JP2022066732A - Composite thread and use thereof - Google Patents

Abstract

To provide a composite thread that is more practical, a method for producing the same, and an uterine cervix treatment device.SOLUTION: Provided is a method for producing composite thread that includes a step 1 in which a thread-shaped core material is fixed to a plate-shaped hydrogel or plate-shaped vitrigel in the longer direction thereof, and then is subjected to drying, and a step 2 in which the thread-shaped core material-fixed plate-shaped hydrogel dry material or plate-shaped vitrigel dry material is twisted to make it thread-shaped while moistening with an aqueous solution in order to yield a thread-shaped vitrigel composite material.SELECTED DRAWING: None

Description

The present invention relates to composite yarns and their use.
In particular, the present invention relates to a method for producing a composite yarn, a composite yarn, and a cervical treatment device.

The present inventor has developed a new technique for treating tissue regeneration of the skin, esophagus, and eardrum using a membranous atelocollagen vitrigel, and a new treatment for tissue regeneration of the peritoneum using a filamentous atelocollagen vitrigel. Has developed technology. These new therapeutic techniques for tissue regeneration are techniques for suppressing pathological contractions and fibrosis (see, for example, Patent Documents 1 to 3).

Against this background, for example, if the filamentous atelocollagen vitrigel can be inserted into the residual cervical canal after cervical conical resection by utilizing the myofibroblast regulation and antifibrotic action of atelocollagen vitrigel. , It is thought that basic technology to prevent cervical stenosis can be developed.

International Publication No. 2014/20825 International Publication No. 2017/110776 International Publication No. 2018/21187

However, since the filamentous atelocollagen vitrigel is inferior in breaking strength as compared with a suture of the same thickness, it is difficult to insert it into a tissue rich in connective tissue such as the cervix.
.. In addition, when filamentous atelocollagen vitrigel was inserted into a tissue and indwelled, it was gradually digested in vivo, so it was difficult to confirm the indwelling site over time.

The present invention has been made in view of the above circumstances, and further provides a highly practical composite yarn, a method for producing the same, and a cervical treatment device.

The present invention includes the following aspects.
[1] Step 1 of fixing the filamentous core material in the longitudinal direction of the plate-shaped hydrogel or the plate-shaped Vitrigel and then drying it, and drying the plate-shaped hydrogel dried body or the plate-shaped Vitrigel to which the filamentous core material is fixed. A method for producing a composite yarn, comprising the step 2 of obtaining a filamentous Vitrigel composite by twisting the body while moistening it with an aqueous solution to form a filament.
[2] The method for producing a composite yarn according to [1], wherein in the step 1, the plate-shaped hydrogel or the plate-shaped vitrigel is alternately penetrated and fixed on the front and back sides of the filamentous core material.
[3] The method for producing a composite yarn according to [1] or [2], which comprises the step 3 of drying the filamentous Vitrigel complex after the step 2 to obtain a dried filamentous Vitrigel complex.
[4] The method for producing a composite yarn according to [3], which comprises the step 4 of irradiating the dried filamentous Vitrigel composite with ultraviolet rays after the step 3 and then rehydrating and further drying.
[5] The method for producing a composite yarn according to any one of [1] to [4], wherein the hydrogel is an atelocollagen gel or a native collagen gel.
[6] The method for producing a composite yarn according to any one of [1] to [5], wherein the aqueous solution is an atelocollagen sol or a native collagen sol.
[7] A composite yarn obtained by twisting a plate-shaped hydrogel dried body or a plate-shaped Vitrigel dried body and having a thread-like core material.
[8] The composite thread according to [7], wherein the plate-shaped hydrogel dried body or the plate-shaped Vitrigel dried body has a sewn portion of the thread-shaped core material.
[9] The composite yarn according to [7] or [8], wherein the plate-shaped Vitrigel dried product is a plate-shaped atelocollagen Vitrigel dried product.
[10] A cervical treatment device comprising the composite thread according to any one of [7] to [9].
[11] A method for treating a cervix, comprising a step of excising the cervical cone and a step of inserting the cervical treatment device according to [10] into the residual uterus after the cervical conical resection.

According to the present invention, it is possible to provide a composite yarn having further excellent practicality and a method for producing the same.

(A) It is a photograph of a plate-shaped atelocollagen Vitrigel membrane. (B) It is a photograph of a plate-shaped atelocollagen Vitrigel membrane having a through hole. (A) It is a photograph of a plate-shaped atelocollagen Vitrigel membrane to which a nylon suture is fixed. (B) It is a photograph of a plate-shaped atelocollagen Vitrigel membrane dried body to which a nylon suture is fixed. (A)-(C) It is a photograph showing the process of obtaining a filamentous atelocollagen vitrigel complex by twisting a dried plate-shaped atelocollagen vitrigel membrane to which a nylon suture is fixed while moistening it with an atelocollagen sol. (A)-(B) is a photograph of a filamentous atelocollagen vitrigel complex rehydrated after irradiation with ultraviolet rays. It is a photograph of the filamentous atelocollagen Vitrigel complex dried body. (A)-(B) is a phase-difference micrograph of a dried filamentous atelocollagen Vitrigel complex. (A) It is a photograph which performed conical excision using an electric scalpel on the left and right sides of the rabbit cervix (bicornuate uterus). (B) It is a photograph that the filamentous atelocollagen vitrigel complex produced in Production Example 1 was inserted into the cervical canal and fixed. (A) It is a photograph of the 21st day after the operation in which only the cervical resection was performed. (B) It is a photograph on the 21st day after the operation that the cervix was excised and the filamentous atelocollagen Vitrigel complex was placed in the cervical canal. (C) It is a section-stained image on the 21st day after the operation in which only the cervical resection was performed. (D) It is a section-stained image of the 21st day after the operation in which the cervix was excised and the filamentous atelocollagen Vitrigel complex was placed in the cervical canal.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings as the case may be.

≪Manufacturing method of composite yarn≫
In one embodiment, the present invention relates to step 1 in which a thread-like core material is fixed in the longitudinal direction of a plate-shaped hydrogel or a plate-shaped vitrigel and then dried, and a plate-shaped hydrogel dried product to which the thread-shaped core material is fixed. Alternatively, the present invention provides a method for producing a composite yarn, which comprises step 2 of obtaining a filamentous Vitrigel composite by twisting the dried plate-shaped Vitrigel while moistening it with an aqueous solution to form a filament.

<Step 1>
First, a method for producing a plate-shaped hydrogel will be described.
The method for producing a plate-shaped hydrogel includes a step A of injecting a sol into a mold, gelling the sol, and then removing the mold to obtain a plate-shaped hydrogel.

The plate-shaped hydrogel may have a protrusion at the end for ease of twisting. Further, the plate-shaped hydrogel may be in the shape of a strip or may have a narrow width, but the width is not limited to this and can be appropriately adjusted. The wider the width of the plate-shaped hydrogel, the thicker the thread, and the narrower the width of the plate-shaped hydrogel, the thinner the thread. In this way, the thickness of the thread can be controlled by adjusting the width of the plate-shaped hydrogel.
Further, the width of the plate-shaped hydrogel does not have to be uniform, and the width may be appropriately different as in the gourd type, and the width may be gradually different as in the triangular shape. You may.

[Step A]
Step A is a step of injecting sol into a mold, gelling the sol, and then removing the mold to obtain a plate-shaped hydrogel.
The mold is not particularly limited as long as the desired plate-shaped hydrogel shape is hollowed out, and examples thereof include PET films.
As used herein, the term "sol" means that the dispersoidal colloidal particles (size: about 1 to several hundred nm) using a liquid as a dispersion medium are particularly composed of a polymer compound. More specific examples of the sol include an aqueous solution of a natural product polymer compound or a synthetic polymer compound. 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 the plate-shaped hydrogel may be any material having biocompatibility, for example, gelling extracellular matrix-derived components, natural polymer compounds such as fibrin, agar, agarose, and cellulose, and poly. Examples thereof include synthetic polymer compounds such as acrylamide, polyvinyl alcohol, polyethylene oxide, and poly (II-hydroxythylmetrylate) / 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 components (trade name: Matrigel), glycosaminoglycan, hyaluronic acid, proteoglycan, gelatin and the like, and are not limited thereto. It is possible to produce a desired plate-shaped 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 a plate-shaped hydrogel that imitates 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 from which the antigenic terrorpeptide is deleted is further preferable when transplanted into a living body.

The term "vitrigel" refers to a gel in a stable state obtained by rehydration of a conventional hydrogel after vitrification, and is "vitrigel" (registered) by the present inventor. It is named "Trademark)".
Further, in the present specification, when the term "Vitrigel" is used, the term "(registered trademark)" may be omitted.

In step A, when the sol is injected into the mold, if the amount of the sol is increased, a thick plate-like hydrogel can be obtained, and as a result, a thick thread can be obtained. Further, if the amount of sol is reduced, a thin plate-shaped hydrogel can be obtained, and as a result, fine threads can be obtained. In this way, the thickness of the yarn can be controlled by adjusting the amount of the sol to be injected.
The thickness of the plate-shaped hydrogel is preferably 0.1 mm to 20 mm, more preferably 0.5 mm to 20 mm, still more preferably 1 mm to 20 mm.
The length of the long side of the plate-shaped hydrogel is appropriately adjusted according to the length of the composite yarn used. For example, 1 cm to 100 cm is preferable, 2 cm to 50 cm is more preferable, and 3 cm to 10 cm is further preferable.
The length of the short side of the plate-shaped hydrogel is, for example, preferably 0.5 mm to 20 mm, more preferably 1 mm to 10 mm, still more preferably 2 mm to 5 mm.

In step A, the temperature at which the sol is kept warm during gelation may be appropriately adjusted according to the type of sol to be used. For example, when the sol is a collagen sol, the heat retention during gelation may be a temperature lower than the denaturation temperature of collagen depending on the animal species of collagen used, and is generally a temperature of 20 ° C. or higher and 37 ° C. or lower. By keeping warm in, gelation can be performed in a few minutes to a few hours.

Further, the plate-shaped hydrogel obtained in step A may be cut out to obtain a strip-shaped hydrogel having a desired width.

[Filament core material]
The filamentous core material is not particularly limited as long as it imparts breaking strength to the composite yarn obtained by using the production method of the present embodiment, and is appropriately selected depending on the intended use. Examples of the thread-like core material include chemical fibers such as nylon yarn, polyester yarn, rayon yarn, and polygractin yarn; and natural material yarns such as silk yarn, cotton yarn, hemp yarn, and wool yarn.
Even if the dried plate-shaped hydrogel or dried plate-shaped Vitrigel is digested in vivo, the filamentous core material is preferably non-absorbable from the viewpoint of making it possible to confirm the placement site of the composite yarn over time. ..
The filamentous core material may be a single yarn, a twin yarn in which the same type or two types of yarns are twisted together, or a yarn in which three or more yarns are twisted together.

In step 1, the filamentous core material is fixed in the longitudinal direction of the plate-shaped hydrogel or the plate-shaped vitrigel. The fixing method is not particularly limited, and may be fixed with an adhesive, or may be physically fixed when the plate-shaped hydrogel dried product or the plate-shaped Vitrigel dried product is twisted in step 2.

From the viewpoint of strengthening the fixing strength between the plate-shaped hydrogel or the plate-shaped vitrigel and the filamentous core material, it is preferable to alternately penetrate the front and back surfaces of the plate-shaped hydrogel or the plate-shaped vitrigel and fix the filamentous core material.
That is, it is preferable that the plate-shaped hydrogel or the plate-shaped vitrigel is fixed by penetrating the thread-shaped core material so as to be sewn with the thread-shaped core material. By such an operation, the plate-shaped hydrogel or the plate-shaped vitrigel can be brought into close contact with the filamentous core material.
The position for fixing the thread-like core material is preferably on the central axis that bisects the short side of the plate-like hydrogel or plate-like vitrigel, and the thread-like core material is penetrated along the axis at equal intervals to sew. It is preferable to form. The length of the pitch between the sewn portions is preferably 0.5 mm to 10 mm, more preferably 1 mm to 4 mm, and particularly preferably 1 mm to 2 mm.
As a method of penetrating the thread-like core material, the thread-like core material may be sewn through a needle, and after making through holes at regular intervals in a plate-shaped hydrogel or a plate-shaped vitrigel using a cylindrical or conical blade or the like. , The thread-like core material may be penetrated. The diameter of the through hole is, for example, preferably 0.01 mm to 5 mm, more preferably 0.1 mm to 3 mm, and particularly preferably 0.5 mm to 1 mm.
Examples of the cylindrical blade include a medical device such as a biopsy trepan or an injection needle.

Next, in step 1, the plate-shaped hydrogel or plate-shaped vitrigel to which the filamentous core material is fixed is dried.

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), drying in an environment in which silica gel is placed, and the like. .. 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. can.

<Step 2>
In step 2, the plate-shaped Vitrigel dry body to which the thread-like core material is fixed is twisted while being moistened with an aqueous solution to form a thread, to obtain a thread-like Vitrigel complex.
The aqueous solution is not particularly limited, and examples thereof include sterile water, physiological saline, PBS, atelocollagen sol, native collagen sol, and the like, and atelocollagen sol from which the antigenic telopeptide is removed is preferable when transplanting into a living body. By coating with atelocollagen sol or native collagen sol, the strength of the yarn can be increased. Further, by such an operation, the plate-shaped Vitrigel and the thread-shaped core material can be brought into close contact with each other.

<Process 3>
After step 2, it is preferable to dry the filamentous Vitrigel complex to obtain a dried filamentous Vitrigel complex. The preferred drying method is the same as in step 1.

<Step 4>
After step 3, it is preferable that the dried filamentous Vitrigel complex is irradiated with ultraviolet rays, rehydrated, and further dried.
By irradiating with ultraviolet rays, a crosslinked structure can be formed between and within the molecules of collagen constituting Vitrigel and the coated collagen, and the strength of the composite yarn can be increased. Further, by such an operation, the plate-shaped Vitrigel and the thread-shaped core material can be brought into close contact with each other.
The above-mentioned ultraviolet irradiation energy may be appropriately adjusted according to the composition and content of the plate-shaped Vitrigel dried product. The irradiation energy of ultraviolet rays may be, for example, 0.1 mJ / cm ² or more and 6000 mJ / cm ² or less, for example, 10 mJ / cm ² or more and 4000 mJ / cm ² or less, for example 20 mJ / cm ² or more and 500 mJ / cm ² . It may be as follows.
Examples of the aqueous solution used for rehydration include sterile water, physiological saline, PBS and the like.
After rehydration, the dried filamentous Vitrigel complex is dried and revitrified.

According to the method for producing a composite yarn of the present embodiment, the breaking strength of the filamentous atelocollagen vitrigel can be improved, so that the obtained composite yarn can be suitably used for a hard structure.
In addition, when the obtained composite yarn is inserted into the tissue and placed in place, the plate-shaped Vitrigel dried product is gradually digested in vivo, but the filamentous core material remains undigested, or is more than Atelocollagen Vitrigel. Since it is a filamentous core material that digests slowly, it is possible to confirm the placement site of the composite yarn over time.
Further, by using the filamentous core material, the hydrogel or vitrigel can be used only in the required region of the filamentous core material, and the expensive hydrogel or vitrigel can be saved.

≪Composite yarn≫
In one embodiment, the present invention provides a composite yarn obtained by twisting a plate-shaped hydrogel dried body or a plate-shaped Vitrigel dried body and having a filamentous core material. As an example of the method for producing a composite yarn of the present embodiment, the above-mentioned << method for producing a composite yarn >> can be mentioned, but the method is not limited thereto.
By having the filamentous core material, the composite yarn of the present embodiment can improve the breaking strength. Further, by using a bio-non-absorbable filamentous core material, it is possible to confirm the placement site of the composite yarn over time even if the hydrogel or vitrigel is digested in vivo. Examples of the filamentous core material include the same as the above-mentioned << manufacturing method of composite yarn >>.

The length of the composite yarn of this embodiment is appropriately adjusted according to the intended use. For example, 1 cm to 100 cm is preferable, 2 cm to 50 cm is more preferable, and 3 cm to 10 cm is further preferable.
The diameter of the composite yarn of the present embodiment is appropriately adjusted according to the intended use. For example, 0.1 mm to 10 mm is preferable, 0.2 mm to 4 mm is more preferable, and 0.5 mm to 2 mm is particularly preferable.

From the viewpoint of improving the bonding strength between the plate-shaped hydrogel dried body or the plate-shaped Vitrigel dried body and the thread-shaped core material, the plate-shaped hydrogel dried body or the plate-shaped Vitrigel dried body preferably has a sewn portion of the thread-shaped core material. .. The plate-shaped hydrogel dried body or the plate-shaped bitrigel dried body preferably has a plurality of sewn portions. The pitch between the sewn portions is preferably constant. The length of the pitch between the sewn portions is preferably 0.5 mm to 10 mm, more preferably 1 mm to 4 mm, and particularly preferably 1 mm to 2 mm.

The composite yarn of the present embodiment has a spiral structure and elasticity by being twisted.
Examples of the sol used as a raw material for the dried plate-shaped hydrogel or the dried plate-shaped Vitrigel include the same as those exemplified in the above-mentioned << Method for producing composite yarn >>. Among them, the dried Vitrigel body constituting the composite yarn of the present embodiment is preferably a dried Atelocollagen Vitrigel because it is a biocompatible material.

<Use>
Since the composite yarn of the present embodiment has sufficient breaking strength, it can be suitably used for a hard structure such as a structure rich in connective tissue.

≪Cervical treatment device≫
The cervical treatment device of the present embodiment includes the composite yarn of the present embodiment described above. The cervical treatment device of the present embodiment can also be suitably used for the cervix rich in connective tissue.

[Cervical treatment method]
The method for treating the cervix of the present embodiment includes a step of excising the cervical cone and a step of inserting the cervical treatment device of the present embodiment into the residual uterus after the cervical conical resection. According to this embodiment, postoperative cervical stenosis can be easily prevented by indwelling a region in which Vitrigel is in close contact with the tissue to be treated.

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

[Production Example 1] Production of Thread A rectangular atelocollagen vitrigel membrane (atelocollagen amount: 10 mg / cm ² ) was cut out to obtain a plate-shaped atelocollagen vitrigel membrane having a size of 40 mm × 3 mm (see FIG. 1 (A)). On the central axis of the plate-shaped atelocollagen Vitrigel membrane in the longitudinal direction, through holes having a diameter of about 0.5 mm were opened at 2 mm intervals with a 27 G injection needle (see FIG. 1 (B)). After immersing a plate-shaped atelocollagen Vitrigel membrane with a through hole in PBS, a nylon suture (Nescosture (registered trademark), number: 3-0, standard: GA03NA) is passed through the through hole in a zigzag manner to form nylon. The suture made of nylon was fixed to the plate-shaped atelocollagen Vitrigel membrane (see FIG. 2 (A)). This was dried to obtain a plate-shaped atelocollagen Vitrigel membrane dried product to which a nylon suture was fixed (see FIG. 2 (B)).
Next, the plate-shaped atelocollagen vitrigel membrane dried product to which the nylon suture was fixed was wrapped with the nylon suture while being moistened with 0.5% atelocollagen sol and then dried to obtain a filamentous atelocollagen vitrigel complex. (See FIGS. 3 (A) to 3 (C).).
Then, the dried filamentous atelocollagen Vitrigel complex was irradiated with ultraviolet rays and then rehydrated (see FIGS. 4A to 4B).
Then, the rehydrated filamentous atelocollagen vitrigel complex was hung and dried to obtain a dried filamentous atelocollagen vitrigel complex (see FIG. 5). FIG. 6 shows a phase-contrast microscope image of this dried filamentous atelocollagen Vitrigel complex. It was confirmed that the shortest width of this dried product was 0.55 mm (see FIG. 6 (A)) and the longest width was 0.97 mm (see FIG. 6 (B)).

[Example 1] Treatment method after cervical conical resection On the day of surgery: After conical resection using an electric scalpel on the left and right sides of the rabbit cervix (bicornuate uterus) (see FIG. 7 (A)). , The filamentous atelocollagen vitrigel complex produced in Production Example 1 was inserted into the cervical canal and fixed (see FIG. 7 (B)).

21st day after surgery: The cervical canal was closed or narrowed and the cervix was swollen as a whole by cervical resection alone (see FIG. 8 (A)). On the other hand, when the filamentous atelocollagen Vitrigel complex was placed in the cervical canal, no swelling of the cervix was observed (see FIG. 8 (B)).
Furthermore, according to the section-stained image, the cervical canal part dilated like a cyst and a coarse papillary structure was observed in the lumen only by cervical resection (see FIG. 8C). On the other hand, when the filamentous atelocollagen Vitrigel complex was placed in the cervical canal, cystic dilation of the cervix was not observed, and a fine papillary structure similar to normal was observed (see FIG. 8 (D)). ..
As described above, the effect of the filamentous atelocollagen Vitrigel complex to prevent cervical stenosis / closure after uterine conical resection was confirmed.

According to the present invention, it is possible to provide a more practical composite yarn, a method for producing the same, and a cervical treatment device.

Claims (10)

Step 1 of fixing the filamentous core material in the longitudinal direction of the plate-shaped hydrogel or plate-shaped vitrigel and then drying it.
Production of a composite yarn comprising the step 2 of obtaining a filamentous Vitrigel composite by twisting a plate-shaped hydrogel dried product or a plate-shaped Vitrigel dried product to which the filamentous core material is fixed while moistening it with an aqueous solution to form a filament. Method. The method for producing a composite yarn according to claim 1, wherein in the step 1, the plate-shaped hydrogel or the plate-shaped vitrigel is alternately penetrated and fixed on the front and back sides of the filamentous core material. The method for producing a composite yarn according to claim 1 or 2, further comprising a step 3 of drying the filamentous Vitrigel complex after the step 2 to obtain a dried filamentous Vitrigel complex. The method for producing a composite yarn according to claim 3, further comprising a step 4 in which the dried filamentous Vitrigel composite is irradiated with ultraviolet rays after the step 3, then rehydrated, and further dried. The method for producing a composite yarn according to any one of claims 1 to 4, wherein the hydrogel is an atelocollagen gel or a native collagen gel. The method for producing a composite yarn according to any one of claims 1 to 5, wherein the aqueous solution is an atelocollagen sol or a native collagen sol. A composite yarn obtained by twisting a plate-shaped hydrogel dried body or a plate-shaped Vitrigel dried body and having a thread-like core material. The composite thread according to claim 7, wherein the plate-shaped hydrogel dried body or the plate-shaped Vitrigel dried body has a sewn portion of the thread-shaped core material. The composite yarn according to claim 7 or 8, wherein the plate-shaped Vitrigel dried product is a plate-shaped atelocollagen Vitrigel dried product. A cervical treatment device comprising the composite yarn according to any one of claims 7 to 9.

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