WO2020137628A1

WO2020137628A1 - Cell capsule, cell transplantation device, method for extracting oxygen-generating material of cell transplantation device, method for replacing oxygen-generating material of cell transplantation device, and oxygen sustained-release material

Info

Publication number: WO2020137628A1
Application number: PCT/JP2019/048959
Authority: WO
Inventors: 優史丸山; 正樹松森; 泰佐々木; 真理子宮崎
Original assignee: 株式会社日立製作所
Priority date: 2018-12-28
Filing date: 2019-12-13
Publication date: 2020-07-02

Abstract

The purpose of the present invention is to provide a technique whereby an adequate amount of oxygen can be stably supplied for a long time to cells/tissue transplanted by cell capsules. A cell capsule pertaining to the present invention is provided with a structure for supplying an adequate amount of oxygen to cells, using an oxygen sustained-release material.

Description

Cell capsule, cell transplantation device, method for taking out oxygen generating material of cell transplantation device, method for exchanging oxygen generating material for cell transplantation device, and oxygen-releasing material

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.

In the treatment of regenerative medicine, when cells/tissues are transplanted, cell death due to lack of oxygen supply to the transplanted cells/tissues has become a problem. The following 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).

Special table 2012-508584 gazette

As described in 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.

According to the cell capsule of the present invention, the transplanted cells can survive in the body for a longer period of time. The above-mentioned and other objects and novel features of the present invention will become apparent from the description of this specification and the accompanying drawings.

It is a block diagram of the cell capsule 100 which concerns on 1st Embodiment. It is a block diagram of the cell capsule 100 which concerns on 2nd Embodiment. It is a block diagram of the cell capsule 100 which concerns on 3rd Embodiment. It is a modification of the cell capsule 100 according to the third embodiment. It is a block diagram of the cell capsule 100 which concerns on 4th Embodiment. It is a block diagram of the cell capsule 100 which concerns on 5th Embodiment. It is a schematic cross section explaining 6th Embodiment of a cell transplantation device. It is a schematic cross section explaining one mode using a 6th embodiment of a cell transplantation device. It is a schematic cross section explaining a mode that an oxygen generating material is exchanged in one mode using a 6th embodiment of a cell transplantation device. It is a perspective view explaining one mode of the oxygen generating material in a 6th embodiment of a cell transplantation device. It is a schematic cross section explaining 7th Embodiment of a cell transplantation device. It is a schematic cross section explaining a mode that an oxygen generating material in a 7th embodiment of a cell transplantation device is exchanged. It is a perspective view explaining one mode of the oxygen generating material in a 7th embodiment of a cell transplantation device. It is a schematic cross section explaining 8th Embodiment of a cell transplantation device. It is a schematic cross section explaining a mode that an oxygen generating material is exchanged in an 8th embodiment of a cell transplantation device. It is the figure which showed the flow path of the oxygen generating material accommodation part in 8th Embodiment of a cell transplantation device. It is a schematic cross section explaining 9th Embodiment of a cell transplantation device. It is a schematic cross section explaining 10th Embodiment of a cell transplantation device. It is a schematic cross section explaining 11th Embodiment of a cell transplantation device. It is a flowchart explaining one Embodiment of the oxygen generating material extraction method of a cell transplantation device. It is a flowchart explaining one Embodiment of the oxygen generating material exchange method of a cell transplantation device. 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.

<Cell capsule, cell transplant device>
<First Embodiment>
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. For convenience of illustration in the drawings, the cell holding carrier 103 is hatched. Here, 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. In the first embodiment, 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. Further, by using the cell holding carrier 103, the cells 101 can be encapsulated even when the cell capsule 100 is not covered with a container. Further, by providing an oxygen permeable film (for example, PDMS) between the oxygen-releasing material and the oxygen-releasing material, it is desirable because oxygen can be gently supplied without harming cells.

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. As 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. In this case, as 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. Examples of peroxides that react with water to generate oxygen include calcium peroxide, magnesium peroxide, hydrogen peroxide-urea, and the like. In this case, as a method of controlling the amount of oxygen released by the oxygen-controlled release material 102 per unit time, it is conceivable to supply water to the vicinity of the oxygen-controlled release material 102. Alternatively, for example, if the viscosity of the cell holding carrier 103 (oxygen-releasing material carrier 106 in the third and fourth embodiments described later) is increased, 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.

As a specific configuration example of the cell capsule 100 according to the first embodiment, for example, 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.

<Second 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. When the cells 101 are directly exposed to the body, immune cells in the body may attack the cells 101. By separating the cells 101 from the immune cells by the container 104, the survival rate of the cells 101 can be improved. 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.

As a specific configuration example of the cell capsule 100 according to the second embodiment, for example, 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.

<Third Embodiment>
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, and 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. When 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. For example, 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. When a peroxide is used as the oxygen sustained release material 102, hydrogen peroxide may be generated and damage the cells 101. Although 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. In FIG. 3B, a portion of the container 104 that covers the cells 101 and the cell holding carrier 103 is constituted by the first film 104A, and 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).

When a peroxide that reacts with water to generate oxygen is used as the oxygen-controlled release material 102, 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.

In the same manner as described in the second embodiment, from the viewpoint of improving the oxygen supply amount to the cells 101, 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.

In the third embodiment, since 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. As 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.

As a specific configuration example of the cell capsule 100 according to the third embodiment, for example, the following can be used: MIN6 (mouse insulinoma 6) cells as the cells 101, magnesium peroxide as the oxygen sustained release material 102, and cells. It is possible to use porous polystyrene as the holding carrier 103, porous polytetrafluoroethylene as the container 104, polydimethylsiloxane as the oxygen permeable film 105, and alginic acid gel as the oxygen sustained release material carrier 106.

<Fourth Embodiment>
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. When 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.

<Fifth 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. In this case, the cell capsule 100 includes at least the container 104 as an initial state. In 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. Similarly, when 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.

According to the cell capsule 100 according to the fifth embodiment, 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.

<Sixth Embodiment>
In the conventional cell transplantation device, oxygen diffuses into the body, and it is difficult to maintain it in the cell transplantation device for a long period of time, and the amount of oxygen that can be supplied to cells is low. Therefore, the problem of cell death due to insufficient oxygen supply to the transplanted cells/tissues has not been sufficiently solved. Therefore, in the sixth to eleventh embodiments, a cell transplantation device capable of improving the survival time of the transplanted cells/tissue in the body will be described.

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.

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. As an example, 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.

(Oxygen generating material storage part)
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. In this embodiment, 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.

In the present embodiment, 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. By doing so, when 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. Further, in this way, 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.

Of course, in the present embodiment, 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.

(Cell storage part)
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. As 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. Furthermore, it is not necessary to administer an immunosuppressive drug to a patient or to devise such that immunity does not act on the cells 208 used. 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. However, in the present embodiment, oxygen is used. Since the generating material 205 can generate and supply oxygen, the demerit can be eliminated. As 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. As the semipermeable membrane, hydrogels such as alginic acid, polysulfonic acid, and the like can be used in addition to the physically porous membranes.

(Oxygen delivery part)
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). As 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. Further, as the oxygen permeable film, a film having holes physically can be used. As such 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) can be fixed to a predetermined position of the housing 204 by using an arbitrary adhesive or can be fixed by welding a part of the housing 204 with a welding machine. preferable.

(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.

First, in the cell transplantation device 200A, as shown in FIG. 7, 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.

Note that 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. When 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. When peroxide is used, 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. You can As the peroxide, for example, a metal peroxide or a hydrogen peroxide inclusion body can be used. As the metal peroxide, for example, calcium peroxide, magnesium peroxide, sodium peroxide, barium peroxide, potassium peroxide, zinc peroxide or the like can be used. As the hydrogen peroxide inclusion body, for example, hydrogen peroxide urea can be used.

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. Here, in the present embodiment, since 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. You can Note that 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.

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. Examples of such a dispersion medium 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. In addition to aqueous solutions of polymers and the like, higher fatty acids, oils, terpenes, etc. may be mentioned, but are not limited thereto. 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. In addition, in order to prevent the oxygen generating material 205 housed in the tubular cartridge 210 from leaking to the outside of the cartridge 210, both ends of the tubular cartridge 210 are sealed. Further, 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. Examples of the cells 208 preferably include insulin-producing cells, isolated pancreatic islets, mesenchymal stem cells, and the like. In addition, in this embodiment, the origin, type, phenotype, presence or absence of gene modification, passage number, etc. of the cells 208 are not limited. In addition, the cell 208 is not limited in properties and morphology such as floating cells, adherent cells, single cells, cell sheets, and organoids. Moreover, 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.

<Seventh Embodiment>
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.

As shown in FIG. 10 and FIG. 7, 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.

As shown in FIG. 10, in the seventh embodiment, 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. 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. As 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.

<Eighth Embodiment>
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.

As shown in FIGS. 13 and 7, 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. Is different from 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.

Further, as shown in FIG. 15, 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.

In the cell transplantation device 200C according to the eighth embodiment having such a configuration, when removing the oxygen generating material 205 from the oxygen generating material accommodating portion 201, as shown in FIGS. 14 and 15, 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.

Since 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. In addition, in the present embodiment, as shown in FIG. 13 and FIG. 14, 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. Further, 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).

<Ninth Embodiment>
FIG. 16: is a schematic cross section explaining 9th Embodiment of a cell transplantation device.
As shown in FIG. 16 and FIG. 7, 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.

In addition, in the cell transplantation device 200D according to the ninth embodiment and the cell transplantation device 200A according to the sixth embodiment, 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.

As shown in FIG. 16, in the cell transplantation device 200D according to the ninth embodiment, 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. This can be easily done by puncturing the septum plug 206a with another injection needle and injecting the replacement oxygen generating material 205 after or while removing it. Since 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.

<Tenth Embodiment>
FIG. 17 is a schematic cross-sectional view illustrating the tenth embodiment of the cell transplantation device.
As shown in FIGS. 17 and 7, 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.

As shown in FIG. 17, a cell transplantation device 200E according to the tenth embodiment 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. .. As 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. In addition, for example, as shown in FIG. 17,

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. By electrolyzing water with such an electrolysis member 220, oxygen can be supplied to the cells 208 in the cell transplantation device 200E. Note that 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. As the cathode 223 and the anode 224, any one made of metal can be used. As 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.

<Eleventh Embodiment>
FIG. 18 is a schematic cross-sectional view illustrating the eleventh embodiment of cell transplantation device.
As shown in FIGS. 18 and 7, 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.

As shown in FIG. 18, in the cell transplantation device 200F according to the eleventh embodiment, 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. Further, the oxygen generating material 205 in the oxygen generating material accommodating portion 201 can be easily replaced. When exposing the entire oxygen generating material accommodating portion 201 to the outside of the body, 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.

Since the cell transplantation devices 200A to 200F according to the sixth to eleventh embodiments described above 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.

<Oxygen generating material removal method for cell transplantation device>
Next, an embodiment of the oxygen generating material removal method for the cell transplantation device according to the sixth to eleventh embodiments will be described.

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.

As shown in FIG. 19, 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.

Then, 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.

Finally, the lid closing step S3 is a step of closing the opened portion of the lid portion 206 after the extracting step S2.

In the takeout method according to the present embodiment, 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. In such a case, for example, 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.

(Oxygen generating material replacement method for cell transplantation device)
Next, an embodiment of the oxygen generating material exchange method for the cell transplantation device according to the sixth to eleventh embodiments will be described.

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.

As shown in FIG. 20, 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.

By performing the exchange method according to this embodiment including these steps S11 to S14, 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.

<Oxygen-releasing material>
In the cell capsule according to the first embodiment to the fifth embodiment and the cell transplantation device according to the sixth embodiment to the eleventh embodiment, the oxygen sustained release material shown below can be used.

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. With 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. On the other hand, 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.

③ 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.

In the oxygen sustained release material, hydrogen peroxide is generated by the reaction between the metal peroxide and the weak acid, and the generated hydrogen peroxide is decomposed to generate oxygen. At this time, a by-product is produced by the reaction between the metal and the weak acid, but the by-product generally has lower reactivity and lower toxicity than metal hydroxide.
(Protonation reaction of metal peroxide)
M _x (O ₂ ) _y + 2yH ⁺ → xM ^2y/x+ + yH ₂ O ₂
(Hydrogen peroxide decomposition reaction)
2H ₂ O ₂ → 2H ₂ O + O ₂

Since the increase/decrease in the solid surface area of the metal peroxide due to the progress of the reaction can be considered to be almost constant, 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. By setting the rate-determining step, smooth oxygen generation can be realized. As 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. With 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. Examples of 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. There are things. The above metal peroxide has no extreme toxicity to cells or living bodies. As the metal peroxide, calcium peroxide or magnesium peroxide is preferable from the viewpoint of safety to the living body. Among these, 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.

In the oxygen sustained release material according to one embodiment of the present invention, 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 μM 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. Further, 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.

ㆍWeak 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. Examples of 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 sulfate and the like. 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. A monovalent or divalent carboxylic acid having a structure substituted with an oxygen atom, benzoic acid, phthalic acid, or a derivative in which any hydrogen atom thereof is substituted with a C1-C18 alkyl group, alkoxy group or acyl group. , A monovalent or divalent carboxylic acid containing an oligoethylene glycol or polyethylene glycol structure, or a polymer compound having a carboxylic acid group in its side chain. 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. Among these, 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.

As the dispersion medium, for example, as the polymer compound, 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. Examples of the low molecular weight compound include water, ethanol and isopropyl alcohol. Examples thereof include alcohols, oils and fats, lower alcohol diesters of succinic acid such as dimethyl succinate and diethyl succinate, lower fatty acids such as ethyl acetate, for example, lower alcohol ester of acetic acid. The use of the above dispersion medium facilitates the control of the reaction between the metal peroxide and the weak acid, as described below. Among these, the dispersion medium may contain only one kind alone, or may contain two or more kinds as a mixture.

The following is an example of how to make the reaction of metal peroxide and weak acid the rate-determining step.

As a method of keeping the rate at which the poorly soluble weak acid is dissolved in the system at a low and constant level, which is the first mode described above, there is a method of controlling the affinity between the weak acid and the dispersion medium. 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.

As an example of the combination of the weak acid and the dispersion medium in the first mode, sodium dihydrogen phosphate is used as the weak acid, and polyethylene glycol dimethyl ether (average molecular weight 250)/water (90/10% by weight) is used as the dispersion medium. Combinations can be mentioned.

As a method for slowing the reaction between the weak acid and the metal peroxide by lowering the diffusion rate of the weak acid in the system, which is the second mode, there is a method of controlling the diffusion by viscosity. Generally, viscosity is one of the factors that govern the speed with which molecules move, and the higher the viscosity, the slower the diffusion rate. By utilizing this, the diffusion rate control can be realized. In such a case, for example, 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.

As a method of keeping the reaction rate low at the time of chemically generating a weak acid from the weak acid precursor, which is the above-mentioned third mode, a protic compound to be reacted with the weak acid precursor, for example, the concentration of water or alcohol is used. One way is to keep it low.

As an example of the reaction between the weak acid precursor and the protic compound, 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. Examples include a reaction of obtaining a carboxylic acid that is a weak acid by alcoholysis (that is, the protic compound is alcohol). In addition, when 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.

As the weak acid precursor, the above-mentioned weak acid anhydrides or chlorides can be used. Among them, examples of 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. Further, 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. A monovalent or divalent carboxylic acid anhydride or acid chloride having a structure in which a part of the methylene structure of a saturated hydrocarbon having a structure is replaced by an oxygen atom, or a monovalent or monovalent structure containing an oligoethylene glycol or polyethylene glycol structure. 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. By using the above weak acid precursor, a weak acid can be obtained by the reaction between the weak acid precursor and a protic compound such as water or alcohol. Among these, 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.

Further, in the third mode, when a certain amount of weak acid is contained in advance instead of containing water as the above-mentioned protic compound, first, 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.

In any of the modes, the oxygen sustained release material according to the embodiment of the present invention can control the initiation of oxygen generation by utilizing the melting point (or softening point in some cases) of the constituent composition. 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.

When the initiation of oxygen generation is controlled using the melting point, 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. There is no limitation. For example, since liquid nitrogen can be used for storage and solidification at the liquid nitrogen temperature is required, the preferable melting point is −196° C. or higher. On the other hand, in consideration of the freezing point depression, 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.

When using the melting point of the dispersion medium, polyethylene glycol dimethyl ether, polyether such as polyethylene glycol, dimethyl succinate, etc. can be used. When the melting point of a weak acid is used, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid or the like can be used. When utilizing the melting point of the weak acid precursor, caprylic anhydride, pelargonic anhydride, capric anhydride, lauric anhydride, myristic anhydride, 2,2-dimethylsuccinic anhydride, etc. can be used. .. When utilizing the melting point of the protic compound, water, ethanol or the like can be used.

In one embodiment of the present invention, 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. 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.

Example of oxygen-releasing material is explained below.

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.

In 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.

Low dissolution rate of weak acid by using calcium peroxide as metallized oxide, sodium dihydrogen phosphate as weakly soluble acid, and polyethylene glycol dimethyl ether (average molecular weight 1000)/water (95/5 wt%) as dispersion medium I kept it. 0.3 g of calcium peroxide, 0.6 g of sodium dihydrogen phosphate, 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 adjusted. When quantified, almost uniform oxygen generation was confirmed over 5 days (FIG. 21).

In 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.

In 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. When 0.3 g of calcium peroxide, 1.6 g of capric anhydride and 30 μL 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). ..

In 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.

In Example 5, V79 cell culture using the sustained-release oxygen material of the present invention was examined (FIG. 23).

Calcium peroxide (0.6 g), capric anhydride (3.2 g) and water (50 μL) were mixed to obtain an oxygen sustained-release material. 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.

When 0.3 g of calcium peroxide and 1 g of water were uniformly mixed and the amount of oxygen generated at 37°C was quantified, the generation of oxygen was not confirmed because water did not function as a weak acid.

(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.

(Comparative example 3)
In Comparative Example 3, V79 cell culture was investigated without using the oxygen sustained release material of the present invention (FIG. 24).

When 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%.

From the above results, it is clear that the oxygen sustained-release materials of Examples 1 to 5 are self-reactive, which does not depend on external supply of the substance required for oxygen generation, and do not produce a highly toxic by-product. Became.

<Regarding Modifications of the Present Invention>
The present invention is not limited to the above embodiment, and various modifications are included. For example, 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. Further, 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. Further, it is possible to add/delete/replace other configurations with respect to a part of the configurations of the respective embodiments.

In the above embodiment, it is possible to use the oxygen-controlled release materials 102 having different characteristics in combination. For example, 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. Further, it is preferable to use, as the oxygen-releasing material 102, a combination of the above-exemplified material that releases oxygen by reacting with water and an oxygen adsorbing material. For example, 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.

In the above embodiments, 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. However, in view of improving the oxygen supply capacity by the oxygen sustained release material 102, the effect of the present invention can be most effectively exerted on the cells 101 that require a large amount of oxygen. For example, human pancreatic cells are considered as an example, but the present invention is not limited to this.

100: Cell Capsule 101: Cell 102: Oxygen Sustained Release Material 103: Cell Retaining Carrier 104: Container 105: Oxygen Permeation Membrane 106: Oxygen Sustained Release Material Carrier 200A to 200F: Cell Transplanting Device 201: Oxygen Generating Material Housing 202: Cell Housing 203:

Oxygen transfer parts

204, 204a, 204b Case 205: Oxygen generating material (oxygen-releasing material)
206: Lid 206a: Septum plug 207: Opening 208: Cell 209: Discharge part 210: Cartridge 211: Flow path 212: Top part 220: Electrolytic member 221: Battery 223: Cathode 224: Anode 225: Hard cartridge 226:

Water storage part

227a, 227b: Semipermeable membrane S1: Lid opening step S2: Taking out step S3: Lid closing step S11: Lid opening step S12: Taking out step S13: Housing step S14: Lid closing step 301: Oxygen sustained release material 302: Gap 303: Oxygen permeable membrane 304: V79 cells for evaluation 305: Cell culture fluid 306: Housing

Claims

A cell capsule for encapsulating cells,
A cell-retaining carrier that retains the cells,
A solid oxygen sustained release material contained in the cell capsule,
A cell capsule comprising:
The cell capsule according to claim 1, wherein the oxygen sustained-release material is constituted by using one or both of a peroxide and a porous material.
The cell capsule according to claim 1, wherein the cell-holding carrier is made of a gel material or a porous polymer material.
The cell capsule according to claim 1, further comprising a container that contains the cell holding carrier and the oxygen sustained release material.
The cell capsule according to claim 4, wherein the container is formed using a semipermeable membrane.
The cell capsule according to claim 5, wherein the semipermeable membrane is formed of a porous polytetrafluoroethylene membrane.
The cell capsule according to claim 5, wherein the amount of oxygen released by the oxygen sustained release material per unit time is larger than the amount of oxygen permeated through the semipermeable membrane per unit time.
The cell capsule further comprises an oxygen permeable membrane permeable to oxygen,
The interior of the container is divided into a first compartment and a second compartment by the oxygen permeable membrane,
The cell capsule according to claim 4, wherein the cells are arranged in the first compartment, and the oxygen sustained-release material is arranged in the second compartment.
The container is formed using a semipermeable membrane,
The cell capsule according to claim 8, wherein an amount of oxygen permeating the oxygen permeable membrane per unit time is larger than an amount of oxygen permeating the semipermeable membrane per unit time.
The cell capsule according to claim 8, wherein the oxygen permeable membrane is formed of a polydimethylsiloxane or a fluorine-containing polymer membrane.
The container includes a first film covering the first section and a second film covering the second section,
The cell capsule according to claim 8, wherein the first membrane is formed by using a semipermeable membrane.
The oxygen sustained release material is composed of a peroxide that reacts with water to generate oxygen,
The cell capsule according to claim 11, wherein the second membrane is configured by using a membrane that allows water to permeate or pass therethrough.
The cell capsule according to claim 8, further comprising an oxygen sustained-release material carrier that is disposed in the second compartment and holds the oxygen sustained-release material.
The cell capsule according to claim 13, wherein the oxygen sustained-release material carrier is constituted by using an acidic gel material.
The cell capsule further comprises a second oxygen permeable membrane permeable to oxygen,
The inside of the container is divided into the first section and the second section by the oxygen permeable film, and is divided into the second section and the third section by the second oxygen permeable film,
The cell capsule according to claim 8, wherein the cells are arranged in the third compartment in addition to the first compartment.
The cell capsule according to claim 4, wherein the container has an immunoisolation property.
The cell capsule according to claim 4, wherein the cells are human pancreatic cells.
A cell capsule for encapsulating cells,
A container containing the cells,
A partition membrane for partitioning the inside of the container into a first compartment and a second compartment,
Equipped with
The cell capsule, wherein the partition membrane is configured by using an oxygen permeable membrane that allows oxygen to pass therethrough.
The container includes a first film covering the first section and a second film covering the second section,
The cell capsule according to claim 18, wherein the first membrane is formed using a semipermeable membrane.
The cell capsule according to claim 19, wherein an amount of oxygen permeating through the oxygen permeable membrane per unit time is larger than an amount of oxygen permeating through the semipermeable membrane per unit time.
The cell capsule according to claim 19, wherein the second membrane is configured by using a membrane that allows water to permeate or pass therethrough.
The cell capsule according to claim 18, wherein the oxygen permeable membrane is formed of polydimethylsiloxane or a fluorine-containing polymer membrane.
The cell capsule according to claim 19, wherein the semipermeable membrane is formed of a porous polytetrafluoroethylene membrane.
The cell capsule further comprises a second oxygen permeable membrane permeable to oxygen,
The inside of the container is divided into the first compartment and the second compartment by the oxygen permeable membrane, and is divided into the second compartment and the third compartment by the second oxygen permeable membrane. The cell capsule according to claim 18.
The first compartment contains the cells,
The cell capsule according to claim 18, wherein the second compartment contains a solid oxygen-releasing material.
The cell capsule according to claim 25, wherein the oxygen-releasing material is constituted by using one or both of a peroxide and a porous material.
The cell capsule according to claim 18, wherein the first compartment contains a cell holding carrier that holds the cells.
The cell capsule according to claim 27, wherein the cell-holding carrier is made of a gel material or a porous polymer material.
The container is formed using a semipermeable membrane,
The cell capsule according to claim 25, wherein the amount of oxygen released by the oxygen sustained release material per unit time is larger than the amount of oxygen permeated through the semipermeable membrane per unit time.
26. The cell capsule according to claim 25, wherein the cell capsule further comprises an oxygen sustained release material carrier that is disposed in the second compartment and holds the oxygen sustained release material.
The cell capsule according to claim 30, wherein the oxygen-releasing material carrier is constituted by using an acidic gel material.
The cell capsule according to claim 18, wherein the container has an immunoisolation property.
The cell capsule according to claim 18, wherein the cells are human pancreatic cells.
An oxygen generating material accommodating portion that accommodates an oxygen generating material that generates oxygen,
A cell containing portion for containing cells,
Provided between the oxygen generating material storage portion and the cell storage portion, and with an oxygen transfer portion that transfers oxygen generated from the oxygen generating material to the cell storage portion,
The oxygen generating material storage unit includes a lid unit that allows the oxygen generating material storage unit to move in and out, and the cell storage unit includes a release unit that releases the products produced by the cells to the outside of the device. ..
An oxygen generating material storage portion that stores an oxygen generating material that generates oxygen, a cell storage portion that stores cells, and is provided between the oxygen generating material storage portion and the cell storage portion, and is generated from the oxygen generating material. The oxygen generating part for sending oxygen to the cell containing part, the oxygen generating material containing part is provided with a lid part capable of entering and exiting, and the cell containing part is produced by the cells. A method of taking out an oxygen generating material from a cell transplantation device having a release part for releasing the produced product to the outside of the device,
A lid opening step of opening at least a part of the lid,
A step of taking out the oxygen generating material from the opened portion of the lid after the lid opening step,
A lid closing step of closing the opened portion of the lid portion after the removing step,
And a method for removing an oxygen generating material from a cell transplantation device including the same.
An oxygen generating material storage portion that stores an oxygen generating material that generates oxygen, a cell storage portion that stores cells, and is provided between the oxygen generating material storage portion and the cell storage portion, and is generated from the oxygen generating material. The oxygen generating part for sending oxygen to the cell containing part, the oxygen generating material containing part is provided with a lid part capable of entering and exiting, and the cell containing part is produced by the cells. Is a method of exchanging an oxygen generating material from a cell transplantation device having a release part for releasing the produced product to the outside of the device,
A lid opening step of opening at least a part of the lid,
A step of taking out the oxygen generating material from the opened portion of the lid after the lid opening step,
After the removing step, a storing step of storing a replacement oxygen generating material in the oxygen generating material storing section,
A lid closing step of closing the opened portion of the lid portion after the housing step,
And a method for exchanging an oxygen generating material in a cell transplantation device including the same.
An oxygen-releasing material that is self-reactive and contains a metal peroxide and a weak acid or a weak acid precursor.