JP2010029684A - Collagen material and process for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a collagen material that possesses physical properties to an extent that allows suturing while still maintaining the biochemical properties inherently possessed by collagen, and retains its shape for a certain amount of time even after application to the body; its production process; and, a medical material on which it is based. <P>SOLUTION: A collagen material is filled or had inside a substance having biocompatibility that can be degraded and absorbed in the body into a matrix of a non-woven fabric-like multi-element structure of collagen fibers having ultra-fine fibers of collagen as its basic unit. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention has biocompatibility in a matrix of a collagen ultrafine fibrous non-woven multilayer body, or in a non-woven matrix of a substance that is biocompatible and can be decomposed and absorbed in vivo, and The present invention relates to a collagen material containing a substance that can be decomposed and absorbed in a living body, a specific form of material containing the collagen material, a medical material made of the material, and a method for producing them.

  Among various materials used as medical materials, animal-derived collagen is excellent in biocompatibility and tissue compatibility, has low antigenicity, has an action of promoting differentiation and proliferation of host cells, has a hemostatic action, Since it is completely decomposed and absorbed in vivo, it has particularly excellent characteristics as a raw material for medical materials. Currently, types I to XIX have been discovered as animal-derived collagen, and among these, types I to V are used in various ways as medical materials. Among them, type I collagen which is useful as an extracellular matrix is most frequently used. These collagens are obtained from connective tissues of various organs such as bovine, porcine, avian and kangaroo skins, bones, cartilage, tendons, organs, acid solubilization method, alkali solubilization method, neutral solubilization method, Extracted and purified by an enzyme solubilization method or the like. Conventionally used extracted collagen has been decomposed to the order of monomers to oligomers at the molecular level, and is stored in powder or liquid form. Since these extracted collagens are in a state in which collagen molecules are decomposed to the order of monomers to oligomers, they become sols very quickly when they come into contact with water, body fluids or blood. For this reason, when molding and using these collagens as medical materials, the surface of a synthetic polymer material such as nylon or silicone is coated with collagen in order to have a certain degree of strength during processing. Alternatively, in order to maintain the shape for a certain period of time when applied to a living body, the molded product of extracted collagen is subjected to a chemical cross-linking treatment with a cross-linking agent, or a physical cross-linking treatment with radiation, electron beam, ultraviolet light, heat or the like It is attached to. Further, these extracted collagens are processed into yarns and used as medical yarns, and a wet spinning method is adopted for spinning.

  However, in the case of a material in which collagen is combined with a synthetic polymer material, the synthetic polymer material remains as a foreign substance in the living body and easily causes problems such as granulation and inflammation. It cannot be applied to organs. Further, even if the collagen material is subjected to a crosslinking treatment, the physical properties of the collagen material, in particular, the tear strength, hardly increase. Therefore, it has been impossible to process the collagen material into a medical material that requires suturing. In addition, when a cross-linking agent such as glutaraldehyde or epoxy is used, not only the toxicity of the cross-linking agent itself to the living body becomes a problem, but also the biochemical properties inherent in collagen, particularly the effect of promoting cell proliferation is lost. There are also drawbacks. Further, in the physical crosslinking treatment, the crosslinking rate is unstable, sufficient physical properties cannot be imparted, and it is difficult to carry out the crosslinking treatment so that the absorption rate in vivo can be controlled. On the other hand, spun collagen is not sufficient as a suture because it does not have sufficient strength.

  On the other hand, due to various diseases or trauma, when the surgical operation of the brain or various organs is performed and the surgical wound is closed, the incised brain dura mater, pericardium, pleura, peritoneum or serosa are closed by re-stitching However, there are many cases where a shortened portion due to a sewing margin occurs, or because the membrane is partially excised, the surgical wound cannot be completely closed, and a defect is formed in the membrane. If such a defect is left as it is, organs such as the brain, heart, lungs, and intestines escape from the area where the membrane is missing, causing serious damage, or water and air leaking from the organ and surrounding organs. Wound does not heal. In addition, since the organs adhere to surrounding tissues, the tissues are damaged and a good prognosis cannot be obtained. For this reason, conventionally, as a medical substitute membrane that can be used as a filling material for this defect portion, a freeze-dried human brain dura mater collected from a cadaver or a porous expanded polytetrafluoroethylene film material (EPTFE) (for tissue) Gore-Tex, registered trademark), polypropylene mesh, Teflon sheet, Dacron sheet and the like are used, and a copolymer of lactic acid and ε-caprolactone (50:50) is currently being developed. In addition, methods using the own thigh fascia, own pericardium, skin, muscle, etc. are unavoidably performed.

  However, the use of human dura mater not only has the drawback that the supplemented human dura mater and the brain parenchyma will cause adhesions and cause seizures after surgery, but also human cadaver There is an ethical problem of collecting from the brain, and there is a problem that the supply amount is very limited. Recently, Creutzfeldt-JakobDisease ( CJD) has been reported (Neurosurgical Surgery, 21 (2): 167-170, 1993), and human dura mater is not currently used in Japan. In addition, EPTFE materials are not decomposed in the living body and remain as foreign substances, so that they are susceptible to infection, and when they come into contact with living tissue, postoperative complications such as tissue cell degeneration occur. It is known that there are many. A copolymer of lactic acid and ε-caprolactone is biodegradable and gradually degrades after application to a living body, but it takes a long period of time of approximately 2 years to be decomposed and absorbed. Therefore, it may remain in the living body as a foreign substance for a while and cause inflammation in the tissue during the degradation process, thereby forming granulomas. Since this copolymer uses (L) lactic acid as a monomer, lactic acid may crystallize in the copolymer and cause inflammation. Furthermore, none of EPTFE and the copolymer of lactic acid and ε-caprolactone has an effect of promoting the regeneration of the biological membrane. In addition, the method using the own thigh fascia is a heavy burden for both patients and doctors.

  As the pericardium filling material, EPTFE, polypropylene mesh (Marlex), human dry brain dura mater, glutaraldehyde (GA) -treated bovine pericardium, etc. have been conventionally used. The membrane has the above-mentioned drawbacks. Polypropylene mesh also causes strong adhesion with the heart. Since the GA-treated bovine pericardium remains in vivo without being absorbed and decomposed, it causes deterioration due to calcification, and complications of interstitial pneumonia due to an immune reaction against the bovine pericardium have been observed.

  Polyglycolic acid nonwoven fabric and bovine pericardium are used as a pleural prosthesis or for auto-suture to reduce air leakage from the surgical site after lung surgery, but polyglycolic acid is opaque Therefore, it is difficult to use with auto-suturer. In addition, bovine pericardium has the disadvantages described above.

  For the above reasons, a collagen material that retains the biochemical properties inherent in collagen, has physical properties that can be sutured, and can retain its shape for a period of time after application to a living body, Production method thereof and medical materials based thereon, for example, artificial neural tube, artificial spinal cord, artificial esophagus, artificial trachea, artificial blood vessel, artificial valve, artificial medical substitute membrane such as alternative brain dura mater, artificial ligament, artificial tendon, surgical use There has been a demand for the development of sutures, surgical fillers, surgical reinforcements, wound protection materials, artificial skin, or artificial corneas. Among various medical materials, there is no particular ethical problem, and it is supplied stably. After application to the living body, it prevents adhesion of postoperative wounds, there is no risk of infection, and tissue degeneration is prevented. Development of materials that can be used as a medical substitute membrane that can control the degradation rate after application without causing it, and also has a regeneration promoting effect on biological membranes, particularly cerebral dura mater, pericardium, pleura, peritoneum or serosa Has also been strongly sought after in the clinical setting.

  As a result of earnest research to solve the above-mentioned problems, the present inventor has biocompatibility in a matrix of a non-woven multi-component structure having ultrafine fibers of collagen as a basic unit, and is decomposed and absorbed in vivo. In a non-woven matrix of a collagen material filled with or intervened with a substance that can be treated, or a substance that is biocompatible and can be decomposed and absorbed in vivo. It has been found that a collagen material filled with a substance that can be decomposed and absorbed in the body has particularly excellent properties as a medical material and has physical properties that can be sutured.

  That is, the present invention is a collagen material, and has biocompatibility and can be decomposed and absorbed in vivo in a matrix of a non-woven multi-component structure of collagen fibers whose basic unit is ultrafine fibers of collagen. It is characterized by being filled with or interposing a substance.

  The collagen material of the present invention has a basic structure as shown in FIG. 1, and the matrix of the non-woven multi-component structure of collagen fibers that forms the center of the collagen material has different sizes and shapes as described below. It is composed of various types of fibrous collagen.

  That is, the non-woven multi-component structure of collagen fibers has ultrafine fibers 15 having a diameter of 3 to 7 nm consisting of several collagen molecules as its basic unit, and the ultrafine fibers are bundled to form fine fibers 14 having a diameter of 30 to 70 nm. And the fine fibers are further bundled to form fine fibers 13a and 13b having a diameter of 1 to 3 μm, and then bundles of the fine fibers are alternately stacked vertically and horizontally to form fibers 12 having a diameter of 5 to 8 μm. Then, the fibers overlap in the coaxial direction to form a plate-like fiber 11 having a diameter of 20 to 50 μm. Finally, the plate-like fibers 11 are entangled randomly to form fibrous collagen as the maximum unit in the collagen ultrafine fibrous nonwoven multilayer 10.

  The collagen material of the present invention contains a substance having biocompatibility and capable of being decomposed and absorbed in a living body in a matrix of a multi-component structure of fibrotic collagen in which the plate-like fibers 11 are aggregated in a nonwoven fabric. It will be. Here, as the substance having biocompatibility and biodegradability and absorbability, a hydrochloric acid solution of the extracted collagen introduced into the matrix is subjected to freezing and lyophilization treatment, thereby newly adding in the matrix. Collagen fibers containing ultrafine fibers of collagen that have been fibrillated are representative, and the extracted collagen solution or hyaluronic acid solution is introduced into the matrix and the solution is air-dried (hereinafter referred to as collagen). The one derived from that is referred to as amorphous collagen).

  Furthermore, the collagen material of the present invention may be one in which a layer made of an air-dried solution of extracted collagen is further formed at a predetermined site on the surface of the collagen material.

  The collagen material of the present invention is based on the structure shown in FIG. 1, but depending on the use of the material, a sheet or tube made of a biodegradable absorbent material inside the non-woven multi-component structure of collagen fibers. You may further have a mesh-like intermediate material.

  Furthermore, the collagen material according to the present invention is a substance having biocompatibility and capable of being decomposed and absorbed in vivo, such as polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone. , A non-woven sheet or cylindrical body made of a material selected from the group consisting of a copolymer of glycolic acid and trimethylene carbonate, or a mixture of polyglycolic acid and polylactic acid, and is biocompatible with the matrix The substance that has the above and can be decomposed and absorbed in vivo may be the same collagen (collagen fiber or amorphous collagen) or hyaluronic acid as that filled in the matrix.

  Such a collagen material of the present invention can be produced by a process comprising the following steps.

[Basic process]
Step a
A collagen solution layer is formed by casting a hydrochloric acid solution of extracted collagen to a desired thickness. Here, the casting may be performed by appropriately selecting a known method according to the shape of the target collagen material. For example, when a membrane-like collagen material is to be obtained, a bat or the like may be used as the mold, and when a tubular collagen material is to be obtained, a wall-type mold may be used. (The same applies hereinafter).

Step b
The collagen solution layer is once frozen, kept in that state for a desired time, and then lyophilized (at this point, a multi-structure of collagen fibers based on the ultrafine fibers of collagen is formed, provided that the collagen solution layer is formed. The multi-component structure of collagen fibers is a matrix, and therefore, there are a large number of voids in the matrix (meaning a space into which a solution can invade, not a so-called pore).

Step c
The freeze-dried product is subjected to thermal dehydration crosslinking (giving predetermined fibrosis resistance in the next step to the fibrillated collagen constituting the matrix).

Step d
A hydrochloric acid solution of extracted collagen is introduced into the matrix subjected to the thermal dehydration cross-linking (as a result, voids in the matrix are filled with non-fibrotic collagen. It is not necessary that the total volume of the voids in the matrix is a specific method of introduction, for example, a method of sucking in a weak vacuum. If it is a thing, it is not limited to the same method).

Step e
The solution into which the extracted collagen solution has been introduced is frozen again, and kept in that state for a desired time, and then freeze-dried (this operation causes at least a part of the voids in the matrix to be newly fibrillated. It is filled with collagen fibers including ultrafine fibers of collagen, and exactly “filled” means collagen containing ultrafine fibers of collagen newly fibrillated within the voids in the matrix. It means that the fibers are entangled with each fiber of the fibrillated collagen constituting the matrix).

Step g
The lyophilized product is compressed.

Step i
The compressed product is subjected to thermal dehydration cross-linking (predetermined water resistance in a further step performed as a final product or as a modified method on collagen fibers including ultrafine fibers of newly formed collagen. Imparts solubility).

  Further, the following steps may be sequentially performed between step e and step g (completed with collagen fibers including ultrafine fibers of collagen in which the voids in the matrix are further fibrillated. It is preferable to fill the void as much as possible in order to obtain a desired strength as long as characteristics other than the strength required for the collagen material, such as “feel” and “flexibility”, are allowed. The void volume ratio shown is generally 50-60% of that of the matrix, about 10% after step e, and about 5% after step e of step d and step e. In normal applications of the collagen material, such as a medical substitute membrane, steps f1 and f2 need only be performed once).

Step f1
A hydrochloric acid solution of the extracted collagen is introduced into the matrix of the lyophilized product.

Step f2
The extracted collagen-introduced hydrochloric acid solution is frozen once again, kept in that state for a desired time, and then freeze-dried.

  Furthermore, the following steps may be performed between step g and step i.

Step h1
A collagen solution layer is formed at a predetermined site on the surface of the compressed material (specifically, the compressed material is extracted at least once with a hydrochloric acid solution of extracted collagen-preferably a collagen concentration of 2.0%). In the following, it is sufficient to immerse and air dry for a predetermined time.If you intend to use collagen materials that want to suppress the strength reduction due to intrusion of body fluid from the part as much as possible.Collagen solution layer to "predetermined part" In the formation of (3), a portion that does not require the formation of the collagen solution layer in the immersion of the extracted collagen in a hydrochloric acid solution may be blocked by a known appropriate means.

  In the case of performing this step h1, the following step h2, that is, the operation of “compressing the collagen layer again” may be performed before performing step i, which is the next step (relief on the surface of the collagen material). (If you want to improve the "texture" and "texture" by eliminating or reducing it).

  In addition, a hydrochloric acid solution or hyaluronic acid solution of extracted collagen (replaced “hydrochloric acid solution of extracted collagen” in the above step d as “hyaluronic acid solution”) is introduced into the matrix as a substance to be filled in the matrix. In the case of using a caulked one, the operations in the steps e to i are omitted, and the matrix into which the hydrochloric acid solution or hyaluronic acid solution of the extracted collagen is introduced is pressurized for a predetermined time in the matrix. Thermal dehydration crosslinking may be applied. Here, the reason why the matrix is pressurized is to suppress the influence of the air remaining in the matrix, that is, the occurrence of local “blowing” of the collagen material as much as possible.

  On the other hand, polyglycolic acid, polylactic acid, copolymers of glycolic acid and lactic acid, polydioxanone, glycolic acid and trimethylene carbonate are biocompatible and can be decomposed in vivo. When a material selected from the group consisting of a copolymer of polyglycolic acid and a mixture of polyglycolic acid and polylactic acid (hereinafter referred to as polyglycolic acid or the like) is cast in the hydrochloric acid solution of extracted collagen in step a above. Is performed in two steps, and a sheet-like or cylindrical mesh-like material made of the above-described material is simply interposed between the casting operations (specifically, the first-cast collagen solution layer is cast for the first time). The material is placed on the substrate-when a film-like material is obtained-). Since these materials have poor hydrophilicity, it is preferable to modify the surface with plasma or the like immediately before the interposition. In addition, when such a material is interposed in the matrix, since a predetermined strength is obtained by the combined effect of these materials and the matrix, in principle, the collagen fibrillated into the matrix It is not necessary to newly reinforce collagen fibers including ultrafine fibers (system configuration: partially changed step a → step b → step c → step g). However, it is preferable to form a collagen solution layer or a gelatin solution layer in the sense of adjusting the biochemical state of the compressed surface.

  In addition, as the collagen material of the present invention, the matrix is biocompatible and can be decomposed and absorbed in vivo, such as polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone. , A non-woven sheet or cylindrical body made of a material selected from the group consisting of a copolymer of glycolic acid and trimethylene carbonate, or a mixture of polyglycolic acid and polylactic acid, and is biocompatible with the matrix In the case where the same substance (collagen fiber or amorphous collagen) or hyaluronic acid as the one filled in the matrix is used as a substance that has a substance that can be decomposed and absorbed in vivo, as shown below What is necessary is just to manufacture. For convenience of explanation, a case where the substance introduced into the matrix is collagen and the collagen material to be created is a film-like material will be described below as an example.

Step j
Non-woven fabric made of a material selected from the group consisting of polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone, a copolymer of glycolic acid and trimethylene carbonate, or a mixture of polyglycolic acid and polylactic acid A hydrochloric acid solution of extracted collagen is introduced into a matrix composed of sheets, and then air-dried. This extraction collagen hydrochloric acid solution is introduced by immersing the matrix in a container in a slightly reduced pressure environment, for example, a water flow aspirator or the like in which the air therein is removed and the atmosphere is slightly lower than atmospheric pressure. A hydrochloric acid solution of extracted collagen having a predetermined concentration (stored in a separate container) is added and the state is maintained for a predetermined time. Specifically, this is done by allowing the hydrochloric acid solution of the extracted collagen to penetrate into the matrix. As is clear from this operation, a thin layer made of a hydrochloric acid solution of the extracted collagen is inevitably formed not only inside the matrix but also on the surface thereof.

Step l
A collagen solution layer is formed on at least one surface of the extracted collagen hydrochloric acid solution introduced and air-dried. Specifically, a solution obtained by introducing the extracted collagen hydrochloric acid solution into the hydrochloric acid solution of the extracted collagen and air-dried may be immersed and air-dried (preferably about 1 to 5 times. The result is collagen. In order to form this collagen solution layer only on one side, the other side may be blocked by an appropriate means and this step may be performed).

Step o
A gelatin solution layer is formed on the collagen solution layer. Specifically, a gelatin aqueous solution having a predetermined concentration may be applied or immersed in the gelatin aqueous solution. This step is an optional step required when adhesion prevention ability is required as the final product.

Step p
The gelatin solution layer formed is subjected to thermal dehydration crosslinking for a predetermined time (the purpose is to impart water solubility resistance to collagen fibers and the like in the above-described method).

  This is the basic step in this method, but there are variations in this method. One of them is the fibrosis of the collagen solution performed between step j and step l and between step l and step o, respectively. Specifically, similar to the method described above, a series of operations of freezing → holding → freeze drying is added to the extracted collagen and collagen solution layer introduced into the matrix (that for the former: addition step k, that for the latter). : Additional step m1). This additional step is a step employed when the strength of the matrix as the strength developing member to be used is weak (specifically, the thickness of the nonwoven fabric matrix is thin). Here, following the adding step m1, it is preferable to compress the freeze-dried product (adding step m2). This is because the overall strength increases.

  An additional step includes thermal dehydration crosslinking. The place of execution is between step l and step o, or between step m2 and step o (additional step n. The purpose is the same as described in the previous method for the water solubility resistance of the resulting product. Grant).

  The collagen material of the present invention includes an artificial neural tube, an artificial spinal cord, an artificial esophagus, an artificial trachea, an artificial blood vessel, an artificial valve, an artificial ligament, an artificial tendon, a surgical prosthetic material, a surgical reinforcing material, a wound protective material, and artificial skin. Although it can be used as the main constituent material of medical materials, it can be used almost as it is, and in addition, there is a great demand for it. In particular, biological membranes, especially brain dura mater, pericardium, pleura, peritoneum, Suitable for artificial medical substitute membrane applications such as serosa or cornea.

  The membrane-like material such as a surgical filling material, a surgical reinforcing material, and a wound protection material further has a gelatin gel layer or a hyaluronic acid layer that is crosslinked on one or both sides of the collagen material of the present invention. May be.

  The collagen material of the present invention can also be used as a thread material and a medical material comprising the thread material, such as a surgical suture. The filamentous material can be produced in the same manner as the other materials except that the collagen solution layer is formed in the above step a and the wet spinning is performed to obtain the collagen yarn first.

  The collagen material of the present invention can be widely used as various medical materials because it has the physical properties that can be sutured while retaining the biochemical properties inherent in collagen. In addition, the medical substitute membrane of the present invention can be sutured to a surgical wound as a material that can be supplied stably without ethical problems, and can be used as a material for filling a defect portion of a biological membrane or as an adhesion prevention material. In addition, it remains for a period of time until the biological membrane regenerates after suturing, and exhibits an anti-adhesion effect. On the other hand, it is gradually decomposed and absorbed, so that it remains in the living tissue for a long period of time and does not cause inflammation. Can be used.

The structure of the collagen material of this invention is shown.

10 ········· Collagen ultrafine fibrous non-woven multilayered body 11 ······· Plate-like fibers 12 ······ Fibers 13a, 13b ··· Fine fibers 14 ··· ..Fine fibers 15 ... Ultrafine fibers 20 ... Fiber collagen newly formed

  As the collagen used as the raw material of the collagen material of the present invention, various conventionally used collagens, preferably neutral solubilized collagen, acid solubilized collagen, alkali solubilized collagen or enzyme solubilized collagen may be used. it can. Among these, enzyme-solubilized collagen is obtained by treating insoluble collagen with an enzyme (for example, pepsin, trypsin, chymotrypsin, papain, pronase, etc.). By these treatments, a strong antigenic telopeptide portion in the collagen molecule is obtained. It is particularly preferred because it is removed to reduce antigenicity. The origin of these collagens is not particularly limited, and is generally type I collagen obtained by extraction and purification from the skin, bones, cartilage, tendons, organs, etc. of animals such as cows, pigs, rabbits, sheep, kangaroos, birds and fish. Alternatively, mixed collagens of type I and type III can be used.

  As described above, the collagen material of the present invention having a non-woven multi-dimensional structure of collagen fibers based on the ultrafine fibers of collagen as a matrix, and the collagen molecules conventionally used as various medical materials are in a monomer-oligomer state Compared with materials consisting only of non-fibrotic collagen with an amorphous structure dispersed in the former, the former retains its natural action on the living body, but has superior physical properties, particularly superior tear strength, compared to the latter. In addition, the absorption rate in vivo is sufficiently extended. Further, the filamentous material containing the collagen material of the present invention is the same as that described above except that the form thereof is a filamentous shape, and the medical material containing the collagen material of the present invention The material is obtained by processing a collagen material formed by filling a similar matrix and a substance having biocompatibility therein and capable of being decomposed and absorbed in vivo into various medical materials. Examples of the form of the medical material include a film shape, a tubular shape, a bag shape, and a lump shape. As the use of the present medical material, a medical substitute film can be mentioned in particular, and a medical substitute film having a gelatin gel layer or a hyaluronic acid layer cross-linked on one side or both sides can be particularly preferably mentioned. The thickness in this case is preferably about 0.1 to 5 mm.

  The gelatin gel layer that the medical substitute membrane of the present invention can have on the surface thereof has a function of hindering adhesion and proliferation of cells possessed by gelatin. It acts as an anti-adhesion layer to prevent the cells from spreading. Further, hyaluronic acid has an effect of improving the stability of collagen and also has an adhesion preventing ability. In the medical alternative membrane of the present invention, the gelatin gel layer or the hyaluronic acid layer needs to remain without being decomposed and absorbed for about 3 to 4 weeks after application to the living body. Cross-linked.

  In order to prepare the collagen material of the present invention, about 1N hydrochloric acid solution (pH about 3) of the above extracted collagen (of course after purification) (non-fibrosis in which collagen molecules are dispersed in a monomer-oligomer state) The collagen concentration is preferably about 0.5 to 3% by weight, particularly about 1% by weight), and is prepared in a container such as a petri dish by a conventional method such as pouring. Form a layer of collagen hydrochloric acid solution so that the liquid layer has an arbitrary uniform thickness (in the case of obtaining a tubular one, for example, a mold having a hollow wall portion may be used. It may be formed by coating on the surface of a substrate such as a mandrel, air drying, etc. Substances other than collagen that are biocompatible and can be decomposed and absorbed in vivo (intermediate into the collagen matrix). When polyglycolic acid or the like is used as a material), a sheet-like or cylindrical mesh-like material of the material itself may be interposed in the collagen hydrochloric acid solution layer during this operation. In addition, when such a material is used as a matrix (non-woven sheet-like material or cylindrical body), collagen such as amorphous collagen or fiberized collagen (hyaluronic acid or the like in some cases) is contained in the matrix. The matrix may be filled (soaked under a negative pressure, etc.) In the following description, the matrix is filled with collagen and the like, and further treatment for the filled collagen and the like are performed. Descriptions of further treatments to the applied matrix will be made with this non-collagen material unless otherwise stated There, biocompatible, and using a substance which can be degraded and absorbed in vivo as a matrix, it is also applied to the case of collagen material forms filling the collagen or the like in the matrix). The layer thickness of the collagen hydrochloric acid solution is determined according to the use of the collagen material of the present invention. For example, when used as a brain dura mater which is a medical substitute membrane, it is preferably about 1 to 5 cm, particularly about 1 to 3 cm. And This is preferably frozen at about −10 to −196 ° C., in particular about −20 ° C., for at least about 6 hours, preferably about 6 to 48 hours, in particular about 24 hours. By freezing, fine ice is formed between the collagen molecules dispersed in the hydrochloric acid solution, the collagen hydrochloric acid solution undergoes layer separation, and the collagen molecules rearrange to form fine fibers. When the freezing time is less than 6 hours, the collagen hydrochloric acid solution does not freeze sufficiently, and the collagen fibers are not sufficiently fibrillated and sufficient physical properties cannot be obtained. The frozen collagen hydrochloric acid solution is then lyophilized under vacuum, preferably at about -40 to -80 ° C, particularly about -80 ° C, preferably about 24 to 48 hours, particularly about 48 hours. By freeze-drying, fine ice between collagen molecules evaporates, and ultrafine fibers composed of collagen molecules become the basic unit, and are multidimensional from fine fibers, fine fibers, fibers, and plate fibers as described above. A non-woven collagen structure having a structure as described above is obtained. The operation of freezing → (holding) → freeze-drying this collagen hydrochloric acid solution is an indispensable operation for obtaining fibrillated collagen even in the case of a collagen material using a non-collagen material such as polyglycolic acid. It is.

Next, non-fibrotic collagen as one of materials that can be biocompatible in the matrix of the non-woven collagen structure obtained above and can be decomposed and absorbed in vivo, specifically, In the case of using polyglycolic acid or the like to introduce a hydrochloric acid solution of extracted collagen (as a material that has biocompatibility and can be decomposed and absorbed in vivo (as an intervening material in the collagen matrix) This operation is unnecessary in principle). Here, the collagen concentration of the solution is preferably 0.5% by weight or less. This is because the introduction is smooth and the introduced solution is more uniformly diffused in the matrix, and as a result, the remaining air in the matrix is smoothly removed. As a specific method for introducing the solution, since the matrix does not have such a large resistance, a method of sucking the collagen hydrochloric acid solution using a weak vacuum of about 50 cmH ₂ O, for example, an aspirator, is simple (of course. Other methods, for example, a method in which the collagen hydrochloric acid solution is allowed to naturally soak into the matrix by using a vacuum atmosphere in lyophilization which is the previous operation). In order to prevent the collagen fibers in the matrix formed in the previous operation from being dissolved in the collagen hydrochloric acid solution (which naturally contains water), the collagen hydrochloric acid solution is introduced. Prior to heating, the non-woven collagen layer is thermally dehydrated (heated under vacuum, preferably at about 105-150 ° C., especially at about 140 ° C., preferably about 6-48 hours, especially about 24 hours. However, when the temperature is less than about 105 ° C., sufficient crosslinking reaction does not occur, while when the temperature exceeds about 150 ° C., the collagen is denatured. It is preferable that the adjustment is made so that it remains for a period of time, which is the original purpose of this operation.

Next, the non-woven collagen structure into which the collagen hydrochloric acid solution has been introduced into the matrix is once frozen, kept in that state for a predetermined time, and then freeze-dried to convert the introduced collagen hydrochloric acid solution into fibrillar collagen. (As a result, a predetermined space in the void of the matrix is filled with newly fibrillated collagen, that is, the newly fibrillated collagen is entangled with the fibrillated collagen constituting the matrix. The voids in the matrix are filled with the newly fibrillated collagen, and the conditions are the same as in the above-mentioned freeze / freeze-drying, a substance that is biocompatible and can be decomposed and absorbed in vivo. If polyglycolic acid or the like is used (as an intervening material in the collagen matrix), this operation is also a principle. It required a is). Next, the matrix filled with a predetermined space of the voids is compressed with the newly fibrillated collagen (for example, 500 kgf / cm ² × 15 sec.), And then subjected to thermal dehydration crosslinking (conditions are the above-described heat Same as dehydration crosslinking).

  The collagen material of the present invention produced as described above has a one-point support tension of at least 30 N and a breaking resistance of at least 65 N in a dry state, and a one-point support tension of at least 1.4 N and a resistance to at least 6.5 N in a wet state. A material having a breaking tension (in the case of a thickness of 1 mm, having biocompatibility filled in a matrix and capable of being decomposed and absorbed in vivo-hereinafter referred to as a biodegradable absorbent material) Collagen fibers comprising ultrafine fibers of collagen newly microfibrinated in a matrix (hereinafter referred to as filled collagen fibers), or at least 10 N single point support tension and at least 25 N breaking resistance in the dry state, It has a single point support tension of at least 5N and a breaking strength of at least 15N in the wet state (thickness 1 mm, interspersed in the matrix) When the biodegradable material to be absorbed is polyglycolic acid, etc. When a non-collagen material is used as the matrix, it naturally exhibits an ability higher than this value), and has superior strength compared to conventional collagen materials Therefore, it can be processed into various medical materials and can be sutured (especially, in the latter collagen material, regardless of the skill of the operator's suture technique because the strength in the wet state becomes better, That is advantageous). When applied in vivo, it can retain its shape for about 3 to 8 weeks. Furthermore, the characteristic as a medical material which collagen originally has is also hold | maintained.

  If further enhancement of strength is desired, the operation of introducing the collagen hydrochloric acid solution into the matrix (conditions are the same as above) → freezing / freeze-drying (conditions are the same as above) is at least performed. You may repeat once (usually one time is enough).

The collagen material of the present invention can be obtained by the above steps. Next, if necessary, a non-fibrotic collagen layer is formed at a predetermined site on the surface of the collagen material. The specific method is as follows.
(1) The compressed collagen material is immersed in a hydrochloric acid solution of extracted collagen (collagen concentration: about 0.5 to 3% by weight, particularly about 2% by weight) and air-dried (at least once. Times are sufficient); and
(2) Thermal dehydration crosslinking is applied to a collagen material having a non-fibrotic collagen layer at a predetermined site on the surface (under the same conditions as described above).

  Here, a collagen material having a non-fibrotic collagen layer at a predetermined site on the surface may be further compressed between the operations (1) and (2). This is because the unevenness of the surface of the collagen material finally obtained is reduced, and the “texture” and “feel” are improved.

Heretofore, collagen hydrochloric acid solution is used as a raw material as a material that has biocompatibility to be filled in the matrix and can be decomposed and absorbed in the living body. After introducing the solution into the matrix, However, depending on the application, other materials such as the solution or the solution of hyaluronic acid may be simply air-dried after being introduced into the matrix. The reason why the filler is simply air-dried after introduction is that the strength of the wet state is reduced by the further penetration of the body fluid into the void when the medical material made of the collagen material of the present invention is applied to the living body. Since it is intended to suppress by eliminating the voids to some extent, the operation after introduction into the matrix and air drying operation is, in principle, only application of thermal dehydration crosslinking (however, in this operation, 200 kg / cm ² ), and in some cases, compression and the additional operation (1) may be performed prior to application of thermal dehydration crosslinking.

  Further, if necessary, the collagen material obtained in the above basic step or basic step + addition step is sterilized by treatment with ethylene oxide gas or irradiation with ultraviolet rays or γ rays.

  When the collagen material of the present invention prepared as described above is processed into a medical substitute film having a gelatin gel layer or a hyaluronic acid layer crosslinked on one side or both sides, it is preferable in the case of a gelatin gel layer. The gelatin gel layer is formed using an aqueous gelatin solution of about 2 to 70% by weight, particularly about 60% by weight, but when an aqueous solution of gelatin of about 60% by weight is used, it is preferably about 0.1 to 5 mm when wet. The gelatin gel layer is formed so as to have a thickness of about 1 mm, preferably about 0.06 to 3 mm, particularly about 0.6 mm when dried. The gelatin gel layer may be formed by any method such as coating and dipping. For example, an aqueous gelatin solution is poured into a container such as a petri dish so that it has a required thickness, and the above is applied as described above. The collagen material of the present invention thus obtained is placed and allowed to stand to gelatinize the gelatin. When gelatin gel layers are formed on both sides, the same treatment is performed on the other side to form gelatin gel layers on both sides.

  Next, the collagen material having a gelatin gel layer formed on one or both sides thus obtained is subjected to a crosslinking treatment. By carrying out the crosslinking treatment, the degradation absorption rate of the gelatin gel layer is controlled. As the crosslinking method, thermal dehydration crosslinking is preferable. In order to leave the gelatin gel layer for about 3 to 4 weeks after application to the living body, the collagen material on which the gelatin gel layer has been formed is preferably at about 105 to 150 ° C, particularly about 140 ° C, preferably about It is subjected to a thermal dehydration cross-linking treatment for 6 to 48 hours, particularly about 24 hours (less than about 105 ° C., a crosslinking reaction does not occur sufficiently, and if it exceeds about 150 ° C., collagen is denatured, which is not preferable).

  The cross-linked gelatin gel layer formed in this way has a role of preventing the collagen portion of the medical substitute membrane from adhering to surrounding tissues until each biological membrane is regenerated. The gelatin gel layer remains without being decomposed and absorbed for about 3 to 4 weeks until the biological membrane stretches and regenerates from the periphery and plugs the defective portion of the membrane.

  On the other hand, when the hyaluronic acid layer is formed, the present invention obtained as described above is preferably used by using about 0.5 to 2.0 mg / ml, particularly about 1.0 mg / ml sodium hyaluronate aqueous solution. A sodium hyaluronate aqueous solution layer is formed on one or both surfaces of the collagen material by a method such as coating or dipping, and this aqueous solution layer is air-dried to form a hyaluronic acid layer. The sodium hyaluronate aqueous solution layer remains without being decomposed and absorbed for about 3 to 4 weeks until the biological membrane grows and regenerates from the periphery of the defective portion of the membrane to be repaired, and closes the defective portion of the membrane. The thickness is preferably about 0.5 to 4.0 mm, especially about 2 mm when wet, and preferably about 0.1 to 2.0 mm, especially about 1.0 mm when dry. (In the case of an aqueous solution of about 1.0 mg / ml). In order to fix hyaluronic acid to the surface of the collagen material to form a hyaluronic acid layer, a second crosslinking treatment is further performed. In the case of hyaluronic acid, it is preferable to perform a crosslinking treatment with water-soluble carbodiimide (WSC). . In this case, it is preferable to crosslink the carboxyl group of collagen and the amino group of hyaluronic acid by previously mixing WSC in a sodium hyaluronate aqueous solution and applying it to the collagen material together with sodium hyaluronate. The concentration of WSC contained in the aqueous sodium hyaluronate solution is preferably about 5 to 20 mg / ml, particularly about 8 to 15 mg / ml. Prepare an aqueous solution containing this sodium hyaluronate and WSC, stir well, apply to both or one side of the collagen material so that the thickness is preferably about 1 mm, and air dry to form a hyaluronic acid layer To do.

  Since the collagen material of the present invention has excellent strength, it can also be used as a surgical suture. In the filamentous material containing the collagen material of the present invention, the first step of the preparation method of the collagen material is the extraction (of course after purification) about 1N hydrochloric acid solution (pH about 3) (the collagen concentration is preferably about 3%). Instead of 0.5 to 3% by weight, in particular about 1% by weight), which is wet spun by jetting it into a coagulation bath from a nozzle with a pore size of preferably about 50 to 300 μm, in particular about 100 μm. The other steps can be prepared by carrying out in the same manner as the method for preparing the collagen material.

  The collagen material of the present invention prepared as described above has excellent physical properties, particularly excellent tear strength, compared to conventional extracted collagen materials. It can be processed into medical material and can be sutured. In addition, when applied in vivo, the collagen material of the present invention does not dissolve immediately but can retain its shape for about 3 to 8 weeks. For these reasons, the collagen material of the present invention can be used as various medical materials by further processing into a film shape, a tubular shape, a bag shape, a lump shape or the like according to the application. For example, artificial neural tube, artificial spinal cord, artificial esophagus, artificial trachea, artificial blood vessel, artificial valve, artificial substitute membranes such as artificial dura mater, artificial ligament, artificial tendon, surgical suture, surgical filler, surgical It can be used as a reinforcing material, wound protection material, artificial skin or artificial cornea, etc., to promote recovery and regeneration of the damaged living tissue. Alternatively, it can also be used as a compression hemostatic material or a three-dimensional medium in cell culture.

  In addition, the medical substitute membrane made of the medical material of the present invention obtained as described above prevents adhesion between the organ and the surrounding tissue in the membrane defect portion by filling the membrane defect portion after various surgical operations. Can be used for. In the medical alternative membrane of the present invention, the gelatin gel layer or hyaluronic acid layer is formed on one side or both sides so that the crosslinked gelatin gel layer or hyaluronic acid layer faces the side in contact with the surrounding tissue that needs to prevent adhesion. The medical substitute membrane of the present invention is used. When this medical substitute membrane is used as a substitute membrane for the pericardium, a substitute membrane in which a gelatin gel layer or a hyaluronic acid layer is formed on both sides, and when used as a substitute membrane for the pleura, peritoneum or serosa, on one side An alternative film formed with a gelatin gel layer or hyaluronic acid layer is used so that the gelatin gel layer or hyaluronic acid layer faces the side in contact with the surrounding tissue. When used as an alternative membrane for brain dura mater, any of alternative membranes in which a gelatin gel layer or a hyaluronic acid layer is formed on both sides or one side can be used. When an alternative membrane having a gelatin gel layer or hyaluronic acid layer formed on one side is used, the gelatin gel layer or hyaluronic acid layer is used so as to face the side in contact with the brain parenchyma. Furthermore, in addition to the above uses, it can also be used as a reinforcing material for sutures of blood vessels, gastrointestinal tract, trachea, ureter, bladder, mucous membrane, periodontal ligament and the like.

  As described above, the medical substitute membrane of the present invention as a material for filling a defect portion of a biological membrane can be used as a substitute membrane for the brain dura mater, pericardium, pleura, peritoneum or serosa. When this substitute membrane is applied to a surgical wound, the biological membrane such as cerebral dura mater, pericardium, pleura, peritoneum, or serosa remaining around the wound is removed from the contact area with the substitute membrane. While the tissue is in contact with the gelatin gel layer or the hyaluronic acid layer, the invasion / extension of the cells is prevented, and adhesion is prevented. The replacement membrane is blocked by the regenerated biological membrane, and the substitute membrane is decomposed and absorbed by the living body and completely disappears.

  As described above, the collagen material of the present invention and the medical material containing the collagen material of the present invention, particularly the medical substitute membrane, have superior tear strength compared to the conventional collagen material and the medical material containing the collagen material, When the medical material is used as, for example, an artificial bladder, further strength may be required. Therefore, as the collagen material of the present invention and the medical material containing the collagen material of the present invention, a sheet-like mesh-like intermediate material made of a biodegradable and absorbable material may be interposed in the matrix. Biodegradable and absorbable materials include polyglycolic acid, polylactic acid, copolymers of glycolic acid and lactic acid, polydioxanone, copolymers of glycolic acid and trimethylene carbonate, or mixtures of polyglycolic acid and polylactic acid Can do. The sheet-like mesh-like intermediate material made of these materials has, for example, a mesh sheet, a woven fabric, a non-woven fabric, a sheet with punch holes formed therein having a pore diameter of about 50 to 2,000 μm, and the thickness thereof. Is about 100 to 2,000 μm, for example, but the pore diameter and thickness of the mesh-like intermediate material may be appropriately changed depending on the application.

  In order to prepare such a collagen material in which a sheet-like mesh-like intermediate material composed of a biodegradable and absorbable material is interposed in a matrix, a collagen hydrochloric acid solution, which is the first step in the method for preparing the collagen material, is described above. The collagen hydrochloric acid solution layer may be subjected to subsequent steps such as freezing and freeze drying while the sheet-like mesh-like intermediate material is immersed in the hydrochloric acid solution of collagen cast when forming the layer. . However, in the case of this form, it is not necessary in principle to fill the matrix with new collagen ultrafine fibers, so the steps required for the filling, for example, additional introduction of hydrochloric acid solution of extracted collagen → refreezing → refreezing The drying step and the final thermal dehydration crosslinking step need not be performed. On the other hand, other additional steps, i.e. the formation of additional layers on the surface (one or both sides) of the collagen material, e.g. the formation of collagen solution layers, gelatin gel layers or hyaluronic acid layers (in principle after these operations The thermal dehydration crosslinking) may be performed as necessary.

  Hereinafter, the present invention will be described by way of an example in which a membranous collagen material is produced.

Example 1
Using collagen derived from pig skin, a 1N hydrochloric acid solution of extracted collagen (collagen concentration: 1% by weight) was prepared and poured into a petri dish to obtain a collagen solution layer having a thickness of 18 mm. This was frozen at −20 ° C. for 24 hours and then lyophilized at −80 ° C. for 48 hours. Next, the freeze-dried collagen fiber multi-component structure (hereinafter simply referred to as multi-component structure) is subjected to thermal dehydration crosslinking treatment at 140 ° C. for 24 hours under vacuum, and then the interior of the multi-component structure is formed with a running water aspirator. 1N hydrochloric acid solution (collagen concentration: 0.5% by weight) of extracted collagen is introduced into the multi-component structure by generating a negative pressure (50 cmH ₂ O) in the multi-component structure, and the voids inside the multi-component structure are made non-fibrous After filling with collagen and then freezing and freeze-drying under the same conditions as above (operation to reduce voids in the multi-component structure with newly formed fibrotic collagen), the thickness is compressed to 1 mm ( 500 kgf / cm ² ), and then the compressed product is immersed in a 1N hydrochloric acid solution (collagen concentration: 2% by weight) of extracted collagen and air-dried (formation of a collagen solution layer. The number of times is the same as above). Condition The collagen material of the present invention was obtained by performing the thermal dehydration crosslinking treatment.

  About the collagen material of this invention prepared above, the one-point support tension | tensile_strength and fracture | rupture-proof tension | tensile_strength were measured by the method described below in the dry state and the wet state. The results are shown in Table 1.

  A strip-shaped test piece having a size of 10 × 25 mm was prepared. Using a digital push-pull gauge (AIKOHENGINEERING CPU gauge) in a constant temperature and humidity chamber at 25 ° C and 50% humidity, the test piece is tensioned uniformly at the ISO B speed (5 mm / min) in the major axis direction as follows. And the maximum tension until the membrane broke was measured both in a dry state and in a wet state (hydrated for 1 minute or 30 minutes in physiological saline at 37 ° C.).

1. One-point support tension A part 5 mm inside from the center of one end of the test piece was fixed by stitching with a thread (4-O proline or 2 dexons), and the other end was uniformly held by a clip to apply tension.

2. Fracture resistance Tension was applied by holding both ends of the test piece uniformly with clips.
The results are shown in Table 1 (in the table, “wet state A” is data with a hydration time of 1 minute, and “wet state B” is data with a hydration time of 30 minutes).

Example 2
A collagen material of the present invention was obtained in the same manner as in Example 1 except that the number of formation of the collagen solution layer on the compressed product was five. With respect to the collagen material, the one-point supporting tension and breaking resistance were measured in a dry state and a wet state by the same method as in Example 1. The results are shown in Table 1.

Example 3
Between the second freeze-drying operation and the compression operation, an operation for reducing voids inside the multi-component structure in this order by thermal dehydration crosslinking treatment and newly formed fibrotic collagen under the same conditions as those described above. The one-point support tension and breaking resistance were measured in a dry state and a wet state by the same method as in Example 1 except that it was performed and the collagen solution layer was not formed on the compressed one. did. The results are shown in Table 1.

Example 4
A collagen material of the present invention was obtained in the same manner as in Example 1 except that the collagen solution layer was not formed on the compressed product. With respect to the collagen material, the one-point supporting tension and breaking resistance were measured in a dry state and a wet state by the same method as in Example 1. The results are shown in Table 1.

Example 5
At the time of forming the first collagen solution layer, a polyglycolic acid mesh sheet (aperture: 1 mm) preliminarily subjected to plasma discharge treatment was interposed, and the multi-structure was formed by newly formed fibrotic collagen. A collagen material of the present invention was obtained in the same manner as in Example 1 except that the operation for reducing the voids inside the body was not performed. With respect to the collagen material, the one-point supporting tension and breaking resistance were measured in a dry state and a wet state by the same method as in Example 1. The results are shown in Table 1.

Example 6
Similar to Example 5 except that instead of forming the collagen solution layer on the compressed material, a gelatin gel layer was formed on one surface of the compressed material (15% gelatin aqueous solution was applied and dried on the surface). Thus, the collagen material of the present invention was obtained. With respect to the collagen material, the one-point support tension and fracture resistance were measured in a dry state and a wet state by the same method as in Example 1. The results are shown in Table 1.

Example 7
A collagen material of the present invention was obtained in the same manner as in Example 6 except that the gelatin gel layer was formed on both sides of the compressed one. With respect to the collagen material, the support tension and breaking resistance were measured in a dry state, and the wet tension and breaking resistance were measured in a dry state and a wet state. The results are shown in Table 1.

  As shown in Table 1, it was confirmed that the collagen material of the present invention has excellent physical properties that endure suturing. In the table, “reference” refers to data of only a mesh sheet of polyglycolic acid.

Example 8
A polyglycolic acid non-woven fabric (2 plies -thickness: 0.20 mm, porosity: 88.75%-) subjected to plasma discharge treatment in a container and a sufficient amount of an extracted collagen hydrochloric acid solution (collagen concentration: 1%), the container is accommodated in a desiccator, the inside of the desiccator is depressurized (-50 cmH ₂ O) with a water aspirator, and the state is maintained for a predetermined time (1 to 2 minutes). The extract was thoroughly soaked with the extracted collagen hydrochloric acid solution, and the nonwoven fabric was taken out of the desiccator and allowed to air dry. The air-dried nonwoven fabric is subjected to the operations of freezing → holding → freeze drying → thermal dehydration crosslinking under the same conditions as in Example 1, and then immersed in an extracted collagen hydrochloric acid solution (collagen concentration: 1%) and air-dried. Repeated twice, an amorphous collagen solution layer was formed on the surface of the nonwoven fabric filled with fibrotic collagen. Subsequently, a gelatin gel layer was formed on the surface of the amorphous collagen solution layer (executed by repeating immersion in a 20% gelatin aqueous solution and air drying twice), followed by thermal dehydration crosslinking under the same conditions as in Example 1. To obtain a collagen material of the present invention.

Example 9
4 plies (thickness: 0.55 mm, porosity: 75.1%) used as the non-woven fabric of polyglycolic acid and the non-woven fabric in which the extracted collagen hydrochloric acid solution was sufficiently impregnated was frozen and held. The collagen material of the present invention was obtained in the same manner as in Example 8 except that the series of operations of freeze drying → thermal dehydration crosslinking was not performed. In addition, since it was confirmed that the strength was obtained in the preliminary test, a further detailed strength test was not performed as in the case of Example 8.

Claims (28)

  Collagen material in which a matrix of a non-woven multi-component structure of collagen fibers having ultrafine collagen fibers as a basic unit is filled with or interspersed with a biocompatible substance that can be decomposed and absorbed in the living body .   A substance which is filled in the matrix and has biocompatibility and can be decomposed and absorbed in vivo is newly fibrillated from the extracted collagen hydrochloric acid solution introduced into the matrix by freezing and freeze-drying operations. The collagen material according to claim 1, which is a collagen fiber containing ultrafine fibers of collagen.   Substances intervening in the matrix and having biocompatibility and capable of being decomposed and absorbed in vivo are polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone, glycolic acid and triglyceride. A methylene carbonate copolymer or a mixture of polyglycolic acid and polylactic acid is selected from the group consisting of a mesh-like sheet or cylinder, or a non-woven sheet or cylinder. Item 2. The collagen material according to Item 1.   The non-woven multi-component structure of the collagen fibers is composed of randomly intertwined collagen plate fibers having a diameter of 20 to 50 μm, and the plate fibers have collagen fibers having a diameter of 5 to 8 μm. The fibers are composed of overlapping layers in the same direction, and the fibers are composed of bundles of bundles of collagen fibrils having a diameter of 1 to 3 μm, which are alternately stacked vertically and horizontally. The fibrils have a diameter of 30 to 70 nm. A collagen fine fiber is a bundle, and the microfiber is a bundle of collagen ultrafine fibers having a diameter of 3 to 7 nm consisting of several collagen molecules. The collagen material according to 2 or 3.   A collagen material obtained by filling a non-woven matrix of a substance having biocompatibility and capable of being decomposed and absorbed in vivo with a substance having biocompatibility and capable of being decomposed and absorbed in vivo.   The materials that constitute the nonwoven matrix and have biocompatibility and can be decomposed and absorbed in vivo are polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone, glycolic acid and triglyceride. The collagen material according to claim 5, wherein the collagen material is selected from the group consisting of a copolymer of methylene carbonate or a mixture of polyglycolic acid and polylactic acid.   A substance that is biocompatible and that can be decomposed and absorbed in vivo, which is filled in the matrix, is amorphous collagen obtained by air-drying a hydrochloric acid solution of extracted collagen introduced into the matrix, or the extraction. 6. The collagen material according to claim 5, wherein the collagen material is a collagen fiber containing fine fibers of collagen that are fibrillated by freezing and freeze-drying operations from a hydrochloric acid solution of collagen.   The collagen fibers are composed of randomly entangled collagen plate fibers having a diameter of 20 to 50 μm, and the plate fibers are formed by overlapping collagen fibers having a diameter of 5 to 8 μm in the coaxial direction. The fibers are made by laminating bundles of collagen fine fibers having a diameter of 1 to 3 μm alternately and vertically, and the fine fibers are bundled with collagen fine fibers having a diameter of 30 to 70 nm. The collagen material according to claim 7, wherein the fine fibers are made of bundles of ultrafine fibers of collagen having a diameter of 3 to 7 nm consisting of several collagen molecules. .   A single point support tension of at least 30 N and a break strength of at least 65 N in the dry state, a single point support tension of at least 1.4 N in the wet state, and a break strength (at a thickness of 1 mm) of at least 6.5 N. The collagen material according to 2 or 4.   5. A single point support tension of at least 10N and a break strength of at least 25N in the dry state, a single point support tension of at least 5N in the wet state and a break strength of at least 15N (when the thickness is 1 mm). The collagen material according to any one of 6 to 8. A method for producing a collagen material comprising performing at least the following steps in the order described:
a. Casting a collagen solution of extracted collagen to a desired thickness to form a collagen solution layer;
b. Freeze the collagen solution layer once, hold it for a desired time, and then freeze-dry;
c. The freeze-dried product is subjected to thermal dehydration crosslinking for a predetermined time;
d. Introducing a hydrochloric acid solution of the extracted collagen into the matrix of the thermally dehydrated crosslink;
e. The one introduced with the extracted collagen solution is once frozen, kept in that state for a desired time, and then freeze-dried;
g. Compress the lyophilized one; and i. The compressed product is subjected to thermal dehydration crosslinking for a predetermined time. The method according to claim 11, wherein the following steps are sequentially performed between the step e and the step g.
f1. Reintroducing the hydrochloric acid solution of the extracted collagen into the matrix of the lyophilized one;
f2. The product into which the extracted collagen solution has been introduced is once frozen, kept in that state for a desired time, and then freeze-dried. The method according to claim 11 or 12, wherein the following steps are performed between step g and step i.
h1. A collagen solution layer is formed at a predetermined site on the surface of the compressed product. 14. The method according to claim 13, wherein the following steps are performed between step h1 and step i.
h2. The collagen solution layer is compressed.   The method according to any one of claims 11 to 14, wherein a freeze holding time during the freezing operation in the steps b, e and f2 is 6 to 48 hours.   The method according to any one of claims 11 to 14, wherein the collagen concentration of the hydrochloric acid solution of the extracted collagen in the steps d and f1 is 0.5% or less.   The method according to claim 13 or 14, wherein the collagen concentration in the hydrochloric acid solution of extracted collagen for forming the collagen solution layer in the step h1 is 2.0% or less.   In the above step a, the hydrochloric acid solution of the extracted collagen is cast in two steps, and during both casting operations, polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone, glycolic acid and triglyceride are added. A mesh sheet or cylinder made of a material selected from the group consisting of a copolymer of methylene carbonate or a mixture of polyglycolic acid and polylactic acid is interposed, and the above step c is followed by the above step g. The method according to claim 11 or 15, wherein the step i is not further performed. The method of claim 18, further comprising the following steps after the step g.
h3. Forming a collagen solution layer or a gelatin solution layer on at least one side of the compressed one;
h4. Thermal dehydration crosslinking is performed on the collagen solution layer or gelatin solution layer.   The method according to claim 19, wherein the collagen concentration of the hydrochloric acid solution of the extracted collagen for forming the collagen solution layer is 2% or less.   The method according to claim 19, wherein the gelatin concentration of the aqueous gelatin solution for forming the gelatin solution layer is 5 to 25%. A method for producing a collagen material comprising performing at least the following steps in the order described:
j. Non-woven fabric made of a material selected from the group consisting of polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, polydioxanone, a copolymer of glycolic acid and trimethylene carbonate, or a mixture of polyglycolic acid and polylactic acid Introduce a hydrochloric acid solution of extracted collagen into the matrix of the sheet or cylinder and then air dry;
l. Forming a collagen solution layer on at least one surface of the extracted collagen hydrochloric acid solution introduced and air-dried;
o. Forming a gelatin solution layer on the collagen solution layer; and p. The gelatin solution layer formed is subjected to thermal dehydration crosslinking for a predetermined time. The method according to claim 22, wherein the following step k is performed between the step j and the step l, and the following step m is performed between the step l and the step o.
k. The one into which the extracted collagen has been introduced is once frozen, kept in that state for a desired time, and then lyophilized; and m1. Once the collagen solution layer is formed, it is frozen, kept in that state for a desired time, and then lyophilized; and m2. The lyophilized product is compressed. The method according to claim 22 or 23, wherein the following step n is performed between the step l and step o or between the step m2 and step o:
n. The collagen solution layer-formed one or the freeze-dried one is subjected to thermal dehydration crosslinking for a predetermined time.   The method according to any one of claims 22 to 24, wherein the collagen concentration of the hydrochloric acid solution of the extracted collagen in steps j and l is 2.0% or less.   The method according to any one of claims 22 to 24, wherein the gelatin concentration of the aqueous gelatin solution in step o is 5 to 25%.   The produced collagen material has a one-point support tension of at least 30 N and a breaking resistance of at least 65 N in the dry state, a single-point support tension of at least 1.4 N in the wet state, and a breaking resistance of at least 6.5 N (thickness 1 mm). The method according to claim 11, further comprising:   The produced collagen material has a one-point supporting tension of at least 10N and a breaking strength of at least 25N in a dry state, and a one-point supporting tension of at least 5N in a wet state and a breaking strength of at least 25N (when the thickness is 1 mm). 27. A method according to any one of claims 18 to 26.

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