WO2022092198A1 - 免疫隔離デバイス - Google Patents

免疫隔離デバイス Download PDF

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Publication number
WO2022092198A1
WO2022092198A1 PCT/JP2021/039818 JP2021039818W WO2022092198A1 WO 2022092198 A1 WO2022092198 A1 WO 2022092198A1 JP 2021039818 W JP2021039818 W JP 2021039818W WO 2022092198 A1 WO2022092198 A1 WO 2022092198A1
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Prior art keywords
membrane
layer
hydrogel
immunoisolation
immune
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PCT/JP2021/039818
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English (en)
French (fr)
Japanese (ja)
Inventor
悟朗 小林
雅子 川越
賢 綾野
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Kuraray Co Ltd
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Kuraray Co Ltd
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Priority to CN202180087916.3A priority Critical patent/CN116710155A/zh
Priority to AU2021372119A priority patent/AU2021372119A1/en
Priority to US18/033,974 priority patent/US20230414832A1/en
Priority to CA3200418A priority patent/CA3200418A1/en
Priority to JP2022559228A priority patent/JPWO2022092198A1/ja
Priority to EP21886315.7A priority patent/EP4238591A4/en
Publication of WO2022092198A1 publication Critical patent/WO2022092198A1/ja
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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/36—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
    • 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
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/02—Membranes; Filters
    • 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
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/14—Scaffolds; Matrices

Definitions

  • Immune isolation devices have been developed as a means of performing cell transplantation therapy without the need for administration of immunosuppressive drugs.
  • macroencapsulation immunoisolation devices are capable of identifying transplantation sites and exchanging devices in the event of iPS cell-derived somatic cell transplantation or functional deterioration of transplanted cells, where there is concern about the risk of canceration. It is said to be an effective method.
  • the functions required for a macroencapsulated immunoseparation device are that cells or cell clusters can be dispersed and fixed without being uniformly associated, that oxygen and / or nutritional components can be easily permeated into transplanted cells, and that they are necessary for therapeutic effects.
  • the target physiologically active substances (cytokines, hormones, growth factors, etc.) released by the cells can be easily released according to the cell response, and the immune response cells and the immune response factors are not allowed to permeate, and the cells are transplanted. It is important that the device has excellent biocompatibility and is less likely to cause inflammatory reactions such as adhesion to surrounding tissues and granulation.
  • the present invention provides a macro-encapsulated immuno-isolation device suitable for easy removal of the device in long-term transplantation, no damage to the device, maintenance of immuno-isolation effect, and improvement of diffusion efficiency of physiologically active substances required for transplantation.
  • One purpose is to provide.
  • the present invention has excellent biocompatibility without interfering with the engraftment of implants such as cells and cell clumps, maintains immunoisolation, reduces the diffusion distance in the device, and at the same time improves durability.
  • the other purpose is to provide the invention to be achieved.
  • the present invention provides the following immunological isolation devices.
  • An immunoisolation device comprising an embedding chamber for a transplant to be implanted, wherein the embedding chamber is covered with an immunoisolation membrane.
  • the immunoisolation membrane comprises at least two selected from the group consisting of a fibrous structure, a porous membrane and a hydrogel.
  • the immune isolation membrane is a multi-layered membrane including at least two layers selected from the group consisting of a fibrous structure layer, a porous membrane layer and a hydrogel layer.
  • the immune isolation device according to any one of [1] to [3], wherein the immune isolation membrane suppresses the invasion of immune response cells and immune system humoral factors into the embedding chamber. .. [5]
  • the immune isolation membrane blocks the permeation of immune-responsive cells, the transmittance of insulin and glucose is 50% or more, and the permeability of immune system humoral factors is 30% or less [1].
  • the immunoisolation device according to any one of [4].
  • [10] to [8] include the immunoseparator membrane in which a fiber structure is used as a base material, a polymer raw material is applied to the fiber structure, and a porous film is formed between the short fibers of the fiber structure.
  • the immunoseparator according to any one of the following items.
  • the immunoseparator film is formed by applying a hydrosol solution directly to the fiber structure using the fiber structure as a base material and hydrogelizing the fiber structure by heat, temperature, light or chemical action.
  • the immunological isolation device according to any one of [10].
  • the above-mentioned immunoseparator membrane which comprises a porous membrane as a base material, a hydrosol solution directly applied to the porous membrane, and hydrogelled by heat, temperature, light or chemical action, [1] to The immunoseparation device according to any one of [9].
  • the hydrogel is composed of a polyvinyl alcohol-based polymer.
  • the immunoisolation device according to any one of [1] to [14], wherein the outermost surface of the immunoisolation membrane is composed of an ethylene-vinyl alcohol copolymer.
  • the outermost surface of the immunoisolation membrane is a fiber structure of an ethylene-vinyl alcohol copolymer, and the surface is smoothly compressed.
  • Immune isolation device as described in section.
  • the immunoisolation device according to any one of [1] to [16], wherein the immunoisolation membrane has a thickness of 10 ⁇ m or more and 300 ⁇ m or less.
  • the immune isolation device according to any one of [1] to [17], wherein the thickness of the multilayer layer of the hydrogel constituting the immunoisolation membrane and the porous membrane is 10 ⁇ m or more and 300 ⁇ m or less.
  • the immune isolation device according to any one of [1] to [18], wherein the multi-layer thickness of the fibrous structure constituting the immunoisolation membrane and the porous membrane is 10 ⁇ m or more and 300 ⁇ m or less.
  • the immunological isolation device according to any one of [1] to [19], wherein the multi-layer thickness of the fibrous structure constituting the immunoisolation membrane and the hydrogel is 10 ⁇ m or more and 300 ⁇ m or less.
  • an immunoisolation device that realizes both reduction of diffusion distance effective for improving the transmittance of substances such as physiologically active substances and nutrients and improvement of durability that can withstand long-term transplantation. can.
  • FIG. 1 Perspective view of a bag-shaped immunological isolation device
  • Cross section of tubular immunoisolation device Cross-sectional view of a two-layer immunoisolation membrane consisting of a porous membrane and a non-woven fabric
  • Cross-sectional view of an immunoseparator membrane in which a non-woven fabric and hydrogel are multi-layered Cross-sectional view of an immunoisolation membrane having a three-layer structure consisting of a hydrogel layer, a non-woven fabric layer, and a porous membrane layer.
  • the immunoisolation device of the present invention includes an embedding chamber and an immunoseparation membrane capable of embedding an implant, and the embedding chamber is covered with the immunoseparation membrane to embed immune cells and cytokines. Invasion into the room can be suppressed.
  • the immunoseparator membrane comprises at least two selected from the group consisting of fibrous structures, porous membranes and hydrogels.
  • fiber structure examples include non-woven fabrics, woven fabrics, and knitted fabrics, and non-woven fabrics are preferable.
  • material of the fiber structure gelatin, collagen, chitin, chitosan, fibronectin, dextran, cellulose, polyethylene (PE), polypropylene (PP), polyurethane, polyamide, polyester, polyvinyl alcohol (PVA), ethylene-vinyl alcohol co-weight.
  • PVA modified with monomers such as coalescence, polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, methacrylic-modified PVA, acrylic-modified PVA, polycaprolactone, polyglycerol sebacic acid, polyhydroxyalkanoic acid, poly Examples thereof include butylene succinate, polyvinylene carbonate, cellulose diacetate, cellulose triacetate, methyl cellulose, propyl cellulose, benzyl cellulose, carboxymethyl cellulose, fibroin, silk and the like.
  • the fiber structure layer may be composed of one kind of fiber structure layer, or two or more kinds of fiber structure layers may be laminated to form one fiber structure layer. Further, when the immunoseparation device of the present invention contains two or more kinds of fiber structure layers, the fiber structure layers may be directly laminated, and a porous membrane layer or a hydro may be formed between the two fiber structure layers. A gel layer may be interposed.
  • the thickness of the fiber structure layer is not particularly limited, but is preferably 10 ⁇ m or more and 290 ⁇ m or less, and more preferably 15 ⁇ m to 150 ⁇ m.
  • Hydrosols for producing "hydrogels” include, for example, sol that gels in the presence of metal ions to form a hydrogel, sol that gels in response to temperature to form a hydrogel, and responds to pH. Examples thereof include a sol that gels to form a hydrogel, and a sol that forms a hydrogel in response to light.
  • Metal ions and pH are examples of chemical action. In order to gel these hydrosols, depending on the characteristics of the gel used, metal ions are brought into contact, the temperature is adjusted to the gelling conditions, the pH is adjusted to the gelling conditions, and the light of the gelling conditions is applied. Operations such as irradiating and applying a magnetic field under gelation conditions may be performed.
  • Hydrogels that gel in the presence of metal ions include alginate gels that gel in the presence of divalent or trivalent metal ions, preferably alkaline earth metal ions such as calcium and magnesium ions; calcium ions and / Or a carrageenan gel that gels in the presence of potassium ions; an acrylic acid-based synthetic gel that gels in the presence of sodium ions, and the like.
  • alkaline earth metal ions such as calcium and magnesium ions
  • calcium ions and / Or a carrageenan gel that gels in the presence of potassium ions
  • an acrylic acid-based synthetic gel that gels in the presence of sodium ions, and the like.
  • a temperature-responsive hydrogel obtained by cross-linking poly (N-isopropylacrylamide) with polyethylene glycol, methyl cellulose, hydroxypropyl cellulose, a copolymer of lactic acid and ethylene glycol, and polyethylene glycol.
  • a triblock copolymer of polypropylene oxide (trade name: Pluronic (registered trademark), poloxamer), agarose, polyvinyl alcohol and the like can be mentioned.
  • pH-responsive hydrogel examples include alginate gel, chitosan gel, carboxymethyl cellulose gel, and acrylic acid-based synthetic gel.
  • Photoresponsive hydrogels include synthetic gels that combine azobenzene and cyclodextrin in the skeleton, gels consisting of supermolecules with fumaric acid amide as a spacer, gels that are crosslinked or bonded via a nitrobenzyl group, and modified polyvinyl alcohol. Examples include gels made of.
  • the thickness of the hydrogel layer is not particularly limited, but is preferably 10 ⁇ m to 290 ⁇ m, more preferably 20 ⁇ m to 200 ⁇ m, and further preferably 30 ⁇ m to 100 ⁇ m.
  • the hydrogel layer may be composed of one kind of hydrogel layer, or two or more kinds of hydrogel layers may be laminated to form one hydrogel layer. Further, when the immunoseparation device of the present invention contains two or more hydrogel layers, the hydrogel layers may be directly laminated, and a porous membrane layer or a fiber structure layer may be formed between the two hydrogel layers. It may be intervened.
  • Hydrogel can regulate the transmittance, intensity, etc. of nutritional substances such as glucose, physiologically active substances such as insulin, and humoral factors of the immune system by cross-linking.
  • the "porous film” is a film having a plurality of pores, and the porous film can be confirmed by a scanning electron microscope (SEM) image or a transmission electron microscope (TEM) image of the cross section of the film. ..
  • the thickness of the porous membrane is not particularly limited, but is preferably 15 ⁇ m to 290 ⁇ m, and more preferably 30 ⁇ m to 150 ⁇ m.
  • the average pore size of the porous membrane is not particularly limited, but is preferably 0.01 ⁇ m to 10 ⁇ m, more preferably 0.01 ⁇ m to 5 ⁇ m, and even more preferably 0.01 to 3 ⁇ m.
  • the average pore size can be determined from the SEM image or the TEM image.
  • the maximum pore size of the porous membrane is not particularly limited, but is preferably 0.01 ⁇ m to 10 ⁇ m, more preferably 0.01 ⁇ m to 5 ⁇ m, and further preferably 0.01 ⁇ m to 4 ⁇ m.
  • the maximum pore size is within the above range, the invasion of immune response cells into the embedding chamber is suppressed, and nutritional substances such as carbon sources such as amino acids, vitamins, inorganic salts and glucose, oxygen, carbon dioxide and cytokines. , Hormones, insulin and other physiologically active substances can be sufficiently permeated.
  • the average pore diameter or the maximum pore diameter can be determined from the SEM captured image or the TEM captured image.
  • the porous membrane contains a polymer and is substantially composed of the polymer.
  • the polymer forming the porous membrane is preferably biocompatible.
  • polymers include thermoplastic or thermosetting polymers.
  • the polymer may be biocompatible.
  • Specific examples of the polymer include ethylene-vinyl alcohol copolymer, polysulfone, cellulose acylate such as cellulose acetate, nitrocellulose, sulfonated polysulfone, polyethersulfone, polyacrylonitrile, styrene-acrylonitrile copolymer, and styrene-butadiene copolymer.
  • Ethylene-vinylacetate copolymer saken polyvinyl alcohol, polycarbonate, organosiloxane-polypolypolymer, polyester carbonate, organopolysiloxane, polyphenylene oxide, polyamide, polyimide, polyamideimide, polybenzimidazole, polytetrafluoroethylene (PTFE), etc. Can be mentioned. These may be homopolymers, copolymers, polymer blends, polymer alloys and the like from the viewpoints of solubility, optical properties, electrical properties, strength, elasticity and the like.
  • the polymer constituting the porous membrane may contain a hydrophilic polymer such as polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose and polyethylene glycol. Biocompatibility can be improved by combining a hydrophilic polymer and a hydrophobic polymer.
  • the porous membrane is preferably a membrane formed from one composition as a single layer, and preferably does not have a laminated structure of a plurality of layers.
  • the porous membrane layer may be composed of one kind of porous membrane layer, or two or more kinds of porous membrane layers may be laminated to form one porous membrane layer. Further, when the immunoisolation device of the present invention contains two or more porous membrane layers, the porous membrane layers may be directly laminated, and a hydrogel layer or a fiber structure may be formed between the two porous membrane layers. Layers may be interposed.
  • the permeation of glucose, insulin, immune system humoral factors, etc. in the immunoisolation membrane is a known concentration in chamber A under stirring at 37 ° C. with the porous membrane sandwiched between two glass chambers of the same volume. It can be measured by adding a sample solution of insulin or the like and quantifying the amount of insulin or the like contained in the solution sampled from the chamber B after a certain period of time by using ELISA or the like.
  • the liquid volumes in chambers A and B are adjusted to be equal when the sample solution is placed in chamber A.
  • the transmittance of glucose, insulin, immune system humoral factors, etc. in the immune isolation membrane is the concentration at which the permeation amount of each substance into chamber B measured by the above method after 24 hours reaches an equilibrium, that is, put into chamber A.
  • the permeability of insulin and glucose of the immunoisolation membrane of the present invention is preferably 50% or more, more preferably 90% or more, still more preferably 95% or more.
  • the transmittance of the immune system humoral factor of the immune isolation membrane of the present invention is preferably 30% or less, more preferably 10% or less.
  • the immunoseparator membrane of the present invention contains two or more kinds selected from the group consisting of a fibrous structure, a hydrogel, and a porous membrane, and may contain all three kinds, a fibrous structure, a hydrogel, and a porous membrane. Each form a layer, the boundaries of which may be clearly separated, or the boundaries of the two layers may not be clear, and the two or three types may be integrated to form one layer. May be good.
  • the immunoseparator membrane containing two types of fiber structure and hydrogel may be a multi-layered immunoseparator membrane in which the fibrous structure layer and the hydrogel layer are clearly separated, and the fibrous structure layer and the hydrogel may be used.
  • the fiber structure layer and the hydrogel may be mixed between the layers, or the fiber structure and the hydrogel may be completely integrated to form one layer.
  • the immunoseparator membrane containing two types of fibrous structure and porous membrane may be a multi-layered immunoseparator membrane in which the fibrous structure layer and the porous membrane layer are clearly separated, and the fibrous structure layer and the porous membrane are porous.
  • a layer in which a fiber structure layer and a porous membrane are mixed may be provided between the membrane layers, or the fiber structure and the porous membrane may be completely integrated to form one layer.
  • the immunoseparator membrane containing two types of hydrogel and porous membrane may be a multi-layered immunoseparator membrane in which the hydrogel layer and the porous membrane layer are clearly separated, and the hydrogel layer and the porous membrane layer may be formed.
  • a layer in which a hydrogel layer and a porous membrane are mixed may be provided between them, or the hydrogel and the porous membrane may be completely integrated to form one layer.
  • the immunoisolation membrane has multiple layers, those layers may be adhered by an adhesive, heat, pressure, etc., and if the adjacent layers are made of a highly compatible material, the layers are sequentially formed. It can be adhered by forming.
  • the thickness of the immunoisolation membrane is not particularly limited, but is preferably 10 ⁇ m or more and 300 ⁇ m or less.
  • the tensile strength of the immunoisolation membrane is preferably 1 MPa or more.
  • the tensile strength can be measured according to JIS K 7127; 1999.
  • the outer layer of the immunoisolation membrane may be any of a fibrous structure, a hydrogel, and a porous membrane, and may be a mixture of these two or three types.
  • the inner layer of the immunoisolation membrane may be any of a fibrous structure, a hydrogel, and a porous membrane, and two or three of these may be mixed.
  • the outer layer of the immunoisolation membrane is preferably biocompatible in order to prevent it from being recognized as a foreign substance.
  • the immunoisolation membrane is required to have the permeability necessary to allow sufficient oxygen and nutrients to permeate the internal implant.
  • the introduction of the implant into the embedding chamber may be performed using a device such as a syringe that injects a suspension of the implant, from which an opening is provided in the immunoisolation membrane through which the implant is introduced. It may be introduced into the embedding chamber and then closed to block the invasion of immune response cells and immune system humoral factors through the opening. Since oxygen and nutrients can permeate through immunoisolation membranes other than the openings, the openings can be closed to suppress the permeation of substances, including nutrients.
  • a transplant with reduced function of the embedding chamber is taken out, a new functional transplant is introduced, this operation is repeated, and the immuno-isolation device is repeated.
  • the immuno-isolation device may be used to introduce the implant or the immunoisolation device may be removed with the implant.
  • the immuno-isolated device When an immuno-isolated device is indwelled and only the transplant is exchanged, the immuno-isolated device is provided with a tubular access port that can be accessed from the outside in advance, and the end of the access port is placed externally or subcutaneously for access. It is possible to exchange implants through the port. It is important that the joint between the access port and the device is joined with a highly biocompatible resin such as an ethylene-vinyl alcohol copolymer without leakage.
  • infection control measures are taken by using a sterilized injection needle or catheter under infection control measures, and after the replacement work is completed, sealing the end part with a biocompatible material. It is important to take.
  • the immunoisolation membrane of the present invention Since the immunoisolation membrane of the present invention has sufficient strength, is stably present in the recipient's body, and can suppress the invasion of immunocompetent cells into the embedding chamber, the implantee in the embedding chamber. Invasion into the recipient's body can be suppressed at the same time. Therefore, even if the transplanted product is derived from iPS cells, which may become cancerous, it can be used with confidence.
  • a fiber structure having excellent durability is used as a base material, and a polymer porous film or hydrogel is formed on the fiber structure, or a porous film and hydrogel are formed on the fiber structure.
  • the immunoisolation device of the preferred embodiment of the present invention preferably has a shape-retaining property for having sufficient strength in vivo in the preferred embodiment.
  • immune response cells include macrophages, cytotoxic T cells, natural killer cells, dendritic cells, helper T cells, and examples of immune system humoral factors include antibodies, complement, and cytokines.
  • the immunoisolation device of the preferred embodiment of the present invention is bag-shaped, tubular, cylindrical, square-cylindrical, spherical, cubic, rectangular parallelepiped, sheet-shaped or hollow filament-shaped, and embeds cells for transplantation therein. ..
  • the implant may be a cell, a cell mass, a cell sheet, or a graft, and a bioactive substance such as an enzyme, hormone, cytokine, or drug other than cells can also be used.
  • Preferred cells, cell clumps, and grafts are those that release bioactive substances out of the immunological isolation device. That is, cells, cell masses, and grafts contain cells that produce physiologically active substances.
  • a particularly preferable immunoisolation device of the present invention is composed of any one of the following four types of multilayer structures (i) to (iv).
  • a porous film is formed on the fiber structure using the fiber structure or hydrogel as a base material. or
  • the fiber structure is impregnated with hydrogel to form. or
  • hydrogel is impregnated on the porous membrane. or
  • a porous film is formed and a hydrogel is further formed.
  • the fiber structure, porous membrane and hydrogel are materials with excellent safety and biocompatibility.
  • the control of the material transmittance can be controlled by the pore size of the porous membrane or the strength and degree of cross-linking of the hydrogel.
  • the pore size of the porous membrane should be smaller than the size that does not permeate cells, and hydrogel does not suppress the permeation of physiologically active substances and can suppress the permeation of immune response factors such as cells and antibodies. desirable.
  • the immunoisolation membrane be made of a material with excellent biocompatibility.
  • the biocompatible material is the contact surface of the transplant side, that is, the outermost layer in contact with the transplant site of the recipient.
  • the material having excellent biocompatibility include an ethylene-vinyl alcohol copolymer.
  • the schematic diagram of the device shows a bag-shaped (FIG. 1) or tubular (FIG. 2) molded immune isolation membrane.
  • the sac-shaped device (Fig. 1) uses the multi-layered immunoprotective membranes (a1 and a2) shown below at a fixed distance (a4) to secure space for the embedding chamber, and heat, ultrasonic waves, and high frequencies. , It is molded by welding (a3) with an electron beam or the like. A spacer may be provided to secure a certain distance (a4).
  • the tubular device (Fig. 2) is composed of each immunoseparator membrane (b1, b2, b3) formed into a tubular shape, and the embedding chamber is embedded in the tubular interior (b4), and both ends of the tubular tube are heated. It is molded by welding and sealing with ultrasonic waves, high frequency, electron beam, etc.
  • FIGS. 3-9 the outermost layer is in contact with the transplantation site and the innermost layer is in contact with the embedding chamber.
  • 3 and 4 show the multi-layering of the porous membrane (1) and the fiber structure (2).
  • FIG. 3 has a two-layer structure in which the porous membrane (1) is the outer layer and the fiber structure (2) is the inner layer, the outermost layer (3) is in contact with the transplanted site, and the innermost layer (4) is encapsulated. It touches the buried room.
  • FIG. 4 has a two-layer structure in which the fiber structure (6) is the outer layer and the porous membrane (5) is the inner layer, the outermost layer (7) is in contact with the transplanted site, and the innermost layer (8) is encapsulated. It touches the buried room.
  • FIG. 5 shows a composite layer in which a porous film (10) is directly coated on a base material of a fiber structure (9).
  • the outermost layer surface (11) has a porous film (10) covering the fiber structure (9), and the innermost layer surface (12) is either the porous film (10) or the fiber structure (9). But it's okay.
  • FIG. 6 shows the multi-layering of the porous membrane (13) and the hydrogel (15).
  • the hydrogel (15) is impregnated and immobilized (14) on the porous membrane (13), the outermost layer surface (16) is composed of the porous membrane (10), and the innermost layer surface is the hydrogel (14). It is composed of 17).
  • FIG. 7 shows the multi-layering of the fiber structure (18) and the hydrogel (19).
  • the hydrogel (19) is impregnated and fixed to the fiber structure (18)
  • the outermost layer surface (20) is composed of the fiber structure (18)
  • the innermost layer surface (21) is attached to the hydrogel (19). It is composed of.
  • FIG. 8 shows a composite layer in which the multilayer devices of FIGS. 3 and 7 are composited, and the outermost layer surface (22) is composed of a porous film and the innermost layer surface (23) is composed of hydrogel.
  • FIG. 9 shows a composite layer in which the multilayer devices of FIGS. 5 and 6 are composited, and the outermost layer surface (24) is composed of a porous film and the innermost layer surface (25) is composed of hydrogel.
  • the present invention relates to a transplant device used for cell transplantation therapy and the like, and more particularly to an immunoisolation device for protecting against immune rejection of a transplanted object.
  • the immunoisolation device is supposed to be used mainly for cell transplantation therapy as a product for regenerative medicine, but it can also be applied to transplantation of bioactive substances such as enzymes, hormones and drugs other than cells.
  • the device conceptual diagram has a bag-like or tubular shape, and an object to be transplanted, such as a cell or a cell mass, is embedded as an embedding chamber inside the device.
  • the embedding chamber refers to an object to be transplanted such as a cell or a cell mass uniformly dispersed and fixed to a fixing material inside the embedding chamber.
  • the fixing material may be the above-mentioned hydrogel or hydrosol, or may be a cell scaffold material such as collagen fiber.
  • a person who has been sterilized can be used for all of the hydrosol, hydrogel, and cell scaffold material.
  • the fixation material may be present in an embedding chamber surrounded by an immunoisolation membrane prior to the introduction of the implant, and encloses the implant and the fixation material in an immunoisolation device composed of the immunoisolation membrane. It may be introduced later into the buried room.
  • the immunoseparator membrane of the present invention is a porous membrane alone or a combination of a porous membrane and a fiber structure
  • hydrogel as a fixing material. This is because hydrogels can effectively suppress contact between immune system humoral factors and the implant.
  • the immunoseparator membrane is a multi-layer (two or three layers) in which a porous membrane and / or a fibrous structure and a hydrogel are combined, the hydrogel in the immunoseparator membrane invades the immune system humoral factor.
  • the fixing material may be a hydrogel, and a scaffold material capable of dispersing and fixing an implant other than the hydrogel can be widely used.
  • the embedding chamber can be provided with a role of uniformly immobilizing cells by adjusting a fixing material such as hydrogel, and also preventing the invasion of immune system humoral factors such as antibodies into the implant. ..
  • the immunoisolation membrane shown in FIGS. 3 to 9 is composed of a combination of a plurality of materials shown below.
  • the outermost layer is in contact with the recipient's transplant site tissue and the innermost layer is in contact with the embedding chamber.
  • these immunoisolation membranes they are molded into a bag shape (Fig. 1) or tubular (Fig. 2), and an embedding chamber in which cells or cell masses to be transplanted are fixed is embedded inside, and an immunoisolation device is used. And.
  • 3 and 4 show the multi-layering of the porous membrane (1, 5) and the fiber structure (2, 6). It is an immunoisolation membrane formed by forming a porous membrane layer on a fiber structure layer.
  • the thickness of the multilayer of the fibrous structure constituting the immunoisolation membrane and the porous membrane is not particularly limited, but is preferably 10 ⁇ m or more and 300 ⁇ m or less.
  • FIG. 3 has a two-layer structure in which the porous membrane (1) is the outer layer and the fiber structure (2) is the inner layer, the outermost layer (3) is in contact with the transplanted site, and the innermost layer (4) is encapsulated. It touches the buried room.
  • FIG. 4 has a two-layer structure in which the fiber structure (6) is the outer layer and the porous membrane (5) is the inner layer, the outermost layer (7) is in contact with the transplanted site, and the innermost layer (8) is encapsulated. It touches the buried room.
  • the porous membrane needs to have a function of suppressing cell infiltration from the recipient and preventing leakage of the cells to be transplanted, so that the pore diameter smaller than the cell diameter is preferably 5 ⁇ m or less.
  • the membrane material a material having excellent biocompatibility that does not easily cause adhesion or inflammation with the tissue surrounding the transplantation of the recipient is desirable, and for example, ethylene-vinyl alcohol copolymer or cellulose is desirable.
  • the film thickness of the multi-layered membrane is preferably as thin as possible, 100 ⁇ m or less, considering the material diffusion efficiency of the physiologically active substance from the implant.
  • a fiber structure is made by adhering or entwining fibers by thermal, mechanical or chemical action, and by adjusting the texture (weight per unit area) according to the fiber diameter and amount, in addition to strength, It is possible to control the transmittance and filterability.
  • the basis weight for example, 10 to 200 g / m 2 is preferable, and 50 to 150 g / m 2 is more preferable.
  • the basis weight can be measured by cutting out a fiber structure having a predetermined area and weighing the fiber structure.
  • the fiber structure preferably has an average pore size of 1 to 100 ⁇ m, more preferably 1 to 50 ⁇ m, from the viewpoint of retention of the cell mass to be transplanted.
  • the average pore size can be measured by the method described in JIS K 3832-1990 (test solution: distilled water, test gas: air, method of moistening the test filter: method B).
  • Figure 2. Shows a conceptual diagram in which a porous membrane, which is an outer layer, and a fiber structure are bonded and fixed by thermal, mechanical, or chemical action to form a multi-layered structure.
  • the thickness of the fiber structure is preferably as thin as possible of 100 ⁇ m or less in consideration of the material diffusion efficiency of the physiologically active substance from the implant, but the main purpose of the multi-layered fiber structure is to include a porous membrane. It is necessary to fully consider that it is an improvement in the durability of the immune isolation membrane.
  • the fiber material of the fiber structure a material having excellent biocompatibility is desirable as in the case of the porous film, but in the case of FIG. 3, the contact with the recipient is the porous film which is the outermost layer. Therefore, this does not apply as long as the material does not adversely affect the implant.
  • the outermost layer is a fiber structure, it is desirable that the fiber material of the fiber structure is also a material having excellent biocompatibility. It is also desirable to smooth the surface of the fiber structure by thermal, mechanical or chemical treatment.
  • the material having excellent biocompatibility include an ethylene-vinyl alcohol copolymer.
  • FIG. 5 shows a composite layer in which a porous film (10) is directly coated on a base material of a fiber structure (9).
  • the difference from FIGS. 3 and 4 is not a two-layer structure in which the fiber structure and the porous film are separately prepared and bonded, but a one-layer structure in which the porous film exists in the fiber structure of the fiber structure. It is in the point that it is.
  • a polymer solution is applied onto the base material of the fiber structure, the polymer raw material is solidified by phase separation, which is a phase transition phenomenon, and a porous film is formed between the short fibers of the fiber structure. It becomes possible to form.
  • a fiber structure is used as a base material, and a solution of a porous membrane constituent polymer is applied and impregnated, and then the polymer is exposed to an insoluble poor solvent or a low temperature environment.
  • the porous membrane layer is multi-layered on the surface of the fiber structure or inside the fiber structure.
  • the thickness of the porous membrane is determined by the cloth thickness of the fiber structure, and it is possible to reduce the thickness of the immunoseparator membrane as compared with FIGS. 3 and 4, and at the same time, the fiber structure can be made smaller. It is possible to improve the strength of the porous membrane depending on the strength of the porous membrane.
  • the outermost layer surface (11) has a porous film (10) covering the fiber structure (9), and the innermost layer surface (12) is either the porous film (10) or the fiber structure (9). But it's okay.
  • the fiber material of the fiber structure a material having excellent biocompatibility is desirable as in the case of the porous film, but since the contact with the recipient is the porous film which is the outermost layer, the porous film is a living body.
  • a material having excellent compatibility is desirable, and the fiber structure is not limited to this as long as it is a material that does not adversely affect the implant.
  • FIG. 6 shows the multi-layering of the porous membrane (13) and the hydrogel (15).
  • the hydrogel (15) is impregnated and immobilized (14) on the porous membrane (13), the outermost layer surface (16) is composed of the porous membrane (10), and the innermost layer surface is the hydrogel (14). It is composed of 17).
  • It is an immunoisolation membrane formed by forming a hydrogel layer on a porous membrane layer.
  • the thickness of the multilayer layer of the hydrogel constituting the immunoisolation membrane and the porous membrane is not particularly limited, but is preferably 10 ⁇ m or more and 300 ⁇ m or less.
  • the porous membrane needs to have a function of suppressing cell infiltration from the recipient and preventing leakage of the cells to be transplanted, so that the pore diameter smaller than the cell diameter is preferably 5 ⁇ m or less.
  • the membrane material a material having excellent biocompatibility that does not easily cause adhesion or inflammation with the tissue surrounding the transplantation of the recipient is desirable, and for example, ethylene-vinyl alcohol copolymer or cellulose is desirable.
  • the porous membrane Although cell infiltration and cell leakage can be suppressed by the porous membrane, it is easy to suppress infiltration of immune system humoral factors such as IgG antibody without suppressing the permeability of necessary bioactive substances. Not. Therefore, by adjusting the gel strength or crosslink density of the hydrogel impregnated and fixed in the porous membrane, the infiltration of immune system humoral factors such as IgG antibody is suppressed without suppressing the transmittance of the physiologically active substance. Is possible.
  • Preferred examples of the hydrogel include polyvinyl alcohol-based polymers, chitosan, alginate and the like.
  • a hydrosol solution is directly applied to the porous membrane, and hydrogelization is performed by heat, temperature, light or chemical action to form multiple layers.
  • a polymer solution of a porous film is directly applied, and the polymer raw material is solidified by phase separation, which is a phase transition phenomenon, and the porous film is made into short fibers of a fiber structure. It can be formed between them.
  • a pretreatment for lowering the water content by pre-drying the hydrogel may be required.
  • the outer layer, the porous membrane is preferably made of a material that is more biocompatible than hydrogel, and also plays a role in preventing adhesion of hydrogel to the recipient transplant site tissue and the induction of inflammation.
  • FIG. 7 shows the multi-layering of the fiber structure (18) and the hydrogel (19).
  • the hydrogel (19) is impregnated and fixed to the fiber structure (18), the outermost layer surface (20) is composed of the fiber structure (18), and the innermost layer surface (21) is attached to the hydrogel (19). It is composed of. It is an immunoisolation membrane formed by forming a hydrogel layer on a fiber structure layer.
  • the thickness of the multilayer of the fibrous structure constituting the immunoseparator membrane and the hydrogel is not particularly limited, but is preferably 10 ⁇ m or more and 300 ⁇ m or less.
  • the fiber structure monolayer it is not easy to suppress not only cell infiltration and cell leakage but also the permeability of necessary bioactive substances and the infiltration of immune system humoral factors such as IgG antibody. .. Therefore, by adjusting the gel strength or cross-linking density of the hydrogel impregnated and fixed in the fiber structure, in addition to cell infiltration and cell leakage, like an IgG antibody, without suppressing the permeability of the physiologically active substance. It is possible to suppress infiltration of immune system humoral factors.
  • Preferred examples of the hydrogel include polyvinyl alcohol-based polymers, chitosan, alginate and the like.
  • the polyvinyl alcohol-based polymer can be produced, for example, by saponifying a polyvinyl ester obtained by polymerizing a vinyl ester-based monomer and converting the ester group in the polyvinyl ester into a hydroxyl group.
  • vinyl ester-based monomer examples include vinyl formate, vinyl acetate, vinyl propionate, n-vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl versatic acid, vinyl caproate, vinyl caprilate, and vinyl caprate.
  • Alibi-vinyl esters such as vinyl laurate, vinyl myristate, vinyl palmitate, vinyl stearate, and vinyl oleate; aromatic vinyl esters such as vinyl benzoate and the like.
  • One of these may be used alone or in combination of two or more.
  • the polyvinyl ester is preferably polyvinyl acetate obtained by polymerizing vinyl acetate.
  • the polyvinyl ester may contain a structural unit derived from a monomer other than the vinyl ester-based monomer, if necessary, as long as the effect of the present invention is not impaired.
  • the other monomer include ⁇ -olefins such as ethylene, propylene, n-butyl and isobutylene; acrylic acid or a salt thereof; methyl acrylate, ethyl acrylate, n-propyl acrylate, i-acrylate.
  • Acrylic acid alkyl esters such as propyl, n-butyl acrylate, i-butyl acrylate, t-butyl acrylate, 2-ethylhexyl acrylate, dodecyl acrylate, octadecyl acrylate; methacrylic acid or a salt thereof; methyl methacrylate , Ethyl methacrylate, n-propyl methacrylate, i-propyl methacrylate, n-butyl methacrylate, i-butyl methacrylate, t-butyl methacrylate, 2-ethylhexyl methacrylate, dodecyl methacrylate, octadecyl methacrylate, etc.
  • Alkyl methacrylate esters acrylamide, N-methylacrylamide, N-ethylacrylamide, N, N-dimethylacrylamide, diacetoneacrylamide, acrylamidepropanesulfonic acid or its salts, acrylamidepropyldimethylamine or its salts or quaternary salts, N -Acrylamide derivatives such as methylolacrylamide or derivatives thereof; methacrylamide, N-methylmethacrylate, N-ethylmethacrylate, methacrylate propanesulfonic acid or a salt thereof, methacrylamidepropyldimethylamine or a salt thereof or a quaternary salt, N- Methylamide derivatives such as methylolmethacrylamide or derivatives thereof; N-vinylamide derivatives such as N-vinylformamide and N-vinylacetamide; methylvinyl ether, ethylvinyl ether, n-propylvinyl ether, i-propy
  • the average degree of polymerization of the polyvinyl alcohol polymer in the present specification means the average degree of polymerization measured according to JIS K 6726: 1994 as described above. Specifically, it can be obtained from the ultimate viscosity measured in water at 30 ° C. after saponifying and purifying the raw material PVA.
  • the saponification degree of the polyvinyl alcohol-based polymer is preferably 50 mol% or more, more preferably 60 mol% or more, still more preferably 65 mol% or more, from the viewpoint of improving the water solubility of the polyvinyl alcohol-based polymer.
  • the saponification degree of the polyvinyl alcohol-based polymer is preferably 99 mol% or less.
  • the degree of saponification of a polyvinyl alcohol-based polymer is the vinyl with respect to the total number of moles of structural units (for example, vinyl acetate units) and vinyl alcohol units that can be converted into vinyl alcohol units by saponification in the raw material PVA. It means the ratio (mol%) occupied by the number of moles of alcohol unit, and can be measured according to JIS K 6726: 1994.
  • a compound containing an ethylenically unsaturated group and a glycidyl group in the molecule (for example, glycidyl (meth) acrylate, allyl glycidyl ether, etc.) is added to the hydroxyl group, which is a side chain of the polyvinyl alcohol-based polymer, as a base.
  • a (meth) acryloyl group and / or an allylic group can be introduced.
  • a hydrosol solution is directly applied to the fiber structure, and hydrogelization is performed by heat, temperature, light or chemical action to form a multi-layer.
  • the fiber structure as the outer layer is preferably made of a material having better biocompatibility than hydrogel, and examples thereof include ethylene-vinyl alcohol copolymers. It is also desirable to smooth the surface of the outermost fiber structure by thermal, mechanical or chemical treatment, as it also plays a role in preventing adhesion of the hydrogel to the recipient tissue and the induction of inflammation.
  • FIG. 8 shows a composite layer in which the multilayer devices of FIGS. 3 and 7 are composited, and the outermost layer surface (22) is composed of a porous film and the innermost layer surface (23) is composed of hydrogel.
  • a hydrosol solution is applied to the fibrous structure portion of the composite layer of the porous film and the fibrous structure, and the hydrogel is formed by heat, temperature, light or chemical action to form a multi-layer.
  • the three-layer structure has stronger immunoisolation than the two-layer structure, and the strength as an immunoseparation membrane is also improved.
  • the compatibility between permeability and immunoisolation can be adjusted by adjusting the pore size of the porous membrane, which is the outer layer, and the gel strength and degree of cross-linking of the hydrogel, which is the inner layer.
  • FIG. 9 shows a composite layer in which the multilayer devices of FIGS. 5 and 6 are composited, and the outermost layer surface (24) is composed of a porous film, and the innermost layer surface is composed of (25) and hydrogel.
  • the immunoisolation property becomes stronger and the strength as an immunoseparation membrane is also improved.
  • the compatibility between permeability and immunoisolation can be adjusted by adjusting the pore size of the porous membrane, which is the outer layer, and the gel strength and degree of cross-linking of the hydrogel, which is the inner layer.
  • Example 1 (bonding and multi-layering) 1) A porous film (average pore size 1.8 ⁇ m, maximum pore size 3.4 ⁇ m) formed by a polymer phase separation reaction using a multilayered ethylene-vinyl alcohol copolymer and an ethylene-vinyl alcohol copolymer. It was multi-layered with a non-woven fabric (grain size 51.5 g / m 2 , average pore size 20 ⁇ m) prepared by the melt blow method.
  • a porous membrane is layered on a non-woven fabric that has been sprayed with a mist of dimethyl sulfoxide containing 5 wt% ion-exchanged water on the junction with the porous membrane, and heated at 60 ° C. Pressurized from the non-woven fabric side at a pressure of 200 kg / cm 2 and crimped.
  • a bag-shaped device consisting of a porous membrane and a multi-layer membrane encapsulating mouse fibroblast NIH / 3T3 (2 * 10 6 ) was prepared, placed in a well of a 6-well plate and cultured, and cultured on day 7.
  • a bag-shaped device consisting of a porous membrane and a multi-layer membrane encapsulating mouse fibroblast NIH / 3T3 (2 * 10 6 ) was prepared, placed in a well of a 6-well plate and cultured, and cultured on day 7.
  • Example 2 (impregnated multi-layering) A non-woven fabric prepared by the melt blow method using polypropylene fibers was used as a base material, and a porous film was formed on the non-woven fabric by a polymer phase separation reaction using an ethylene-vinyl alcohol copolymer.
  • a 200 ⁇ m thick polypropylene non-woven fabric was used for the trial production.
  • the tensile strength of the non-woven fabric was 5 MPa.
  • the non-woven fabric is immersed in a dimethyl sulfoxide solution of 20 wt% ethylene-vinyl alcohol copolymer heated to 80 ° C for 90 seconds, and then coagulated liquid DMSO / water 50%, 40 ° C for 15 minutes.
  • a porous film was formed by a phase separation reaction. Due to the impregnation multi-layering, the film thickness was 200 ⁇ m, which was the same as that of the non-woven fabric single layer, and the tensile strength was improved from 1.5 MPa of the porous membrane single layer to 5 MPa.
  • the average pore diameter was 0.1 ⁇ m and the maximum pore diameter was 1.5 ⁇ m.
  • Example 3 (membrane + PVA hydrogel) 1) Multilayering A porous film formed by a polymer phase separation reaction using an ethylene-vinyl alcohol copolymer was layered with a hydrogel containing polyvinyl alcohol as a main component.
  • a 100 ⁇ m thick porous membrane was used for the trial production.
  • water-soluble light so as to be 0.1% by mass with respect to 10% of a polyvinyl alcohol (average polymerization degree 1700, saponification degree 98.0-99.0 mol%, methacryl group modification rate 1.2 mol%) solution modified with a methacryloyl group.
  • a sol dissolved by adding a lithium phosphinic acid salt of phenyl (2,4,6-trimethylbenzoyl) as a radical polymerization initiator was used.
  • This sol was coated on a PET film with a bar coater to a thickness of 200 ⁇ m, a porous film was placed on the sol, and the sol and the porous film were brought into close contact with each other with a laminator. Then, with the sol side facing up, a hydrogel was formed on the porous membrane by irradiating with light of 365 nm at an intensity of 15 mW / cm 2 for 3 minutes.
  • the permeability of glucose was 93.4%
  • the permeability of insulin was 62.8%
  • the permeability of IgG was 2.5% (Table 2).
  • a bag-shaped device in which mouse fibroblasts NIH / 3T3 (2 * 10 6 cells) were encapsulated in the multilayer membrane was prepared, placed in a well on a 6-well plate and cultured, and the culture surface was observed on day 7.
  • the culture surface was observed on day 7.
  • no cell infiltration was observed as in the case of the porous membrane monolayer.
  • the conventional device for embedding the implant in the hydrogel has a lower limit on the thickness of the hydrogel in order to completely embed the implant.
  • a thickness of about 500 ⁇ m is required.
  • a hydrogel having a thickness of 500 ⁇ m was prepared using the above-mentioned polyvinyl alcohol modified with a methacryloyl group and a substance permeability test was performed, the permeability of glucose was 54% and the permeability of insulin was 6.8%. From this, it was confirmed that the composite membrane of the thin layer PVA gel shows higher substance diffusion efficiency than the conventional device.
  • Example 4 (nonwoven fabric + PVA hydrogel) A non-woven fabric prepared by a melt blow method using an ethylene-vinyl alcohol copolymer and a hydrogel containing polyvinyl alcohol as a main component were multi-layered.
  • a 200 ⁇ m thick ethylene-vinyl alcohol copolymer non-woven fabric was used for the trial production.
  • the tensile strength of the non-woven fabric was 5 MPa.
  • the polyvinyl alcohol solution modified with the methacryloyl group described in Example 3 was used for the multi-layering.
  • a hydrogel was formed on the non-woven fabric film by the same method as in Example 3.
  • the permeability of glucose, insulin, and IgG in the multi-layered membrane was measured in the same manner as in the method described in Example 3.
  • the glucose permeability was 95.3% and the insulin permeability was 74.3%.
  • the transmittance of IgG was 19.7% with the non-woven fabric alone, but it could be reduced to 7.8% by multi-layering with hydrogel (Table 3).
  • a bag-shaped device in which mouse fibroblasts NIH / 3T3 (2 * 10 6 cells) were encapsulated in the multilayer membrane was prepared, placed in a well of a 6-well plate and cultured, and the culture surface was observed on day 7.
  • the culture surface was observed on day 7.
  • Example 5 (impregnated double glazing + PVA hydrogel) It is possible to carry out multi-layering of the multi-layer film produced in Example 2 and a hydrogel containing polyvinyl alcohol as a main component. For multi-layering, a hydrogel can be formed on the multi-layer film prepared in Example 2 by using the same method as in Example 3.

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