WO2021090617A1

WO2021090617A1 - Hydrogel membrane dried product or vitrigel membrane dried product, apparatus and method for manufacturing same, and tympanic membrane treatment device and injury part treatment device

Info

Publication number: WO2021090617A1
Application number: PCT/JP2020/037429
Authority: WO
Inventors: 俊明竹澤; 武憲宮下; 茂久青木
Original assignee: 国立研究開発法人農業・食品産業技術総合研究機構; 国立大学法人香川大学; 国立大学法人佐賀大学
Priority date: 2019-11-05
Filing date: 2020-10-01
Publication date: 2021-05-14
Also published as: JP7350238B2; JPWO2021090617A1

Abstract

This hydrogel membrane dried product or vitrigel membrane dried product is provided with a face part and a thread part to be held, which are integrally molded.

Description

Hydrogel membrane dry matter or Vitrigel membrane dry matter, its manufacturing equipment and its manufacturing method, eardrum treatment device and wound treatment device

The present invention relates to a hydrogel membrane dried product or a Vitrigel membrane dried product, an apparatus for producing the same, a method for producing the same, and an eardrum treatment device and a wound treatment device.

The present inventors have developed a method and an apparatus for producing not only a flat thin film but also a flat thick film in a collagen vitrigel film (see, for example, Patent Document 1). Furthermore, the present inventors have also developed a method for producing a tubular or filamentous collagen vitrigel membrane (see, for example, Patent Documents 2 to 3).

In the field of regenerative medicine, animal experiments have demonstrated that the atelocollagen bitrigel membrane attached to the wound is useful for tissue regeneration (see, for example, Patent Document 4).

Japanese Patent No. 5892611 Japanese Patent No. 467759 International Publication No. 2018/21187 International Publication No. 2014/20825

However, the only approach to the wound was to pinch and move one end of the atelocollagen Vitrigel membrane dried body under tweezers or an endoscope, so handling was sometimes difficult.

The present invention has been made in view of the above circumstances, and provides a hydrogel membrane dried product or a Vitrigel membrane dried product having excellent handling performance, a manufacturing apparatus thereof and a manufacturing method thereof, and a tympanic membrane treatment device and a wound treatment device. To do.

The present invention includes the following aspects.
[1] A hydrogel membrane dried product or a bitrigel membrane dried product, which comprises a gripping thread portion and a surface portion and is integrally molded with these.
[2] The hydrogel membrane dried product or Vitrigel membrane dried product according to [1], which has a plurality of through holes penetrating one side and the other side.
[3] The hydrogel membrane dried product or the Vitrigel membrane dried product according to [1] or [2], wherein the hydrogel is an atelocollagen gel and the vitrigel is an atelocollagen vitrigel.
[4] Described in any one of [1] to [3], comprising a frame portion, an upper surface film and a lower surface film sandwiching the upper and lower sides of the frame portion, and a tubular portion penetrating the upper surface film. Hydrogel film dried product or Vitrigel membrane dried product.
[5] A step A of injecting sol from the tubular portion of a manufacturing apparatus including a frame portion, an upper surface film and a lower surface film sandwiching the upper and lower surfaces of the frame portion, and a tubular portion penetrating the upper surface film. A hydrogel film dried product comprising a step B of allowing the sol to stand and gelling to obtain a hydrogel film, a step C of irradiating the hydrogel film with ultraviolet rays, and a step D of drying the hydrogel film. Manufacturing method.
[6] The method for producing a dried hydrogel film according to [5], wherein in the step D, the tubular portion and the lower surface film are removed from the hydrogel film and the hydrogel film is dried.
[7] After the step D, a step E in which the sol is layered from the lower surface film side to the frame portion, a step F in which the layered sol is allowed to stand and gelled to obtain a layered hydrogel film, and the layered hydrogel The method for producing a hydrogel membrane dried sol according to [6], which comprises a step G of drying the membrane and a step H of irradiating the layered hydrogel membrane dried sol with ultraviolet rays.
[8] Step I to obtain a Vitrigel membrane by hydrating the hydrogel membrane dried product obtained by using the method for producing a hydrogel membrane dried product according to any one of [5] to [7]. A method for producing a dried Vitrigel membrane, which comprises the step J of drying the Vitrigel membrane to obtain a dried Vitrigel membrane.
[9] A tympanic membrane therapeutic device comprising the hydrogel membrane dried product or the Vitrigel membrane dried product according to any one of [1] to [3].
[10] The step of gripping the gripping thread portion of the eardrum treatment device according to [9] and passing the eardrum treatment device through the eardrum perforation from the outer ear side to the middle ear side, and the eardrum through the eardrum perforation. A method for treating tympanic membrane perforation, which comprises a step of pulling the treatment device from the middle ear side to the outer ear side and attaching the surface portion of the tympanic membrane treatment device to the surface of the tympanic membrane on the middle ear side.
[11] A wound treatment device comprising the hydrogel membrane desiccant or the Vitrigel membrane desiccant according to any one of [1] to [3].
[12] A method for treating a wound, which comprises a step of piercing a gripping thread portion of the wound treatment device according to [11] from an open wound to a deep tissue to fix the wound treatment device.

According to the present invention, it is possible to provide a hydrogel membrane dried product or a bitrigel membrane dried product having excellent handling performance, and a technique for producing the same.

It is a perspective view of the hydrogel membrane dried product or the Vitrigel membrane dried product 100. (A) It is a perspective view of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 having through holes. (B) is a cross-sectional view taken along the line bb'of FIG. 2 (a). It is a figure which shows an example of the hydrogel membrane dried body or the Vitrigel membrane dried body of this embodiment. It is a figure which shows an example of the manufacturing apparatus of this embodiment. It is a photograph of the manufacturing apparatus in Example 1. It is a photograph of the state where the atelocollagen sol was injected from the cylinder part of the manufacturing apparatus in Example 1. It is a photograph of the state in which the atelocollagen sol injected into the manufacturing apparatus in Example 1 is gelled. It is a photograph of the atelocollagen gel irradiated with ultraviolet rays in Example 1. It is a photograph of the atelocollagen gel of the gripping thread portion in Example 1. It is a photograph which vitrified the atelocollagen gel of the gripping thread part in Example 1. It is a photograph which shows the state which vitrifies the atelocollagen gel of the surface part in Example 1. FIG. It is a photograph of the atelocollagen gel film dried body with the vitrified gripping thread part in Example 1. It is a photograph of the atelocollagen Vitrigel membrane with a rehydrated gripping thread portion in Example 1. It is a photograph of the revitrified atelocollagen Vitrigel membrane dried body with the gripping thread part which was revitrified in Example 1. It is a photograph of the manufacturing apparatus in Example 2. It is a photograph of the state where the atelocollagen sol was injected from the cylinder part of the manufacturing apparatus in Example 2. It is a photograph of the state in which the atelocollagen sol injected into the manufacturing apparatus in Example 2 is gelled. It is a photograph of the atelocollagen gel irradiated with ultraviolet rays in Example 2. It is a photograph of the atelocollagen gel of the gripping thread portion in Example 2. It is a photograph which vitrified the atelocollagen gel of the gripping thread part in Example 2. It is a photograph which shows the state which vitrifies the atelocollagen gel of the surface part in Example 2. FIG. (A) It is a photograph of the atelocollagen gel of the vitrified surface portion in Example 2. (B) It is a photograph which shows the state which the atelocollagen sol was layered in the washer (frame part) in Example 2. FIG. (C) It is a photograph which shows the gelled state of the layered atelocollagen sol in Example 2. FIG. It is a photograph which vitrified the layered atelocollagen gel in Example 2. (A) It is a photograph of the atelocollagen Vitrigel membrane with a rehydrated gripping thread in Example 2. (B) It is a photograph of the atelocollagen Vitrigel membrane with a rehydrated gripping thread portion in Example 2. (C) It is a photograph which shows the state which put the atelocollagen Vitrigel membrane with the gripping thread part on vinyl with a hole after rehydration in Example 2. (D) After (c), it is a photograph which shows the state of reglazing with the gripping thread part down. (A) It is a photograph of the surface portion of the atelocollagen Vitrigel membrane dried body with a gripping thread portion after revitrification in Example 2. (B) It is a photograph of the surface portion of the atelocollagen Vitrigel membrane dried body with a gripping thread portion after revitrification in Example 2. (C) It is a photograph of the gripping thread portion of the atelocollagen Vitrigel membrane dried body with the gripping thread portion after revitrification in Example 2. (A) It is a photograph of the surface of a rat liver that was thermally coagulated by the surgical bipolar in Example 3. (B) It is a photograph which covered the wound part of the liver with the Vitrigel membrane in Example 3. (A) It is a photograph of the liver wound in the Vitrigel membrane uncoated group 7 days after the treatment in Example 3. (B) It is a photograph of the liver wound in the Vitrigel membrane-coated group 7 days after the treatment in Example 3. It is a section-stained image of the liver wound in the Vitrigel membrane uncoated group 7 days after the treatment in Example 3. It is a section-stained image of the liver wound in the Vitrigel membrane-coated group 7 days after the treatment in Example 3. It is a photograph of the temporal bone surgery model in Example 4. It is a graph of the time required for endoscopic otologic surgery using each Vitrigel membrane in Example 4. (A)-(d) It is a photograph of each Vitrigel membrane used for endoscopic otologic surgery in Example 4.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings in some cases. The dimensional ratio in each figure is exaggerated for explanation and does not necessarily match the actual dimensional ratio.

≪Hydrogel membrane dried product or Vitrigel membrane dried product≫
In one embodiment, the present invention provides a hydrogel membrane dried product or a bitrigel membrane dried product, which comprises a gripping thread portion and a surface portion, which are integrally molded.

FIG. 1 is a perspective view of a hydrogel membrane dried product or a Vitrigel membrane dried product 100. The hydrogel film dried body or the bitrigel film dried body 100 includes a gripping thread portion 101 and a surface portion 102, which are integrally molded.
By having the gripping thread portion, it becomes easy to move the hydrogel membrane dried product or the Vitrigel membrane dried product not only in the horizontal direction but also in the vertical direction.
The hydrogel membrane dried product or the Vitrigel membrane dried product could be produced by adhering the surface portion and the gripping thread portion with collagen sol or the like, but not only the strength and suppleness of the adhesively bonded portion are inferior, but also the produced product is produced. The reproducibility was also poor.
On the other hand, the hydrogel film dried body or the bitrigel film dried body 100 can be used with good operability because the gripping thread portion 101 and the surface portion 102 are integrally molded.
Further, from the viewpoint of strength, the hydrogel membrane dried product or the Vitrigel membrane dried product 100 may have a crosslinked structure between the polymer compounds in the hydrogel membrane dried product or the Vitrigel membrane dried product 100 by irradiation with ultraviolet rays. preferable.

In the present specification, the "sol" means a dispersoid colloidal particle (size: about 1 to several hundred nm) using a liquid as a dispersion medium, particularly composed of a polymer compound. More specific examples of the sol include aqueous solutions of natural polymer compounds and synthetic polymer compounds. When these polymer compounds are crosslinked by chemical bonds to form a network structure, they are transferred to "hydrogel", which is a semi-solid substance having a large amount of water in the network. That is, "hydrogel" means a gelled sol.

The sol used as a raw material for hydrogel may be any material having biocompatibility, for example, extracellular matrix-derived components that gel, natural polymer compounds such as fibrin, agar, agarose, and cellulose, and polyacrylamide. Examples thereof include synthetic polymer compounds such as polyvinyl alcohol, polyethylene oxide, and poly (II-hydroxiethelymethyllate) / polycaprolactone.

Examples of the extracellular matrix-derived component that gels include collagen (type I, type II, type III, type V, type XI, etc.), mouse EHS tumor extract (type IV collagen, laminin, heparan sulfate proteoglycan, etc.). ), Basement membrane component (trade name: Matrigel), glycosaminoglycan, hyaluronic acid, proteoglycan, gelatin, etc., which are reconstituted from), and are not limited thereto. It is possible to produce a desired hydrogel by selecting components such as salts most suitable for each gelation, their concentrations, pH and the like. In addition, by combining raw materials, it is possible to obtain hydrogels that imitate various in-vivo tissues.

Among them, as the sol, an extracellular matrix-derived component that gels is preferable, and collagen is more preferable. Further, as a more preferable raw material among collagens, native collagen or atelocollagen can be exemplified, and atelocollagen is further preferable.

The "vitrigel" is obtained by rehydrating a conventional hydrogel after vitrification, in which the free water in the hydrogel is completely removed and then the partial removal of the bound water proceeds. It refers to a gel in a stable state and has been named "vitrigel®" by the present inventor.
Further, in the present specification, the dried hydrogel product immediately after the vitrification step and not undergoing the rehydration step is simply referred to as “hydrogel dried product”. Then, the gel obtained through the rehydration step after the vitrification step was distinguished and represented as "Vitrigel", and the dried product obtained by vitrifying the Vitrigel was referred to as "Vitrigel dried product". Therefore, "Vitrigel" is a hydrate.
Further, in the present specification, when the term "Vitrigel" is used, the term "(registered trademark)" may be omitted.

The surface portion 102 of the hydrogel film dried body or the Vitrigel film dried body 100 may be a flat surface, a curved surface, or an uneven surface, and is used properly according to the intended use. The thickness of the face portion 102 can be appropriately set as needed, and may be, for example, 0.1 μm to 5 mm, for example, 2 μm to 1 mm, or 20 μm to 400 μm. Further, the thickness of the surface portion 102 may be uniform or non-uniform. For example, the thickness of the face portion 102 can be made non-uniform in various shapes such as radial or concentric.

The area of the surface portion 102 can be appropriately set as needed, and may be, for example, 1 mm ² to 400 cm ² , for example 20 mm ² to 40 cm ² , and for example 80 mm ² to 4 cm ^2. May be good.

The hydrogel membrane dried product or the Vitrigel membrane dried product 100 may have a plurality of through holes penetrating one side and the other side. That is, the surface portion 102 may have a plurality of through holes penetrating the one surface and the other surface. FIG. 2A is a perspective view of a hydrogel membrane dried product or a Vitrigel membrane dried product 100 having through holes. FIG. 2B is a cross-sectional view taken along the line bb'of FIG. 2A. The hydrogel membrane dried product or the Vitrigel membrane dried product 100 has one side 110 and the other side 120. Further, the hydrogel membrane dried product or the Vitrigel membrane dried product 100 has a plurality of through holes 130 penetrating the one side surface 110 and the other side surface 120.

The hydrogel film dried body or the bitrigel film dried body 100 has through holes, so that it can be easily brought into close contact with the uneven surface. Further, even when the uneven surface is the wound portion of the living body and the exudate exudes from the uneven surface, the exudate can be passed through the through hole, so that the uneven surface of the hydrogel membrane dried body or the Vitrigel membrane dried body 100 It is possible to maintain close contact with. In the present specification, the "hydrogel membrane dried product or Vitrigel membrane dried product having through holes" may be referred to as "porous hydrogel membrane dried product or Vitrigel membrane dried product".

Further, the opening area of the through hole on one surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 is the same as the opening area of the through hole on the other surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100. It may be different or it may be different.

For example, the opening area of the through hole on one surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 may be smaller than the opening area of the through hole on the other surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100. .. In this case, the area of one surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 is larger than the area of the other surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100. When such a hydrogel membrane dried product or a Vitrigel membrane dried product 100 is brought into close contact with the uneven surface, if one side of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 is brought into close contact with the uneven surface, the other There is a tendency that the contact can be performed better than the case where the direction side is brought into close contact with the uneven surface so as to face the uneven surface.

Further, for example, when the uneven surface is a wound of a living body, the exudate is introduced through the through hole because the through hole is open even if the opening area is small on one surface of the hydrogel membrane dried body or the Vitrigel membrane dried body 100. It can be passed through, and the adherence of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 to the uneven surface can be maintained.

When the opening area of the through hole on one surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 is different from the opening area of the through hole on the other surface of the hydrogel membrane dried product or the Vitrigel membrane dried product 100, the hydrogel The ratio of the opening area of the through hole on one surface of the dried membrane or Vitrigel membrane dried product 100 to the opening area of the through hole on the other surface of the dried membrane hydrogel or Vitrigel membrane dried product 100 is, for example, 100: 1. It may be about 1: 100, 50: 1 to 1:50, or 10: 1 to 1:10.

The shape of the surface perpendicular to the axial direction of the through hole (hereinafter, may be referred to as the cross-sectional shape of the through hole) is not particularly limited, and for example, a triangle, a quadrangle (including a square, a rectangle, and a trapezoid), a pentagon, a hexagon, and the like. Polygons such as seven-sided and octagonal; circular, oval, substantially circular, elliptical, substantially elliptical, semi-circular, fan-shaped and the like. In one through hole, the cross-sectional shape of the through hole may be constant or may change in the middle. Further, the hydrogel membrane dried product or the Vitrigel membrane dried product 100 may have a plurality of types of through holes having different shapes.

In the present specification, the diameter of the through hole of the hydrogel film dried body or the Vitrigel film dried body 100 is assumed to be a circle having the same area as the widest cross-sectional area of the cross-sectional areas of the plane perpendicular to the axial direction of the through hole. However, it shall mean the diameter of the circle. The diameter of the through hole of the dried hydrogel membrane or dried Vitrigel membrane 100 of the present embodiment may be 0.1 μm to 5 mm, 1 μm to 2 mm, or 10 μm to 1 mm. ..

The diameter of the through hole does not have to be constant. For example, a plurality of types of through holes having different diameters may be mixed. Alternatively, the diameter of the through hole may differ depending on the position of the hydrogel membrane dried product or the Vitrigel membrane dried product 100.

In the hydrogel membrane dried product or the Vitrigel membrane dried product 100, the density of the through holes can be appropriately set as needed, and may be 1 to 1,000,000 pieces / cm ² and 1 to 10 It may be 000 pieces / cm ² or 1 to 100 pieces / cm ^2. When the diameter of the through hole is about 0.1 μm, the density of the through hole may be more than ^{1,000,000 pieces / cm 2.}

Further, the density of the through holes may differ depending on the position of the hydrogel membrane dried product or the Vitrigel membrane dried product 100. For example, in the central portion of the hydrogel membrane dried product or the Vitrigel membrane dried product 100, the density of through holes may be higher than that of the surroundings. Alternatively, the density of through holes may be lower in the central portion of the hydrogel membrane dried product or the Vitrigel membrane dried product 100 than in the surrounding area.

The method of forming the through hole 130 is not particularly limited, and in the state of a hydrogel film or a bitrigel film, a method of forming a through hole by hollowing out using a cylindrical blade such as a trepan or a method of hollowing out by laser irradiation is performed. A method of forming a through hole and the like can be mentioned.

The gripping thread portion 101 of the hydrogel membrane dried product or the bitrigel membrane dried product 100 is integrally molded together with the surface portion 102. The length of the gripping thread portion 101 varies depending on the use of the hydrogel membrane dried product or the Vitrigel membrane dried product 100, but may be 1 mm to 10 cm, 2 mm to 5 cm, or 5 mm to 2 cm. You may.
The thickness of the gripping thread portion 101 may be 1 μm to 2 mm, 5 μm to 500 μm, or 10 μm to 100 μm as the diameter of the circular cross section. Further, the thickness of the gripping thread portion 101 may be uniform or non-uniform. For example, the thickness of the gripping thread portion 101 can be made non-uniform at a desired portion, such as by making the surface portion 102 side thicker and the tip end side thinner.

The hydrogel membrane dried product or the bitrigel membrane dried product 100 may have a plurality of gripping thread portions 101. For example, as shown in FIG. 3 (a), a plurality of gripping threads 101 may be provided on one surface, and as shown in FIG. 3 (b), gripping threads may be provided on both surfaces. It may have a part 101.
Further, from the viewpoint of operability, the position where the gripping thread portion is attached can be shifted from the center of the surface portion.

<Use>
Since the hydrogel membrane dried product or the bitrigel membrane dried product of the present embodiment has a gripping thread portion integrally molded with the surface portion, for example, in an operation or the like in which a complicated operation is required to reach the application site. It is preferably used. Specifically, it is preferably used when it is applied to the inner wall of the esophagus via the esophagus, when it is applied to the eardrum via the ear canal, and when it is fixed to various wounds.

[Eardrum treatment device]
The eardrum treatment device of the present embodiment includes the hydrogel membrane dried product or the Vitrigel membrane dried product of the present embodiment. In the eardrum treatment, the device of the present embodiment is suitably used for the treatment of eardrum perforation due to its shape. In refractory otitis media, perforation of the eardrum did not heal spontaneously, and the fascia was usually used, but the patient was heavily invasive and the surgical procedure was difficult.
The eardrum treatment device of the present embodiment has less patient invasion and can facilitate surgery.

[Treatment method for eardrum perforation]
The method for treating the eardrum perforation of the present embodiment includes a step of gripping the gripping thread portion of the eardrum treatment device of the present embodiment and passing the eardrum treatment device through the eardrum perforation from the outer ear side to the middle ear side, and the eardrum. It has a step of pulling the eardrum treatment device through the perforation from the middle ear side to the outer ear side, and attaching the surface portion of the eardrum treatment device to the surface of the eardrum on the middle ear side.

[Wound treatment device]
The wound treatment device of the present embodiment includes the hydrogel membrane dried product or the Vitrigel membrane dried product of the present embodiment. The device of this embodiment can be fixed to an open wound by using the gripping thread portion as a pin. In addition, when the gripping thread is made of collagen, it has a hemostatic effect, serves as a scaffold for cells, and promotes the migration of cells necessary for tissue regeneration. Therefore, a blood product that has been indispensable in the past. It can be fixed to the wound without it.

[Treatment method for wounds]
The wound treatment method of the present embodiment includes a step of piercing the gripping thread portion of the wound treatment device of the present embodiment from the open wound to the deep part of the tissue to fix the wound treatment device. For example, in liver cancer resection therapy, since the hepatectomy surface cannot be sewn together, the operation is completed with the open wound, and there is a high risk of bleeding and pathological adhesion. On the other hand, according to the treatment method of the present embodiment, the wound can be easily covered with the wound treatment device of the present embodiment.

≪Manufacturing equipment≫
In one embodiment, a manufacturing apparatus including a frame portion, an upper surface film and a lower surface film sandwiching the upper and lower sides of the frame portion, and a tubular portion penetrating the upper surface film is provided. The manufacturing apparatus of this embodiment manufactures the above-mentioned hydrogel membrane dried product or Vitrigel membrane dried product.

FIG. 4 is a diagram showing an example of the manufacturing apparatus of this embodiment. As shown in FIG. 4, the manufacturing apparatus 200 has four removable members, a frame portion 210, an upper surface film 220 and a lower surface film 230 sandwiching the upper and lower sides of the frame portion 210, and a tubular portion penetrating the upper surface film 220. 240 and.

As will be described later, in the production of the hydrogel film dried product or the Vitrigel membrane dried product, first, the frame portion 210 is sandwiched between the upper surface film 220 and the lower surface film 230, and sol is injected from the tubular portion 240 to gel. Irradiate the entire gel with ultraviolet rays. Next, the tubular portion 240 is removed, the gel is inverted, and the gripping thread portion is vitrified. Subsequently, the lower surface film 230 is removed to vitrify the surface portion, and then rehydration and revitrification are performed to obtain a hydrogel membrane dried product in which the gripping thread portion and the surface portion are integrated without a joint portion. A dried Vitrigel membrane is obtained.

Examples of the materials of the frame portion 210, the upper surface film 220, the lower surface film 230, and the tubular portion 240 constituting the manufacturing apparatus 200 include glass material, polyacrylate (acrylic resin), polystyrene, nylon, stainless steel, and the like. Not limited to.

More specific examples of the glass material include soda-lime glass, Pyrex (registered trademark) glass, Vicor (registered trademark) glass, and quartz glass. More specifically, as polyacrylate (acrylic resin), for example, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), Poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecil acrylate), etc. Can be mentioned.

The shape of the frame portion 210 is set according to the shape of the hydrogel membrane dried product or the Vitrigel membrane dried product to be manufactured. For example, polygons such as triangles, quadrangles (including squares, rectangles, trapezoids), pentagons, hexagons, heptagons, octagons; Can be mentioned.
The height of the frame portion 210 is set according to the thickness of the hydrogel membrane dried product or the Vitrigel membrane dried product to be manufactured. When it is desired to increase the thickness of the hydrogel membrane dried product or the Vitrigel membrane dried product, it is preferable to increase the height of the frame portion 210.

The tubular portion 240 is fixed to the upper surface film 220 in a state of penetrating the upper surface film 220. The tubular portion 240 serves as an injection port for injecting the sol into the frame portion 210.

[Manufacturing method of dried hydrogel membrane]
In one embodiment, the present invention is a step of injecting sol from a cylinder portion of a manufacturing apparatus including a frame portion, an upper surface film and a lower surface film sandwiching the upper and lower portions of the frame portion, and a tubular portion penetrating the upper surface film. A hydrogel film comprising A, a step B in which the sol is allowed to stand and gelled to obtain a hydrogel film, a step C in which the hydrogel film is irradiated with ultraviolet rays, and a step D in which the hydrogel film is dried. A method for producing a dried product is provided.

[Step A]
Step A is a step of injecting sol from the tubular portion of the manufacturing apparatus (see FIG. 6).
When the sol injected in step A is a collagen sol, the collagen sol has an optimum salt concentration, for example, physiological saline, phosphate buffered saline (PBS), HBSS (Hank's Balanced Salt Solution). ), A basal culture solution, a serum-free culture solution, a serum-containing culture solution, or the like. Further, the pH of the solution at the time of gelation of collagen can be set to, for example, 6 to 8. The collagen sol may be prepared at, for example, about 4 ° C.

Especially when a serum-free culture solution is used, it is possible to prevent the hydrogel from containing substances (for example, antigens, virulence factors, etc.) that are contained in the serum components of other animals and are not suitable for application to the wound of the living body. Therefore, the hydrogel membrane obtained by using the serum-free culture solution is suitably used for medical purposes.

Further, the concentration of the collagen sol for producing the hydrogel is preferably 0.1 to 1.0% by mass, more preferably 0.2 to 0.6% by mass. When the concentration of collagen sol is not more than the above lower limit value, gelation is not too weak, and when the concentration of collagen sol is not more than the above upper limit value, a hydrogel made of uniform collagen gel can be obtained. ..

[Step B]
Step B is a step of allowing the sol to stand and gelling to obtain a hydrogel film (see FIG. 7).
The temperature at which the sol is kept warm can be appropriately adjusted according to the type of sol used. For example, when the sol is a collagen sol, the heat retention during gelation can be a temperature lower than the denaturation temperature of collagen depending on the animal species of collagen used, and is generally 20 ° C. or higher and 37 ° C. or lower. By keeping the temperature at that temperature, gelation can be performed in a few minutes to a few hours.

[Step C]
Step C is a step of irradiating the hydrogel film with ultraviolet rays (see FIG. 8). A known ultraviolet irradiation device can be used for the irradiation of ultraviolet rays. The irradiation energy, the total irradiation dose per unit area ^is preferably from 0.1mJ / cm 2 ~ 6000mJ / cm 2, more preferably 10mJ / cm 2 ~ 4000mJ / cm 2, 100mJ / cm 2 more preferably from ~ 3000mJ / cm ^{^2,} and particularly preferably 200mJ / cm 2 ~ 1500mJ / cm 2.
When the total irradiation amount is in the above range, the transparency and intensity of the hydrogel membrane dried product or the Vitrigel membrane dried product obtained by the subsequent rehydration can be particularly preferable.

When the total amount of ultraviolet rays per unit area is the same, it is obtained by repeatedly irradiating the hydrogel membrane with ultraviolet rays in a plurality of times to obtain a dried hydrogel membrane or subsequent rehydration. The transparency and strength of the dried Vitrigel membrane can be further enhanced.
When the hydrogel film is repeatedly irradiated with ultraviolet rays, the ultraviolet irradiation site is divided into the surface portion of the hydrogel film and the gripping thread portion, and the total irradiation amount is calculated per unit area of the hydrogel film. It may be the total ultraviolet irradiation amount of.

It is considered that the reason why the strength and transparency are increased by irradiating the hydrogel membrane with ultraviolet rays is that the polymer compounds in the hydrogel membrane are crosslinked by the ultraviolet rays.

[Step D]
Step D is a step of drying the hydrogel film (see FIGS. 10 to 11).
By drying the hydrogel membrane, free water in the hydrogel membrane can be completely removed, and partial removal of bound water can proceed.
The longer the period of this vitrification step (the step of completely removing the free water in the hydrogel membrane and then proceeding with the partial removal of the bound water), the more the vitrigel having excellent transparency and strength when rehydrated. A membrane can be obtained.

As the drying method, various methods can be used, for example, air drying, drying in a closed container (circulating the air in the container and constantly supplying dry air), and drying in an environment in which silica gel is placed. .. For example, as an air-drying method, a method of drying in an incubator kept sterile at 10 ° C. and 40% humidity for 2 days, or drying in a sterile clean bench all day and night at room temperature can be exemplified. it can.

From the viewpoint of drying efficiency, it is preferable to remove the tubular portion and the lower surface film from the hydrogel film and dry the hydrogel film in step D. Further, it is more preferable to separately dry the surface portion of the hydrogel film and the gripping thread portion. For example, after step C, it is more preferable that the tubular portion is removed from the hydrogel film to dry the gripping thread portion, and then the lower surface film is peeled off from the hydrogel film to dry the surface portion. From the viewpoint of preventing adhesion between the tip and the surface of the gripping thread portion, it is particularly preferable to dry the hydrogel film in an inverted state so that the gripping thread portion hangs down.
By going through the above steps (A) to (D), a hydrogel film dried body in which the gripping thread portion and the surface portion are integrally molded can be obtained (see FIG. 12).

When it is desired to manufacture the gel with a thickened surface portion, the manufacturing method of the present embodiment further comprises a step E in which the sol is layered from the lower surface film side to the frame portion after the step D, and a gel in which the layered sol is allowed to stand still. It is preferable to have a step F for obtaining a layered hydrogel film, a step G for drying the layered hydrogel film, and a step H for irradiating the layered hydrogel film dried product with ultraviolet rays.

[Step E]
The step E is a step of overlaying the sol on the frame portion from the lower surface film side after the step D (see FIG. 22B). By going through step D, the thickness of the hydrogel membrane dried product obtained by gelling the first injected sol and then vitrifying it is less than 1/100 of that before drying. Therefore, in step D, after the lower film is peeled off and dried, in step E, the sol can be layered in the space generated in the frame portion (see FIG. 22 (b)).

[Step F]
Step F is a step of allowing the layered sol to stand and gelling to obtain a layered hydrogel film (see FIG. 22 (c)). The details of gelation are the same as in step B.

[Process G]
Step G is a step of drying the layered hydrogel film (see FIG. 23 (a)). The drying method is the same as in step D.

[Step H]
Step H is a step of irradiating the layered hydrogel film dried product with ultraviolet rays (see FIG. 23 (a)). By going through step H, the bond between the first layer and the second layer can be strengthened on the surface portion (see FIGS. 23 (b) to 23 (d)). The details of the ultraviolet irradiation are the same as in step C.

Steps E to H may be repeated, and by repeating the steps, the surface portion can be further thickened.

[Manufacturing method of dried Vitrigel membrane]
In one embodiment, the present invention comprises a step I of hydrating a hydrogel membrane dried product obtained by using the method for producing a hydrogel membrane dried product described above to obtain a Vitrigel membrane, and a step I of drying the Vitrigel membrane to obtain a Vitrigel membrane. Provided is a method for producing a Vitrigel membrane-dried product, which comprises step J for obtaining a membrane-dried product.

[Step I]
Step I is a step of hydrating a hydrogel membrane dried product produced through the steps A to D or steps A to H to obtain a Vitrigel membrane. Examples of the aqueous solution used for hydration include sterilized water, physiological saline, PBS and the like. It is preferable to replace the aqueous solution as appropriate and repeat hydration.

[Process J]
Step J is a step of drying the Vitrigel membrane to obtain a dried Vitrigel membrane. The drying method is the same as in step D.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to the following Examples.

[Example 1] Manufacture of Vitrigel membrane with gripping thread 1.4 Detachable members (upper surface film, frame portion, lower surface film having holes having the same shape as the cross section of the tubular portion and the tubular portion lumen) were prepared. ..
Specifically, a 1 mL pipette (inner diameter 3 mm, outer diameter 4.5 mm) cut into a length of 1 cm was prepared as a tubular portion. As a top film having holes having the same shape as the cross section of the tubular cavity, a square vinyl (50 mm × 50 mm) having a hole in the center with a trepan having a diameter of 2.5 mm was prepared. A polystyrene washer (manufactured by Kishimoto Kogyo, size: inner diameter 25.24 mm, outer diameter 31 mm, transparent) was prepared as the frame portion. As the bottom film, square vinyl (50 mm × 50 mm) was prepared. These were sterilized with 70% ethanol and dried in a clean bench before use.
2. A 1 mL pipette (cylinder) having a length of 1 cm was fixed with double-sided tape so as to be concentric with the holes in the top film.
3. 3. The lower surface film was attached to the lower surface of the washer (frame portion) with double-sided tape, and the upper surface film formed by attaching a 1 mL pipette having a length of 1 cm to the upper surface was attached with double-sided tape (see FIG. 5).
4. Preparation of atelocollagen sol: On ice, 3 mL of serum-free culture solution was dispensed into 50 mL of conical tube, then 7 mL of porcine atelocollagen solution was added, and pipetting was performed 3 times to prepare 0.7% atelocollagen sol. An indwelling needle was attached to a syringe filled with 0.7% atelocollagen sol, and the sol was injected through the cavity of the 1 mL pipette so as to fill the inside of the washer and the inside of the 1 mL pipette (see FIG. 6).
5. Gelation: A manufacturing apparatus infused with atelocollagen sol was left in a 5% CO ₂ incubator at 37 ° C. for 2 hours for gelation (see FIG. 7).
6. UV irradiation: The manufacturing apparatus was placed on a conical tube with the upper surface (1 mL pipette portion) facing down, and UV was ^{irradiated at 800 mJ / cm 2} from the back surface side of the lower surface film (see FIG. 8 (a)). Next, the surface portion of the manufacturing apparatus is vertically installed and ^{irradiated with UV at 800 mJ / cm 2,} and then the surface portion of the manufacturing apparatus is vertically re-installed so that the gripping thread portion of the manufacturing apparatus is inverted and the UV is 800 mJ / cm / cm again. It ^{was irradiated with cm 2} (see FIG. 8 (b)).
7. Pipette Removal: The 1 mL pipette was removed from the top film to obtain a columnar atelocollagen gel to form the gripping thread (see FIG. 9).

8. Vitrification (grasping thread): The manufacturing apparatus from which the 1 mL pipette was removed was inverted and placed in a conical tube so that the columnar atelocollagen gel forming the gripping thread hangs down. This conical tube was installed in a constant temperature and humidity chamber (temperature 10 ° C., humidity 40%) in a state where Kimwipes was adsorbed on the tip of the columnar atelocollagen gel forming the gripping thread and hung down (Fig. 10). reference.).
9. Vitrification (face): The lower surface film of the manufacturing apparatus was removed to expose the upper surface of the atelocollagen gel film. This conical tube was installed again in a constant temperature and humidity chamber (temperature 10 ° C., humidity 40%) (see FIG. 11).
10. Preparation of Atelocollagen Vitrigel Membrane with Gripping Thread: A vitrified Atelocollagen Vitrigel Membrane with Gripping Thread was taken out from the washer (frame) and the top film (see FIG. 12). The dried product was submerged in a Petri dish infused with 10 mL of sterile water for 10 minutes. By exchanging the sterilized water and rehydrating by repeating this operation three times, an atelocollagen bitrigel membrane with a gripping thread was prepared. An atelocollagen vitrigel membrane with a gripping thread was placed on the conical tube so that the gripping thread portion hangs down from a vinyl hole having a hole having a diameter of 2.5 mm (see FIG. 13).
11. Re-glazing: This conical tube was placed again in a constant temperature and humidity chamber (temperature 10 ° C., humidity 40%), and the atelocollagen vitrigel membrane with a gripping thread was re-vitrified.
12. Preparation of dried Atelocollagen Vitrigel Membrane with Gripping Thread: It was taken out from a constant temperature and humidity chamber to obtain a revitrified dried Atelocollagen Vitrigel Membrane with Gripping Thread (see FIG. 14).

[Example 2] Manufacture of double-thick collagen rigel film with gripping thread 1.4 Detachable members (upper surface film, frame, lower surface having holes having the same shape as the cross section of the tubular portion and the lumen of the tubular portion) Film) was prepared.
Specifically, a sapphire extension tube (Terumo SF-ET1725L 50 cm 1.7 mL, inner diameter: about 2.3 mm, outer diameter: about 4.0 mm) cut to a length of 1 cm was prepared as a tubular portion. As a top film having holes having the same shape as the cross section of the tubular cavity, a square vinyl (50 mm × 50 mm) having a hole in the center with a trepan having a diameter of 2.5 mm was prepared. A polystyrene washer (manufactured by Kishimoto Kogyo, size: inner diameter 25.24 mm, outer diameter 31 mm, transparent) was prepared as the frame portion. As the bottom film, square vinyl (50 mm × 50 mm) was prepared. These were sterilized with 70% ethanol and dried in a clean bench before use.
2. A 1 cm long tube was fixed with double-sided tape so as to be concentric with the holes in the top film.
3. 3. The lower surface film was attached to the lower surface of the washer (frame portion) with double-sided tape, and the upper surface film formed by attaching a tube having a length of 1 cm to the upper surface was attached with double-sided tape (see FIG. 15).
4. Preparation of atelocollagen sol: On ice, 3 mL of serum-free culture solution was dispensed into 50 mL of conical tube, then 7 mL of porcine atelocollagen solution was added, and pipetting was performed 3 times to prepare 0.7% atelocollagen sol. An indwelling needle was attached to a syringe filled with 0.7% atelocollagen sol, and the sol was injected through the cavity of the tube so as to fill the inside of the washer and the inside of the tube (see FIG. 16).
5. Gelation: A manufacturing apparatus infused with atelocollagen sol was left in a 5% CO ₂ incubator at 37 ° C. for 2 hours for gelation (see FIG. 17).
6. UV irradiation: The manufacturing apparatus was placed on a conical tube with the upper surface (tube portion) facing down, and UV was ^{irradiated at 800 mJ / cm 2} from the back surface side of the lower surface film (see FIG. 18 (a)). Next, the surface portion of the manufacturing apparatus is vertically installed and ^{irradiated with UV at 800 mJ / cm 2,} and then the surface portion of the manufacturing apparatus is vertically re-installed so that the gripping thread portion of the manufacturing apparatus is inverted and the UV is 800 mJ / cm / cm again. It ^{was irradiated with cm 2} (see FIG. 18 (b)).
7. Tube removal: The tube was removed from the top film to obtain a columnar atelocollagen gel to form a gripping thread (see FIG. 19).

8. Vitrification (grasping thread part): The manufacturing apparatus from which the tube was removed was inverted so that the columnar atelocollagen gel forming the gripping thread part hung down, and installed in the frame gap of the rack. Kimwipes was adsorbed on the tip of the columnar atelocollagen gel that forms the gripping thread, and the gel was allowed to stand for about 1 hour (see FIG. 20). Then, the manufacturing apparatus was transferred onto a conical tube and installed in a constant temperature and humidity chamber (temperature 10 ° C., humidity 40%).
9. Vitrification (face): The lower surface film of the manufacturing apparatus was removed to expose the upper surface of the atelocollagen gel film. This conical tube was installed again in a constant temperature and humidity chamber (temperature 10 ° C., humidity 40%) (see FIG. 21).
10. Preparation of double-thick Atelocollagen Vitrigel membrane with gripping thread: A vitrified Atelocollagen gel membrane dried sol with washer attached, which is installed so that the gripping thread hangs down (Fig. 22). In the washer of (a) (before sol injection), 1 mL of the collagen sol prepared in "4. Preparation of atelocollagen sol" was layered and spread over the entire washer. Then, it was left in a 5% CO ₂ incubator at 37 ° C. for 2 hours to gel the layered atelocollagen sol in the washer of the atelocollagen gel film dried body with a gripping thread (FIG. 22 (b) (sol injection). Later), see FIG. 22 (c) (after gelation).
11. Vitrification and UV irradiation (double-thick surface): Atelocollagen gel with gripping thread The atelocollagen gel layered in the washer of the dried body is installed in a constant temperature and humidity chamber (temperature 10 ° C, humidity 40%). After vitrifying to prepare a double-thickness atelocollagen gel film dried body with a gripping thread portion, UV was irradiated at ^{400 mL / cm 2 from above the double-thick surface portion.} The washer and the top film of the manufacturing apparatus were removed from the double-thick Atelocollagen gel film dried product with a gripping thread (see FIG. 23), and the dried product was placed in a Petri dish infused with 10 mL of sterilized water for 10 minutes. It sank. The sterilized water was replaced and this operation was repeated 3 times to rehydrate. Vinyl was laid on the conical tube, and a double-thick atelocollagen gel membrane with a gripping thread was placed so that the gripping thread hung down from a hole with a diameter of 2.5 mm opened in the vinyl (see FIG. 24).
12. Re-glazing: This conical tube was placed again in a constant temperature and humidity chamber (temperature 10 ° C., humidity 40%) to re-glass the double-thick atelocollagen gel membrane with a gripping thread.
13. Preparation of double-thickness atelocollagen gel membrane dried product with gripping thread: Taken out from a constant temperature and humidity chamber to obtain a revitrified double-thicked atelocollagen gel membrane dried product with gripping thread (see FIG. 25). .).

[Example 3] Method for promoting hemostasis and tissue regeneration using a Vitrigel membrane with a gripping thread The excised surface excised by liver surgery of a rat is used on the surface of the Vitrigel membrane with a gripping thread prepared in Example 1. We have developed a method to promote hemostasis and tissue regeneration by covering and fixing to the inside of the liver remaining by the gripping thread part of the Vitrigel membrane with gripping thread.
Specifically, after making a hole having a diameter of 4 mm from the surface of the rat liver by thermal coagulation with a surgical bipolar (see FIG. 26 (a)), the liver tissue deeper from the hole using an injection needle. The wound portion of the liver was covered with a Vitrigel membrane while inserting a gripping thread into the liver (see FIG. 26 (b)).
Gross and histopathological observations after 1 week showed fibrous adhesions between the liver wound and the mural peritoneum in some of the uncoated groups (see FIGS. 27 (a) and 28). Fibrosis with extensive coagulative necrosis and formation of inflammatory granulation tissue were observed at the liver wound, and sporadic foreign body giant cell infiltration was observed (see FIGS. 27 (a) and 28).
No adhesion between the liver wound and the wall-side peritoneum was observed in the Vitrigel-coated group with a gripping thread (see FIGS. 27 (b) and 29). The degree of coagulative necrosis of the wound, inflammatory granulation tissue, and fibrosis was smaller than that of the uncoated group. Fibrosis around the grip that penetrated into the liver tissue was slight. No clear foreign body-type giant cell infiltration was observed around Vitrigel.

[Example 4] Evaluation of operability of a Vitrigel membrane with a gripping thread in a temporal bone surgery model The following four types of Vitrigel membranes were prepared using the method of Example 2.

1) Atelocollagen Vitrigel membrane with grip thread (double thickness)
2) Atelocollagen Vitrigel membrane without gripping thread (double thickness)
3) Atelocollagen Vitrigel membrane with grip thread (3 times thick)
4) Atelocollagen Vitrigel membrane without gripping thread (3 times thick)

Using the above four types of Vitrigel membranes as collagen membranes for tympanic membrane reconstruction, endoscopic otologic surgery was performed on the temporal bone surgery model shown in FIG. 30, and the required time and operability were evaluated. The conditions for operability evaluation are as follows. The results are shown in Table 1.

Perforation size: 4 mm in diameter
Vitrigel membrane size: 6 mm in diameter
Endoscope used: Diameter 4 mm Rigid mirror Olympus Ear wheat grain forceps Rosen probe Weak

The graph corresponding to the above table is shown in FIG. The triple thickness with gripping thread was the easiest to operate, and it was strong and had moderate elasticity.
After the above surgical simulation, the used Vitrigel membrane was observed with a stereomicroscope to evaluate deformation and the like. The results are shown in FIG. FIG. 32 (a) is a photograph of a vitrigel film having a double-thickness with a gripping thread, and FIG. 32 (b) is a photograph of a vitrigel film having a double-thickness without a thread for gripping. Almost no scratches were observed on the double-thick Vitrigel membrane with a gripping thread. On the other hand, in the double-thick Vitrigel membrane without a thread for gripping, scratches generated when grasped with forceps were observed.

The double-thick Vitrigel film with a gripping thread is very easy to use once you get used to it, and it is supple and fits the object to be covered even if there are fine irregularities.
The double-thick gripping threadless Vitrigel membrane could not be attached neatly if the angle and the degree of catching were not correct, and it sometimes took a considerable amount of time. The disadvantage was that the operation time was quite uneven and the Vitrigel could be injured.

The left side of FIG. 32 (c) is a photograph of a vitrigel film with a gripping thread portion having a thickness of 3 times, and the right side of FIG. No scratches were observed on the 3-fold thick Vitrigel membrane with gripping thread. It was confirmed that the three-fold-thick Vitrigel membrane with a gripping thread has moderate elasticity and easily adheres to the eardrum.
On the other hand, in the three-fold thick gripping threadless Vitrigel membrane, small scratches generated when grasped with forceps were observed. The three-fold thick gripping threadless Vitrigel film can be scratched like the double-thick gripping threadless Vitrigel film, but because of its thickness, it is difficult to wrinkle and it is easy to recover.

FIG. 32 (d) is a photograph showing a state in which the gripping thread portion of the Vitrigel membrane with a gripping thread portion having a thickness of 3 times is held by tweezers.
As shown in FIG. 32 (d), it was confirmed that there was little deflection even when held with tweezers and it was easy to attach. The three-fold-thick Vitrigel membrane with a thread for gripping was the most excellent Vitrigel membrane evaluated because it had good operability, was easy to grip, and was not easily scratched as a human eardrum reconstruction material.

In tympanic membrane reconstruction surgery, it can be attached to the tympanic membrane by grasping the Vitrigel membrane with a gripping thread, pushing it through a hole opened in the tympanic membrane, and pulling it from the other side (inside) to the front side (outside). As for the Vitrigel film with the gripping thread portion, the integrally molded one is more difficult to remove the gripping thread portion than the one to which the gripping thread is retrofitted, and the film can be evenly attached. The translucent Vitrigel membrane can be attached to the eardrum while looking at the other side (inside) through the membrane, so surgery can be performed with peace of mind.
Further, since the Vitrigel membrane with the gripping thread is transplanted in a hydrated state, the membrane may be doubly folded when the gripping thread is gripped. It was confirmed that this point can be improved by (1) thickening the film and (2) shifting the position where the gripping thread portion is attached from the center.

According to the present invention, it is possible to provide a hydrogel membrane dried product or a bitrigel membrane dried product having excellent handling performance, an apparatus for producing the same, and a method for producing the same.

100 ... Hydrogel film dried body or Vitrigel film dried body, 101 ... Gripping thread part, 102 ... Face part, 110 ... One side, 120 ... The other side, 130 ... Through hole, 200 ... Manufacturing equipment, 210 ... Frame part, 220 ... Top film, 230 ... Bottom film, 240 ... Cylinder.

Claims

A hydrogel membrane dried product or a bitrigel membrane dried product, which is provided with a gripping thread portion and a surface portion and is integrally molded.
The hydrogel membrane dried product or Vitrigel membrane dried product according to claim 1, which has a plurality of through holes penetrating one side and the other side.
The hydrogel membrane dried product or the Vitrigel membrane dried product according to claim 1 or 2, wherein the hydrogel is an atelocollagen gel and the vitrigel is an atelocollagen vitrigel.
With the frame
An upper surface film and a lower surface film that sandwich the upper and lower parts of the frame portion, respectively.
The tubular portion that penetrates the top film and
The apparatus for producing a dried hydrogel membrane or a dried Vitrigel membrane according to any one of claims 1 to 3.
A step A of injecting sol from the tubular portion of a manufacturing apparatus including a frame portion, an upper surface film and a lower surface film sandwiching the upper and lower surfaces of the frame portion, and a tubular portion penetrating the upper surface film.
Step B, in which the sol is allowed to stand and gelled to obtain a hydrogel film,
Step C of irradiating the hydrogel film with ultraviolet rays,
Step D to dry the hydrogel film and
A method for producing a dried hydrogel membrane.
The method for producing a dried hydrogel film according to claim 5, wherein in the step D, the tubular portion and the lower surface film are removed from the hydrogel film, and the hydrogel film is dried.
After the step D, a step E of overlaying the sol on the frame portion from the lower surface film side,
Step F to obtain a layered hydrogel film by allowing the layered sol to stand and gelling,
Step G to dry the layered hydrogel film and
Step H of irradiating the layered hydrogel membrane dried product with ultraviolet rays,
The method for producing a dried hydrogel membrane according to claim 6.
Step I to obtain a Vitrigel membrane by hydrating the hydrogel membrane dried product obtained by using the method for producing a hydrogel membrane dried product according to any one of claims 5 to 7.
Step J of drying the Vitrigel membrane to obtain a dried Vitrigel membrane,
A method for producing a dried Vitrigel membrane.
A tympanic membrane therapeutic device comprising the hydrogel membrane desiccant or the Vitrigel membrane desiccant according to any one of claims 1 to 3.
A wound treatment device comprising the hydrogel membrane desiccant or the Vitrigel membrane desiccant according to any one of claims 1 to 3.