention relates to a growth direction control method of neuronal dendrites.
  • Cells which are the basic elements of an organism, are arranged with certain rules according to the characteristics of each organ or tissue. Among them, many cells grow in a certain direction, and the representative organs / tissues that function based on this structure include the nervous system and muscles including the brain. In particular, research on growth direction using neurons is directly related to the development of treatment methods for spinal cord injury patients and the development of long-term chips that mimic brain structures.
  • Patterning nanosilica particles on the surface of the substrate by a two-dimensional neuronal dendritic growth direction control method to cover the graphene layer on the substrate to control the growth of the neuronal dendritic cells along the pattern (A. Solanki, et al., Advanced material, 5477-5482, 2013) and polylysine, a cell-friendly polymer, is patterned on a substrate to induce the generation of neurite branches mainly on polylysine (W. R Kim, et. al., Lab chip, 799-805, 2014).
  • the control of the growth direction of the neural cell processes in two dimensions was performed through the method of allowing the cells to grow according to the treatment or structure formation of a specific material on the bottom, thus limiting the performance of studies such as the formation of three-dimensional neural networks in vivo. .
  • Hydrogels such as collagen, gelatin, and matrigel have been used to form three-dimensional networks and form structures of nerve cells, but the neurite branches are disordered. There was a growing problem. Random neuronal connections through neurites can develop into diseases such as neuroma, and thus, development of cell growth direction control technology that can be applied within a three-dimensional structure is required.
  • these methods were able to induce growth in a limited direction through the immobilized structure, but it was not possible to change directions in the middle or to control the individual growth direction between different cells, and to form neurites only in the direction of the structure.
  • the magnetic nanoparticles that can specifically bind to the cells to grow the cells in three dimensions and induce the formation of neurites in the hydrogel by controlling the direction of the magnetic field of the neurites in the desired direction
  • various types of neuronal dendritic growth can be controlled in a desired direction without the formation of a patterned support or additional structure on the hydrogel, and thus can be used for various long-term simulation studies.
  • the present inventors have tried to regulate the growth of neurites.
  • the present invention was completed by confirming that the magnetic nanoparticles and the magnetic field were used to control the growth of the projections of nerve cells, thereby controlling the projections of the nerve cells in the direction in which the magnetic field was applied (vertical direction) without cytotoxicity. .
  • Another object of the present invention is to provide a neuronal cell culture.
  • the present invention provides a method for regulating growth direction of nerve cell processes, comprising the following steps:
  • step (d) applying a magnetic field to the product of step (c) to control the growth direction of the projections of the nerve cells.
  • the present inventors have tried to regulate the growth of neurites. As a result, it was confirmed that the magnetic nanoparticles and the magnetic field were used to regulate the growth of the projections of the nerve cells so that there was no cytotoxicity and the projections of the nerve cells were adjusted in the direction in which the magnetic field was applied (vertical direction).
  • the growth direction control method of the neural cell protrusion of the present invention will be described in detail step by step.
  • magnetic nanoparticles are prepared.
  • the magnetic nanoparticles are one or more materials selected from the group consisting of alloys such as iron oxides such as Fe3O4 and ⁇ -Fe2O3, pure metals such as iron and cobalt, ferromagnets such as MgFe2O4, MnFe2O4 and CoFe2O4, CoPt3 and FePt Magnetic nanoparticles can be prepared.
  • alloys such as iron oxides such as Fe3O4 and ⁇ -Fe2O3, pure metals such as iron and cobalt
  • ferromagnets such as MgFe2O4, MnFe2O4 and CoFe2O4, CoPt3 and FePt Magnetic nanoparticles can be prepared.
  • the present invention prepares magnetic nanoparticles by mixing a metal precursor, a surfactant, and a solvent.
  • the metal precursor is an iron precursor.
  • the iron precursor is iron (II) acetylacetonate (Fe (acac) 2 ), iron nitrate (II) (Fe (NO 3 ) 2 ), iron nitrate (III) (Fe (NO 3 ) 3 ), iron sulfate (II) (FeSO 4 ), iron sulfate (III) (Fe 2 (SO 4 ) 3 ), iron (III) acetylacetonate (Fe (acac) 3 ), iron (II) trifluoroacetylacetonate (Fe (tfac) 2 ), iron (III) trifluoroacetylacetonate (Fe (tfac) 3 ), iron (II) acetate (Fe (ac) 2 ), iron (III) acetate (Fe (ac) 3 ), Iron (II) chloride (FeCl 2 ), iron chloride (III) (FeCl 3 ), iron bromide (II
  • the iron precursor is iron (II) acetylacetonate.
  • the surfactant may include oleic acid, cetyl trimethyl ammonium bromide, oleyl amine, trioctyl phosphine oxide, tributyl phosphine hexyl phosphonic acid ( tributyl phosphine, hexyl phosphonic acid), polyvinylpyrrolidone, lauric acid, palmitic acid, stearic acid, poly (1-vinylpyrrolidone)- Graft- (1-hexadysine) [poly (1-vinylpyrrolidone) -graft- (1-hexadecene)], poly (1-vinylpyrrolidone) -graft- (1-secretpyrrolidone) -graft- (1 -Hexadicin) [poly (1-vinylpyrrolidone) -graft- (1-vinylpyrrolidone) -graft- (1-hexadecene)], poly (1
  • the surfactant is oleic acid.
  • the solvent is trioctylamine, hexadecane, hexadecene, hexadecene, octadecane, octadecene, octadecene, icocosane, eicosane, eicosene, phenanthrene ), Pentacene, anthracene, biphenyl, phenyl ether, octyl ether, decyl ether, benzyl ether, squalene ) And combinations thereof.
  • the solvent is trioctylamine.
  • the magnetic nanoparticles may be prepared by various methods known in the art.
  • the magnetic nanoparticles may be thermal decomposition, co-precipitation, microemulsion, micelle synthesis, laser pyrolysis. ) Or by hydrothermal synthesis.
  • the magnetic nanoparticles are prepared by thermal decomposition.
  • the thermal decomposition method may control the size and shape of the magnetic nanoparticles by adjusting the ratio of the metal precursor, the surfactant, and the solvent as starting materials.
  • the size and shape of the magnetic nanoparticles may be controlled by adjusting the reaction temperature, the reaction time and the aging period.
  • the metal precursor, the surfactant and the solvent are mixed and heated to 100-400 ° C. in a stirrer to prepare magnetic nanoparticles.
  • the reaction is performed for 0.5-3 hours at 100-150 ° C., 1-4 hours at 150-250 ° C., and 0.5-3 hours at 250-350 ° C.
  • the reaction is carried out for 0.7-2 hours at 110-140 °C, 1.5-3 hours at 170-230 °C, 0.7-2 hours at 270-330 °C.
  • the reaction is carried out at 125-135 ° C. for 0.8-1.5 hours, at 180-220 ° C. for 1.7-2.5 hours, at 280-320 ° C. for 0.8-1.5 hours.
  • step (a) may further comprise the step of introducing a functional group to the magnetic nanoparticles.
  • the functional group is an amine group (NH 2), carboxyl group (COOH), mercapto group (SH), amide group (CONH 2 ), phosphonate group (PO 3 H), sulfone group (SO 3 H), sulfuric acid group (SO 4 One or more functional groups selected from H) and hydroxyl (OH).
  • the functional group is an amine group.
  • the amine group may be introduced by aminosilane, wherein the aminosilane is aminoethylaminoisobutylmethyldimethoxysilane (APTES), (ethyldiminepropyl) -trimethoxysilane [(ethylenediaminepropyl) -trimethoxysilane] and It is introduced by aminosilane selected from the group consisting of gammaaminopropyltriethoxysilane.
  • APTES aminoethylaminoisobutylmethyldimethoxysilane
  • the aminosilane is aminoethylaminoisobutylmethyldimethoxysilane.
  • antibody-binding magnetic nanoparticles are prepared by binding an antibody specific for cell membrane protein to the magnetic nanoparticles.
  • the magnetic nanoparticles In order to bind the magnetic nanoparticles to the surface of nerve cells, the magnetic nanoparticles bind specific antibodies to cell membrane proteins.
  • the antibody specific for the cell membrane protein is an antibody specific for membrane receptors, transport proteins, membrane enzymes or cell adhesion molecules. to be.
  • membrane receptor refers to a receptor contained in membrane proteins involved in the interaction of the cell with the extracellular environment.
  • Extracellular signal molecules eg, hormones, neurotransmitters, cytokines, growth factors or cell recognition molecules
  • the membrane receptors are ion channel linked receptors, such as acetylcholine receptors, enzyme-linked receptors, such as EGF (Epidermal Growth Factor), and Platelet Derived Growth Factor (PDGF).
  • G protein-coupled receptors Receptors for growth factors such as fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin, and insulin growth factor (NGF)], and G protein-coupled receptors (G protein-coupled receptors).
  • FGF fibroblast growth factor
  • HGF hepatocyte growth factor
  • NGF insulin growth factor
  • G protein-coupled receptors G protein-coupled receptors
  • the term “transport protein” refers to a protein that passes through a membrane involved in the movement of ions, small molecules, or large molecules, and is a channel / pore (eg, a voltage-gated ion channel, aqua).
  • Aquaporin electrochemical potential-driven transporters such as glucose transporters, dopamine transporters, primary active transporters such as ATP -ATP-binding cassette transporters, proton pumps and electron carriers.
  • the term “membrane enzyme” is an enzyme included in a cell membrane, and includes an oxidoreductase, a transferase, and a hydrolase.
  • the term “cell adhesion molecule” refers to a protein located on the cell surface involved in the binding of a cell-cell or cell-extracellular matrix. The cell adhesion molecule includes immunoglobulins, integrins, cadherins and selectins.
  • the antibody-binding magnetic nanoparticles are contacted with nerve cells.
  • the nerve cell is a cell constituting the nervous system, expresses the sodium channel, potassium channel and can transmit a signal through an electrical method.
  • the nerve cell is composed of a cell body (dendrite), axons (axon) and synapses (synapse).
  • the growth direction control method of the neural cell protrusion of the present invention can adjust the growth direction of the dendrites of the nerve cell of the three-dimensional culture.
  • the nerve cells are cultured on a hydrogel.
  • hydrogel refers to a water-swellable polymeric matrix, which absorbs water to form gels of various elasticities.
  • the matrix refers to a macromolecular 3D network coupled in covalent and / or non-covalent bonds.
  • the antibody-binding magnetic nanoparticles are treated to nerve cells cultured on the hydrogel.
  • the antibody-binding magnetic nanoparticles are specifically bound to nerve cell membrane proteins.
  • step (c) a magnetic field is applied to the resultant of step (c) to control the growth direction of the dendrites of the nerve cells.
  • the direction of growth of the dendrites of the nerve cell is determined according to the direction of the magnetic field and the magnetic flux density.
  • magnetic flux density is the amount of magnetic flux passing through a unit area, and despite the difference in magnetic field strength (amount of magnetization inside the magnetic material) according to the type of magnetic material, the characteristics of the magnetic material are uniform. Physical quantity that can be handled. Tesla (T) is used as the MKS system of units.
  • the magnetic flux density is 10 to 20 mT.
  • the magnetic flux density is 13-18 mT.
  • the magnetic flux density is 14 to 17 mT.
  • Appropriate magnetic flux density is important for regulating the growth direction of the dendrites of the nerve cells. If the magnetic flux density is too high, the cells move at once, and if too low, it is difficult to affect the growth of the dendritic protrusions.
  • the magnetic field controls the growth direction of the dendrites of the nerve cells in the vertical direction.
  • vertical direction means the direction of gravity toward the center of the earth or the direction perpendicular to any straight line or plane.
  • the present invention provides a nerve cell culture prepared by the above method.
  • the nerve cell culture of the present invention uses the growth regulation method of the nerve cell dendrites, the contents common between the two are omitted in order to avoid excessive complexity of the present specification.
  • the present invention provides a method for regulating the growth direction of nerve cell dendrites and a nerve cell culture cut by the method.
  • the present invention can control the dendrites growth direction of nerve cells by an easy method using magnetic nanoparticles and a magnetic field.
  • FIG. 1 shows magnetic nanoparticles before and after separation on ethanol solution (B) and projection electron microscopy images (C) thereof.
  • Figures 4a and 4b is a result of comparing the growth of nerve cells with or without magnetic field
  • Figure 4a is an image of a cell treated with magnetic nanoparticles but not applied to the magnetic field
  • Figure 4b is a vertical after treating the magnetic nanoparticles It shows the image of the cell which formed the magnetic field in the direction and induced the growth in the downward direction.
  • Figures 5a and 5b is a table showing the distribution of neurites according to the angle and length
  • Figure 5a is a distribution of neurites of the cells not applied to the magnetic field
  • Figure 5b is a magnetic field in the vertical direction to induce growth downward
  • the distribution of neurites of cells is shown.
  • Iron acetylactonate the basic constituent of magnetic nanoparticles, was added to trioctylamine solution at a molar ratio of 1:11 with oleic acid, oleylamine, etc. Add and mix. The mixture was placed in a stirrer and reacted for 1 hour at 130 ° C., 2 hours at 200 ° C., and 1 hour at 300 ° C., and then cooled to a temperature similar to room temperature (25 ° C.).
  • the synthesized magnetic nanoparticles were centrifuged at 10,000 rpm for 5 minutes, the precipitates were collected and dispersed in ethanol, and then dispersed using an ultrasonic mill. Three or more redispersion and washing steps were repeated to obtain magnetic nanoparticles dispersed in ethanol.
  • the magnetic nanoparticles are oxidized using an oxygen plasma technique to obtain oxidized magnetic nanoparticles in which a hydroxyl group (OH) is formed on a surface thereof.
  • Oxidized magnetic nanoparticle solution diluted to 0.1 mg / ml concentration and 3-aminopropyltriethoxysilane (APTES) solution diluted to 5% concentration in ethanol at 9: 1 ratio for 2 hours The reaction was performed to prepare magnetic nanoparticles in which an amine group (NH 2 ) was exposed.
  • anti-noradrenergic antibodies (Abcam, USA), 10 ⁇ M EDC, and NHS, each of which acts specifically on the noradrenaline cell membrane protein, were added to 125 ⁇ l of magnetic nanoparticle solution and reacted for 2 hours. Magnetic nanoparticles that can be attached to were synthesized.
  • FIG. 1 is a photograph (B) of a magnetic nanoparticle (A) dispersed in ethanol through a separation and purification process by a magnet and a projection electron microscope (TEM) photograph (C) of the particle.
  • A magnetic nanoparticle
  • TEM projection electron microscope
  • the average size of the magnetic nanoparticles is 29.4 nm.
  • Hydrogels were used for three-dimensional cell culture.
  • the hydrogel consists of a 1: 1 mixture of 30 ⁇ l MAtrigel and 30 ⁇ l collagen.
  • Collagen was prepared by mixing 26.4 ⁇ l collagen Type I, 3 ⁇ l Dubelco's Modified Eagle Medium (DMEM) medium and 0.6 ⁇ l 1M NaOH.
  • DMEM Dubelco's Modified Eagle Medium
  • the cells used in this study were SHSY-5Y cells, a neuroblastoma, and were cultured in DMEM medium with 10% Fetal Bovine Serum (FBS) and 1% penicillin streptomycin.
  • FBS Fetal Bovine Serum
  • Example 1 60 ⁇ l of hydrogel was added onto the substrate made of cover glass and gelled in the cell incubator for 30 minutes.
  • SHSY-5Y cells 1 ⁇ 10 4 were fixed to the formed hydrogel layer, and then cultured in a cell incubator for 2 hours for stabilization.
  • the magnetic nanoparticles obtained in Example 1 were treated to cells to attach magnetic nanoparticles to SHSY-5Y cells.
  • Magnetic nanoparticles were dissolved in DMEM and treated to cells at a concentration of 0.1 mg / ml.
  • Figure 3 shows that no toxicity appeared for 72 hours as a result of confirming the toxicity of the treatment of the magnetic nanoparticles.
  • Example 2 when the magnetic nanoparticles were fixed to SHSY-5Y cells in the hydrogel, a magnetic field was formed using a magnet to induce growth.
  • the direction of the magnetic field and the magnetic flux density determine the direction of growth of nerve cell projections, where the magnetic flux density is 15.4 mT.
  • the magnetic flux density is 15.4 mT.
  • the magnetic flux density is too high, the cells move at once, so determining the proper magnetic flux density is one of the important factors of nerve cell growth induction technology.
  • FIGS. 4A and 4B In order to see the growth of neurites with or without magnetic field, a magnetic field was applied for one week after the treatment of the magnetic nanoparticles, and the results are shown in FIGS. 4A and 4B. In the case of neurons cultured without a magnetic field (FIG.
  • the cells grew with a width of 20 ⁇ m in the vertical direction, whereas the neurons applied with the magnetic field (FIG. 4B) were grown in the vertical direction up to 100 ⁇ m.
  • the neurites formed under the condition of applying the magnetic field are also closer to the vertical direction in terms of angle (FIG. 5).

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Abstract

L'invention concerne un procédé d'orientation de la direction de croissance de dendrites neuronales; et une culture de neurones régulée par ce procédé. Selon l'invention, la direction de croissance de dendrites neuronales peut être orientée par un procédé facile utilisant des nanoparticules magnétiques et un champ magnétique.
PCT/KR2016/007383 2016-07-07 2016-07-07 Procédé d'orientation de la direction de croissance de dendrites neuronales Ceased WO2018008779A1 (fr)

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PCT/KR2016/007383 WO2018008779A1 (fr) 2016-07-07 2016-07-07 Procédé d'orientation de la direction de croissance de dendrites neuronales

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PCT/KR2016/007383 WO2018008779A1 (fr) 2016-07-07 2016-07-07 Procédé d'orientation de la direction de croissance de dendrites neuronales

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005530127A (ja) * 2001-11-27 2005-10-06 バースタイン テクノロジーズ，インコーポレイティド 光磁気バイオディスクおよび関連の方法を含むシステム
KR20090055486A (ko) * 2007-11-28 2009-06-02 김승찬 자기장을 이용한 신경세포 돌기의 방향성 유도방법
KR20090110101A (ko) * 2008-04-17 2009-10-21 재단법인서울대학교산학협력재단 자성 나노입자를 이용한 신경세포의 패터닝 방법
US20140134698A1 (en) * 2012-11-15 2014-05-15 Hong Kong Baptist University Method of extracting neural stem cells using nanoparticles
KR20160150173A (ko) * 2015-06-18 2016-12-29 서강대학교산학협력단 신경 세포 수상돌기의 성장 방향 조절 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005530127A (ja) * 2001-11-27 2005-10-06 バースタイン テクノロジーズ，インコーポレイティド 光磁気バイオディスクおよび関連の方法を含むシステム
KR20090055486A (ko) * 2007-11-28 2009-06-02 김승찬 자기장을 이용한 신경세포 돌기의 방향성 유도방법
KR20090110101A (ko) * 2008-04-17 2009-10-21 재단법인서울대학교산학협력재단 자성 나노입자를 이용한 신경세포의 패터닝 방법
US20140134698A1 (en) * 2012-11-15 2014-05-15 Hong Kong Baptist University Method of extracting neural stem cells using nanoparticles
KR20160150173A (ko) * 2015-06-18 2016-12-29 서강대학교산학협력단 신경 세포 수상돌기의 성장 방향 조절 방법

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RIGGIO, CRISTINA: "The orientation of the neuronal growth process can be directed via magnetic nanoparticles under an applied magnetic field", NANOMEDICINE: NANOTECHNOLOGY, BIOLOGY, AND MEDICINE, vol. 10, 2014, pages 1549 - 1558, XP055601665 *

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