WO2021025005A1 - Gel de collagène creux - Google Patents

Gel de collagène creux Download PDF

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Publication number
WO2021025005A1
WO2021025005A1 PCT/JP2020/029770 JP2020029770W WO2021025005A1 WO 2021025005 A1 WO2021025005 A1 WO 2021025005A1 JP 2020029770 W JP2020029770 W JP 2020029770W WO 2021025005 A1 WO2021025005 A1 WO 2021025005A1
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WIPO (PCT)
Prior art keywords
collagen
hollow
collagen gel
gel
cells
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PCT/JP2020/029770
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English (en)
Japanese (ja)
Inventor
茂久 青木
貴行 成田
結衣 岩本
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国立大学法人佐賀大学
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Priority to JP2021537315A priority Critical patent/JPWO2021025005A1/ja
Publication of WO2021025005A1 publication Critical patent/WO2021025005A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body

Definitions

  • the present invention relates to a hollow collagen gel and a method for producing the same.
  • Collagen material is widely used as a surgical medical device (TERUMO: Terumo, GUNZE: Pernac). In recent years, it has also attracted attention in the development of new medical technologies such as regenerative medicine.
  • filamentous collagen that assists nerve regeneration has been put on the market (NIPRO: Linab).
  • This product is formed as a filamentous hydrogel by discharging collagen into an organic solvent.
  • the filamentous collagen can be used as a suture to a tissue dissection, a cell carrier seeded with cells, and a derivative of cell migration in tissue regeneration. Since the tissue is composed of epithelial cells and mesenchymal cells, it is necessary to simultaneously transplant different cells consisting of parenchymal cells (such as epithelial cells) and mesenchymal cells (such as vascular endothelium) for its regeneration.
  • the organic solvent remains in the above method, it is a problem to solve the toxicity problem.
  • a cell carrier required in regenerative medicine when it is filamentous, it is impossible to enclose cells or a granular drug having a large diameter inside the material.
  • filamentous cells when two or more types of cells are seeded on the surface, cells with low proliferative ability are expelled by cells with high proliferative ability, so that they are not suitable for use as a culture carrier.
  • filamentous atelocollagen can be produced by subjecting a columnar hydrogel to ultraviolet irradiation, vitrifying it, and rehydrating it (Non-Patent Document 1: Biomater Sci. 2019 7 (1). ): 125-138).
  • Non-Patent Document 2 Keiichi Kanda, Takahiro Oka, Takehisa Matsuda-Artificial Organ, 1994
  • Collagen tubes characterized by having a wall formed of continuous, cylindrical, and continuous coaxial collagen films It is known (Patent Document 1: Japanese Patent Application Laid-Open No. 2009-540896). Further, as a method for producing a collagen tube, in Japanese Patent Application Laid-Open No.
  • Patent Document 2 molding with a cylindrical nozzle
  • Patent Document 3 Japanese Patent Application Laid-Open No. 2011-130995
  • Patent Document 4 a molding method using a cylindrical nozzle, in GB1007978 (Patent Document 5), an extruded collagen tube containing collagen fibrils, and in FR2902661 (Patent Document 6), A method of winding a collagen film into a tube is disclosed.
  • the hollow thread type collagen material by encapsulating vascular endothelial cells inside and seeding parenchymal cells such as epithelial cells outside, it is possible to easily co-culture cells without considering the difference in proliferative capacity. It can be an epoch-making transplant device that reproduces the tissue construction with a basic vascular network. In nerve tissue regeneration, seeding nerve cells inside and Schwann cells outside is expected to have a much higher rate of nerve regeneration effect than existing products. Further, this hollow fiber type collagen material makes it possible to easily produce an artificial organ by combining different cells for each hollow fiber and bundling each of them. Therefore, it has been desired to develop a method capable of producing a hollow collagen gel more easily than a conventional method for producing a hollow fiber type collagen material.
  • the present inventor has made a hollow by infiltrating a gelling agent into collagen sealed in a material having holes (for example, a hollow tube or a hollow cylindrical container). Succeeded in forming a collagen gel in the form of a collagen gel, and completed the present invention.
  • the present invention includes the following embodiments.
  • a method for producing a hollow collagen gel which comprises contacting a collagen solution filled in the pores of a material having pores with a gelling agent.
  • the present invention provides a hollow collagen gel.
  • the hollow collagen gel produced by the present invention is (i) a cell, drug or cell encapsulation device, (ii) a heterologous cell simultaneous transplantation device, (iii) a cell transplantation device with capillaries, and (iv) an in vitro artificial organ. It can be used for hollow fibers for organ production. Hollowing of the thread can be expected to greatly contribute to the high functionality of the thread, for example, it can contain a drug that promotes early healing after suturing.
  • FIG. 1 It is a schematic diagram of the manufacturing method of the hollow collagen gel of this invention. It is a figure which shows the collagen concentration which a hollow gel is formed. It is a figure which shows the relationship between the capillary diameter and the cavity diameter. It is a figure which shows that the endothelial cell can cover the lumen of a hollow fiber.
  • a schematic diagram of an experiment in which collagen gel yarn was prepared using a syringe is shown on the left side, and the results are shown on the right side. It is a figure which shows the presence or absence of the coating of the endothelial cell in the lumen of a hollow fiber for two kinds of collagen gels.
  • A shows the result of the collagen gel prepared according to the procedure described in Example 2 of the present application
  • B shows the result of the collagen gel prepared according to the manufacturing method described in the first example of JP-A-2019-123845.
  • the present invention provides a hollow collagen gel (hollow tube made of collagen gel) by contacting a collagen solution filled in a material having holes (a container with holes) with a gelling agent. It relates to a method for producing and a hollow collagen gel. In one embodiment, the present invention relates to a method for producing a hollow collagen gel, which comprises contacting a collagen solution filled in the pores of a material having pores with a gelling agent.
  • the present invention is based on the finding that when a collagen solution filled in the pores of a material having pores is brought into contact with a gelling agent, the collagen solution gels and a hollow portion is formed due to shrinkage accompanying the gelation. It is a completed product.
  • a collagen solution is filled in a perforated material, such as a hollow elongated tube or hollow columnar container, and then one of the pores of the perforated material is sealed and the other.
  • the gelling agent from the surface of the above, the collagen solution is gelled and the collagen gel is hollowed out.
  • even a three-dimensional porous material with innumerable pores and intricately curved pores the shape is particularly as long as the filled collagen solution forms cavities. It is not limited.
  • the collagen used as a raw material is not particularly limited, and commercially available collagen can be used. Further, the origin of the animal is not limited, and for example, those derived from pigs, cattle, fish, and birds can be used.
  • the concentration of the collagen solution is, for example, 0.5 to 3% by weight (wt%), preferably 1% by weight.
  • the solvent of the collagen solution is not particularly limited as long as it is an aqueous solvent.
  • the aqueous medium may contain alcohol, glycerin, a surfactant and the like.
  • the gelling agent for gelling the collagen solution is not particularly limited, and any solution, gas or solid can be used.
  • the gelling agent is a buffer solution such as PBS, EDTA, Tris-HCl, TE, TAE, SSC, TBE, SSPE, phosphate buffer solution, carbonic acid-bicarbonate buffer solution, citric acid.
  • Examples include sodium buffer, borate buffer, HEPES, BES, MOPS, TES, TAPSO, POPSO, HEPSO, EPPS, Tricine, Bicine, TAPS, CHES, CAPS and the like.
  • the pH of the gelling agent is 7 to 13.
  • the gelling agent when used as a vapor, is not particularly limited as long as it becomes a basic solution when the vapor is dissolved in water, for example, ammonia gas. , Methylamine, ethanolamine and the like.
  • the gelling agent when the gelling agent is a solid include sodium carbonate, sodium acetate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide and the like.
  • the method of the present invention does not require a gelation control agent in the gelation step.
  • the gelation control agent is a substance different from the gelling agent that changes the presence or absence of gelation or the rate thereof.
  • examples of the gelation control agent include acids such as hydrochloric acid, sulfuric acid, and acetic acid that adjust the pH; bases such as sodium hydroxide and ammonia; electrolytes such as sodium chloride that change the ionic strength; and combinations thereof.
  • acids such as hydrochloric acid, sulfuric acid, and acetic acid that adjust the pH
  • bases such as sodium hydroxide and ammonia
  • electrolytes such as sodium chloride that change the ionic strength
  • the material of the material having holes is not particularly limited, but plastic (Teflon, polystyrene, polyethylene, etc.) and glass are preferable.
  • the inner diameter of the material having holes may be, for example, 0.05 mm or more, 0.1 mm or more, or 0.2 mm or more, 2.0 mm or less, 1.9 mm or less, 1.8 mm or less, 1.7 mm or less, 1.6. It may be mm or less, 1.5 mm or less, 1.4 mm or less, 1.3 mm or less, 1.2 mm or less, 1.1 mm or less, or 1.0 mm or less.
  • the inner diameter (diameter of the hollow portion) of the material having holes is, for example, 0.1 mm to 2.0 mm, 0.1 mm to 1.0 mm, preferably 0.2 mm to 1 mm. Capillaries, perforated substrates, etc. can also be used.
  • one surface of the perforated material is in contact with the gelling agent and the other surface is not in contact with the gelling agent.
  • the gelling agent is a solution
  • one surface of the material having the pores is covered with a sealing seal
  • the other surface is covered with a semipermeable membrane such as a dialysis membrane
  • the gelling agent is covered with the semipermeable membrane. Infiltrate.
  • the columnar container is covered with a fluorine seal, the other surface is covered with a dialysis membrane, and the container is sealed with sealing tape or silicone rubber.
  • the container is then immersed in the gelling agent so that the gelling agent can penetrate the dialysis membrane.
  • the immersion time is 10 minutes to 10 days, and the reaction temperature between the collagen solution and the gelling agent at the time of immersion is 0 to 37 ° C.
  • the gelling agent acts on the collagen filled in the container through the dialysis membrane to gel the collagen, and the collagen gel is hollowed out due to the shrinkage accompanying the gelation.
  • the hollow collagen gel formed in the pores by the contact is discharged from the pores into the gelling agent.
  • the gel can be continuously prepared by discharging the gelling agent at a rate slower than the rate at which the gel is formed by contact.
  • the discharge rate depends on the shape of the container for discharging and is not limited, but may be, for example, 100 mm / h or less, 50 mm / h or less, 20 mm / h or less, 15 mm / h or less, or 10 mm / h or less. , 1 mm / h or more, 2 mm / h or more, or 5 mm / h or more.
  • continuous preparing a gel means that gel formation is continuously performed by contact between a collagen solution and a gelling agent, and gel preparation is performed without including a rest period. Not only that, it also includes the case where multiple gel preparations are performed with a rest period in between.
  • Continuous gel preparation can be performed, for example, by filling a container such as a syringe with a gelling agent and discharging the collagen solution from a discharge portion such as an injection needle.
  • the needle corresponds to a perforated material, where the gel is formed.
  • the gel may be discharged manually or mechanically in order to accurately control the discharge rate.
  • the inner diameter of the hollow collagen gel produced in this manner is, for example, 0.01 mm to 2.0 mm, preferably 0.05 mm to 1 mm or 0.1 mm to 0.6 mm.
  • the outer diameter of the hollow collagen gel (diameter of the collagen gel tube) is, for example, 0.1 mm to 2.0 mm, 0.1 mm to 1.0 mm, and preferably 0.2 mm to 1 mm.
  • the outer diameter of the hollow collagen gel may be the same as the inner diameter of the material having the pores.
  • the length of the hollow collagen gel produced in this manner may be, for example, 3 cm or more, 4 cm or more, 5 cm or more, 8 cm or more, 10 cm or more, 15 cm or more, or 20 cm or more.
  • the length of the hollow collagen gel may be 100 m or less, 10 m or less, less than 1 m, or 50 cm or less.
  • the collagen gel in the form of a hollow thread. Since the collagen gel described in the present specification can provide a long and thin hollow thread, when used as a suture, a thread conforming to a standard (for example, JIS medical silk suture) can be provided. Further, when a three-dimensional cell tissue in which heterologous cells are arranged and knitted on this hollow fiber is prepared, it may be possible to prepare various and dense tissues.
  • a standard for example, JIS medical silk suture
  • the present invention relates to a medical material containing the collagen gel described in the present specification, wherein cells are seeded on the inner wall or the outer wall of the collagen gel.
  • a collagen material is used as a culture carrier, the physiological functions of cells can be enhanced as compared with the case where polystyrene, polycarbonate material, etc. are used as the culture carrier (for example, Ko JA et al., Invest. See Ophthalmol. Vis. Sci., 2008, 49 (1), pp. 113-9, and Ko JA et al., Invest. Ophthalmol. Vis. Sci., 2009, 50 (5), pp. 2054-60. ).
  • the cells seeded on the inner wall of the collagen gel may be endothelial cells, and the cells seeded on the outer wall may be parenchymal cells such as epithelial cells.
  • endothelial cells such as epithelial cells
  • parenchymal cells such as epithelial cells.
  • the cells seeded on the inner wall of the collagen gel may be nerve cells, and the cells seeded on the outer wall may be Schwann cells.
  • Such collagen gel can be used for nerve tissue regeneration and can have a high rate of nerve regeneration effect.
  • the medical material described herein is for blood vessels or nerves.
  • Method 1 3 or 6 wt% porcine-derived collagen solution (manufactured by Nippon Ham) was filled in a glass capillary tube (inner diameter: 0.47, 1.05 or 1.89 mm). One of the capillaries was sealed with fluorine sealing tape. This was immersed in a buffer solution (pH 10) and allowed to stand in a cold and warm room (7 ° C.) for 5 days.
  • a buffer solution pH 10
  • a 1 wt% porcine-derived collagen solution (manufactured by Nippon Ham) is filled in a PTFE capillary tube having an inner diameter of 1 mm, one of the capillaries is sealed with fluorine sealing tape in the same manner as in Example 1, and carbonate buffering is performed.
  • a hollow collagen gel was prepared by immersing it in a solution (pH 10) for about 5 days. After gelation, the fluorine sealing tape at one end was removed, the gel in the capillary was extruded with a dropper, and the collagen gel was taken out from the capillary. The removed gel was hung from one end on a glass rod and air-dried at 20 ° C. and 60% humidity for 1 day to obtain a xerogel.
  • Hollow filamentous collagen gel is placed in a culture dish with a diameter of 10 cm, 1 million endothelial cells are mixed per 10 ml of culture medium, and the cells are statically cultured to obtain endothelial cells (cell line, MS-1, MS-1, ATCC) was seeded on collagen gel. Medium exchange was performed every 2 days.
  • the hollow filamentous collagen gel was fixed in formalin, embedded in paraffin, sliced, and HE-stained to confirm cell adhesion and distribution.
  • Method Collagen gel yarn was prepared using a syringe according to the following procedure.
  • A A 1 wt% porcine-derived collagen solution (manufactured by Nippon Ham) was used.
  • B A carbonate buffer (pH 10) was used as the buffer solution, and 20 ml was placed in a vial.
  • C A PTFE tube (50 mm long) with an inner diameter of 1.89 mm was attached to the tip of a plastic disposable syringe with a capacity of 10 ml.
  • D 6 ml of the collagen aqueous solution of (a) was sealed in a syringe equipped with a PTFE tube.
  • Results A schematic diagram of this experiment is shown on the left side of Fig. 5, and the results are shown on the right side of Fig. 5.
  • the length of the prepared collagen gel thread was 6 cm to 15 cm.
  • Collagen gel is placed in a culture dish with a diameter of 10 cm, 1 million endothelial cells are mixed per 10 ml of culture medium, and the cells are statically cultured to obtain endothelial cells (cell line, MS-1, ATCC).
  • cell line MS-1, ATCC
  • Medium exchange was performed every 2 days.
  • the collagen gel was fixed in formalin, embedded in paraffin, sliced, and HE-stained to confirm cell adhesion and distribution.

Abstract

Dans un mode de réalisation, la présente invention concerne un gel de collagène creux. Dans un mode de réalisation, la présente invention concerne : un procédé de production d'un gel de collagène creux, caractérisé par la mise en contact d'une solution de collagène, remplie dans un matériau ayant un trou, avec un agent gélifiant ; ou un tube de gel de collagène creux produit à l'aide dudit procédé.
PCT/JP2020/029770 2019-08-05 2020-08-04 Gel de collagène creux WO2021025005A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015178427A1 (fr) * 2014-05-20 2015-11-26 国立大学法人 東京大学 Microfibre creuse
JP2019123845A (ja) * 2018-01-19 2019-07-25 国立大学法人北海道大学 ゲルの製造方法及びコラーゲンゲル

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015178427A1 (fr) * 2014-05-20 2015-11-26 国立大学法人 東京大学 Microfibre creuse
JP2019123845A (ja) * 2018-01-19 2019-07-25 国立大学法人北海道大学 ゲルの製造方法及びコラーゲンゲル

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHAMBERLAIN M. DEAN, BUTLER MARK J., CIUCUREL EMA C., FITZPATRICK LINDSAY E., KHAN OMAR F., LEUNG BRENDAN M., LO CHUEN, PATEL RITE: "Fabrication of Micro-tissues using Modules of Collagen Gel Containing Cells", JOURNAL OF VISUALIZED EXPERIMENTS, vol. 13, no. 46, 13 December 2010 (2010-12-13), pages E2177-1 - E2177-6, XP055791484, ISSN: 1940-087X *
SHEN, CHONG ET AL.: "Fabrication of Collagen Gel Hollow Fibers by Covalent Cross-Linking for Construction of Bioengineering Renal Tubules", ACS APPLIED MATERIALS & INTERFACES, vol. 7, no. 35, 2015, pages 19789 - 19797, XP055713311, ISSN: 1944-8244, DOI: 10.1021/acsami.5b05809 *

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