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WO2020137628A1 - Capsule de cellule, dispositif de transplantation cellulaire, méthode d'extraction de matériau de génération d'oxygène de dispositif de transplantation cellulaire, méthode de remplacement de matériau de génération d'oxygène de dispositif de transplantation cellulaire, et matériau à libération prolongée d'oxygène - Google Patents

Capsule de cellule, dispositif de transplantation cellulaire, méthode d'extraction de matériau de génération d'oxygène de dispositif de transplantation cellulaire, méthode de remplacement de matériau de génération d'oxygène de dispositif de transplantation cellulaire, et matériau à libération prolongée d'oxygène Download PDF

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Publication number
WO2020137628A1
WO2020137628A1 PCT/JP2019/048959 JP2019048959W WO2020137628A1 WO 2020137628 A1 WO2020137628 A1 WO 2020137628A1 JP 2019048959 W JP2019048959 W JP 2019048959W WO 2020137628 A1 WO2020137628 A1 WO 2020137628A1
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WO
WIPO (PCT)
Prior art keywords
oxygen
cell
generating material
cells
capsule according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2019/048959
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English (en)
Japanese (ja)
Inventor
優史 丸山
正樹 松森
泰 佐々木
真理子 宮崎
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Hitachi Ltd
Original Assignee
Hitachi Ltd
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Filing date
Publication date
Priority claimed from JP2018246947A external-priority patent/JP2020103713A/ja
Priority claimed from JP2019037561A external-priority patent/JP2020137495A/ja
Priority claimed from JP2019065623A external-priority patent/JP2020164452A/ja
Application filed by Hitachi Ltd filed Critical Hitachi Ltd
Publication of WO2020137628A1 publication Critical patent/WO2020137628A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B13/00—Oxygen; Ozone; Oxides or hydroxides in general
    • C01B13/02—Preparation of oxygen

Definitions

  • the present invention relates to a cell capsule for encapsulating cells, a cell transplantation device, a method for taking out an oxygen generating material from a cell transplantation device, and a method for exchanging an oxygen generating material in a cell transplantation device.
  • patent document 1 proposes a method using a solvent having higher oxygen solubility than water, such as a perfluoroorganic compound, in order to improve oxygen availability and delivery to encapsulated cells or tissues. (See 0096 of the same document).
  • Patent Document 1 in the method of dissolving oxygen in a liquid solvent, the solvent diffuses into the body, so it is difficult to retain the solvent in the cell capsule for a long period of time. Moreover, since the amount of oxygen that can be supplied to the cells is small, there is a problem that the survival rate of the cells is low.
  • the present invention has been made in view of the above problems, and a technique capable of stably supplying a sufficient amount of oxygen to a cell/tissue transplanted by a cell capsule over a long period of time.
  • the purpose is to provide.
  • the cell capsule according to the present invention is equipped with a mechanism for supplying a sufficient amount of oxygen to cells using an oxygen sustained release material.
  • the transplanted cells can survive in the body for a longer period of time.
  • FIG. 5 is a graph showing the relationship between the number of days and the amount of sustained release of oxygen in the sustained release oxygen material of Example 1.
  • 7 is a graph showing the relationship between the number of days and the amount of sustained release of oxygen in the sustained release oxygen material of Example 3.
  • 9 is a schematic diagram of a device used for evaluation in Example 5.
  • FIG. 9 is a schematic diagram of a device used for evaluation in Comparative Example 3.
  • FIG. 9 is a schematic diagram of a device used for evaluation in Comparative Example 3.
  • FIG. 1 is a configuration diagram of a cell capsule 100 according to the first embodiment of the present invention.
  • the cell capsule 100 encapsulates cells 101.
  • the cell capsule 100 includes an oxygen sustained release material 102 and a cell holding carrier 103.
  • the cell holding carrier 103 is hatched.
  • the cell capsule is a microcapsule type cell transplantation device capable of protecting target cells, for example, pancreatic cells, from host immune cells by coating them with an immunoisolation membrane.
  • the oxygen sustained release material 102 is solid and has a function of releasing oxygen.
  • the oxygen released from the sustained-release material is dissolved in the liquid and partly released as bubbles. Since the oxygen-releasing material 102 is solid, it can be stably placed in the vicinity of the cells 101. Therefore, the oxygen sustained-release material 102 can continue to supply oxygen to the cells 101 for a long time without being scattered from the vicinity of the cells 101. As a result, the cells 101 that require a large amount of oxygen can survive for a long period of time.
  • the cell holding carrier 103 is a medium for holding the cells 101.
  • the oxygen sustained release material 102 is also held.
  • the position of the cells 101 in the cell capsule 100 can be stabilized by the cell holding carrier 103. This is effective because oxygen can be uniformly supplied from the oxygen sustained release material 102 to the cells 101.
  • the material of the cell holding carrier 103 is not particularly limited, but for example, a gel material such as alginic acid gel or a porous polymer material such as porous polystyrene can be used.
  • the cells 101 can be encapsulated even when the cell capsule 100 is not covered with a container.
  • an oxygen permeable film for example, PDMS
  • the oxygen sustained release material 102 can be configured using a porous material that adsorbs and releases oxygen. This is effective because a large amount of oxygen can be stored.
  • a porous material for storing oxygen cerium oxide (ceria), zirconium oxide (zirconia), cerium oxide-zirconium oxide (CeO 2 —ZrO 2 ) (ceria-zirconia), porous coordination polymer, metal organic structure, Etc. can be used.
  • a method of controlling the amount of oxygen released by the oxygen-controlled release material 102 per unit time (a) the amount of oxygen adsorbed to the porous material is controlled, (b) the oxygen-controlled release material. After arranging 102 in the cell capsule 100, it is possible to change the oxygen concentration in the cell holding carrier 103 (the oxygen sustained release material carrier 106 in the third and fourth embodiments described later).
  • the oxygen-releasing material 102 can also be configured using a peroxide that reacts with water to generate oxygen.
  • peroxides that react with water to generate oxygen include calcium peroxide, magnesium peroxide, hydrogen peroxide-urea, and the like.
  • the viscosity of the cell holding carrier 103 oxygen-releasing material carrier 106 in the third and fourth embodiments described later
  • the mobility of water decreases, so that the oxygen-releasing material 102 is supplied to the vicinity thereof.
  • the amount of released water is reduced, so that the amount of released oxygen can be suppressed.
  • the following can be used: HePG2 cells (human liver cancer-derived cells) as the cells 101, ceria-zirconia as the oxygen sustained release material 102, Alginic acid gel can be used as the cell holding carrier 103. It is assumed that the oxygen release rate in this embodiment is about 0.7 mL/day/cm 3 , the number of cells required for treatment is about 10 8 and the oxygen requirement of cells is about 22 mL/day.
  • the cell capsule 100 according to the first embodiment was immersed in a HePG2 medium and cultured in a low oxygen atmosphere of 90% nitrogen, 5% oxygen, and 5% carbon dioxide. After 7 days, the number of cells 101 increased to 1.9 times the initial number, and after 14 days, the number increased to 3.9 times. It was confirmed that the cell capsule 100 according to the first embodiment exhibits good proliferative property.
  • Comparative form 1 A cell capsule in which the oxygen sustained release material 102 was not placed in the cell capsule 100 according to the first embodiment was manufactured as Comparative Example 1. When cell proliferation was confirmed in the same low oxygen atmosphere as above, the number of cells was 1.1 times the initial number after 7 days and 1.2 times after 14 days. It was confirmed that the cell capsule of Comparative form 1 exhibited lower proliferation properties than the cell capsule 100 according to the first embodiment.
  • FIG. 2 is a configuration diagram of the cell capsule 100 according to the second embodiment of the present invention.
  • the cell capsule 100 according to the second embodiment includes a container 104 in addition to the configuration described in the first embodiment. Other configurations are similar to those of the first embodiment.
  • the container 104 covers the entire cell capsule 100.
  • the container 104 can be configured using a semipermeable membrane.
  • a semipermeable membrane is a membrane that allows only molecules and ions of a certain size or smaller to permeate.
  • the container 104 can supply oxygen and nutrients from the body to the cells 101 through this semipermeable membrane, and can discharge hormones and waste products produced by the cells 101. This contributes to improving the survival rate of the cells 101.
  • the material of the semipermeable membrane forming the container 104 is not particularly limited, but a porous polymer membrane can be used. As a polymer material used for the porous polymer membrane, polytetrafluoroethylene is particularly desirable because of its high biocompatibility.
  • the semipermeable membrane that constitutes the container 104 can also receive oxygen from the body. However, from the viewpoint of improving the amount of oxygen supplied to the cells 101, it is desirable that the amount of oxygen released by the oxygen-releasing material 102 per unit time be larger than the amount of oxygen permeating through the semipermeable membrane.
  • the container 104 can also provide immunoisolation to the cells 101.
  • immune cells in the body may attack the cells 101.
  • the method of immunoisolation is not particularly limited, but by using a porous polymer membrane as the container 104, it is possible to have both a function as a semipermeable membrane and an immunoisolation function. Further, since the cell holding carrier 103 also exerts an immunoisolation function, it is more effective to use these in combination.
  • the following can be used: HePG2 cells as the cells 101, calcium peroxide as the oxygen sustained release material 102, and alginic acid as the cell holding carrier 103.
  • Porous polytetrafluoroethylene can be used as the gel and the semipermeable membrane.
  • FIG. 3A is a configuration diagram of the cell capsule 100 according to the third embodiment of the present invention.
  • the cell capsule 100 according to the third embodiment includes an oxygen permeable membrane 105 and an oxygen sustained release material carrier 106 in addition to the configuration described in the second embodiment.
  • Other configurations are similar to those of the first embodiment.
  • the inside of the container 104 is divided into a first section and a second section by the oxygen permeable membrane 105.
  • the first compartment accommodates the cells 101 and the cell holding carrier 103
  • the second compartment accommodates the oxygen sustained release material 102 and the oxygen sustained release material carrier 106. That is, the cells 101 and the oxygen sustained release material 102 are arranged via the oxygen permeable membrane 105.
  • the oxygen sustained release material 102 has an adverse effect such as decreasing the survival rate of the cells 101
  • the oxygen permeable film 105 can alleviate the adverse effect.
  • the case where the oxygen concentration generated from the oxygen sustained release material 102 is excessive corresponds to this. Since the oxygen permeable film 105 allows oxygen to permeate, the oxygen supply by the oxygen sustained release material 102 can be maintained and the above adverse effects can be mitigated.
  • the oxygen-controlled release material carrier 106 is a medium for holding the position of the oxygen-controlled release material 102 in the cell capsule 100. Thereby, oxygen can be uniformly supplied to the cells 101 without any bias.
  • the oxygen permeable film 105 can be configured using, for example, polydimethylsiloxane or a fluorine-containing polymer film. Since polydimethylsiloxane is highly biocompatible, the present invention works effectively.
  • the oxygen sustained release material carrier 106 can be configured by using an acidic gel material.
  • a peroxide is used as the oxygen sustained release material 102, hydrogen peroxide may be generated and damage the cells 101.
  • the oxygen permeable film 105 blocks hydrogen peroxide to prevent damage to some extent, the oxygen sustained release material carrier 106 is made of an acidic gel material, so that damage can be further suppressed. That is, since it is acidic, hydrogen ions are present, and the hydrogen ions react with hydrogen peroxide to generate water, so that the adverse effects of hydrogen peroxide can be suppressed.
  • FIG. 3B is a modified example of the cell capsule 100 according to the third embodiment.
  • a portion of the container 104 that covers the cells 101 and the cell holding carrier 103 is constituted by the first film 104A
  • a portion of the container 104 that covers the oxygen sustained release material 102 and the oxygen sustained release material carrier 106 is the second film. It is composed of 104B.
  • the first film 104A is a semipermeable film similar to that of FIG. 3A.
  • the second film 104B is a film that allows water to permeate (or pass, the same applies hereinafter).
  • the amount of oxygen generated can be controlled by controlling the amount of water given to the oxygen-controlled release material 102. it can. Therefore, by using a water-permeable film as the second film 104B, the amount of water given from outside the cell capsule 100 can be controlled to control the amount of oxygen generated from the oxygen sustained release material 102.
  • the amount of oxygen permeating the oxygen permeable membrane 105 per unit time is equal to that of the semipermeable membrane forming the container 104. Is preferably larger than the amount of permeation per unit time.
  • the cells 101 and the oxygen sustained release material 102 are isolated via the oxygen permeable membrane 105, for example, only the oxygen sustained release material 102 can be periodically refilled and used. This allows the cells 101 to survive for a long period of time.
  • the method for refilling the oxygen sustained-release material 102 (a) the cell capsule 100 is taken out of the body and the oxygen sustained-release material 102 is refilled, and (b) the oxygen sustained-release material carrier 106 is sucked with a syringe to obtain new oxygen. It is possible to inject the sustained release material carrier 106.
  • FIG. 4 is a configuration diagram of the cell capsule 100 according to the fourth embodiment of the present invention.
  • the cell capsule 100 according to the fourth embodiment has a second oxygen permeable membrane 105 in addition to the configuration described in the third embodiment. Therefore, the inside of the cell capsule 100 is divided into three compartments.
  • An oxygen sustained-release material 102 and an oxygen sustained-release material carrier 106 are arranged in the central compartment, and cells 101 and a cell holding carrier 103 are arranged in the compartments on both sides thereof.
  • the first film 104A is arranged in a portion covering the cells 101 and the cell holding carrier 103, and the second film 104B is arranged in a portion covering the oxygen sustained release material 102 and the oxygen sustained release material carrier 106. Therefore, the second film 104B is arranged in a band shape in the central portion of the cell capsule 100.
  • the cell capsule 100 according to the fourth embodiment contains approximately twice as many cells 101 as in the third embodiment.
  • the cells 101 secreting C-peptide were used to compare the third embodiment with the fourth embodiment, it was confirmed that the fourth embodiment secreted about twice as much C-peptide as the third embodiment.
  • FIG. 5 is a configuration diagram of the cell capsule 100 according to the fifth embodiment of the present invention.
  • the cells 101 and each medium contained in the cell capsule 100 can be put into the cell capsule 100 immediately before using the cell capsule 100.
  • the cell capsule 100 includes at least the container 104 as an initial state.
  • FIG. 5 an example including the configuration described in FIG. 3B is shown. That is, the cell capsule 100 has a configuration in which the first membrane 104A and the second membrane 104B accommodate the oxygen permeable membrane 105.
  • the configuration corresponding to that described in the other embodiments is provided, only the configuration other than the cell 101 and each medium is provided.
  • the cells 101 and each medium are put into the cell capsule 100 immediately before use, so that there is an advantage that they can be put into the body in a fresh state. Further, the cell capsule 100 and each substance or the like contained in the cell capsule 100 can be separately conveyed.
  • FIG. 6 is a schematic cross-sectional view illustrating a sixth embodiment of the cell transplantation device.
  • FIG. 7 is a schematic cross-sectional view illustrating one aspect using the sixth embodiment of the cell transplantation device.
  • FIG. 8 is a schematic cross-sectional view illustrating how to replace the oxygen generating material in one aspect using the sixth embodiment of the cell transplantation device.
  • FIG. 9 is a perspective view illustrating one aspect of the oxygen generating material in the sixth embodiment of the cell transplantation device.
  • the cell transplantation device 200A As shown in FIG. 6, the cell transplantation device 200A according to the sixth embodiment is provided between the oxygen generating material container 201, the cell container 202, and the oxygen generating material container 201 and the cell container 202. And an oxygen transfer unit 203.
  • the cell transplantation device 200A has these elements housed in one housing 204.
  • the shape and size of the housing 204 are not particularly limited, and can be arbitrarily set according to a target such as a site to be implanted in a living body or cells/tissue to be implanted.
  • the housing 204 is a circular or polygonal tubular body in a plan view, and it is possible to use a housing without a bottom.
  • the oxygen generating material storage unit 201 stores an oxygen generating material (also referred to as oxygen sustained release material) 205 (see FIG. 7) that generates oxygen. That is, the oxygen generating material storage unit 201 has a predetermined capacity for storing the oxygen generating material 205. In other words, the oxygen generating material 205 is formed with a capacity that can be stored in the oxygen generating material storage portion 201. The oxygen generating material 205 will be described later with reference to FIG. 7.
  • the oxygen generating material container 201 is provided with a lid 206 that allows the oxygen generating material container 201 to move in and out.
  • the oxygen generating material 205 is taken out through the lid 206 and a new replacement oxygen generating material 205 is stored in the oxygen generating material storage portion 201.
  • the lid 206 may be provided so as to close the opening 207 (see FIG. 8) of the oxygen generating material containing portion 201, and the attachment method is not limited.
  • the lid 206 can be fixed so as to close the opening 207 by an appropriate means such as screwing, adhesion, or locking.
  • the lid 206 is preferably attached to the opening 207 of the oxygen generating material containing portion 201 so as to be openable and closable.
  • the lid 206 can be provided so as to be exposed outside the body when the cell transplantation device 200A is implanted in a living body.
  • the oxygen generating material 205 stored in the oxygen generating material storage portion 201 cannot generate a sufficient amount of oxygen, the oxygen generating material 205 can be removed or easily replaced with a replacement oxygen generating material 205. it can.
  • the lid 206 exposed to the outside of the living body can be opened and closed, so that the oxygen generating material 205 can be easily removed or replaced without lowering the patient's QOL (Quality of life). You can do it.
  • the lid 206 may be provided so as to be placed inside the body when the cell transplantation device 200A is implanted in the living body. That is, the entire cell transplantation device 200A may be implanted in the body. Even in this case, if the lid 206 is opened and closed using an endoscope or the like, the oxygen generating material 205 can be easily removed or replaced without significantly lowering the QOL of the patient.
  • the aforementioned housing 204 and lid 206 can be manufactured using a 3D printer, but the manufacturing method is not limited to this.
  • Various resins that can be used in a 3D printer can be used as the material for forming the housing 204 and the lid 206, but it is desirable to use a resin that does not cause an immune reaction in the living body in which the device is implanted.
  • Examples of the material forming the housing 204 and the lid 206 include, but are not limited to, known biocompatible polypropylene, polyetheretherketone, polystyrene, polyacrylonitrile, polymethylmethacrylate, and the like. ..
  • the housing 204 and the lid 206 are preferably provided with antibacterial properties by including a known antibacterial agent.
  • the cell storage unit 202 stores cells 208.
  • the cell 208 can be used without particular limitation as long as it produces a substance useful for a living body.
  • the cells 208 that can be used in this embodiment will be described later.
  • the cell storage unit 202 includes a release unit 209 that releases the product produced by the cells 208 to the outside of the cell transplantation device 200A. Examples of the product include insulin and the like, but as described above, any product can be used as long as it is a product produced by the cell 208 and is a substance useful to the living body.
  • the release unit 209 preferably has a hole for releasing the product produced by the cell 208 to the outside of the cell transplantation device 200A, but it is sufficient if the substance produced by the cell 208 can be released to the outside of the cell transplantation device 200A, It is not particularly limited.
  • the releasing part 209 can use an immunoisolation membrane in order to protect the cells 208 in the cell containing part 202 from the immune system of the transplant destination.
  • the immunoisolation membrane for example, a semipermeable membrane can be used.
  • the semipermeable membrane is a membrane that allows only molecules or ions of a certain size or smaller to permeate, so that the size of the molecule or the like to be permeated is set to a pore size that is equal to or smaller than the cells 208 of the immune system or an antibody, thereby accommodating cells.
  • the cells 208 in the portion 202 can be protected from the immune system of the transplant destination. That is, it is possible to suppress cell death of the cells 208 in the cell container 202 due to the immune system of the transplant destination. Further, in this way, oxygen and nutritional components can be obtained from the transplant destination in the cells 208 in the cell housing portion 202, so that the survival time of the transplanted cells 208 in the body can be improved.
  • the use of the immunoisolation membrane has a merit that the cells 208 in the cell transplantation device 200A can be protected from the immune system of the transplant destination, but has a demerit that the supply of oxygen from the blood vessel is reduced.
  • oxygen is used. Since the generating material 205 can generate and supply oxygen, the demerit can be eliminated.
  • the semipermeable membrane in the present embodiment for example, a stretched polytetrafluoroethylene (ePTFE) membrane, a polytetrafluoroethylene (PTFE) nonwoven fabric, a porous polycarbonate or the like can be used.
  • hydrogels such as alginic acid, polysulfonic acid, and the like can be used in addition to the physically porous membranes.
  • the oxygen transfer unit 203 transfers the oxygen generated from the oxygen generating material 205 to the cell accommodation unit 202.
  • 6 to 8 show an example in which an oxygen permeable film is used as the oxygen transfer part 203 (the same applies to oxygen permeation in FIGS. 10, 11, 13, 14, 16, and 17 described later). An example using a membrane is shown).
  • the material of the oxygen permeable film for example, silicone or the like can be used, but if the oxygen transmission coefficient is large, it is not limited to this and any material can be used. It is preferable that the oxygen permeability coefficient is, for example, 1 ⁇ 10 11 cc ⁇ cm/(cm 2 ⁇ sec ⁇ atm) or more.
  • oxygen permeable film a film having holes physically can be used.
  • a film for example, an ePTFE film or a PTFE non-woven fabric can be used. Since the ePTFE membrane and the PTFE non-woven fabric are highly hydrophobic, it is difficult for water to soak into them, and even when they are in contact with water, they function as an oxygen permeable membrane.
  • the oxygen transfer part 203 oxygen permeable film
  • the cell transplantation device 200A (Usage mode of the sixth embodiment)
  • the cell transplantation device 200A according to the present embodiment has the above configuration and is used as follows.
  • the oxygen generating material 205 is accommodated in the oxygen generating material accommodating portion 201 and the cells 208 are accommodated in the cell accommodating portion 202. Then, at least a part of the cell transplantation device 200A is implanted in the body. For example, the release part 209 of the cell containing part 202 is implanted in the body so as to be located at a portion planned for the transplant destination.
  • the oxygen generating material 205 can be accommodated in the oxygen generating material accommodating section 201 and the cells 208 can be accommodated in the cell accommodating section 202, respectively, in a timely manner. That is, these may be housed in the field immediately before implanting the cell transplantation device 200A, or one of these may be housed at the time of factory shipment and the other may be housed in the site immediately before implanting. Alternatively, both of them may be stored at the time of factory shipment.
  • the cells 208 are stored in the cell storage unit 202 at the time of factory shipment, in order to prevent the cells 208 from being killed or weakened by the time the cell transplantation device 200A is implanted in the body, for example, temperature and oxygen concentration, It is preferable to control the carbon dioxide concentration and the like.
  • the oxygen generating material 205 in the sixth embodiment shown in FIG. 7 uses a chemical reactant that chemically reacts with peroxide to generate oxygen. It should be noted that in the present invention, other modes in which no chemical reaction agent is used can be applied. Other aspects not using the chemical reaction agent will be described later.
  • the above-mentioned chemical reaction agent includes, for example, peroxide.
  • peroxide hydrogen peroxide is dissociated from the peroxide, and hydrogen peroxide is disproportionated to generate water and oxygen. Therefore, the generated oxygen should be delivered (supplied) to the transplanted cells 208.
  • the peroxide for example, a metal peroxide or a hydrogen peroxide inclusion body can be used.
  • the metal peroxide for example, calcium peroxide, magnesium peroxide, sodium peroxide, barium peroxide, potassium peroxide, zinc peroxide or the like can be used.
  • hydrogen peroxide inclusion body for example, hydrogen peroxide urea can be used.
  • oxygen generating material 205 When a chemical reactant is used as the oxygen generating material 205, oxygen is generated by the chemical reaction, so that when the chemical reaction stops, the generation of oxygen also stops. Therefore, in this embodiment, it is preferable to exchange the chemical reaction agent at regular intervals as needed. Since it is necessary, for example, when the oxygen generating material 205 is sufficient for the first time, the oxygen generating material 205 is not replaced and is simply taken out (removed) from the oxygen generating material accommodating portion 201. ) Can also be set. This is because, for example, the first one-time oxygen generating material 205 sufficiently promotes angiogenesis around the device, and after removing the oxygen generating material 205, oxygen and nutrient components are supplied from the newly formed blood vessels.
  • the method can be applied when the cells 208 in the cell containing portion 202 can survive.
  • the lid portion 206 described above is provided, as shown in FIG. 8, the oxygen generating material 205 can be easily removed or replaced by opening and closing at least a part of the lid portion 206.
  • FIG. 8 illustrates a state where the entire lid 206 is opened (removed) to open the opening 207, and the oxygen generating material 205 is removed or replaced.
  • the replacement frequency of the oxygen generating material 205 is not limited, but the lower the replacement frequency, the higher the QOL of the patient.
  • a preferable oxygen partial pressure when oxygen generated from the oxygen generating material 205 using a chemical reaction agent reaches the cells 208 is 1 kPa to 40.5 kPa (0.01 atm to 0.4 atm), and more preferably 5 kPa to 20. It is 0.3 kPa (0.05 atm to 0.2 atm). When the oxygen partial pressure is in this range, oxygen can be sufficiently supplied to the cells 208, and the oxygen partial pressure does not become too high, so that cytotoxicity is unlikely to occur.
  • the oxygen generating material 205 When the oxygen generating material 205 is a chemical reaction agent, it may be liquid, solid, powder, or a mixture thereof. When the oxygen generating material 205 is a chemical reactant and is a liquid, it can be realized by using a fluid dispersion medium.
  • a fluid dispersion medium examples include liquid polymers such as oligoethylene glycol, polyethylene glycol, polypropylene glycol, and silicone oil, low-molecular liquids such as mineral oil, fluorine-based liquids such as perfluoroethers, water and hydrophilicity.
  • higher fatty acids, oils, terpenes, etc. may be mentioned, but are not limited thereto.
  • the oxygen generating material 205 When the oxygen generating material 205 is a chemical reaction agent and is a liquid or a powder, it may be housed in a tubular cartridge 210 as shown in FIG. 9, for example.
  • the shape of the tubular cartridge 210 is not limited as long as it is hollow.
  • both ends of the tubular cartridge 210 are sealed.
  • the number of cartridges 210 arranged in the cell transplantation device 200A is not limited.
  • the tube-shaped cartridge 210 can be formed of, for example, silicone resin.
  • the cells 208 that can be stored in the cell storage unit 202 include, for example, totipotent stem cells, pluripotent stem cells, unipotent stem cells (eg, neural stem cells, epithelial stem cells, hepatic stem cells, reproductive stem cells, hematopoietic stem cells, mesenchymal stem cells, Skeletal muscle stem cells, etc.), stem cells such as induced pluripotent stem cells, and various cells obtained by differentiating these stem cells (eg, nerve cells, hepatocytes, muscle cells, white blood cells, etc.) and the like.
  • the cells 208 can also be obtained from animals such as humans, dogs, cats, cows, pigs, sheep, rats, mice and birds.
  • the cells 208 are not limited to those described above, and cells of microorganisms such as plant cells, eubacteria, archaea, algae, and protists can also be used.
  • the cells 208 preferably include insulin-producing cells, isolated pancreatic islets, mesenchymal stem cells, and the like.
  • the origin, type, phenotype, presence or absence of gene modification, passage number, etc. of the cells 208 are not limited.
  • the cell 208 is not limited in properties and morphology such as floating cells, adherent cells, single cells, cell sheets, and organoids.
  • the use of the cell 208 is not limited.
  • the cells 208 can be accommodated in the cell accommodating portion 202 together with an arbitrary gel, cultivated agar medium or liquid medium.
  • the cells 208 can also be housed in the cell housing unit 202 together with angiogenic factors, growth (proliferation) factors, biologically active agents such as hormones, and the like.
  • FIG. 10 is a schematic cross-sectional view illustrating the seventh embodiment of the cell transplantation device.
  • FIG. 11 is a schematic cross-sectional view explaining how to replace the oxygen generating material in the seventh embodiment of the cell transplantation device.
  • FIG. 12 is a perspective view illustrating one aspect of the oxygen generating material in the seventh embodiment of the cell transplantation device.
  • the cell transplantation device 200B according to the seventh embodiment and the cell transplantation device 200A according to the sixth embodiment contain the oxygen generating material of the cell transplantation device 200B according to the seventh embodiment.
  • the oxygen generating material 205 accommodated in the part 201 is accommodated in the sheet-shaped (bag-shaped) cartridge 210, and thus the oxygen generating material 205 is accommodated in the tube-shaped cartridge 210 according to the sixth embodiment.
  • This is different from the cell transplant device 200A.
  • the other components of the cell transplantation device 200B according to the seventh embodiment are the same as those of the sixth embodiment, and thus the description thereof will be omitted and only the differences will be described.
  • the oxygen generating material 205 is housed in one sheet-shaped cartridge 210 having a size substantially the same as the internal volume of the oxygen generating material housing portion 201. Then, as shown in FIG. 10, the oxygen generating material 205 accommodated in the sheet-like cartridge 210 is accommodated in the oxygen generating material accommodating portion 201. In such a mode, since the oxygen generating material 205 is housed in one cartridge 210, as shown in FIG. 11, after the lid 206 is opened, the cartridge 210 can be easily oxygen-generated by one operation. It can be removed or replaced from the material container 201.
  • the sheet-shaped cartridge 210 When the sheet-shaped cartridge 210 is used for the oxygen-generating material containing portion 201 having the same volume, the sheet-shaped cartridge 210 has a larger volume than the tube-shaped cartridge 210. Therefore, when the oxygen-generating material 205 is a chemical reaction agent and is solid. Can be suitably used.
  • the sheet-shaped cartridge 210 can be formed of the same material as the tube-shaped cartridge 210.
  • the number of the sheet-shaped cartridges 210 arranged in the oxygen generating material container 201 may be two or more.
  • the oxygen generating material 205 (chemical reaction agent) housed in the sheet-shaped cartridge 210 the same material as in the sixth embodiment can be used.
  • the shape of the sheet-shaped cartridge 210 is not limited as long as it is hollow.
  • FIG. 12 is a three-dimensional view of an example of the sheet-shaped cartridge 210. As shown in FIG. 12, the sheet-shaped cartridge 210 can be formed into, for example, a rectangular parallelepiped shape in accordance with the shape of the oxygen generating material accommodation portion 201.
  • FIG. 13 is a schematic cross section explaining 8th Embodiment of a cell transplantation device.
  • FIG. 14 is a schematic cross-sectional view illustrating how to replace the oxygen generating material in the eighth embodiment of the cell transplantation device.
  • FIG. 15 is a diagram showing the flow path of the oxygen generating material accommodation portion 201 in the eighth embodiment of the cell transplantation device.
  • the cell transplantation device 200C according to the eighth embodiment and the cell transplantation device 200A according to the sixth embodiment are the oxygen generating material accommodation of the cell transplantation device 200C according to the eighth embodiment.
  • the cell transplantation device 200A according to the sixth embodiment in which the oxygen generating material accommodating portion 201 is formed in a cubic shape or a rectangular parallelepiped shape in that the portion 201 is formed as a flow path 211 having a substantially L shape in a longitudinal cross section.
  • the other components of the cell transplantation device 200C according to the eighth embodiment are the same as those of the sixth embodiment, and thus the description thereof will be omitted and only the differences will be described.
  • the oxygen generating material storage unit 201 in the eighth embodiment has a plurality of (two in FIG. 15) flow paths 211 each having a substantially L-shape in a longitudinal section, and these flow paths are provided.
  • the ends of 211 are bent at right angles and communicate with each other. That is, as shown in FIG. 15, in the oxygen generating material container 201 according to the eighth embodiment, a plurality of lids 206 (FIG. 13) and openings 207 (FIGS. 14 and 15) are provided on the upper surface 12 of the housing 204. And the openings 207 are interconnected within the housing 204.
  • the flow path 211 has a substantially U shape when viewed in a plan view.
  • the lids of both openings 207 are provided. After opening the portion 206, air can be easily removed by injecting air into either one of the openings 207 or sucking the oxygen generating material 205 through the one of the openings 207. Further, in the cell transplantation device 200C according to the eighth embodiment, when exchanging the oxygen generating material 205, the other opening 207 is removed after or while removing the used oxygen generating material 205 as described above. This can be easily carried out by injecting the replacement oxygen generating material 205 from.
  • the cell transplantation device 200C according to the eighth embodiment has such an aspect, it is suitable when the liquid oxygen generating material 205 (chemical reaction agent) is used.
  • the oxygen generating material storage portion 201 formed as the flow path 211 includes the oxygen transfer portion 203.
  • the material 205 does not diffuse or leak into the cell containing portion 202.
  • the cell transplantation device 200C according to the eighth embodiment has such an aspect, and is suitable when the oxygen generating material 205 (chemical reaction agent) is directly contained in the oxygen generating material accommodating portion 201.
  • the cell transplantation device 200C according to the eighth embodiment can also be suitably applied to the powdery oxygen generating material 205 (chemical reaction agent).
  • FIG. 16 is a schematic cross section explaining 9th Embodiment of a cell transplantation device.
  • the cell transplantation device 200D according to the ninth embodiment and the cell transplantation device 200A according to the sixth embodiment contain the oxygen generating material of the cell transplantation device 200D according to the ninth embodiment.
  • the part 201 directly accommodates the oxygen generating material 205 (chemical reaction agent), and thus the oxygen generating material 205 is accommodated in the cartridge 210, and the cartridge 210 is accommodated in the oxygen generating material accommodating portion 201 according to the sixth embodiment. This is different from the cell transplant device 200A.
  • the oxygen generating material storage portion 201 of the cell transplantation device 200D according to the ninth embodiment is particularly used as the lid portion 206.
  • the use of the septum plug 206a is different from the cell transplantation device 200A according to the sixth embodiment in which the form of the lid 206 is not specified.
  • the other components of the cell transplantation device 200D according to the ninth embodiment are the same as those of the sixth embodiment, and therefore the description thereof will be omitted and only the differences will be described.
  • the oxygen generating material container 201 uses the septum plug 206a as the lid 206 and directly accommodates the oxygen generating material 205 (chemical reaction agent). doing. Therefore, when removing the oxygen generating material 205 of the oxygen generating material storage unit 201, this can be done by puncturing the septum plug 206a with an injection needle and sucking the oxygen generating material 205. Further, in the cell transplantation device 200D according to the ninth embodiment, when the oxygen generating material 205 of the oxygen generating material containing portion 201 is replaced, for example, the injection needle is pierced into the septum plug 206a to suck the oxygen generating material 205.
  • the cell transplantation device 200D according to the ninth embodiment has such an aspect, it is particularly suitable when the oxygen generating material 205 (chemical reaction agent) is in a liquid state.
  • the cell transplantation device 200D according to the ninth embodiment can also be suitably applied to the powdery oxygen generating material 205 (chemical reaction agent).
  • the septum plug 206a may be made of a material such as polytetrafluoroethylene or polyethylene.
  • FIG. 17 is a schematic cross-sectional view illustrating the tenth embodiment of the cell transplantation device.
  • the cell transplantation device 200E according to the tenth embodiment and the cell transplantation device 200A according to the sixth embodiment are the same as those of the cell transplantation device 200E according to the tenth embodiment.
  • the use of the electrolyzing member 220 that electrolyzes water to generate oxygen is different from the cell transplantation device 200A according to the sixth embodiment that uses a chemical reaction agent as the oxygen generating material 205. That is, the tenth embodiment employs another mode in which the chemical reaction agent is not used in the present invention.
  • a cell transplantation device 200E includes an electrolyzing member 220 in the oxygen generating material storage portion 201.
  • the electrolysis member 220 is formed of, for example, a battery 2221 and a cathode 223 and an anode 224 connected to the battery 2221.
  • the electrolysis member 220 contains these components in a rigid cartridge 225.
  • the electrolysis member 220 has, for example, a water storage section 226 for storing water inside the hard cartridge 225.
  • the cathode 223 and the anode 224 are provided so as to be exposed in the water storage section 226, and the battery 221 for supplying electricity to the cathode 223 and the anode 224 is provided separately in the hard cartridge 225 so as not to come into contact with water. ..
  • the water used in the electrolysis member 220 sterilized water or the like may be stored in the water storage unit 226 in advance and used.
  • semipermeable membranes 227a and 227b are respectively provided in a part of the oxygen generating material accommodating part 201 and a part of the water storage part 226, through which water of biological origin is stored in the water storage part 226. May be used for electrolysis.
  • oxygen can be supplied to the cells 208 in the cell transplantation device 200E.
  • hydrogen generated by electrolysis diffuses out of the device through the semipermeable membranes 227a and 227b and/or through the emission unit 209.
  • the hydrogen diffused into the blood from the discharge part 209 is expected to be carried in the blood or to any place in the body to reduce active oxygen and render it harmless, which is useful for improving various diseases and preventing aging. it is conceivable that.
  • the hard cartridge 225 can be formed of a conventionally known resin or metal.
  • the cathode 223 and the anode 224 any one made of metal can be used.
  • the semipermeable membranes 227a and 227b those mentioned in the sixth embodiment can be used.
  • a preferable oxygen partial pressure when oxygen generated from the electrolysis member 220 reaches the cells 208 is 0.01 atm to 0.4 atm, and more preferably 0.05 atm for the same reason as in the case of the chemical reaction agent. Is about 0.2 atm.
  • FIG. 18 is a schematic cross-sectional view illustrating the eleventh embodiment of cell transplantation device.
  • the cell transplantation device 200F according to the eleventh embodiment and the cell transplantation device 200A according to the sixth embodiment are the same as those of the cell transplantation device 200F according to the eleventh embodiment.
  • the accommodation unit 201 and the cell accommodation unit 202 are provided in separate housings 204a and 204b, which is different from the cell transplantation device 200A according to the sixth embodiment in which they are provided in one housing 204. ing.
  • an oxygen generating material container 201 and a cell container 202 are provided in separate housings 204a and 204b, and these are hollow tubes. It is connected by the oxygen transfer unit 203 composed of. That is, in the cell transplantation device 200F according to the eleventh embodiment, oxygen generated in the oxygen generating material containing portion 201 is delivered to the cell containing portion 202 via the oxygen delivering portion 203 formed of a hollow tube.
  • Both of the housings 204a and 204b are circular or polygonal tubular bodies in a plan view, and may have a bottomed tubular shape.
  • the oxygen transfer part 203 in the eleventh embodiment preferably has airtightness so that oxygen in the hollow tube is not diffused to the outside.
  • the length of the oxygen transfer part 203 in the eleventh embodiment can be arbitrarily set as required. Therefore, in the cell transplantation device 200F according to the eleventh embodiment, for example, the cell containing portion 202 is installed deep inside the body, and the entire oxygen generating material containing portion 201 or a part of the oxygen generating material containing portion 201 (for example, The lid portion 206) can be provided by being exposed outside the body. With this configuration, the oxygen generating material 205 in the oxygen generating material accommodating portion 201 can be easily taken out by opening and closing the lid 206 outside the body.
  • the oxygen generating material 205 in the oxygen generating material accommodating portion 201 can be easily replaced.
  • it may be exposed to the outside of the body at any position of the oxygen transporting portion 203. By doing so, the invasive area can be reduced, and the QOL of the patient is less likely to decrease.
  • the oxygen transporting portion 203 in the eleventh embodiment can be formed of, for example, polyurethane, polypropylene, polybutylene, or the like, but any material can be used without limitation as long as it is an airtight material that does not diffuse oxygen in the pipe to the outside.
  • the casing 204a of the oxygen generating material storage unit 201 and the casing 204b of the cell storage unit 202 in the eleventh embodiment can be formed of the same material and method as the casing 204 of the cell transplantation device 200A according to the sixth embodiment.
  • the lid portion 206 and the discharge portion 209 in the eleventh embodiment can also be formed of the same material as in the sixth embodiment.
  • a preferable oxygen partial pressure when oxygen generated from the oxygen generating material 205 reaches the cells 208 in the eleventh embodiment is 0.01 atm to 0.4 atm for the same reason as in the sixth embodiment, and more preferable. Is 0.05 atm to 0.2 atm.
  • the cell transplantation devices 200A to 200F according to the sixth to eleventh embodiments described above can be used for animals such as humans, cows, pigs, mice and rats.
  • the cell transplantation devices 200A to 200F include the oxygen generating material container 201, the cell container 202, and the oxygen transfer part 203 described above, transplantation is performed. It is possible to improve the survival time of the cells and tissues in the body. Further, in the cell transplantation devices 200A to 200F described above, since the oxygen generating material container 201 includes the lid 206, the oxygen generating material 205 can be easily taken out and replaced, and the patient's QOL is improved. Hard to drop.
  • FIG. 19 is a flow chart illustrating an embodiment of a method of taking out an oxygen generating material of a cell transplantation device (hereinafter, may be simply referred to as “takeout method”).
  • the takeout method according to the present embodiment is a method for taking out the oxygen generating material 205 of the cell transplantation devices 200A to 200F described above. Therefore, the components of the cell transplantation devices 200A to 200F have already been described, and detailed description thereof will be omitted.
  • the takeout method according to the present embodiment includes a lid opening step S1, a takeout step S2, and a lid closing step S3, and these steps are performed in this order.
  • the lid opening step S1 is a step of opening at least a part of the lid 206.
  • the taking out step S2 is a step of taking out the oxygen generating material 205 from the opened portion of the lid portion 206 after the lid opening step S1.
  • the lid closing step S3 is a step of closing the opened portion of the lid portion 206 after the extracting step S2.
  • the oxygen generating material 205 can be taken out from the oxygen generating material accommodation section 201 of the cell transplantation devices 200A to 200F by performing these steps S1 to S3. In this case, it may be sufficient to use the oxygen generating material 205 only once, and in such a case, the taking-out method according to the present embodiment is effective.
  • the first dose of the oxygen generating material 205 sufficiently promotes angiogenesis around the device, and after removing the oxygen generating material 205, oxygen and nutrients from the newly formed blood vessels are generated.
  • the case where the cells 208 in the cell housing portion 202 can survive by supplying the components can be mentioned. In the present embodiment, it is preferable to appropriately sterilize before and after these steps, but it is not limited to this as long as infectious diseases can be prevented.
  • FIG. 20 is a flow chart illustrating an embodiment of a method for exchanging oxygen generating material of a cell transplantation device (hereinafter, may be simply referred to as “exchange method”).
  • the replacement method according to the present embodiment is a method for replacing the oxygen generating material 205 of the cell transplantation devices 200A to 200F described above. Therefore, the components of the cell transplantation devices 200A to 200F have already been described, and detailed description thereof will be omitted.
  • the replacement method according to the present embodiment includes a lid opening step S11, a removal step S12, a housing step S13, and a lid closing step S14, and these steps are performed in this order.
  • the lid opening step S11 and the take-out step S12 in the exchange method according to the present embodiment are the same as the lid opening step S1 and the take-out step S2 in the above-mentioned take-out method. Further, the lid closing step S14 in the exchanging method according to the present embodiment and the lid closing step S3 in the above-described taking-out method are performed after the lid closing step S14 after the accommodation step S13, whereas the lid closing step S3 takes out the taking step S2. Only the points to be performed later are different, and the others are the same. Therefore, detailed description of the lid opening step S11, the takeout step S12, and the lid closing step S14 in the replacement method according to the present embodiment will be omitted, and the accommodating step S13 will be described.
  • the accommodating step S13 is a step of accommodating the replacement oxygen generating material 205 in the oxygen generating material accommodating portion 201 after the extracting step S12.
  • the oxygen generating material 205 stored in the oxygen generating material storage portion 201 can be replaced with a new replacement oxygen generating material 205. it can. Therefore, by performing the exchange method according to this embodiment, the survival time of the transplanted cells/tissue in the body can be improved.
  • the oxygen release materials shown below are for supplying oxygen to transplanted cells.
  • the cells in the cell capsule (cell transplantation device) are stored at a high density and are relatively distant from the blood vessel. Therefore, when applied to cells with high oxygen demand, oxygen supply from the outside of the device is desirable for long-term cell survival.
  • An oxygen sustained release material for a cell device preferably has the following three characteristics, but an oxygen sustained release material satisfying all of these has not been realized so far.
  • the first point is that oxygen can be generated without supplying a substance from the outside.
  • an oxygen sustained-release material that supplies a substance from the outside the effect depends on the external environment, and the same effect cannot always be expected.
  • an oxygen sustained-release material having a self-reactive property such that the intended reaction is completed only by the composition of the oxygen sustained-release material can be expected to have the same effect without depending on the external environment or the implantation site.
  • the second point is that oxygen can be supplied smoothly. Excessive oxygenation carries the risk of cell damage by reactive oxygen species produced by high partial pressures of oxygen. On the other hand, an oxygen sustained-release material that smoothly supplies oxygen can be expected to avoid this risk.
  • the third point is that highly toxic by-products are not generated. Oxygen sustained-release materials that produce highly toxic by-products carry the risk of leakage of the by-products when the device is damaged. On the other hand, it is expected that this risk can be avoided with an oxygen sustained release material having a composition that produces only by-products that do not adversely react with body fluids.
  • the oxygen sustained release material according to one embodiment of the present invention contains at least a metal peroxide.
  • the concentration of the substantially reactive weak acid existing in the system is kept constant, and the reaction between the metal peroxide and the weak acid is kept constant.
  • smooth oxygen generation can be realized.
  • a method therefor for example, as a first mode, a method of keeping the rate of dissolution of a poorly soluble weak acid in the system at a low constant value, and as a second mode, lowering the diffusion rate of the weak acid in the system.
  • a method of slowing the reaction between a weak acid and a metal peroxide as a third mode, a method of keeping the reaction rate low and constant when chemically generating a weak acid from a weak acid precursor capable of inducing a weak acid, Alternatively, a combination thereof may be considered.
  • the reaction similar to the reaction using a weak acid can be realized by using a strong acid or a precursor of a strong acid, but there is a risk of safety due to an unreacted strong acid or a precursor of a strong acid.
  • the metal peroxide is a peroxide of a group 1 metal, a group 2 metal, or a fourth-period transition metal, and a peroxide that is not extremely toxic to cells or living organisms is preferable.
  • metal peroxides are selected from the group consisting of calcium peroxide, magnesium peroxide, zinc peroxide, nickel peroxide, lithium peroxide, sodium peroxide, potassium peroxide, barium peroxide, and strontium peroxide.
  • the above metal peroxide has no extreme toxicity to cells or living bodies.
  • the metal peroxide calcium peroxide or magnesium peroxide is preferable from the viewpoint of safety to the living body.
  • the metal peroxide may contain only one kind alone, or may contain two kinds or more as a mixture.
  • the oxygen sustained release material according to one embodiment of the present invention can reduce the required amount as the oxygen sustained release amount per volume is higher, and can reduce the size of the cell transplantation device. Therefore, in the present invention, the amount of the metal peroxide is preferably 5% by weight or more and 50% by weight or less based on the total weight of the oxygen sustained release material.
  • the ratio of the amount of the substance capable of dissociating the weak acid to the amount of the substance of the metal peroxide is preferably 0.5 or more and 5 or less.
  • oxygen sustained release material oxygen is smoothly generated by maintaining a low concentration of a weak acid that comes into contact with a metal peroxide during use. If the weak acid concentration is too high, it becomes difficult to generate smooth oxygen and secure a sufficient sustained release period, but if the weak acid concentration is too low, substantial oxygen generation cannot be obtained, so the weak acid concentration is It is preferably 1.0 ⁇ M or more and 1000 mM or less in the liquid phase at 37° C.
  • the pKa of the weak acid is preferably 3 or more and 13 or less.
  • the lower limit of the pKa of the weak acid is 3 or more in terms of safety to the living body.
  • the upper limit of the pKa of the weak acid is substantially 13 or less as the pKa capable of protonating hydrogen peroxide having a pKa of about 12 from the viewpoint of chemical equilibrium.
  • the pKa of the weak acid used in the present invention is more preferably 3.5 or more and 12 or less, still more preferably 4 or more and 10 or less.
  • Valence of weak acid is not limited.
  • ⁇ Weak acid preferably has a structure that does not easily react with hydrogen peroxide.
  • the structure that easily reacts with hydrogen peroxide is, for example, a CC double bond, a CC triple bond, an aldehyde or a ketone.
  • Examples of the weak acid include carboxylic acid, phosphoric acid conjugate base, and sulfuric acid conjugate base.
  • weak acids are acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, OEG carboxylic acid, PEG carboxylic acid, succinic acid, malonic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, maleic acid, (-)-O-acetyl-L-malic acid, diglycolic acid , Poly(maleic anhydride) hydrolyzate or alcoholysis product, polyacrylic acid, polymethacrylic acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, sulfuric acid Examples thereof include sodium hydrogen, potassium hydrogen sulfate, ammonium hydrogen phosphat
  • Examples of the carboxylic acid include a monovalent or divalent carboxylic acid of a saturated hydrocarbon having a C1-C18 linear or branched structure, and methylene which is a part of a saturated hydrocarbon having a C1-C18 linear or branched structure.
  • the carboxylic acid as a weak acid, the conjugate base of phosphoric acid, and the conjugate base of sulfuric acid have a structure that is difficult to react with hydrogen peroxide.
  • the weak acid may contain only one kind alone, or may contain two or more kinds as a mixture.
  • the oxygen-releasing material can include a dispersion medium.
  • the dispersion medium preferably has low toxicity from the viewpoint of risk at the time of leakage.
  • polyalkylene glycols such as oligoalkylene glycol, polyethylene glycol dimethyl ether, polyethylene glycol lauryl ether, or polypropylene glycol, polyisobutylene, polydimethylsiloxane, or any of them is used.
  • examples thereof include derivatives in which a hydrogen atom is substituted with a C1-C18 alkyl group, an alkoxy group, an acyl group, or a copolymer containing them as a partial structure.
  • the low molecular weight compound include water, ethanol and isopropyl alcohol.
  • dispersion medium facilitates the control of the reaction between the metal peroxide and the weak acid, as described below.
  • the dispersion medium may contain only one kind alone, or may contain two or more kinds as a mixture.
  • the guidelines for controlling the affinity include, for example, using a hydrophobic dispersion medium for a weak hydrophilic acid and using a hydrophilic dispersion medium for a weak hydrophobic acid.
  • sodium dihydrogen phosphate is used as the weak acid
  • polyethylene glycol dimethyl ether (average molecular weight 250)/water (90/10% by weight) is used as the dispersion medium. Combinations can be mentioned.
  • viscosity is one of the factors that govern the speed with which molecules move, and the higher the viscosity, the slower the diffusion rate.
  • the diffusion rate control can be realized.
  • a highly viscous dispersion medium or a dispersion medium containing a thickening agent can be used.
  • the dispersion medium in the second mode includes a mixture of polyethylene glycol (average molecular weight 250) and polyethylene glycol (average molecular weight 10000), polyisobutylene, and the like.
  • a protic compound to be reacted with the weak acid precursor for example, the concentration of water or alcohol is used.
  • the concentration of water or alcohol is used.
  • a carboxylic acid anhydride or a carboxylic acid chloride is used as the weak acid precursor, and the weak acid precursor is hydrolyzed (that is, the protic compound is water) or added.
  • the weak acid precursor is hydrolyzed (that is, the protic compound is water) or added.
  • Examples include a reaction of obtaining a carboxylic acid that is a weak acid by alcoholysis (that is, the protic compound is alcohol).
  • the protic compound is water
  • water that is a by-product of the decomposition of hydrogen peroxide can be used in the reaction, and thus the protic compound water can be catalytically reused.
  • the rate of the weak acid generated from the weak acid precursor in the system can be made almost constant.
  • the above-mentioned weak acid anhydrides or chlorides can be used as the weak acid precursor.
  • carboxylic acid anhydrides include acetic acid anhydride, propionic acid anhydride, butyric acid anhydride, valeric acid anhydride, caproic acid anhydride, enanthic acid anhydride, caprylic acid anhydride, pelargonic acid anhydride, capric acid.
  • Acid anhydrides lauric acid anhydrides, myristic acid anhydrides, palmitic acid anhydrides, non-cyclic acid anhydrides such as margaric acid anhydrides or stearic acid anhydrides, succinic acid anhydrides, malonic acid anhydrides, glutaric acid Anhydride, adipic acid anhydride, pimelic acid anhydride, suberic acid anhydride, azelaic acid anhydride, sebacic acid anhydride, phthalic acid anhydride, maleic acid anhydride, (-)-O-acetyl-L-malic acid Examples thereof include anhydrides, cyclic acid anhydrides such as diglycolic acid anhydride, and derivatives in which any hydrogen atom thereof is substituted with a C1-C18 alkyl group, alkoxy group, or acyl group.
  • examples of the weak acid precursor include an acid anhydride or acid chloride of a monovalent or divalent carboxylic acid of a saturated hydrocarbon having a C1-C18 straight chain or branched structure, and a C1-C18 straight chain or branched chain.
  • Examples thereof include acid anhydrides or acid chlorides of divalent carboxylic acids, acid anhydrides or acid chlorides of polymer compounds having a carboxylic acid group in a side chain, and inorganic or organic acidic oxides.
  • a weak acid can be obtained by the reaction between the weak acid precursor and a protic compound such as water or alcohol.
  • the acid anhydride may contain only one kind alone, or may contain two or more kinds as a mixture.
  • An example of the third mode is a method using capric anhydride as a weak acid precursor and water as a protic compound.
  • Capric acid is slowly produced from the hydrolysis reaction of capric anhydride and water, while water is regenerated from the decomposition of hydrogen peroxide produced by the reaction between the metal peroxide and capric acid.
  • the hydrolysis reaction between the acid anhydride and water proceeds at a substantially constant rate. If the amount of water added as a protic compound is small, it is possible to keep the weak acid low.
  • water is produced from the reaction of a metal peroxide, for example, calcium peroxide and a weak acid, Since this water catalytically promotes the hydrolysis reaction of the acid anhydride as described above, it is not necessary to include water in advance.
  • a metal peroxide for example, calcium peroxide and a weak acid
  • the oxygen sustained release material can control the initiation of oxygen generation by utilizing the melting point (or softening point in some cases) of the constituent composition.
  • the oxygen sustained release material At the temperature below the melting point, the oxygen sustained release material has no fluidity and the reaction does not proceed, and at the temperature above the melting point, the oxygen sustained release material has the fluidity and the reaction proceeds. It can also be combined. In such a case, it is preferable that the composition has no fluidity at a storage temperature in a practical range and has fluidity near a body temperature which is a use temperature.
  • Such behavior can be realized by setting the melting point of the dispersion medium, the weak acid, the weak acid precursor, the protic compound, etc. within an appropriate range.
  • the melting point is 25° C. to 37° C., and it is most assumed that it has no fluidity at room temperature and fluidity at body temperature.
  • the preferable melting point is ⁇ 196° C. or higher.
  • the preferable melting point is 50°C or lower.
  • a more preferable melting point is ⁇ 79° C. or higher and 45° C. or lower, and a still more preferable melting point is ⁇ 30° C. or higher and 40° C. or lower.
  • polyethylene glycol dimethyl ether polyether such as polyethylene glycol, dimethyl succinate, etc.
  • polyether such as polyethylene glycol, dimethyl succinate, etc.
  • the melting point of a weak acid caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid or the like can be used.
  • caprylic anhydride, pelargonic anhydride, capric anhydride, lauric anhydride, myristic anhydride, 2,2-dimethylsuccinic anhydride, etc. can be used. ..
  • water, ethanol or the like can be used.
  • the oxygen sustained-release material is self-reactive, which does not depend on external supply of a substance required for oxygen generation, can supply oxygen smoothly over a long period of time, and has high toxicity. No by-products are produced. That is, the oxygen sustained release material of the present invention has few restrictions on the method of use and is highly safe. Therefore, it is possible to realize the transplantation of cells or living tissue using the oxygen-degrading material of the present invention, and further it is possible to realize a cell transplantation device or a living tissue transplantation device having a long-term therapeutic effect.
  • a housing for example, by using the oxygen sustained-release material of the present invention, a housing, the oxygen sustained-release material of the present invention disposed in the housing, preferably at the bottom of the housing, and a gap on the oxygen sustained-release material are provided. It is possible to prepare a cell transplantation device including an oxygen permeable membrane arranged in the gap and cells or living tissue arranged on the oxygen permeable membrane.
  • FIG. 21 shows the result of the amount of oxygen measured in Example 1.
  • FIG. 22 shows the result of the amount of oxygen measured in Example 3.
  • FIG. 23 shows a cell evaluation device equipped with the present invention.
  • the cell evaluation device includes an oxygen sustained release material 301 for supplying oxygen to the cells at the bottom of the device, a gap 302 for uniformly distributing oxygen generated from the oxygen sustained release material, and oxygen generated by the oxygen sustained release material. It is composed of an oxygen permeable membrane 303 supplied to cells from the lower part, an evaluation V79 cell 304 on the upper part of the device and a cell culture solution 305, and a casing 306 supporting the entire device.
  • FIG. 24 shows a cell evaluation device in which the present invention is not mounted.
  • Example 1 an oxygen sustained-release material was prepared based on a method (first mode) of keeping the rate of dissolution of a poorly soluble weak acid in the system at a low level.
  • Example 2 an oxygen sustained-release material was prepared based on a method (second mode) of slowing the reaction of a weak acid with a metal peroxide by reducing the diffusion rate of the weak acid in the system.
  • Calcium peroxide as a metal peroxide, sodium dihydrogen phosphate as a weak acid, polyethylene glycol polyethylene glycol (average molecular weight 1000)/polyethylene glycol (average molecular weight 10000)/water (90/5/5 wt%) as a high-viscosity dispersion medium was used to keep the proton diffusion rate low.
  • 0.3 g of calcium peroxide, 0.6 g of sodium dihydrogen phosphate, 1.0 mL of polyethylene glycol (average molecular weight 1000)/polyethylene glycol (average molecular weight 10000) (90/10 wt%) were uniformly mixed, and at 37°C. When the amount of oxygen generated was quantified, it was confirmed that almost uniform oxygen was generated over 7 days, which is longer than that in Example 1 having a relatively low viscosity.
  • Example 3 an oxygen sustained-release material was prepared based on the method (third mode) of keeping the reaction rate low and constant when a weak acid is chemically generated from a weak acid precursor.
  • the generation rate of the weak acid was kept low by using calcium peroxide as the metal peroxide, capric anhydride as the weak acid precursor, and water as the protic compound.
  • calcium peroxide As the metal peroxide
  • capric anhydride As the weak acid precursor
  • water as the protic compound.
  • 0.3 g of calcium peroxide, 1.6 g of capric anhydride and 30 ⁇ L of water were uniformly mixed and the amount of oxygen generated at 37° C. was quantified, almost uniform oxygen generation was confirmed over 5 days (FIG. 22). ..
  • Example 4 an oxygen sustained-release material was prepared based on the method (third mode) of keeping the reaction rate low and constant when a weak acid is chemically generated from a weak acid precursor.
  • the generation rate of the weak acid was kept low by using calcium peroxide as the metal peroxide, succinic anhydride as the weak acid precursor, and polyethylene glycol dimethyl ether (average molecular weight 1000)/water (95/5% by weight) as the dispersion medium. .. 0.3 g of calcium peroxide, 0.5 g of succinic anhydride, and 1.0 mL of polyethylene glycol dimethyl ether (average molecular weight 1000)/water (95/5 wt%) were uniformly mixed, and the amount of oxygen generated at 37° C. was quantified. However, almost uniform generation of oxygen was confirmed over 7 days.
  • Example 5 V79 cell culture using the sustained-release oxygen material of the present invention was examined (FIG. 23).
  • V79 cells were seeded on a device as shown in FIG. 3 and cultured under anoxic conditions. The survival rate of V79 was 80%, which was a good value.
  • Comparative Example 1 In Comparative Example 1, a combination of metal peroxide and water (pKa15.7) was examined.
  • Comparative example 2 In Comparative Example 2, conditions under which the reactive weak acid concentration existing in the liquid phase was too high were examined. When 0.3 g of calcium peroxide and 1 g of acetic acid were uniformly mixed to prepare a mixture containing a weak acid of 15 M, and the amount of oxygen generated at 37° C. was quantified, the generation of oxygen for 30 minutes or longer was not confirmed.
  • V79 cells were seeded in a device as shown in Fig. 24 without using an oxygen-sustained release material and cultured under anoxic conditions, the survival rate of V79 after 7 days was a low value of 10%.
  • the present invention is not limited to the above embodiment, and various modifications are included.
  • the above-described embodiments have been described in detail in order to explain the present invention in an easy-to-understand manner, and are not necessarily limited to those having all the configurations described.
  • a part of the configuration of a certain embodiment can be replaced with the configuration of another embodiment, and the configuration of a certain embodiment can be added to the configuration of another embodiment.
  • the oxygen-controlled release materials 102 having different characteristics in combination.
  • a combination of a sustained release material capable of releasing a small amount of oxygen for a long period of time and a sustained release material capable of releasing a large amount of oxygen for a short period of time is used.
  • the oxygen adsorbing material tends to release a large amount of oxygen in the initial stage, so that oxygen is first supplied by the oxygen adsorbing material in the initial stage. After the time when the amount of oxygen released from the oxygen adsorbing material begins to decrease, oxygen is released from the peroxide by supplying water. This makes it possible to control the oxygen supply amount over time while maintaining the absolute amount of oxygen supply.
  • the origin, type, phenotype, presence or absence of gene modification, passage number, etc. of the cell 101 are not limited.
  • the nature and morphology of the cells 101 such as floating cells, adherent cells, single cells, sheets, and organoids are not limited.
  • the use of the cell 101 is also not limited. That is, the present invention can be applied to any cell that can be held by the cell holding carrier 103 and stored in the container 104.
  • the effect of the present invention can be most effectively exerted on the cells 101 that require a large amount of oxygen.
  • human pancreatic cells are considered as an example, but the present invention is not limited to this.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Botany (AREA)
  • Dispersion Chemistry (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Le but de la présente invention est de fournir une technique selon laquelle une quantité adéquate d'oxygène peut être fournie de manière stable pendant une longue période à des cellules/tissus transplantés par des capsules de cellule. Une capsule de cellule de la présente invention est pourvue d'une structure pour fournir une quantité adéquate d'oxygène à des cellules, à l'aide d'un matériau à libération prolongée d'oxygène.
PCT/JP2019/048959 2018-12-28 2019-12-13 Capsule de cellule, dispositif de transplantation cellulaire, méthode d'extraction de matériau de génération d'oxygène de dispositif de transplantation cellulaire, méthode de remplacement de matériau de génération d'oxygène de dispositif de transplantation cellulaire, et matériau à libération prolongée d'oxygène Ceased WO2020137628A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2018246947A JP2020103713A (ja) 2018-12-28 2018-12-28 細胞カプセル
JP2018-246947 2018-12-28
JP2019037561A JP2020137495A (ja) 2019-03-01 2019-03-01 細胞移植デバイス、細胞移植デバイスの酸素発生材取り出し方法および細胞移植デバイスの酸素発生材交換方法
JP2019-037561 2019-03-01
JP2019-065623 2019-03-29
JP2019065623A JP2020164452A (ja) 2019-03-29 2019-03-29 細胞移植用酸素徐放材

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01138104A (ja) * 1987-11-25 1989-05-31 Meiwa Kouyu Kk 酸素発生剤
WO2013023013A1 (fr) * 2011-08-09 2013-02-14 Wake Forest University Health Sciences Encapsulation combinée de cellules vivantes avec des particules produisant de l'oxygène
WO2017024076A1 (fr) * 2015-08-04 2017-02-09 The Regents Of The University Of California Dispositif de transplantation de cellules
US20170239391A1 (en) * 2016-02-08 2017-08-24 Beta-O2 Technologies Ltd. Systems and methods for providing oxygen to transplanted cells
JP2017222566A (ja) * 2016-06-10 2017-12-21 宇部マテリアルズ株式会社 酸素徐放剤及びその製造方法並びに酸素供給方法

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Publication number Priority date Publication date Assignee Title
JPH01138104A (ja) * 1987-11-25 1989-05-31 Meiwa Kouyu Kk 酸素発生剤
WO2013023013A1 (fr) * 2011-08-09 2013-02-14 Wake Forest University Health Sciences Encapsulation combinée de cellules vivantes avec des particules produisant de l'oxygène
WO2017024076A1 (fr) * 2015-08-04 2017-02-09 The Regents Of The University Of California Dispositif de transplantation de cellules
US20170239391A1 (en) * 2016-02-08 2017-08-24 Beta-O2 Technologies Ltd. Systems and methods for providing oxygen to transplanted cells
JP2017222566A (ja) * 2016-06-10 2017-12-21 宇部マテリアルズ株式会社 酸素徐放剤及びその製造方法並びに酸素供給方法

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ALEMDAR, N. ET AL.: "Oxygen-generating Photo-Cross-Linkable Hydrogels Support Cardiac Progenitor Cell Survival by Reducing Hypoxia-Induced Necrosis", ACS BIOMATER SCI ENG, vol. 3, 2016, pages 1964 - 71, XP055540147, ISSN: 2373-9878, DOI: 10.1021/acsbiomaterials.6b00109 *
BARKAI, U., ROTEM AVI, DE VOS PAUL: "Survival of encapsulated islets: More than a membrane story, World J Transplant", WORLD JOURNAL OF TRANSPLANTATION, vol. 6, no. 1, 24 March 2016 (2016-03-24), pages 69 - 90, XP055568276, ISSN: 2220-3230 *
EUN MI LEE, JI‐IN JUNG, ZAHID ALAM, HEE‐GYEONG YI, HEEJIN KIM, JIN WOO CHOI, SUNGHOON HURH, YOUNG JUNE KIM, JONG CHEOL JEO: "Effect of an oxygen-generating scaffold on the viability and insulin secretion function of porcine neonatal pancreatic cell clusters", XENOTRANSPLANTATION, vol. 25, no. 2, 10 January 2018 (2018-01-10) - March 2018 (2018-03-01), pages e12378, XP055503037, ISSN: 1399-3089 *
MCQUILLING, J.P . ET AL.: "Applicaitons of particulate oxygen-generating substances (POGS) in the bioartificial pancreas", BIOMATER SCI, vol. 5, no. 12, 21 November 2017 (2017-11-21), pages 2437 - 2447, XP055723153, ISSN: 2047-7830 *
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