JP2022002604A - Biological tissue prosthesis - Google Patents

Abstract

To provide a biological tissue prosthesis excellent in a shape holding performance.SOLUTION: There is provided a biological tissue prosthesis including a porous carrier including gelatin, and a hyaluronate compound, in which, by setting the mass of the hyaluronate compound existing per 1 cm3 of the biological tissue prosthesis, to become greater than 0.3 mg, the porous carrier including gelatin is effectively reinforced by the hyaluronate compound, for improving a shape holding performance. Inventors have found that, on the other hand, when the mass of the hyaluronate compound existing per 1 cm3 of the biological tissue prosthesis is equal to or greater than 16.0 mg, the shape holding performance is reduced relative to the biological tissue prosthesis in prior arts. Therefore, the biological tissue prosthesis excellent in the shape holding performance can be provided, by the biological tissue prosthesis in which the mass of the hyaluronate compound existing per 1 cm3 of the biological tissue prosthesis is greater than 0.3 mg and less than 16.0 mg.SELECTED DRAWING: None

Description

The present invention relates to a biological tissue filling material having excellent shape retention performance.

As a supplementary material used in regenerative medicine that promotes tissue regeneration by supplementing a defective portion of a living tissue, as disclosed in Japanese Patent Application Laid-Open No. 2008-228812 (Patent Document 1), gelatin has been conventionally used. A biological tissue filling material has been proposed in which the surface of a porous carrier made of a material is coated with a hyaluronic acid-based compound. Then, as a specific example thereof, the example of Patent Document 1 was prepared by applying a sulfated hyaluronic acid aqueous solution to a porous carrier made of gelatin having a diameter of about 12 mm, a thickness of about 3 mm, and a porosity of about 90%. A biological tissue filling material having a maximum of 100 μg of sulfated hyaluronic acid is disclosed.

When the biological tissue filling material disclosed in Patent Document 1 was additionally tested as Comparative Example 1 in the item of Examples described later by the applicant of the present application, among the living tissue filling materials disclosed in Cited Document 1, ^{The mass of the hyaluronic acid compound present per 1 cm 3 of the} porous carrier made of gelatin in the biological tissue filling material having the highest content of the hyaluronic acid compound is 0.3 mg at the maximum (the above-mentioned porous carrier made of gelatin is used). With 100 μg of sulfated hyaluronic acid).

Japanese Unexamined Patent Publication No. 2008-228812 (Claims, 0013, 0020, Examples, FIGS. 2 to 4, etc.)

A living tissue filling material according to the prior art, that is, a living tissue filling material in which a hyaluronic acid-based compound is present on the surface of a porous carrier containing gelatin, such as the living tissue filling material disclosed in Patent Document 1. As a result, it was found that the biological tissue filling material according to the prior art has the following problems. When the living tissue filling material according to the prior art is placed in an environment where water is present, such as in a living body, the living tissue filling material easily absorbs water and unintentionally swells to cause a structural change (hereinafter, the shape retention performance is improved). As a result (referred to as inferior), there was a risk that the biological tissue could not be regenerated as intended.

An object of the present invention is to provide a biological tissue filling material having excellent shape retention performance, which can solve the above-mentioned problems.

The present invention is "a living tissue filling material having a porous carrier containing gelatin and a hyaluronic acid-based compound, and the hyaluronic acid-based compound is present on the surface of the porous carrier, and the living tissue filling material 1 cm ³ The mass of the hyaluronic acid-based compound present in the vicinity is more than 0.3 mg and less than 16.0 mg, which is a living tissue filling material. "

The applicant of the present application has adjusted the mass of the hyaluronic acid compound present per ^{1 cm 3 of the} biological tissue filling material in the biological tissue filling material in which the hyaluronic acid compound is present on the surface of the porous carrier containing gelatin. , It has been found that it is possible to provide a living tissue filling material having superior shape retention performance as compared with the living tissue filling material according to the prior art such as the living tissue filling material disclosed in Patent Document 1.

Specifically, by increasing ^{the mass of the hyaluronic acid-based compound present per 1 cm 3 of the} biological tissue filling material to more than 0.3 mg, the porous carrier containing gelatin is effectively reinforced by the hyaluronic acid-based compound. We have found that the shape retention performance can be improved. It is considered that the reason for this is that the hyaluronic acid-based compound forms a film-like or porous network inside the porous carrier, so that the structural change of the porous carrier is suppressed.

On the other hand, initially, it was thought that the larger the mass, the more effective the reinforcement of the porous carrier containing gelatin by the hyaluronic acid compound, but the hyaluronic acid present per ^{1 cm 3 of the biological tissue filling material.} On the contrary, when the mass of the compound is 16.0 mg or more, it has been found that the shape retention performance is lower than that of the biological tissue filling material according to the prior art. The reason for this has not been completely clarified, but when a porous carrier containing gelatin containing a large amount of hyaluronic acid-based compound absorbs water, the hyaluronic acid-based compound swells and the living tissue It is considered that this is because the three-dimensional structure of the filling material is deformed or destroyed and the shape retention performance is deteriorated. Therefore, it has been found that the shape retention performance can be prevented from deteriorating by reducing the mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the} biological tissue filling material to less than 16.0 mg.

From the above, by satisfying the configuration according to the present invention, it is possible to provide a biological tissue filling material having excellent shape retention performance.

In the present invention, various configurations such as the following configurations can be appropriately selected. Unless otherwise specified, the various measurements described in the present invention were carried out under atmospheric pressure. Moreover, the measurement was performed under the temperature condition of 25 ° C. Then, unless otherwise specified, the various measurement results described in the present invention were obtained by measurement up to a value one digit smaller than the desired value, and the value to be obtained was calculated by rounding off the value. As a specific example, if the value up to the first decimal place is the value to be obtained, the value up to the first decimal place is calculated by finding the value up to the second decimal place by measurement and rounding off the obtained value to the second decimal place. Then, this value was used as the desired value. Then, each upper limit value and each lower limit value described below can be arbitrarily combined to determine a numerical range that can be adopted.

The biological tissue filling material of the present invention comprises a porous carrier containing gelatin.
The term "gelatin" as used in the present invention refers to collagen in which amino acids are peptide-bonded to each other and is solubilized by chemical treatment with an acid or an alkali and solubilized by heat denaturation, or a modified product thereof. The type can be selected as appropriate, such as GLS250 from Nitta Gelatin Co., Ltd., pig skin gelatin (A type) or beef bone gelatin (B type), Medigelatin from Nippi Co., Ltd., and GELITA-SPON® POWDER from gelita medical. , Sigma-Aldrich's gelatin from powder skin and the like can be adopted.

The porous carrier referred to in the present invention refers to a structure having voids such as a cloth (fiber web or non-woven fabric, woven fabric, knitting, etc.), a porous film, or a foam. Since the living tissue filling material according to the present invention is provided with a porous carrier containing gelatin, it has high voids and is highly biocompatible, and is flexible and bulky, so that it is suitable as a living tissue filling material. In particular, a porous carrier in which fibers are randomly entangled, such as a fiber web or a non-woven fabric, is preferable because it can provide a biological tissue filling material that is more flexible and bulky and has excellent shape retention performance.

Whether or not the porous carrier contains gelatin can be determined by using a known analytical method. As an example, when a measurement target such as a biological tissue filling material or a porous carrier provided with a linear polymer of amino acids is subjected to an analysis method for measuring the content of hydroxyproline, and the measurement target contains hydroxyproline, the measurement target is subjected to the analysis method. , It can be determined that the measurement target contains gelatin. As a measurement kit capable of performing such analysis, for example, Hydroxyproline Assay Kit manufactured by CBL can be used.

If the manufacturing process of the living tissue filling material or the porous carrier is known, whether or not the porous carrier contains gelatin and whether the living tissue filling material contains gelatin is contained from the manufacturing process. Whether or not the carrier has a porous carrier, and the content and ratio of gelatin can be calculated.

The porous carrier may contain a component other than gelatin as a component. Other such components include, for example, biological constituents such as collagen, collagen peptide, alginic acid, sodium alginate, elastin, heparan sulfate, amino acids, vitamins, polyglycolic acid, polyvinyl alcohol, polyethylene glycol, polycaprolactone, poly. Examples thereof include synthetic polymers such as lactic acid.

However, the larger the mass of gelatin in the mass of the components constituting the porous carrier, the more the biocompatibility tends to be provided. Therefore, the percentage of the mass of gelatin in the mass of the components constituting the porous carrier is preferably 1% by mass or more, preferably 10% by mass or more, and preferably 50% by mass or more. Most preferably, it is preferable to use a porous carrier composed only of gelatin. Specifically, when the porous carrier is a cloth, it is preferable that the cloth is provided with gelatin-containing fibers as constituent fibers, and it is more preferable that the cloth is provided with only gelatin fibers as constituent fibers.

The porous carrier may contain a functional agent as a component other than gelatin and the above-mentioned synthetic polymer as a constituent component. Examples of such functional agents include dispersants, surfactants, viscosity regulators, pH regulators, cross-linking agents, condensing agents, salts and the like. The functional agent is supported by melting a part of the porous carrier and burying a part of the functional agent in the surface or internal voids of the porous carrier, or is supported by a binder component. Can be. Alternatively, the functional agent may be mixed with the porous carrier.

The average fiber diameter of the constituent fibers of the fabric can be appropriately selected, and the lower limit value can be 0.01 μm or more, 0.1 μm or more, and 0.5 μm or more. Further, the upper limit value can be 50 μm or less. The "average fiber diameter" referred to here is an arithmetic average value of each fiber diameter of 50 fibers measured based on a 5000 times electron micrograph of a cross section or a surface of an object such as a cloth. When the fiber diameter is too small to measure, the measurement can be performed based on an electron micrograph having a magnification higher than 5000 times. When the cross-sectional shape of the fiber is non-circular, the diameter of a circle having the same area as the cross-sectional area is regarded as the fiber diameter.

The fiber length of the constituent fibers of the fabric is appropriately selected, but it is a short fiber or a long fiber having a specific length, or a continuous fiber having a fiber length of such a length that it is practically difficult to measure the fiber length. There can be. Since the number of fiber ends in the fabric constituting the biological tissue filling material is small, the surface is smooth, the thickness is uniform, and various physical properties such as mechanical strength are excellent. As a result, the mechanical strength is further improved and the shape retention performance is improved. It tends to be easy to provide an excellent biological tissue filling material. Therefore, it is preferable that the fabric contains fibers having a continuous length as constituent fibers, and it is more preferable that the constituent fibers of the fabric are only continuous fibers. The "fiber length" referred to here can be measured based on a 5000 times electron micrograph of an object such as a cross section or a surface. When it is difficult to measure the fiber length, it can be measured based on an electron micrograph with a magnification lower than 5000 times.

The method for preparing the constituent fibers of the fabric can be appropriately selected, and for example, a melt spinning method, a dry spinning method, a wet spinning method, or a direct spinning method (melt blow method, spunbond method, or a method of applying an electric field to a spinning liquid to spin). A certain electrostatic spinning method, a method of spinning using centrifugal force, a method of spinning using an accompanying air flow described in Japanese Patent Application Laid-Open No. 2011-012372, an electrostatic spinning method described in JP-A-2005-264374 and the like. A known method such as a neutralizing spinning method, which is a kind of the above), and a method of extracting fibers having a small fiber diameter by removing one or more kinds of resin components from the composite fiber can be used. In particular, as disclosed in, for example, JP-A-2017-197876, JP-A-2016-199828, JP-A-2011-047089, etc., by collecting the fibers spun by the direct spinning method, the average fiber diameter can be increased. A thin non-woven fabric can be prepared. Further, by collecting the fibers spun by the direct spinning method, a fiber web or a non-woven fabric composed of only continuous fibers can be prepared.

The fiber web can be prepared by subjecting the fiber prepared by the above method to, for example, a dry method or a wet method, and the constituent fibers of the prepared fiber web can be entangled and / or integrated to prepare a nonwoven fabric. As a method of entwining and / or integrating the constituent fibers with each other, for example, a method of entwining with a needle, a water flow, or a fluid flow such as steam / gas, or a fiber web being subjected to heat treatment, the fibers are composed of a binder or an adhesive fiber. Examples thereof include a method of adhering and integrating fibers with each other or melting and integrating them.

The method of heat treatment can be appropriately selected, but for example, a method of heating and pressurizing with a calendar roll, a method of heating with a hot air dryer, a method of irradiating infrared rays under no pressure to heat the contained binder component, and the like are used. Can be done. Alternatively, a direct spinning method may be used to spin and collect the fibers to prepare a fiber web or non-woven fabric. When the direct spinning method is adopted, it is preferable to use a spinning liquid having a spinnability. By using a spinning liquid having a spinnability, it is possible to prepare a fiber web or a non-woven fabric made of fibers having a smaller average fiber diameter and a uniform fiber diameter, which is preferable. Whether or not the spinning liquid has spinnability can be determined by the method described in JP-A-2017-053078.

In addition to the fiber web, the nonwoven fabric may be used for the above-mentioned method of entwining and / or integrating the constituent fibers with each other.

Each physical property such as the basis weight, thickness and porosity of the porous carrier can be appropriately adjusted as long as the biological tissue filler according to the present invention can be realized. For example, the basis weight may be 1 to 500 g / ^{m 2,} can be a 10 to 300 g / ^{m 2,} can be 30 to 200 g / ^{m 2.} The thickness can be 0.1 to 10 mm, 0.2 to 5 mm, and 0.5 to 3 mm. The void ratio can be 1-99.9%, 10-99.5%, 20-99%.

In addition, "Metsuke" means the mass around ^{1 m 2 of} the main surface calculated from the value measured using the sample of 10 cm × 10 cm collected from the measurement target according to JIS L1085. For the "thickness", use the outer micrometer (0 to 25 mm) specified in JIS B7502: 1994, and use the pressure welder of the outer micrometer (terminal diameter of the pressure welder: 14.3 mm) in the thickness direction of the measurement target. It is a value measured by acting with a load of 0.5N applied. The "porosity" means a percentage of the volume of voids contained in the porosity in the apparent volume obtained by the method described below for the porous carrier.

The biological tissue filling material of the present invention comprises a hyaluronic acid-based compound. The hyaluronic acid-based compound as used in the present invention refers to hyaluronic acid and its derivatives, which are formed by linearly binding N-acetylglucosamine and D-glucuronic acid. The type can be appropriately selected, and sulfated hyaluronic acid, hyaluronic acid, hyaluronic acid sodium, hyaluronic acid ester, carboxylated sodium hyaluronate and the like can be adopted. The biological tissue filling material may include one type of hyaluronic acid-based compound or a plurality of types of hyaluronic acid-based compounds (for example, a mixture of a plurality of types of hyaluronic acid-based compounds). In particular, from the viewpoint of excellent water solubility, it is preferable to use sodium hyaluronate as the hyaluronic acid-based compound, and it is more preferable to use a biological tissue filling material containing only sodium hyaluronate as the hyaluronic acid-based compound.

The molecular weight of the hyaluronic acid-based compound to be used can be appropriately selected, and as an example, a hyaluronic acid-based compound having a molecular weight of 600,000 to 1.2 million can be adopted. Since the hyaluronic acid-based compound has a linear structure as the main structure as described above, the molecular weight of the hyaluronic acid-based compound and the mass of one molecule of the hyaluronic acid-based compound are substantially proportional to each other.

Whether or not the biological tissue filling material contains a hyaluronic acid-based compound can be determined by using a known analysis method. As an example, a dye or a color-developing substrate that binds to a hyaluronic acid-based compound is added to a biological tissue filling material to be measured or a test solution extracted from the biological tissue filling material to obtain a dye or a coloring substrate that is bound to a hyaluronic acid-based compound. It can be judged by the specific color qualitative and the specific color quantification. As a measurement kit capable of such analysis, for example, Hyaluronican Quantification Kit of Iwai Chemicals Co., Ltd., Purple-Jellyy Hyaluronican Assay Stand Kit of QBS, etc. can be used.

If the manufacturing process of the living tissue filling material is known, whether or not the living tissue filling material contains a hyaluronic acid-based compound, and the content and content of the hyaluronic acid-based compound are known from the manufacturing process. The ratio can be calculated.

In the biological tissue filling material of the present invention, a hyaluronic acid-based compound is present on the surface of the porous carrier. Here, the presence of the hyaluronic acid-based compound on the surface of the porous carrier means that the hyaluronic acid-based compound is exposed on the outer peripheral surface such as on the main surface of the porous carrier and is porous. It may be an embodiment in which the hyaluronic acid-based compound is exposed in the internal voids of the quality carrier. In addition, a porous carrier prepared by using the constituent components of the porous carrier mixed with the hyaluronic acid compound may be used.

The hyaluronic acid-based compound may be present on the surface of the porous carrier in the form of a film, or the hyaluronic acid-based compound in the form of particles may be present on the surface of the porous carrier. The hyaluronic acid-based compound may be directly supported so as to be embedded in a part of the surface of the porous carrier, or the hyaluronic acid-based compound may be directly supported so as to coat the surface of the porous carrier. Further, the hyaluronic acid-based compound may be adhered and supported on the surface of the porous carrier via a binder component or the like.

However, since there is a tendency to provide a biocompatibility-rich biotissue filling material, a hyaluronic acid-based compound is directly supported and present on the surface of a porous carrier without the need for an unnecessary binder or the like. It is more preferable that the hyaluronic acid-based compound is directly supported so as to coat a part or all of the surface of the porous carrier. The biological tissue filling material of such an embodiment can be prepared by a production method including a step of applying a coating liquid containing a hyaluronic acid-based compound to the porous carrier.

The living tissue filling material of the present invention is characterized in that the mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the living tissue filling material is more than 0.3 mg and less than 16.0 mg.}

The applicant of the present application has adjusted the mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the} biological tissue-filling material in the biological tissue filling material in which the hyaluronic acid-based compound is present on the surface of the porous carrier containing gelatin. , It has been found that it is possible to provide a living tissue supplement having excellent shape retention performance.

Specifically, by increasing ^{the mass of the hyaluronic acid-based compound present per 1 cm 3 of the} biological tissue filling material to more than 0.3 mg, the porous carrier containing gelatin is effectively reinforced by the hyaluronic acid-based compound. We have found that the shape retention performance can be improved. It is considered that the reason for this is that the hyaluronic acid-based compound forms a film-like or porous network inside the porous carrier, so that the structural change of the porous carrier is suppressed.

On the other hand, initially, it was thought that the larger the mass, the more effective the reinforcement of the porous carrier containing gelatin by the hyaluronic acid compound, but the hyaluronic acid present per ^{1 cm 3 of the biological tissue filling material.} On the contrary, when the mass of the compound is 16.0 mg or more, it has been found that the shape retention performance is lower than that of the biological tissue filling material according to the prior art. The reason for this has not been completely clarified, but when a porous carrier containing gelatin containing a large amount of hyaluronic acid-based compound absorbs water, the hyaluronic acid-based compound swells and the living tissue It is considered that this is because the three-dimensional structure of the filling material is deformed or destroyed and the shape retention performance is deteriorated. Therefore, it has been found that the shape retention performance can be prevented from deteriorating by reducing the mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the} biological tissue filling material to less than 16.0 mg.

The mass of the hyaluronic acid compound present per 1 cm ³ of the biological tissue filling material is the position of the affected area where the biological tissue filling material is to be embedded, the size of the biological tissue filling material to be embedded, and the required rigidity. The mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the} biological tissue filling material is 0.6 to 12. It is preferably 0 mg, preferably 1 to 11.5 mg, and preferably 4.0 to 11.0 mg.

It should be noted that the effective reinforcement of the porous carrier containing gelatin with a hyaluronic acid-based compound can provide a biological tissue supplement having more excellent shape-retaining performance, and thus is present per ^{1 cm 3 of the porous carrier containing gelatin.} The mass of the hyaluronic acid-based compound is preferably 0.6 to 12.0 mg, preferably 1 to 11.5 mg, and preferably 4.0 to 11.0 mg.

The mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the} biological tissue filling material can be determined by the following measuring method.
(Method of measuring the mass of hyaluronic acid-based compound present per ^{1 cm 3 of} biological tissue filling material)
1. 1. Collect a rectangular parallelepiped or cylindrical sample from a measurement target such as a biological tissue filling material.
2. 2. The collected sample is allowed to stand on a plate having a smooth surface under atmospheric pressure and a temperature condition of 25 ° C. Assuming a rectangular parallelepiped having the minimum size to include the sample, the length in the vertical direction, the length in the horizontal direction, and the length in the thickness direction of the rectangular parallelepiped are measured using a caliper. Alternatively, assuming a cylinder having the smallest size to include the sample, the diameter of the cylinder and the height of the cylinder are measured using a caliper.
3. 3. The apparent volume of the rectangular parallelepiped or the cylinder is calculated from each measured value, and the calculated value is used as the volume (unit: cm ³ ) of the collected sample.
4. The sample is dissolved in the proteolytic solution by immersing the sample in a proteolytic solution (temperature: 37 ° C.) containing a proteolytic enzyme (pronase) and incubating it overnight.
5. The mass of the hyaluronic acid compound contained in the test solution is determined.
6. From the value of the mass of the hyaluronic acid compound contained in the collected sample and the volume of the sample obtained as described above, the mass of the hyaluronic acid compound present per ^{1 cm 3 of the collected sample is calculated.} do. Then, the calculated value is taken as the mass (unit: mg) of the hyaluronic acid-based compound present per ^{1 cm 3 of the biological tissue filling material.}
If the manufacturing process of the living tissue filling material is known, the hyaluronic acid system present per ^{1 cm 3 of the} living tissue filling material is based on the volume and mass of the composition used for manufacturing the living tissue filling material. The mass of the compound may be calculated.

Each physical property such as the basis weight, thickness and void ratio of the biological tissue filling material can be appropriately adjusted according to the required characteristics. For example, the basis weight may be 1 to 500 g / ^{m 2,} can be a 10 to 300 g / ^{m 2,} can be 30 to 200 g / ^{m 2.} The thickness can be 0.1 to 10 mm, 0.2 to 5 mm, and 0.5 to 3 mm. The void ratio can be 1-99.9%, 10-99.5%, 20-99%.

The biological tissue filling material according to the present invention has a structure in which other members such as a cloth or film (non-porous film or porous film) or foam (non-porous foam or porous foam) are further laminated. May be good. The method of laminating other members can be appropriately selected, but it may be a mode of simply laminating, or a mode of adhering and laminating with a binder such as a powder binder, a spray binder, or a hot melt web. It may be an embodiment in which components such as adhesive fibers are melted and adhered to be laminated and integrated. In addition, various configurations such as the material, basis weight and thickness of other members can be appropriately adjusted or selected according to the mode required for the biological tissue filling material.

Next, the production method according to the present invention will be illustrated and described. The points having the same configuration as the items already described will be omitted.
(1) Step of preparing a porous carrier containing gelatin,
(2) A step of preparing a coating liquid in which a hyaluronic acid-based compound is dissolved in a solvent or a hyaluronic acid-based compound is dispersed in a dispersion medium.
(3) A step of applying the coating liquid to the porous carrier,
(4) A step of removing a solvent or a dispersion medium from the porous carrier containing the coating liquid.
It is possible to use a method for producing a living tissue filling material comprising.

The type of solvent or dispersion medium is appropriately selected, and examples thereof include water, alcohols such as methanol and ethanol, and polar solvents which are miscible with water such as dimethyl sulfoxide. The solvent or the dispersion medium may be one kind or a mixed solvent or a mixed dispersion medium obtained by mixing a plurality of kinds. Functional agents such as dispersants, surfactants, viscosity regulators, pH regulators, cross-linking agents, condensing agents, and salts may be added to the coating liquid. In particular, it is preferable that the cross-linking agent contains a mixture of N-Hydroxysuccinimide and 1-Ethyl-3- (3-dimethyllaminoppil) carbodimide, because it is possible to provide a biological tissue filling material having a high shape-retaining performance.
The mass of the hyaluronic acid compound contained in 1 ml of the coating liquid can be adjusted as appropriate, but is 0.1.

It can be ~ 100 mg / ml, it can be 1-50 mg / ml, and it can be 2-30 mg / ml.

The method of applying the coating liquid to the porous carrier can be appropriately selected, but the coating liquid is applied to one main surface or both main surfaces of the porous carrier as it is or in a foamed state by using a spray or a gravure roll. A method, a method of immersing the porous carrier in the coating liquid, or the like can be adopted.

A method for removing the solvent or the dispersion medium from the porous carrier containing the coating liquid can be appropriately selected. As an example, a method of subjecting the porous carrier to which the coating liquid is applied to the heat treatment can be adopted. The type of heating device can be appropriately selected. For example, a method using a device that heats or pressurizes with a roll, an oven dryer, a far-infrared heater, a dry heat dryer, a hot air dryer, a device that can irradiate and heat infrared rays, and the like. Can be adopted. The heating temperature of the heating device is appropriately selected, but the temperature is appropriately adjusted so that the solvent or dispersion medium can be volatilized and removed, and the constituent components of the porous carrier such as gelatin fibers do not unintentionally decompose or denature.

Alternatively, the porous carrier to which the coating liquid is applied may be frozen and subjected to a freeze-drying treatment in which the solvent or dispersion medium is volatilized under a reduced pressure environment. In particular, by using the freeze-drying treatment, it is possible to provide a biological tissue filling material containing a film-like or porous hyaluronic acid-based compound in a porous carrier. As a result, the effective reinforcement of the porous carrier containing gelatin with the hyaluronic acid-based compound is preferable because it is possible to provide a biological tissue supplement having more excellent shape retention performance.

The biological tissue filling material of the present invention may further include other members such as a porous body, a film, and a foam. Further, the biological tissue filling material of the present invention may be subjected to a step of pressure treatment for smoothing the surface, such as a reliant press treatment. Furthermore, it is used for various secondary processing processes such as a process of punching a shape according to a usage mode, a process of supporting a functional component, a processing process of improving compatibility with a living body, a hydrophilization treatment process, and an insolubilization treatment process. You may.

Examples of the present invention will be described below, but the present invention is not limited to the following examples.

(Preparation of porous carrier (sample) containing gelatin)
Only gelatin was dissolved in distilled water having a temperature of 60 ° C., and a spinning solution having a temperature of 60 ° C. was prepared. The spinning solution prepared in this way is reduced in diameter by allowing an accompanying air flow to be collected, and ^{is composed of gelatin fiber non-woven fabric (average fiber diameter: 5.5 μm, grain: 100 g / m 2} , and continuous gelatin fibers only. Has been prepared).
Then, after adjusting the porosity of the nonwoven fabric to 90%, a columnar sample (cylindrical diameter: 12 mm, column height: 3 mm, volume: 0.3 cm ³ ) was collected.
In addition, the diameter of the cylinder and the height of the cylinder in the sample were measured by using the method described in (Measuring method of mass of hyaluronic acid-based compound present per ^{1 cm 3 of} biological tissue filling material).

(Preparation of coating liquid for hyaluronic acid compound)
Sodium hyaluronate (Hiabest (registered trademark) J manufactured by Cupy Co., Ltd., molecular weight 600,000 to 1.2 million) is dissolved in pure water, and N-Hydroxysuccinimide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), which is a cross-linking agent, and 1 A coating solution was prepared by adding 1 μmol of each of −Ethyl-3- (3-dimeopolypl) carbodimide (manufactured by Dojin Chemical Research Institute) and hydrogen chloride per 10 mg of sodium hyaluronate.
Further, by changing the solid content mass of sodium hyaluronate to be dissolved in pure water, a plurality of types of coating liquids having different solid content concentrations of hyaluronic acid-based compounds were prepared in the same manner.

(Reference example)
The sample was used as it was as a cylindrical biological tissue filling material (volume: 0.3 cm ³ ).

(Comparative Example 1)
After immersing the sample in the coating liquid at room temperature for 1 hour, the sample was pulled up from the coating liquid. Then, the sample containing the coating liquid was placed in a freezer whose cooling temperature was adjusted to −28 ° C. overnight, and the coating liquid contained in the sample was frozen. Then, the sample containing the frozen coating liquid was subjected to a vacuum dryer and freeze-dried to remove pure water contained in the sample.
Then, by exposing it to a room temperature atmosphere and returning it to room temperature, the hyaluronic acid-based compound is provided on the surface of the porous carrier containing gelatin, and the film-like and porous hyaluronic acid-based compounds are contained in the porous carrier containing gelatin. A columnar-shaped biological tissue filling material (volume: 0.3 cm ³ ) was prepared. The porous carrier containing gelatin constituting the biological tissue filling material also had the same cylindrical shape (volume: 0.3 cm ³ ).
The mass of the hyaluronic acid-based compound contained in the biological tissue filling material thus prepared was 100 μg.
The living tissue filling material prepared in Comparative Example 1 reproduces the living tissue filling material having the highest content of the hyaluronic acid-based compound among the living tissue filling materials disclosed in Cited Document 1, which is a prior art. It is a thing.

(Examples 1 to 5, Comparative Examples 2 to 3)
Similar to Comparative Example 1, the porous carrier containing gelatin is provided with the hyaluronic acid compound except that the coating liquids having different solid content concentrations of the hyaluronic acid compounds are used, and the porous carrier containing gelatin is provided. ^{A columnar-shaped biological tissue filling material (volume: 0.3 cm 3} ) containing a film-like and porous hyaluronic acid-based compound in the material carrier was prepared. The porous carrier containing gelatin constituting the biological tissue filling material also had the same cylindrical shape (volume: 0.3 cm ³ ).
The mass of the hyaluronic acid-based compound contained in the biological tissue filling material thus prepared was higher than that of the biological tissue filling material prepared in Comparative Example 1.

Table 1 summarizes the composition and the measurement results of the thickness change rate (unit:%) of each biological tissue filling material prepared as described above. The thickness change rate (unit:%) was determined by applying the biological tissue filling material to the following measuring method. In addition, the "mass (mg) of hyaluronic acid-based compound" item in the table describes the mass (unit: mg) of the hyaluronic acid-based compound present per ^{1 cm 3 of each biological tissue filling material.}

(Measurement method of thickness change rate)
The thickness A of the biological tissue filling material was measured using a micrometer according to the thickness measuring method described above. In the columnar biological tissue filling material, the length of the column in the height direction was defined as the thickness A.
Then, the biological tissue filling material used for the measurement was immersed in pure water at 25 ° C. for one week. Then, the biological tissue filling material was pulled out from the pure water.
The biological tissue filling material containing pure water was provided overnight in a freezer whose cooling temperature was adjusted to −28 ° C., and the pure water contained in the living tissue filling material was frozen. Then, the living tissue filling material containing the frozen pure water was subjected to a vacuum dryer and freeze-dried to remove the pure water contained in the living tissue filling material.
Then, the thickness B of the biological tissue filling material, which was exposed to a room temperature atmosphere and returned to room temperature, was measured by using a micrometer according to the above-mentioned thickness measuring method.
The values of the thickness A and the thickness B were included in the following formula to calculate the thickness change rate (unit:%).
Thickness change rate (unit:%) = 100 x (thickness B / thickness A)
It should be noted that the more the value of the thickness change rate is 100% or less and the larger the value is, the more the occurrence of structural change due to the occurrence of unintended swelling due to the absorption of water is prevented, and the shape is prevented. It means that it is a biological tissue filling material having excellent holding performance.

From the results of comparing Comparative Example 1 and Examples 1 to 5, the mass of the hyaluronic acid-based compound present per ^{1 cm 3 of} the living tissue filling material (and the porous carrier containing gelatin constituting the living tissue filling material). Is more than 0.3 mg (more preferably 0.6 mg or more), and from the results of comparing Examples 1 to 5 and Comparative Examples 2 to 3, the living tissue filling material (and the living body) Porous carrier containing gelatin constituting the tissue filling material) ^{The mass of the hyaluronic acid-based compound present per 1 cm 3} is less than 16.0 mg (more preferably 12.0 mg or less) by the living tissue filling material. It is possible to provide a living tissue filling material having a significantly improved thickness change rate and excellent shape retention performance as compared with the living tissue filling material disclosed in Patent Document 1 which is a prior art (the living tissue filling material of Comparative Example 1). found.

From the above, it has been found that by satisfying the configuration according to the present invention, it is possible to provide a biological tissue filling material having excellent shape retention performance.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a living tissue filling material having excellent shape retention performance.

Claims (1)

A biological tissue filling material having a porous carrier containing gelatin and a hyaluronic acid-based compound.
The hyaluronic acid-based compound is present on the surface of the porous carrier.
The mass of the hyaluronic acid-based compound present per ^{1 cm 3 of the} biological tissue filling material is more than 0.3 mg and less than 16.0 mg.
Biological tissue filling material.