WO2020085423A1 - Dispositif de maintien de cellule - Google Patents

Dispositif de maintien de cellule Download PDF

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Publication number
WO2020085423A1
WO2020085423A1 PCT/JP2019/041679 JP2019041679W WO2020085423A1 WO 2020085423 A1 WO2020085423 A1 WO 2020085423A1 JP 2019041679 W JP2019041679 W JP 2019041679W WO 2020085423 A1 WO2020085423 A1 WO 2020085423A1
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WO
WIPO (PCT)
Prior art keywords
cell
holding device
cell culture
cells
holding member
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Application number
PCT/JP2019/041679
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English (en)
Japanese (ja)
Inventor
晃輔 堀
紀之 河原
Original Assignee
株式会社幹細胞＆デバイス研究所
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Application filed by 株式会社幹細胞＆デバイス研究所 filed Critical 株式会社幹細胞＆デバイス研究所
Priority to JP2020552586A priority Critical patent/JPWO2020085423A1/ja
Publication of WO2020085423A1 publication Critical patent/WO2020085423A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus

Definitions

  • the present invention relates to a cell holding device, and more particularly to a device capable of measuring contractility of cultured cells.
  • a holder 20 having a holding surface 20a and a plurality of shaft portions 21 is prepared.
  • a base material 10 having a pair of fitting portions 16 and an engagement wall 12 is prepared.
  • a gel Forming a pair of first gel bodies to gel a liquid containing cells and extending in a predetermined direction to form a second gel body of a predetermined shape connecting the pair of first gel bodies to each other, Culturing at least the second gel body to form a cell tissue MS extending in a predetermined direction; fitting a pair of holders provided with the cell tissue to a pair of fitting portions of the base material; Measuring the contractile force of the cellular tissue in response to the elastic deformation of the engagement wall due to the force associated with the contraction of.
  • the above-mentioned method for measuring the contractile force of cellular tissue has the following points to be improved.
  • the above-described method for measuring the contractile force of a cell tissue it is necessary to carry out a plurality of complicated steps over time when culturing cells for measuring the contractile force. Therefore, there is a point to be improved that it takes time to prepare before measuring the contraction force.
  • the structure is different from the cells as the actual tissue, so the contractive force of the cells as the actual tissue may not be measured, There is a point to be improved.
  • an object of the present invention is to provide a cell holding device capable of culturing cells close to an actual tissue and easily measuring the contractility of the cultivated cells. That is, the present invention has solved the above problems by providing the inventions described below.
  • a cell culture part formed of a predetermined fibrous material for culturing and holding cells, a first end and a second end located at both ends of the cell culture part, and the first end And a rim located between the second end and the cell culture holding member, A first fixing portion for directly fixing the first end portion, A second fixing portion for fixing the second end portion, A cell culture holding member placement space that is located between the first fixing portion and the second fixing portion and does not fix the edge portion; And a cell holding device.
  • the second fixing portion is Being positioned to face the first fixing portion along the predetermined direction, A cell holding device characterized by: (3) In the cell holding device according to (1), The second fixing portion is Being located along a direction intersecting with the predetermined direction, A cell holding device characterized by: (4) In the cell holding device according to any one of (1) to (3), The cell culture section, Formed by the fibrous material arranged along a predetermined orientation direction, The edge is Having at least a portion along the alignment direction, A cell holding device characterized by: (5) In the cell holding device according to any one of (1) to (4), The first fixing portion and the second fixing portion are Each is at least a part of a flat base, The cell culture holding member arrangement space, A through hole formed so as to penetrate the base, A cell holding device characterized by: (6) In the cell holding device according to (5), The cell culture holding member, Having an opening at a position corresponding to the through hole, A cell holding device characterized by: (7) In the cell holding device according to any one
  • a cell holding device characterized by: (11) In the cell holding device according to any one of (1) to (9), The cell culture holding member, As the cells, cardiomyocytes are cultured and maintained, The contraction rate of the cell culture holding member in which the cardiomyocytes are cultured is 2.5% or more, A cell holding device characterized by: (12) In the cell holding device according to any one of (1) to (11), The cell holding device, Used to measure the contractility of the cells, A cell holding device characterized by: (13) A cell holding device for measuring the contractility of cells, which comprises a cell culture section for culturing and holding cells formed by fibrous substances arranged along a predetermined orientation direction, and the orientation.
  • a cell holding device having a cell culture holding member having an edge portion having at least a part, A first fixing portion for fixing the first end portion, A second fixing portion for fixing the second end portion, A cell culture holding member placement space that is located between the first fixing portion and the second fixing portion and does not fix the edge portion; And a cell holding device.
  • a cell culture holding member used in a cell holding device for measuring contractility of cells comprising: A cell culture unit that cultures and holds cells formed by fibrous substances arranged along a predetermined orientation direction, A first end and a second end facing each other along a direction intersecting the alignment direction; An edge portion located between the first end portion and the second end portion and having at least a portion along the alignment direction, A cell culture holding member having.
  • a cell holding device is formed of a predetermined fibrous material, cultivates and holds cells, and a cell culturing section, and a first end and a second end located at both ends of the cell culturing section, And a cell culture holding member having an edge portion located between the first end portion and the second end portion, a first fixing portion for directly fixing the first end portion, the second end A second fixing portion for fixing the portion, and a cell culture holding member arrangement space which is located between the first fixing portion and the second fixing portion and does not fix the edge portion.
  • the cultured cells were restrained in all directions. Since the cells can be beat more freely than before, cells can be beat more than before.
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly.
  • cells cultured using the cell holding device can be used for measuring the contraction rate.
  • the cell holding device is characterized in that the second fixing portion is located facing the first fixing portion along the predetermined direction.
  • the cultured cells are kept in all directions.
  • the cells can be beat more freely than in the conventional method, which allows the cells to be beaten more freely than in the conventional method.
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly.
  • cells cultured using the cell holding device can be used for measuring the contraction rate.
  • the cell holding device according to the present invention is characterized in that the second fixing portion is located along a direction intersecting with the predetermined direction.
  • the cell culture portion was cultivated by placing it in the cell culture holding member placement space formed in the base and not constraining the cell culture portion in a predetermined direction and in a direction intersecting the predetermined direction. Since cells can be beat more freely than in the conventional method in which the cells are restrained in all directions, the cells can be beat more greatly than in the conventional method.
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly.
  • cells cultured using the cell holding device can be used for measuring the contraction rate.
  • the cell culture portion is formed by the fibrous material arranged along a predetermined orientation direction, and the edge portion is at least part of a portion along the orientation direction. It is characterized by having.
  • the cell culture section is placed in the cell culture holding member placement space formed in the base, and the cell culture section is cultivated by constraining it only in the orientation direction of the cell culture holding member and not in the intersecting direction.
  • the cells can be beat more freely than in the conventional method in which the cells are restrained in all directions, so that the cells can be beat more greatly than in the conventional method.
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly. That is, cells cultured using the cell holding device 100 can be used for measuring the contraction rate.
  • each of the first fixing portion and the second fixing portion is at least a part of a plate-shaped base portion, and the cell culture holding member placement space penetrates the base portion. It is a through hole formed so that
  • the cell holding device is characterized in that the cell culture holding member has an opening at a position corresponding to the through hole.
  • the cell holding device according to the present invention is characterized in that the edge portion has a portion linearly formed along the orientation direction.
  • the cell holding device according to the present invention is characterized in that the cell culture holding member has an elastic modulus of 2000 MPa or less.
  • the cell holding device further includes an operation unit that can be held by a predetermined holding tool.
  • the cell holding device can be easily moved.
  • the cell holding device is characterized in that the cell culture holding member cultures and holds cardiomyocytes or skeletal muscle cells as the cells.
  • the cell culture holding member is one in which cardiomyocytes are cultured and held as the cells, and the contraction rate of the cell culture holding member obtained by culturing the cardiomyocytes is 2.5% or more. There is a feature.
  • the cell holding device according to the present invention is characterized in that the cell holding device is used for measuring the contractility of the cells.
  • the cell retention device is a cell retention device for measuring the contractility of cells, and is a cell for culturing and retaining cells formed by fibrous substances arranged along a predetermined orientation direction.
  • the cell culture holding member formed on the base portion of the cell culture portion.
  • the cell culture holding member according to the present invention is a cell culture holding member used in a cell holding device for measuring contractility of cells, and cells formed by fibrous substances arranged along a predetermined orientation direction.
  • a cell culture part for culturing and holding cells a first end part and a second end part facing each other in a direction intersecting with the orientation direction, and a position between the first end part and the second end part And an edge portion having at least a portion along the alignment direction.
  • the cells having the same structure as the actual tissue cells are restrained only in the orientation direction of the cell culture holding member.
  • the cultured cells can be beat more freely than in the conventional method in which the cells were constrained in all directions, so that the cells can be beat more than before.
  • the cells can be cultured.
  • FIG. 1 is a perspective view of a cell holding device 100, which is an embodiment of the cell holding device according to the present invention, viewed obliquely from above.
  • FIG. 3 is a perspective view of the cell holding device 100 from an obliquely lower direction.
  • FIG. 3 is a perspective view of the base portion 101 from an obliquely upper direction.
  • FIG. 3 is a perspective view of the base portion 101 from an obliquely lower direction. It is an enlarged view of the cell culture holding member 105. It is a perspective view of the cell culture holding member 105 from an obliquely upper direction.
  • FIG. 1 is a perspective view of a cell holding device 100, which is an embodiment of the cell holding device according to the present invention, viewed obliquely from above.
  • FIG. 3 is a perspective view of the cell holding device 100 from an obliquely lower direction.
  • FIG. 3 is a perspective view of the base portion 101 from an obliquely upper direction.
  • It is
  • FIG. 7 is a diagram showing an operating state of cardiomyocytes cultured in the cell culture holding member 105, where A is a state at the time of contraction and B is a state before the contraction.
  • FIG. 7 is a perspective view of a cell holding device 200, which is another embodiment of the cell holding device according to the present invention, viewed from obliquely above. It is a perspective view of the cell holding device 200 from an obliquely lower direction.
  • FIG. 7 is a perspective view of a cell holding device 300, which is another embodiment of the cell holding device according to the present invention, seen from obliquely above. It is a perspective view of the cell holding device 300 from an oblique lower direction.
  • FIG. 7 is a diagram showing an operating state of cardiomyocytes cultured in the cell culture holding member 105, where A is a state at the time of contraction and B is a state before the contraction.
  • FIG. 7 is a perspective view of a cell holding device 200, which is another embodiment of the cell holding device according
  • FIG. 7 is a perspective view of a cell holding device 400, which is another embodiment of the cell holding device according to the present invention, seen from diagonally above. It is a perspective view of the cell holding device 400 from an obliquely lower direction.
  • FIG. 6 is a perspective view of a cell holding device 500, which is another embodiment of the cell holding device according to the present invention, viewed from obliquely above. It is a perspective view of the cell holding device 500 from an obliquely downward direction.
  • FIG. 7 is a perspective view of a cell holding device 700, which is another embodiment of the cell holding device according to the present invention, viewed from diagonally above. It is a figure which shows the cross section of the cell holding device 700.
  • FIG. 8 is a perspective view of a cell holding device 800, which is another embodiment of the cell holding device according to the present invention, seen from obliquely below. It is a figure which shows the prior art regarding the contractility measurement of a cell.
  • the cell holding device 100 is a device for evaluating the contractility of pulsating cells.
  • FIG. 1 shows a perspective view of the cell holding device 100 from diagonally above
  • FIG. 2 shows a perspective view of the cell holding device 100 from diagonally below.
  • the cell holding device 100 has a base portion 101, a cell culture holding member 105, and an operating portion 107.
  • FIG. 3 shows a perspective view of the base 101 obliquely from above
  • FIG. 4 shows a perspective view of the base 101 obliquely from below
  • the base 101 has a thin disc shape.
  • the base portion 101 has a through hole 101a having a circular cross section in the center.
  • the base 101 has an upper surface P101a (see FIG. 3) and a lower surface P101b (see FIG. 4).
  • the through hole 101a is formed so as to penetrate the base 101 from the upper surface P101a to the lower surface P101b of the base 101.
  • the through hole 101a is formed in a cylindrical shape.
  • the through hole 101a functions as a cell culture holding member placement space.
  • a part of the lower surface P101b of the base 101 functions as a first fixing portion 101b and a second fixing portion 101c.
  • the first fixing portion 101b corresponds to a portion of the lower surface P101b that fixes a first end portion 105b (described later) of the cell culture holding member 105.
  • the second fixing portion 101c corresponds to a portion that fixes the second end portion 105c (described later).
  • the base 101 is formed of, for example, polycarbonate.
  • the cell culture holding member 105 has a thin disc shape and is arranged along the lower surface P101b of the base 101. The cell culture holding member 105 will be described later.
  • the operation portion 107 is formed so as to project from the upper surface P101a (see FIG. 3) of the base portion 101.
  • a plurality of operation portions 107 are radially formed on the upper surface P101a of the base portion 101 with the through hole 101a as the center.
  • Each operation unit 107 has a rectangular shape of a semicircle in the lateral direction in a cross section along the upper surface P101a of the base 101.
  • the operation unit 107 is formed integrally with the base 101 by using a predetermined resin material such as polycarbonate. By disposing the operation unit 107, the operation unit 107 can be held by tweezers or the like, so that the user can easily operate the cell holding device 100.
  • the cell culture holding member 105 is formed of a fibrous material arranged along a predetermined orientation direction, for example, a fiber formed of a polymer material.
  • the fibrous material forming the cell culture holding member 105 will be described. Even if cells are cultivated in a conventional fiber sheet for cell culture, the elasticity of the fiber itself is small and the rigidity is high compared to the force accompanying the movement of the cell itself such as the contraction force accompanying the pulsation The cells cannot move, that is, the cells are restrained by the fiber sheet, and the movement of the cells is small. Therefore, as the fibrous material forming the cell culture holding member 105, a fibrous material having an elastic force that does not hinder the movement of the cells to be cultured is used.
  • the cell culture holding member 105 is formed by using a fiber made of a thermoplastic polyester elastomer having a predetermined elastic modulus.
  • the thermoplastic polyester elastomer is a block copolymer of PBT (polybutylene terephthalate) and polyether.
  • FIG. 5 is an enlarged view of the cell culture holding member 105.
  • a fiber F105 using a thermoplastic polyester elastomer as a fibrous material is arranged along a predetermined orientation direction A105. Further, the fiber F105 is arranged at a predetermined interval from the other fiber F105 located adjacent thereto.
  • the cell culture holding member 105 is formed by stacking a plurality of layers with a plurality of fibers F105 arranged in a predetermined direction at a predetermined interval as shown in FIG.
  • the fibers F105 forming the cell culture holding member 105 are not necessarily arranged in parallel.
  • the orientation direction A105 in the cell culture holding member 105 does not mean the orientation direction of the individual fibers F105, but the orientation direction that appears as the entire fiber F105 forming the cell culture holding member 105.
  • FIG. 6 shows a perspective view of the cell culture holding member 105 from diagonally above.
  • the cell culture holding member 105 has two openings 105a.
  • the opening 105a is formed so as to be located in the through hole 101a formed in the base 101 when the cell culture holding member 105 is arranged in the base 101.
  • the opening 105a has an edge portion 105a1 and an arc portion 105a2.
  • the edge portion 105a1 is formed in a straight line along the alignment direction A105. Therefore, it can be said that the edge portion 105a1 has at least a portion along the alignment direction A105.
  • the arcuate portion 105a2 has an arcuate shape along the through hole 101a formed in the base portion 101, and is connected to both ends of the edge portion 105a1.
  • the cell culture holding unit 105 has a first end 105b, a second end 105c, and a cell culture unit 105d.
  • the first end 105b and the second end 105c are located opposite to each other at both ends of the cell culture unit 105d.
  • the first end portion 105b and the second end portion 105c correspond to portions of the hollow cylindrical portion of the cell culture holding member 105 excluding the cell culture portion 105d, which are located linearly with the cell culture portion 105d.
  • the first end 105b and the second end 105c are fixed to the lower surface P101b of the base 101 by a predetermined adhesive material or the like.
  • the end-to-end portion 105e except the first end portion 105b and the second end portion 105c from the hollow cylindrical portion of the cell culture holding member 105 excluding the cell culture portion 105d is also fixed to the base portion 101 by a predetermined adhesive material or the like. It is fixed to the lower surface P101b.
  • the adhesive is absorbed in the gap between the fibers F105 of the cell culture holding member 105 at the stage where the cell culture holding member 105 is pressure-bonded to the lower surface P101b of the base 101, and becomes integrated with the cell culture holding member 105.
  • the adhesive for example, KE45 is used.
  • the cell culture portion 105d is formed between the edge portion 105a1 of the opening 105a.
  • the cell culture part 105d is fixed to the base part 101 along the alignment direction A101 by the first end part 105b and the second end part 105c.
  • the cell culture unit 105d three-dimensionally cultures and holds predetermined cells, for example, beating cardiomyocytes and skeletal muscle cells.
  • a cell suspension is dropped through the through hole 101a to the cell culture section 105d exposed from the through hole 101a using a pipette or the like. And culture.
  • a cell having a structure similar to that of an actual tissue cell can be cultured.
  • the cell culture section 105d is arranged in the through hole 101a which is a cell culture holding member arrangement space formed in the base 101, and the cell culture section 105d is constrained only in the orientation direction A105 of the cell culture holding member 105 to intersect.
  • the cultured cells can be beat more freely as compared with the conventional method in which the cells were constrained in all directions, so that the cardiomyocytes can be more greatly beat than in the past. .
  • the state when the cell contracts most and the state before the contraction are photographed by the image capturing device, and the two are compared.
  • the contraction rate of cultured cells can be easily measured. That is, cells cultured using the cell holding device 100 can be used for measuring the contraction rate.
  • FIG. 7 shows an operating state of cardiomyocytes cultured in the cell culture holding member 105 formed by using a fiber made of a thermoplastic polyester elastomer (elastic modulus: 10 to 232 MPa) as a fibrous material.
  • the cell holding device 100 was used in which the cell culture holding member 105 was seeded with cardiomyocytes cultured for 7 days or more.
  • An inverted stereomicroscope (OLYMPUS, IX73) was used to acquire the image in FIG. 7.
  • the software (OLYMPUS cellSens standard) attached to the inverted stereomicroscope was used for image acquisition and mutation measurement.
  • the displacement in cultured cardiomyocytes was defined as the distance between the most contracted state at the point where the displacement was greatest and the state before contraction.
  • FIG. 7A shows a state when the cardiomyocytes contract most
  • FIG. 7B shows a state before the cardiomyocytes contract.
  • the dotted line in FIG. 7B shows the outline of the state of the cardiomyocyte shown in FIG. 7A.
  • the maximum displacement X at one end is approximately 54 ⁇ m between the most contracted state (FIG. 7A) and the state before contraction (FIG. 7B).
  • Meters, and thus about 108 micrometers can be observed at both ends.
  • the width W of the cell culture holding member 105 before contraction (FIG. 7B) is about 1225 micrometers. Therefore, the rate of change of the cell culture holding member 105 during contraction is 8.8%.
  • cardiomyocytes were cultured on a cell culture sheet formed of conventional polystyrene (elastic modulus: 2300 to 3300 MPa), the cardiomyocytes could only be observed to have a maximum displacement of several microns.
  • the device 100 it is possible to easily observe the displacement of the cultured cardiomyocytes, and it can be useful for measuring the contraction rate of the cultured cardiomyocytes.
  • Example 1 described above the cell culture holding member 105 had the opening 105a having the linear edge portion 105a1 along the orientation direction A105.
  • the cell culture holding member 205 has an arc-shaped edge portion 205a1.
  • the same components as those in the first embodiment will be designated by the same reference numerals and detailed description thereof will be omitted.
  • FIGS. 8 and 9 show a perspective view of the cell holding device 200 from diagonally above
  • FIG. 9 shows a perspective view of the cell holding device 200 from diagonally below.
  • the cell holding device 200 has a base 101, a cell culture holding member 205, and an operation unit 107.
  • the cell culture holding member 205 has a thin disc shape and is arranged along the lower surface P101b of the base 101.
  • the cell culture holding member 205 is formed of a fibrous material arranged along a predetermined orientation direction, for example, a fiber formed of a polymer material. Similar to the cell culture holding member 105, the cell culture holding member 205 has fibers F105, which are predetermined fibrous substances, arranged along a predetermined orientation direction A105 (see FIG. 5).
  • the cell culture holding member 205 has two openings 205a.
  • the opening 205a is formed so as to be located in the through hole 101a formed in the base 101 when the cell culture holding member 205 is arranged in the base 101.
  • the opening 205a has an edge portion 205a1 and an arc portion 205a2.
  • the edge portion 205a1 is formed in an arc shape.
  • the edge portion 205a1 has at least a portion R205a1 along the alignment direction A105.
  • the arcuate portion 205a2 has an arcuate shape along the through hole 101a formed in the base portion 101, and is connected to both ends of the edge portion 205a1.
  • the cell culture holding unit 205 has a first end 205b, a second end 205c, and a cell culture unit 205d.
  • the first end 205b and the second end 205c are located opposite to each other at both ends of the cell culture unit 205d.
  • the first end portion 205b and the second end portion 205c correspond to portions of the hollow cylindrical portion of the cell culture holding member 205 excluding the cell culture portion 205d, which are located linearly with the cell culture portion 205d.
  • the first end 205b and the second end 205c are fixed to the lower surface P101b of the base 101 by a predetermined adhesive material or the like.
  • the end portion 205e of the cell culture holding member 205 excluding the first end portion 205b and the second end portion 205c from the hollow cylindrical portion excluding the cell culture portion 205d is also fixed to the base portion 101 by a predetermined adhesive material or the like. It is fixed to the lower surface P101b.
  • the cell culture portion 205d is formed between the edge portion 205a1 of the opening 205a.
  • the cell culture part 205d is fixed to the base part 101 along the alignment direction A101 by the first end part 205b and the second end part 205c.
  • the cell culture unit 205d three-dimensionally cultures and holds predetermined cells, for example, beating cardiomyocytes and skeletal muscle cells.
  • a cell having a structure similar to an actual tissue cell can be cultured.
  • the cell culture portion 205d is arranged in the through hole 101a which is the cell culture holding member arrangement space formed in the base 101, and the cell culture portion 205d is constrained only in the orientation direction A105 of the cell culture holding member 205 so that the cell culture holding member 205 intersects.
  • the cultured cells can be beat more freely as compared with the conventional method in which the cells were constrained in all directions, so that the cardiomyocytes can be more greatly beat than in the past. .
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly. That is, cells cultured using the cell holding device 100 can be used for measuring the contraction rate.
  • Example 1 described above the cell culture holding member 105 had the opening 105 having the linear edge portion 105a1 along the orientation direction A105.
  • the cell culture holding member 305 has a flat plate shape having a linear edge portion 305a1 along the orientation direction A105.
  • the same components as those in the first embodiment will be designated by the same reference numerals and detailed description thereof will be omitted.
  • FIG. 10 shows a perspective view of the cell holding device 300 from diagonally above
  • FIG. 10 shows a perspective view of the cell holding device 300 from diagonally below.
  • the cell holding device 300 has a base portion 101, a cell culture holding member 305, and an operating portion 107.
  • the cell culture holding member 305 has a thin flat plate shape and is arranged along the lower surface P101b of the base 101.
  • the cell culture holding member 305 is formed of a fibrous material arranged along a predetermined orientation direction, for example, a fiber formed of a polymer material. Similar to the cell culture holding member 105, the cell culture holding member 305 has fibers F105, which are predetermined fibrous substances, arranged along a predetermined orientation direction A105 (see FIG. 5).
  • the cell culture holding member 305 has an edge portion 305a1.
  • the edge portion 305a1 is formed along the alignment direction A105.
  • the cell culture holding unit 305 has a first end 305b, a second end 305c, and a cell culture unit 305d.
  • the first end 305b and the second end 305c are located opposite to each other at both ends of the cell culture unit 305d.
  • the first end portion 305b and the second end portion 305c correspond to portions that are located linearly with the cell culture portion 305d.
  • the first end 305b and the second end 305c are fixed to the lower surface P101b of the base 101 by a predetermined adhesive material or the like.
  • the cell culture portion 305d is formed between the edge portions 305a1.
  • the cell culture part 305d is fixed to the base part 101 along the orientation direction A101 by the first end part 305b and the second end part 305c.
  • the cell culture unit 305d three-dimensionally cultures and holds predetermined cells, for example, beating cardiomyocytes and skeletal muscle cells.
  • a cell having a structure similar to that of an actual tissue cell can be cultured.
  • the cell culture portion 305d is arranged in the through hole 101a which is a cell culture holding member arrangement space formed in the base 101, and the cell culture portion 305d is restricted only in the orientation direction A105 of the cell culture holding member 305 and intersects.
  • the cultured cells can be beat more freely than in the conventional method in which the cells are constrained in all directions, and thus the cardiomyocytes can be beat more than before. .
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly. That is, cells cultured using the cell holding device 100 can be used for measuring the contraction rate.
  • the base 101 had a hollow cylindrical shape.
  • the base 401 has two flat plate shapes.
  • the same components as those in the first embodiment will be designated by the same reference numerals and detailed description thereof will be omitted.
  • FIGS. 12 and 13 shows a perspective view of the cell holding device 400 from diagonally above
  • FIG. 13 shows a perspective view of the cell holding device 400 from diagonally below.
  • the cell holding device 400 has a base portion 401, a cell culture holding member 405, and an operating portion 407.
  • the base 401 has a thin flat plate shape.
  • the bases 401 are arranged at predetermined intervals.
  • the base portion 401 has an upper surface P401a (see FIG. 3) and a lower surface P401b (see FIG. 4).
  • the space between the bases 401 arranged at predetermined intervals functions as a cell culture holding member arrangement space.
  • a part of the lower surface P401b of the base portion 401 functions as the first fixing portion 401b and the second fixing portion 401c.
  • the first fixing portion 401b corresponds to a portion of the lower surface P401b that fixes a first end portion 405b (described later) of the cell culture holding member 405.
  • the second fixing portion 401c corresponds to a portion that fixes the second end portion 405c (described later).
  • the base 401 is formed of polycarbonate, for example.
  • the cell culture holding member 405 has a thin flat plate shape, and is arranged along the lower surface P401b of the base 401.
  • the operation unit 407 is formed so as to protrude from the upper surface P401a (see FIG. 3) of the base 401.
  • the operation portion 407 is formed so as to suspend the two base portions 401 on the upper surface P401a of the base portion 101.
  • the operation unit 407 is made of a predetermined resin material, for example, polycarbonate, and is integrally formed with the base 401. By disposing the operation unit 407, the operation unit 407 can be held by tweezers or the like, and thus the user can easily operate the cell holding device 400.
  • the cell culture holding member 405 is formed of a fibrous material arranged along a predetermined orientation direction, for example, a fiber formed of a polymer material. Like the cell culture holding member 105, the cell culture holding member 405 has fibers F105, which are predetermined fibrous substances, arranged along a predetermined orientation direction A105 (see FIG. 5).
  • the cell culture holding member 405 has an edge portion 405a1.
  • the edge portion 405a1 is formed along the alignment direction A105.
  • the cell culture holding unit 405 has a first end 405b, a second end 405c, and a cell culture unit 405d.
  • the first end 405b and the second end 405c are located opposite to each other at both ends of the cell culture unit 405d.
  • the first end portion 405b and the second end portion 405c correspond to portions that are located linearly with the cell culture portion 405d.
  • the first end 405b and the second end 405c are fixed to the lower surface P401b of each of the two bases 401 by a predetermined adhesive material or the like.
  • the cell culture part 405d is formed between the edge parts 405a1.
  • the cell culture part 405d is fixed to the base part 101 by the first end part 405b and the second end part 405c along the alignment direction A101.
  • the cell culture unit 405d three-dimensionally cultures and holds predetermined cells, for example, beating cardiomyocytes and skeletal muscle cells.
  • a cell having a structure similar to that of an actual tissue cell can be cultured.
  • the cell culture section 405d is arranged in the cell culture holding member arrangement space formed by the two bases 401, the cell culture section 405d is restricted only in the orientation direction A105 of the cell culture holding member 405, and in the intersecting direction.
  • the cultured cells can be beat more freely as compared with the conventional technique in which the cultured cells are restrained in all directions, so that the cardiomyocytes can be beaten more than before.
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly. That is, cells cultured using the cell holding device 100 can be used for measuring the contraction rate.
  • Example 1 described above the cell culture holding member 105 had the first end 105b and the second end 105c fixed to the base 101.
  • the cell culture holding member 505 has a first end 105b fixed to the base 101 and a second end not fixed to the base 101. And 505b.
  • the same components as those in the first embodiment will be designated by the same reference numerals and detailed description thereof will be omitted.
  • FIG. 14 shows a perspective view of the cell holding device 500 from diagonally above
  • FIG. 14 shows a perspective view of the cell holding device 500 from diagonally below.
  • the cell holding device 500 has a base portion 101, a cell culture holding member 505, and an operating portion 107.
  • the cell culture holding member 505 has a thin flat plate shape, and is arranged along the lower surface P101b of the base 101.
  • the cell culture holding member 505 is formed of a fibrous material arranged along a predetermined orientation direction, for example, a fiber formed of a polymer material. Similar to the cell culture holding member 105, the cell culture holding member 505 has fibers F105, which are predetermined fibrous substances, arranged along a predetermined orientation direction A105 (see FIG. 5).
  • the cell culture holding member 505 has three openings 505a.
  • the opening 505a is formed so as to be located in the through hole 101a formed in the base 101 when the cell culture holding member 505 is arranged in the base 101.
  • the opening 505a is divided into two types, two openings 505aX and one opening 505aY.
  • the two openings 505aX are arranged in a mirror image relationship so that respective alignment direction edge portions 505aX1 (described later) face each other.
  • the opening 505aY is arranged such that its own intersecting direction edge portion 505aY1 (described later) and each intersecting direction edge portion 505aX3 (described later) of the two openings 505aX face each other.
  • the opening 505aX has an orientation direction edge portion 505aX1, a circular arc portion 505aX2, and a cross direction edge portion 505aX3.
  • the alignment direction edge portion 505aX1 is formed in a straight line along the alignment direction A105. Therefore, it can be said that the alignment direction edge portion 505aX1 has at least a portion along the alignment direction A105.
  • the arcuate portion 505aX2 is formed in an arcuate shape along the through hole 101a formed in the base 101, and is connected to one end of the alignment direction edge portion 505aX1.
  • the cross direction edge portion 505aX3 is linearly formed in a direction crossing the alignment direction A105.
  • the arcuate portion 505aX3 is connected to one end of the alignment direction edge portion 505aX1 and one end of the arcuate portion 505aX2.
  • the opening 505aY has a cross direction edge portion 505aY1 and an arc portion 505aY2.
  • the cross direction edge portion 505aY1 is formed in a straight line along a direction crossing the alignment direction A105.
  • the cross direction edge 505aY1 of the opening 505aY1 is arranged to face the cross direction edge 505aX3 of the opening 505aX.
  • the arcuate portion 505aY2 is formed in an arcuate shape along the through hole 101a formed in the base portion 101, and is connected to both ends of the cross direction edge portion 505aY1.
  • the cell culture holding unit 505 has a first end 505b, a second end 505c, a cell culture unit 505d, and a connecting unit 505e.
  • the first end 505b and the second end 505c are located opposite to each other at both ends of the cell culture unit 505d.
  • the first end portion 505b corresponds to a portion of the hollow cylindrical portion of the cell culture holding member 505 excluding the cell culture portion 505d, which is located linearly with the cell culture portion 505d.
  • the first end 505b is directly fixed to the lower surface P101b of the base 101 by a predetermined adhesive material or the like.
  • the second end portion 505c is not directly fixed to the base portion 101, but is connected to the base portion 101 via the connection portion 505e. Therefore, the cell culture portion 505d can be formed similarly to the cantilever.
  • the second end portion 505c of the cell culture unit 505d is not directly fixed, and the degree of fixing is weak, so that the cell culture unit 505d can contract in the alignment direction A101. That is, the cell culture section 505d can be brought into a state in which it is substantially unrestrained in any direction.
  • the cell culture portion 505d is formed between two edge portions 505aX1 located opposite to each other.
  • Predetermined cells for example, beating cardiomyocytes or skeletal muscle cells are three-dimensionally cultured in the cell culture unit 505d.
  • the cell culture unit 505d holds the cultured cells.
  • the connecting portion 505e is formed between the two intersecting direction edge portions 505aX3 of the opening 505aX and the intersecting direction edge portion 505aY1 of the opening 505aY located opposite thereto.
  • the connection portion 505e is formed to connect the second end portion 505c located at one end of the cell culture portion 505d and the base portion 101. That is, one end of the connecting portion 505e is connected to the second end 505c, and the other end, the connecting end 505e1, is connected to the lower surface P101b of the base 101.
  • the connection end portion 505e1 corresponds to a portion of the connection member 505e that is located in the through hole 101a of the base portion 101 and extends toward the base portion 101 side opposite to the second end portion 505c.
  • the first end portion 505b, the second end portion 505c, the cell culture portion 505d, and the connection portion 505e are integrated by forming an opening 505aX and an opening 505aY in a sheet of a predetermined shape formed of a fibrous material. Formed.
  • the first fixing portion 101b corresponds to a portion of the lower surface P101b that fixes the first end portion 505b of the cell culture holding member 105.
  • the second fixing portion 501c corresponds to the portion that fixes the connection end portion 505e1.
  • a cell having a structure similar to an actual tissue cell can be cultured.
  • the cell culture section 505d is arranged in the through hole 101a which is a cell culture holding member arrangement space formed in the base 101, and the cell culture section 505d is also oriented in the orientation direction A105 of the cell culture holding member 305.
  • the cultured cells can be beat more freely than in the conventional method in which the cells are constrained in all directions. Therefore, the cultured cardiomyocytes can be beaten more than before.
  • the contraction rate of the cultured cells can be easily measured by directly measuring the pressure on the cells that beating greatly. That is, cells cultured using the cell holding device 100 can be used for measuring the contraction rate.
  • the cell holding device 700 has a through hole 701c in which cells can be easily cultured, in contrast to the through hole 101c included in the base portion 101 of the cell holding device 100 according to the first embodiment.
  • the same components as those in the first embodiment are designated by the same reference numerals, and detailed description will be omitted.
  • FIG. 16 shows a perspective view of the cell holding device 700 from diagonally above.
  • the cell holding device 700 has a base portion 701, a cell culture holding member 105, an operating portion 707, and an air vent portion 711.
  • the base 701 has a thin disc shape.
  • the base portion 701 has a through hole 701a in the center.
  • the base portion 701 also has an upper surface P701a and a lower surface P701b (see FIG. 17).
  • the through hole 701a is formed so as to penetrate the base 701 from the upper surface P701a to the lower surface P701b of the base 701.
  • the through hole 701a functions as a cell culture holding member placement space.
  • the through hole 701a has a truncated cone shape that narrows from the upper surface P701a where the operation portion 707 is formed toward the lower surface P701b. Accordingly, the opening on the upper surface P701a side of the base portion 701 can be increased, and thus the cell suspension can be easily dropped from the upper side into the through hole 701a. Further, since the capacity of the through hole 701a can be increased, a larger amount of cell suspension can be retained in the through hole 701a.
  • the through hole 701a has an inclined portion S701a at a predetermined distance from the lower surface P701b of the base 701 toward the upper surface P701a.
  • the inclined portion S701a is formed as a surface inclined by a predetermined angle from the axial direction.
  • the axial section of the inclined portion S701a is an inclined straight line.
  • a part of the lower surface P701b of the base portion 701 functions as a first fixing portion and a second fixing portion.
  • the base 701 is formed of, for example, polycarbonate.
  • the operation portion 707 is formed so as to project from the upper surface P701a of the base portion 701.
  • the operation portion 707 is formed on the upper surface P701a of the base portion 701 in parallel with the through hole 701a therebetween.
  • the operating portion 707 can be formed at a distance from the through hole 701a. Therefore, when the cells are cultured, the cell culture solution stored in the through hole 701a exceeds the surface tension of itself and the through hole 701a is formed. Can be prevented from flowing out.
  • the length of the operating portion 707 can be made longer, so that it can be easily pinched with tweezers or the like, and the cell holding device 700 can be easily operated.
  • the cell culture holding member 705 is arranged so that the orientation direction A705 of the fibrous material is oriented in a direction intersecting with the operation portion. Accordingly, the orientation direction A705 of the fibrous material of the cell culture holding member 705 can be easily grasped only by confirming the formation direction of the operation portion 707.
  • the operation unit 707 is formed integrally with the base 701 by using a predetermined resin material such as polycarbonate. By disposing the operation unit 707, the operation unit 707 can be held by tweezers or the like, and thus the user can easily operate the cell holding device 700.
  • the air vent 711 is formed as a region in which a part of the outer peripheral portion of the base 701 is cut off.
  • the small cell culture holding member 701 located below the base 701 is also formed in the same shape as the base 701. Thereby, when the cell holding device 700 is put into a cell content container such as one well of a multi-well plate, the air that has entered the lower part of the cell holding device 700 can be easily discharged.
  • Shape of the opening 105a of the cell culture holding member 105 In the above-described Example 1, the opening 105a of the cell culture holding member 105 has a linear edge portion 105a1 along the orientation direction A101 of the fibrous member, and , The arc-shaped portion 105a2, and the opening 205a of the cell culture holding member 205 has the arc-shaped edge portion 205a1 and the arc-shaped portion 205a2 in the second embodiment described above. It is not limited to the example as long as it has an edge portion having at least a part along the alignment direction.
  • the opening may be circular, elliptical, or rectangular. The same applies to the other examples.
  • an opening not including a portion along the orientation direction of the fibrous material may be formed in each cell culture holding member.
  • cardiomyocytes were shown as cells to be cultured, but the cells are not limited to the exemplified ones.
  • it may be a skeletal muscle cell. It may also be a cardiomyocyte or skeletal muscle cell derived from pluripotent stem cells.
  • the pluripotent stem cells include, for example, embryonic stem cells (ES cells) and iPS cells.
  • the base 101 and the operation unit 107 are formed as one body, but they are formed as separate bodies, and an adhesive or the like is used. You may make it join
  • connection part 505e is formed integrally with the cell culture part 505d and the like, but it may be formed as a separate body.
  • a cell culture holding member 605 is formed with a U-shaped opening 605a in which an opening 505aX and an opening 505aY (see FIG. 15) are integrated, and both are connected.
  • the second end 605c which is not formed is formed, and as shown in FIG. 18B, the formed second end 605c and the base 101 are thin so that both ends of the second end 605c and the base 101 are suspended.
  • the connection member 609 is fixed to the cell culture holding member 605 with a predetermined adhesive material or the like.
  • the cell holding device 600 that connects the second end portion 605c and the base portion 101 by using the thin linear connecting member 609 so as to suspend both ends of the second end portion 605c and the base portion 101
  • the second end portion 605c and the base portion 101 are suspended from one end of the second end portion 605c and the base portion 101, that is, of the cantilever.
  • the connection may be performed using the thin linear connecting member 809.
  • Fibrous material of cell culture holding member In the above-mentioned Examples 1 to 5, thermoplastic polyester elastomer (elastic modulus: 10 to 232 MPa) was exemplified as the fibrous material. It is not limited to the exemplified one as long as it does not restrain the cells cultured in 1. and does not impede movement such as pulsation. As the fibrous material, at least 2000 MPa or less, particularly 500 MPa or less, which is lower than the elastic modulus of conventional polystyrene, is suitable.
  • the cell holding device according to the present invention can be used, for example, for measuring contractility of cardiomyocytes.

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Abstract

Le problème à résoudre par la présente invention est de fournir un dispositif de maintien de cellule, dans lequel des cellules ayant chacune une structure proche d'une structure réelle peuvent être cultivées et la propriété contractile des cellules cultivées peut être facilement mesurée. La solution selon l'invention porte sur un dispositif de maintien de cellule 100 qui est pourvu d'un substrat 101, d'un élément de culture/maintien de cellule 105, et d'une section de fonctionnement 107. Des cellules spécifiques, par exemple des cardiomyocytes, sont cultivées dans une section de culture cellulaire 105d ayant une direction d'orientation spécifique A105. De cette manière, des cellules ayant chacune la même structure que celles des cellules de tissu réelles peuvent être cultivées. La section de culture de cellules 105d est placée dans un trou traversant 101a qui est un espace de placement d'élément de culture/maintien de cellules formé dans le substrat 101, et la section de culture de cellules est contrainte uniquement dans la direction d'orientation A105 de l'élément de culture/maintien de cellules 105 et n'est pas contrainte dans une direction orthogonale à la direction d'orientation A105. Par conséquent, les cellules cultivées peuvent battre plus librement par rapport aux procédés classiques dans lesquels la section de culture cellulaire 105d est contrainte dans toutes les directions. Par conséquent, il devient possible de faire battre les cardiomyocytes fortement par comparaison avec les procédés classiques.
PCT/JP2019/041679 2018-10-25 2019-10-24 Dispositif de maintien de cellule WO2020085423A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008116189A1 (fr) * 2007-03-22 2008-09-25 Worcester Polytechnic Institute (Wpi) Système d'introduction de microfils
WO2016060260A1 (fr) * 2014-10-16 2016-04-21 国立大学法人京都大学 Fragment de tissu
WO2019167960A1 (fr) * 2018-02-28 2019-09-06 株式会社幹細胞＆デバイス研究所 Dispositif de retenue et de transport de cellules

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Publication number Priority date Publication date Assignee Title
JP6739028B2 (ja) * 2016-07-13 2020-08-12 パナソニックＩｐマネジメント株式会社 生物組織または微生物の培地および電位測定装置

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Publication number Priority date Publication date Assignee Title
WO2008116189A1 (fr) * 2007-03-22 2008-09-25 Worcester Polytechnic Institute (Wpi) Système d'introduction de microfils
WO2016060260A1 (fr) * 2014-10-16 2016-04-21 国立大学法人京都大学 Fragment de tissu
WO2019167960A1 (fr) * 2018-02-28 2019-09-06 株式会社幹細胞＆デバイス研究所 Dispositif de retenue et de transport de cellules

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CHROBAK, MEGAN 0. ET AL.: "Design of a Fibrin Microthread-Based Composite Layer for Use in a Cardiac Patch", ACS BIOMATERIALS SCIENCE & ENGINEERING, vol. 3, 1 December 2016 (2016-12-01), pages 1394 - 1403, XP055709464 *
HANSEN, KATRINA J. ET AL.: "Development of a Contractile Cardiac Fiber From Pluripotent Stem Cell Derived Cardiomyocytes", FRONTIERS IN CARDIOVASCULAR MEDICINE, vol. 5, no. 52, 11 June 2018 (2018-06-11), pages 1 - 11, XP055709455 *
PROULX, MEGAN K. ET AL.: "Fibrin microthreads support mesenchymal stem cell growth while maintaining differentiation potential", JOURNAL OF BIOMEDICAL MATERIALS RESEARCH A, vol. 96, 29 November 2010 (2010-11-29), pages 301 - 312, XP055709461 *

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