WO2018131673A1 - Nouveau matériau de régénération tissulaire et sa méthode de production - Google Patents

Nouveau matériau de régénération tissulaire et sa méthode de production Download PDF

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Publication number
WO2018131673A1
WO2018131673A1 PCT/JP2018/000577 JP2018000577W WO2018131673A1 WO 2018131673 A1 WO2018131673 A1 WO 2018131673A1 JP 2018000577 W JP2018000577 W JP 2018000577W WO 2018131673 A1 WO2018131673 A1 WO 2018131673A1
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collagen
cells
stem cells
culture
tissue regeneration
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PCT/JP2018/000577
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English (en)
Japanese (ja)
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裕道 藤江
雅史 山崎
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公立大学法人首都大学東京
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Priority to JP2018561425A priority Critical patent/JP6945242B2/ja
Publication of WO2018131673A1 publication Critical patent/WO2018131673A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix

Definitions

  • the present invention relates to a novel tissue regeneration material and a method for producing the same.
  • the most promising repair material is a stem cell-derived tissue repair material based on stem cells such as iPS cells and mesenchymal stem cells.
  • stem cells are a general term for cells that have both proliferative ability (ability to increase self) and differentiation ability (ability to become other cells). Theoretically, all living tissues can be made up, so stem cells are the basic tissue. Expectations for restoration materials are great.
  • mesenchymal stem cells are a kind of somatic stem cells that exist in the body, and can be easily collected from individuals, and there is little concern about rejection, so they are attracting attention as a realistic trump card for regenerative medicine. Yes.
  • an extracellular matrix such as collagen is self-generated from mesenchymal stem cells (MSCs) collected from the knee synovium.
  • MSCs mesenchymal stem cells
  • scSAT stem cell-based self-assembled tissue
  • TEC tissue engineered construct
  • scSAT is a tissue composed of cells and the extracellular matrix that it self-generates, and it was difficult to handle in the field of transplantation because it was thin and easy to break. Is lower than normal cartilage, and in particular, the collagen density of the surface layer is not as high as that of normal cartilage (Non-patent Document 3).
  • the mesenchymal stem cell-derived tissue regeneration material including the above-described techniques, has the following three problems. a) Potentials such as stem cell differentiation potential are not fully utilized due to restrictions on the culture environment. b) The mechanical strength of the tissue regeneration material is low, and the ability to heal with surrounding tissues is low. c) The tissue regeneration material that can be prepared cannot be used for wide area treatment due to its small volume.
  • Non-patent Document 4 a collagen gel culture method in which cells are cultured in a collagen gel.
  • Nita gelatin Nita gelatin
  • This method solves the above problem from the viewpoint of allowing cells to sufficiently enter the scaffold.
  • this method requires a large amount of cells of 10 6 cells / cm 2 or more and is produced.
  • the amount of collagen in the material is small, and most are low molecular weight fibers with a low degree of refibrosis. It was impossible to contain cells at a high density in a large amount of collagen fibers having a high degree of fibrosis close to the in vivo environment using a smaller amount of cells.
  • the present invention provides a novel tissue regeneration material and a method for producing the same.
  • the inventor of the present case has started research with a focus on culturing stem cells in a collagen solution.
  • a collagen solution or collagen dispersion is mixed in a culture solution containing a small amount of stem cells, and centrifugal force is applied by centrifugation to accumulate the stem cells and collagen on the culture plane at a high density, and the accumulated product is cultured again.
  • the culture method to return to the environment has been developed (Fig. 1).
  • tissue regeneration material having a basic composition of stem cells and collagen fibers having a high degree of fibrosis and extremely high density and adhesion between both materials (also referred to as “stem cell / collagen complex” in the present specification) Succeeded in developing. Based on this finding, the present invention has been completed.
  • the present invention may be as follows.
  • a method for producing a tissue regeneration material which comprises the following steps: (1) mixing a neutral culture medium containing stem cells with a collagen solution or dispersion; (2) The mixture of (1) is centrifuged to accumulate stem cells and collagen; (3) culturing an accumulation of stem cells and collagen; Said method.
  • stem cells are mesenchymal stem cells, ES cells, or induced pluripotent stem cells (iPS cells).
  • stem cells of step (1) is a stem cell cultured to a cell density of 1.0 ⁇ 10 5 cells / cm 2 ⁇ 6.0 ⁇ 10 5 cells / cm 2, the above-mentioned [1] or [2] The method described in 1.
  • a novel tissue regeneration material (stem cell / collagen complex) prepared by the method described in the present application has a higher cell content than a conventional TEC and was obtained as a large tissue.
  • the structure of refibrinated collagen in the stem cell / collagen complex is very similar to the surrounding environment when the cells are placed in the living body. From the viewpoint of mechanobiology, stem cells cultured in that environment There is a high possibility that differentiation potential will be maximized. From these characteristics, it is useful as a tissue regeneration material having desirable characteristics.
  • FIG. 1 is a conceptual diagram of a method for producing a stem cell / collagen complex.
  • FIG. 2 is a comparison of TEC and stem cell / collagen complex by SEM image analysis.
  • A) and (B) are images of 500 times observation, and are images analyzed for different fields of view.
  • C) is an image observed 1000 times.
  • FIG. 3 is a photograph comparing the tissue produced in the experiment lacking the step of centrifuging the stem cell / collagen complex and the collagen fiber / MSCs solution on the 14th day of culture, and the tissue produced in the collagen gel culture. is there.
  • FIG. 1 is a conceptual diagram of a method for producing a stem cell / collagen complex.
  • FIG. 2 is a comparison of TEC and stem cell / collagen complex by SEM image analysis.
  • a and (B) are images of 500 times observation, and are images analyzed for different fields of view.
  • C is an image observed 1000 times.
  • FIG. 3 is a photograph comparing the tissue produced in the experiment lacking the step of
  • FIG. 4 shows tissues, stem cells / collagen complexes (without ascorbic acid 2-phosphate), and stem cells / collagen complexes (with ascorbic acid 2-phosphate) obtained by culture in collagen gel on the seventh day of culture. It is a comparison of the SEM image analysis result about.
  • (A), (B), and (C) are an image observed at 200 times, an image observed at 1000 times, and an image observed at 2500 times, respectively.
  • the present invention includes the following steps: (1) mixing a neutral culture medium containing stem cells with a collagen solution or dispersion; (2) The mixture of (1) is centrifuged to accumulate stem cells and collagen; (3) culturing an accumulation of stem cells and collagen; The present invention relates to a method for producing a tissue regeneration material.
  • the type of stem cell is not particularly limited, but may be selected from the group consisting of mesenchymal stem cells, ES cells, and induced pluripotent stem cells (iPS cells), for example.
  • the stem cell is a mesenchymal stem cell.
  • Stem cells are mammalian cells, preferably human cells.
  • the density of stem cells is not particularly limited.
  • stem cells cultured to a cell density of 1.0 ⁇ 10 5 cells / cm 2 to 1.0 ⁇ 10 6 cells / cm 2 may be used.
  • the stem cells are preferably cultured to a cell density of 1.0 ⁇ 10 5 cells / cm 2 to 6.0 ⁇ 10 5 cells / cm 2 .
  • More preferred are stem cells cultured to a cell density of 2.0 ⁇ 10 5 cells / cm 2 to 4.0 ⁇ 10 5 cells / cm 2 .
  • the culture medium or medium is not particularly limited as long as it is a medium suitable for stem cell culture, and for example, DMEM can be preferably used.
  • the culture medium or medium may contain additional components such as serum and antibiotics, which can be appropriately selected by those skilled in the art depending on the type of stem cells to be cultured.
  • the pH of the medium is neutral, and is adjusted in the range of, for example, pH 6.0 to 8.0, or pH 6.5 to 7.5.
  • the collagen solution or dispersion is not particularly limited as long as it is a solution or dispersion containing collagen.
  • the collagen dispersion is preferably a fiber dispersion of refibrinated collagen. Collagen refibrosis proceeds by placing the collagen solution in a neutral environment. Thus, a fiber dispersion of refibrinated collagen may be prepared by placing the collagen solution under neutral conditions.
  • the collagen contained in the collagen solution or dispersion is not particularly limited as long as it is collagen.
  • it may be any neutral collagen that can be fibrillated by incubation at 37 ° C.
  • Such collagen includes, for example, type I, type II, or type III collagen. More preferably, the collagen may be type I or type II collagen.
  • the temperature at which the above step (1) is performed is not particularly limited as long as it is a temperature suitable for stem cell culture, and can be appropriately selected by those skilled in the art.
  • a preferable temperature is, for example, 35 ° C. to 40 ° C., more preferably 37 ° C.
  • the centrifugation is not particularly limited as long as it is a condition usually used by those skilled in the art to sediment and accumulate cells.
  • conditions such as 1000 rpm to 3000 rpm, preferably 1000 rpm to 1500 rpm, more preferably 1000 rpm, and 5 minutes may be used.
  • the stem cell and collagen aggregate can be cultured in the culture medium or medium as described above.
  • the culture temperature is not particularly limited as long as it is suitable for stem cell culture, and can be appropriately selected by those skilled in the art.
  • a preferable temperature is, for example, 35 ° C. to 40 ° C., more preferably 37 ° C.
  • the culture time may be, for example, between 6 days and 28 days, more preferably between 6 days and 14 days.
  • ascorbic acid or an ascorbic acid derivative or a salt thereof may be added in step (1) or (3). These additions are expected to improve the production of extracellular matrix containing collagen by cells.
  • the ascorbic acid derivative is not particularly limited, but the ascorbic acid hydroxyl group at the 2-position, 3-position, 5-position, and / or 6-position is a sugar, fatty acid (eg, stearic acid, palmitic acid, etc.) such as phosphoric acid, sulfuric acid, and glucose. , Hexyldecanoic acid, etc.), and derivatives etherified with alkyl groups (eg, C 1 -C 20 alkyl).
  • Ascorbic acid derivatives may include ascorbic acid 2-phosphate, ascorbic acid 2-sulfate, ascorbyl-2-glucoside, ascorbyl-6-glucoside.
  • the salt of ascorbic acid or the salt of ascorbic acid derivative is not particularly limited, but includes alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (magnesium salt, potassium salt, etc.).
  • Ascorbic acid or an ascorbic acid derivative or a salt thereof may exist in the form of a hydrate.
  • tissue construct having a three-dimensional structure in which the stem cells involve the collagen dispersion is produced.
  • the obtained tissue construct can be used as a tissue regeneration material.
  • the present invention includes the following steps: (1) mixing a neutral culture medium containing stem cells with a collagen solution or dispersion; (2) The mixture of (1) is centrifuged to accumulate stem cells and collagen; (3) culturing an accumulation of stem cells and collagen; Wherein the ascorbic acid or ascorbic acid derivative or a salt thereof is added in the step (1) or (3) above.
  • the tissue regeneration material has a strong sheet-like tissue form. It is possible to produce a film having a thickness of about 600 ⁇ m to 1500 ⁇ m and an area of about 30 mm 2 to 360 mm 2 . This is about 10 times thicker and about 100 times larger in volume than the conventional TEC described in Non-Patent Document 1.
  • tissue regeneration material produced by the above method When the tissue regeneration material produced by the above method is observed with a scanning electron microscope (SEM), it has a highly porous surface and has a diameter of submicrometer level collagen (fibril, subfibril) structure, It was observed that the higher-order structure of micrometer level collagen (facile) coexisted. The structure of such collagen is very similar to the natural biological fiber structure. It was also observed that the amount of collagen binding to the cells was large and three-dimensional. Therefore, the tissue regeneration material produced by the above method is rich in collagen fibrils in the material, has a high degree of fiber formation, and is close to the surrounding environment when cells are placed in the living body.
  • SEM scanning electron microscope
  • the tissue regeneration material of the present invention can be used for repair of tendons, ligaments and cartilage.
  • the skin is embedded by placing the tissue regeneration material of the present invention on the defect site of the tendon, ligament and cartilage, and covers the defect site Can be sutured. Since the tissue regeneration material of the present invention secretes adhesion factors and the like because stem cells self-generate extracellular matrix, a special procedure for conjugating or adhering tissue repair materials to tendon, ligament and cartilage defect sites Is unnecessary.
  • the tissue regeneration material of the present invention can be obtained as a material having a thickness as compared with the conventional TEC as described above or as a material having a large size. These characteristics are broader compared to conventional TECs, which improves stability when handling materials during surgery, and facilitates implantation into a defect site when tendon and cartilage repair is required It provides advantages such as being usable for transplantation into a defect.
  • Example 1 Preparation of stem cell / collagen complex and SEM observation (1)
  • Preparation of stem cell / collagen complex Mesenchymal stem cells (MSCs) collected from human synovial membrane were cultured in culture medium (DMEM, 10% fetal bovine serum ( FBS) and cultured in 1% P / S (penicillin / streptomycin) to 4.0 ⁇ 10 5 cells / cm 2 or 2.0 ⁇ 10 5 cells / cm 2 .
  • DMEM 10% FBS, 1% P / S, 0.2 mM ascorbic acid 2-phosphate
  • TEC a surface with low porosity was observed, and the collagen structure could not be confirmed. In TEC, it was observed that cells were embedded in a wall-like structure or spherical cells were scattered.
  • the stem cell / collagen complex a highly porous surface is observed, and the diameter of the submicrometer level collagen (fibril, subfibril) structure and its higher order structure, the micrometer level collagen (facile) It was observed that the structures coexisted.
  • the structure of such collagen is very similar to the natural biological fiber structure.
  • a high connectivity between the cells and the collagen structure was also observed.
  • Example 2 Influence of Centrifugation
  • the collagen fiber / MSCs solution was centrifuged in a 6-well plate.
  • the tissue obtained by the experiment without the centrifugation step was compared with the stem cell / collagen complex obtained by the method of Example 1 (1).
  • generated by the collagen gel internal culture shown in the following Example 4 was compared with the stem cell / collagen complex by the method of Example 1 (1).
  • Example 3 Effect of Ascorbic Acid 2-Phosphate Addition
  • a stem cell / collagen complex was prepared by the following method.
  • MSCs Mesenchymal stem cells collected from human synovial membranes were 2.0 ⁇ 10 5 cells / cm 2 in culture medium (DMEM, 10% FBS, 1% P / S (penicillin / streptomycin). The cultured cells were collected in a tube and 2.8 ⁇ 10 5 cells / mL in a culture medium (DMEM, 10% FBS, 1% P / S, 0.2 mM ascorbic acid 2-phosphate). The cell suspension was prepared.
  • the stem cell / collagen complex (with ascorbic acid 2-phosphate) produced by the method of Example 1 (1) and the stem cell / collagen prepared in this example without the addition of ascorbic acid 2-phosphate / SEM images for the collagen complex (no ascorbic acid 2-phosphate) were compared.
  • the appearance of having a highly porous surface, in addition to the submicrometer-level collagen (fibril, subfibril) structure, the higher-order micrometer-level collagen (facile) structure coexists. A large amount and three-dimensional collagen binding to the cells were observed (FIG. 4).
  • Example 4 Comparison with culture in collagen gel
  • the collagen gel shown below Morphological comparison with tissue prepared by culture was performed by morphological observation and SEM image analysis with the naked eye.
  • Collagen gel culture As a general method for culturing cells together with collagen fibers, collagen gel culture is known. Based on the description of Non-Patent Document 4, a tissue was prepared by the following method.
  • the cell suspension containing MSCs having a cell number of 2.0 ⁇ 10 5 cells / cm 2 was centrifuged, the cells were accumulated at the bottom of the centrifuge tube, and the supernatant was removed.
  • the stem cell / collagen complex has a high porosity and a hierarchical structure of collagen fibers having fibrils and fibrils. Moreover, in the stem cell / collagen complex, since the collagen fibers around the cells are dense, it is presumed that cell substrate production is active.
  • a novel tissue regeneration material (stem cell / collagen complex) prepared by the technique described in the present application is obtained as a large tissue with a high cell content, and the structure of refibrinated collagen in the stem cell / collagen complex is: It can be used as a tissue regeneration material because it is very similar to the surrounding environment when cells are placed in a living body.

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Abstract

La présente invention concerne un nouveau matériau de régénération tissulaire et sa méthode de production. La méthode de production du matériau de régénération tissulaire comprend les étapes suivantes : (1) mélanger une solution ou une dispersion de collagène avec un milieu de culture neutre contenant des cellules souches; (2) centrifuger le mélange obtenu dans l'étape (1) et concentrer ainsi les cellules souches et le collagène; et (3) cultiver la matière concentrée constituée des cellules souches et du collagène.
PCT/JP2018/000577 2017-01-13 2018-01-12 Nouveau matériau de régénération tissulaire et sa méthode de production WO2018131673A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN113941032A (zh) * 2020-07-16 2022-01-18 北京中卫医正科技有限公司 一种间充质干细胞复合补片及其制备方法与应用
WO2022075294A1 (fr) * 2020-10-07 2022-04-14 富士フイルム株式会社 Procédé de production d'une formulation cellulaire pour le traitement des articulations, formulation cellulaire pour le traitement des articulations, et procédé de culture de cellules souches mésenchymateuses

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JP2010136655A (ja) * 2008-12-10 2010-06-24 Tama Tlo Ltd 三次元組織培養物の製造方法
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JP2010136655A (ja) * 2008-12-10 2010-06-24 Tama Tlo Ltd 三次元組織培養物の製造方法
JP2014023544A (ja) * 2013-11-08 2014-02-06 Tsuneo Takahashi 培養軟骨製造方法および培養軟骨

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113941032A (zh) * 2020-07-16 2022-01-18 北京中卫医正科技有限公司 一种间充质干细胞复合补片及其制备方法与应用
WO2022075294A1 (fr) * 2020-10-07 2022-04-14 富士フイルム株式会社 Procédé de production d'une formulation cellulaire pour le traitement des articulations, formulation cellulaire pour le traitement des articulations, et procédé de culture de cellules souches mésenchymateuses
EP4227405A1 (fr) * 2020-10-07 2023-08-16 FUJIFILM Corporation Procédé de production d'une formulation cellulaire pour le traitement des articulations, formulation cellulaire pour le traitement des articulations, et procédé de culture de cellules souches mésenchymateuses
EP4227405A4 (fr) * 2020-10-07 2024-05-08 Fujifilm Corp Procédé de production d'une formulation cellulaire pour le traitement des articulations, formulation cellulaire pour le traitement des articulations, et procédé de culture de cellules souches mésenchymateuses

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