JP2007068696A - Sterilization method and biocompatible material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for sterilizing a hydrogel having a good shape/a dynamical property without deteriorating the physical property thereof and a biocompatible material obtained by being sterilized by the sterilization method. <P>SOLUTION: A hydrogel containing water can be safely sterilized while maintaining an original property without deterioration of the physical property thereof water absorbing property like by radiation sterilization, without leaving toxic substances like by ethylene oxide gas sterilization by the sterilization method for sterilizing a polymer hydrogel having a stereoscopic net structure constituted of a polymer of a water-soluble organic monomer and a water-swellable clay mineral by a high-pressure steam processing. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for sterilizing a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral, and a biocompatible material sterilized by the sterilization method.

  Safety is important for medical devices such as syringes, catheters, and wound dressings, and in order to prevent contamination by bacteria and viruses, these medical devices are usually used after sterilization before use. In addition, sterilized materials are also used for physicochemical materials and biochemical materials used when handling living organisms such as cell culture. These medical devices, physicochemical materials, and biochemical materials (hereinafter collectively referred to as medical materials) are composed of various materials such as metals, synthetic polymers such as plastic, glass, natural polymers, Sterilization methods suitable for each are performed. As used herein, sterilization refers to killing microorganisms such as fungi from medical materials.

  On the other hand, among medical materials, biocompatible materials intended to be brought into contact with the living body, particularly materials that are embedded in the living body, have excellent flexibility and stretchability because of their intended use. Materials having various physical properties are desired. As a material having such excellent physical properties, a polymer hydrogel having a three-dimensional network composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral has been disclosed (see Patent Document 1). The polymer hydrogel has characteristics such as excellent water absorption and extremely high extensibility, and is regarded as a promising biocompatible material (see Patent Documents 2 and 3). No sterilization method for application as was disclosed.

  Conventionally, as a sterilization method, radiation sterilization by gamma ray or electron beam irradiation, ethylene oxide gas sterilization, or the like is used. Among these, ethylene oxide gas sterilization uses toxic ethylene oxide gas and can kill microorganisms quite powerfully. However, ethylene oxide gas has a very high solubility in water. When applied to the above-described polymer hydrogel, there is a problem that the ethylene oxide gas is dissolved, and the application is impossible.

  Radiation sterilization uses highly permeable gamma rays and electron beams, so it can be applied to laminated materials and materials with complex shapes, and sterilization can be performed in a very short time. Although it has an advantage, in addition to the problem of handling the radiation, the device becomes large, and when the above-mentioned polymer hydrogel is irradiated with a radiation dose that kills the microorganism, a large amount of water-soluble organic monomer is polymerized. There was a problem that a cross-linking reaction occurred and the excellent physical properties of the polymer hydrogel were lowered.

JP 2002-53629 A JP-A-2005-182 JP 2005-110604 A

  The problem to be solved by the present invention is to provide a method for sterilization without deteriorating the physical properties of a hydrogel having good shape and mechanical properties, and a biocompatible material obtained by sterilization by the sterilization method. It is in.

  In the present invention, a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral is sterilized with high-pressure steam so that the polymer hydrogel has a flexible and The polymer hydrogel can be sterilized without causing a decrease in tough and excellent physical properties or the remaining of harmful substances, and thus a sterilized biocompatible material can be obtained.

  That is, the present invention provides a polymer hydrogel characterized by sterilizing a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral by high-pressure steam treatment. A sterilization method and a biocompatible material comprising a polymer hydrogel sterilized by the sterilization method are provided.

  Furthermore, the polymer hydrogel polymer in the polymer hydrogel is partially partially crosslinked by covalent bonds to further effectively suppress the deformation of the polymer hydrogel and the generation of bubbles during sterilization. Can be sterilized.

  The sterilization method of the present invention comprises a hydrous material by performing high-pressure steam treatment using a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral. Hydrogels that are safe and have no physical properties, such as radiation sterilization, low water absorption, and no toxic substances remain, such as ethylene oxide gas sterilization. It becomes possible to sterilize while keeping. In addition, it is possible to provide a polymer hydrogel having flexible and tough physical properties in a sterilized state necessary for use with medical materials and the like while maintaining the original state and physical properties.

  The sterilization method of the present invention is a method for sterilizing a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral by high-pressure steam treatment.

[Polymer hydrogel]
The polymer hydrogel used in the present invention is a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral (hereinafter referred to as a polymer hydrogel having the three-dimensional network structure). It is simply abbreviated as polymer hydrogel).

  The water-soluble organic monomer in the polymer hydrogel used in the present invention is not limited as long as it has the property of dissolving in water and interacts with a water-swellable clay mineral that can be uniformly dispersed in water. Those having a functional group capable of forming a hydrogen bond, an ionic bond, a coordination bond, a covalent bond and the like with a mineral are preferable. Specific examples of water-soluble organic monomers having these functional groups include water-soluble organic monomers having an amide group, amino group, ester group, hydroxyl group, tetramethylammonium group, silanol group, epoxy group, and the like. Of these, water-soluble organic monomers having an amide group or an ester group are preferred, and those having an amide group are most preferred.

  Specific examples of the polymerizable unsaturated group-containing water-soluble organic monomer having an amide group include acrylamides such as N-alkylacrylamide, N, N-dialkylacrylamide, and acrylamide, or N-alkylmethacrylamide, N, N- And methacrylamides such as dialkylmethacrylamide and methacrylamide. Here, an alkyl group having 1 to 4 carbon atoms is particularly preferably selected. Specific examples of the polymerizable unsaturated group-containing water-soluble organic monomer having an ester group include methoxyethyl acrylate, ethoxyethyl acrylate, methoxyethyl methacrylate, and ethoxyethyl methacrylate.

  Examples of the polymer of the water-soluble organic monomer include poly (N-methylacrylamide), poly (N-ethylacrylamide), poly (N-cyclopropylacrylamide), poly (N-isopropylacrylamide), poly (acryloyl morpholine). Phosphorus), poly (methacrylamide), poly (N-methylmethacrylamide), poly (N-cyclopropylmethacrylamide), poly (N-isopropylmethacrylamide), poly (N, N-dimethylacrylamide), poly (N , N-dimethylaminopropylacrylamide), poly (N-methyl-N-ethylacrylamide), poly (N-methyl-N-isopropylacrylamide), poly (N-methyl-Nn-propylacrylamide), poly (N N-diethylacrylamide), poly (N-acryloylpyrrolidine), poly (N-acryloylpiperidine), poly (N-acryloylmethylhomopiperadine), poly (N-acryloylmethylpiperazine), poly (acrylamide), poly (methoxyethyl acrylate) , Poly (ethoxyethyl acrylate), poly (methoxyethyl methacrylate), and poly (ethoxyethyl methacrylate). As the polymer of the water-soluble organic monomer, in addition to the polymer from the single polymerizable unsaturated group-containing water-soluble organic monomer as described above, a plurality of different polymerizable unsaturated group-containing water-soluble substances selected from these It is also effective to use a copolymer obtained by polymerizing organic monomers. A copolymer of the water-soluble organic monomer and other organic solvent-soluble polymerizable unsaturated group-containing organic monomer can also be used as long as the obtained polymer can form a polymer hydrogel.

  The polymer of the water-soluble organic monomer in the present invention is preferably water-soluble or hydrophilic (including amphiphilic) having a property of absorbing water, and among them, it responds to heat, pH, light, etc. Those having properties such as functionality, biocompatibility including bioabsorbability, biodegradability, and the like are more preferably used depending on the application. For example, water-soluble organic monomer polymers that have characteristics that polymer properties in aqueous solution (for example, hydrophilicity and hydrophobicity) vary greatly with slight temperature changes before and after the lower critical solution temperature (LCST) Specific examples thereof include poly (N-isopropylacrylamide) and poly (N, N-diethylacrylamide). Examples of particularly excellent biocompatibility include poly (methoxyethyl acrylate) and poly (2-polymer xylethyl methacrylate).

  The clay mineral used in the polymer hydrogel used in the present invention needs to have a property of swelling between layers in water or an aqueous solution. More preferably, at least a part can be peeled and dispersed in layers in water, more preferably in water to a thickness of 1 to 10 layers, particularly preferably in water to a thickness of 1 to 3 layers. It is a layered clay mineral that can be dispersed uniformly. For example, water-swellable smectite and water-swellable mica can be used. Specifically, water-swellable hectorite containing sodium as an interlayer ion, water-swellable montmorillonite, water-swellable saponite, water-swellable synthetic mica Is mentioned.

  The ratio of the water-soluble organic monomer and clay mineral constituting the polymer hydrogel used in the present invention is appropriately selected depending on the type of the water-soluble organic monomer and clay mineral used, but both form a three-dimensional network in the solvent. The mass ratio of the swellable clay mineral / water-soluble organic monomer polymer is preferably 0.01 to 3, more preferably 0.1 to 3, particularly preferably 0.3 to 2.5. . When the mass ratio is within this range, preparation is easy, and a high-strength material that exhibits the characteristics of the polymer hydrogel can be obtained.

  Since the polymer hydrogel used in the present invention has a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral, a tensile elastic modulus of 1 kPa or more, a tensile strength of 20 kPa or more, and It is a flexible and tough material that can realize excellent physical properties such as a breaking elongation of 50% or more, preferably a tensile elastic modulus of 5 kPa or more, a tensile strength of 50 kPa or more, a breaking elongation of 50% or more, and more preferably a tensile A material having physical properties of an elastic modulus of 10 kPa or more, a tensile strength of 80 kPa or more, and an elongation at break of 100% or more.

  The polymer hydrogel used in the present invention includes those containing a mixed solvent of water and an organic solvent miscible with water in addition to water.

  The method for producing a polymer hydrogel used in the present invention is carried out by a polymerization reaction of a water-soluble organic monomer in the presence of clay minerals. The polymerization reaction can be carried out by radical polymerization using a conventional method such as the presence of peroxide, heating or ultraviolet irradiation.

  Specifically, first, after preparing a uniform dispersion containing a water-soluble organic monomer, a water-swellable clay mineral, and water, the polymer hydrogel is polymerized in the presence of the water-swellable clay mineral. To prepare. Here, a polymer hydrogel in which a three-dimensional network of a water-soluble organic monomer polymer and a clay mineral is formed can be obtained by the layered exfoliated clay mineral acting as a crosslinking agent. The polymer hydrogel has a three-dimensional network structure formed as described above, so that water or a mixed solvent of water and an organic solvent can be held therein, and has the above-described excellent physical properties.

  Polymerization reaction of water-soluble organic monomers in the presence of water-swellable clay minerals is, for example, radical polymerization using conventional methods such as polymerization using peroxide as a polymerization initiator, heating or irradiation of active energy rays. Can be done. The radical polymerization initiator and the polymerization accelerator can be appropriately selected from conventional radical polymerization initiators and polymerization accelerators, preferably have water dispersibility and are uniformly contained in the entire system. Things can be used. Particularly preferred is a radical polymerization initiator having a strong interaction with the layered clay mineral. As the polymerization initiator, water-soluble peroxides such as potassium peroxodisulfate and ammonium peroxodisulfate, water-soluble azo compounds and the like can be preferably used. Specifically, VA-044 manufactured by Wako Pure Chemical Industries, Ltd. V-50, V-501 and the like can be preferably used. In addition, a water-soluble radical initiator having a polyethylene oxide chain can also be used. As the polymerization accelerator, tertiary amine compounds such as N, N, N ′, N′-tetramethylethylenediamine and β-dimethylaminopropionitrile can be preferably used.

  What is necessary is just to select the temperature at the time of the said polymerization reaction suitably according to the kind etc. of the water-soluble organic monomer to be used, a polymerization accelerator, and an initiator, for example, it can set to the range of 0 to 100 degreeC.

  The polymerization time varies depending on polymerization conditions such as a polymerization accelerator, an initiator, a polymerization temperature, and a polymerization solution amount (thickness) and cannot be generally defined, but generally may be adjusted between several tens of seconds to several tens of hours.

[High pressure steam treatment]
The sterilization method of the present invention is a method of sterilizing the polymer hydrogel by high-pressure steam treatment. The polymer hydrogel has a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral, thereby holding water or a mixed solvent of water and an organic solvent therein, It is a flexible and tough material with excellent physical properties. In order to sterilize such a polymer hydrogel until it can be used as a biocompatible material, it is necessary to perform high-pressure steam treatment, which causes dissolution of toxic gases and a large amount of cross-linking reaction that changes excellent physical properties. It can sterilize suitably, without letting it.

  Sterilization by high-pressure steam treatment in the present invention is generally performed using a high-temperature and high-pressure steam sterilizer (autoclave). A polymer hydrogel, which is an object to be sterilized, is placed in the apparatus, and the inside of the container is subjected to high-temperature and high-pressure. In this method, water vapor is generated under a pressure of 1 atm or higher, and high temperature vapor passes through the surface and the inside of the polymer hydrogel, thereby killing attached microorganisms. At this time, it is preferable to use a method in which the polymer hydrogel is sealed in a vapor-permeable sterilization bag in advance and sterilized by placing it in an airtight container of the apparatus. This sterilization by high-pressure steam treatment is performed within a temperature range of 100 ° C. to 150 ° C. in order to surely kill the microorganisms of the polymer hydrogel, and preferably 121 ° C. or Performed at 132 ° C. In consideration of maintaining the physical properties of the polymer hydrogel, the treatment at about 115 ° C. can be performed.

  According to the sterilization method of the present invention, the polymer hydrogel can be sterilized very suitably. However, depending on the composition of the polymer hydrogel and the conditions of the high temperature treatment, deformation of the polymer hydrogel or generation of bubbles may occur. May occur. In this case, in order to more reliably suppress deformation and bubble generation due to the high-pressure steam treatment, it is preferable to crosslink a part of the polymer of the organic monomer in the polymer hydrogel by a covalent bond.

  In this case, the ratio of the organic monomer polymer crosslinked by the covalent bond contained in the polymer hydrogel varies depending on the water-soluble organic monomer and clay mineral used and the type of crosslinking method, but is not necessarily limited. 0.001 to 10 mol% of the organic organic monomer is preferable, more preferably 0.002 to 1 mol%, and particularly preferably 0.005 to 0.3 mol%. If it is 0.001 mol% or more, the suppression of deformation and bubble generation is effectively exhibited, and if it is 10 mol% or less, physical properties such as flexibility and toughness of the polymer hydrogel are maintained.

  The method for crosslinking a part of the polymer of the organic monomer by a covalent bond is not particularly limited as long as the flexibility and toughness of the polymer hydrogel can be maintained. For example, an organic crosslinking agent is used. And a method of irradiating the polymer hydrogel with active energy rays to covalently bond the organic monomer polymers to each other.

  The organic cross-linking agent used in the case of using an organic cross-linking agent may be any polyfunctional and has a property of being dissolved in water or an organic monomer. For example, amide group, amino group, ester group, hydroxyl group, tetramethyl An organic crosslinking agent having an ammonium group, a silanol group, an epoxy group, or the like can be given. Among them, an organic crosslinking agent having an amide group is preferable. Here, the organic crosslinking agent is a crosslinking agent that functions to crosslink organic monomers constituting the polymer hydrogel by covalent bonds.

  Examples of such organic crosslinking agents include N, N′-methylenebisacrylamide, N, N′-propylenebisacrylamide, di (acrylamidomethyl) ether, 1,2-diacrylamide ethylene glycol, 1,3-di Bifunctional compounds such as acryloyl ethylene urea, ethylene glycol diacrylate, ethylene glycol dimethacrylate, N, N'-diallyl tartardiamide, N, N'-bisacrylyl cystamine, triallyl cyanurate, triallyl isocyania Examples are trifunctional compounds such as nurate.

  In the present invention, the timing for introducing these organic crosslinking agents into the polymer hydrogel is not limited as long as the introduction of the desired covalent bond can be obtained and further varies depending on the type of the organic crosslinking agent, With respect to the polymerizable organic crosslinking agent, a period before the formation of the polymer hydrogel by a polymerization reaction is preferable.

  As the active energy ray irradiated to the polymer hydrogel when performing the crosslinking by the active energy ray, an electron beam, gamma ray, X-ray, ultraviolet ray, visible light, etc. can be used. It is preferable to use a radiation such as an electron beam or a gamma ray capable of causing a crosslinking reaction. The dose of radiation can be arbitrarily adjusted by the degree of covalent bonding introduced into the polymer of the organic monomer, but the weight of the organic monomer crosslinked by the covalent bond contained in the polymer hydrogel described above. In order to adapt to the range of the ratio of coalescence, it is preferably in the range of 0.1 kGy to 20 kGy, more preferably in the range of 1 kGy to 10 kGy. By irradiating with a dose of 0.1 kGy or more, a crosslinking reaction occurs to the inside of the polymer hydrogel, and an effect of suppressing deformation and bubble generation appears. When the dose is 20 kGy or less, the radiation of the polymer hydrogel It becomes possible to suppress deterioration of physical properties due to irradiation.

  In the present invention, the time of performing active energy ray irradiation when introducing a crosslink by covalent bond to the polymer hydrogel is not limited as long as the introduction of the target covalent bond can be sufficiently obtained. Preferably, it is performed during or after the formation of the polymer hydrogel by a polymerization reaction. By performing active energy ray irradiation at such a time, a covalent bond can be introduced without affecting the formation of the polymer hydrogel.

  It is also effective to cover at least a part of the polymer hydrogel with a film in order to more reliably suppress deformation and bubble generation due to high-pressure steam treatment. By covering with a film, deformation and bubble generation can be reliably suppressed by reducing the influence of high temperature steam on the polymer hydrogel.

  As the film covering the polymer hydrogel, any one having adhesion to the polymer hydrogel and one having a peel-off property can be used as long as it has resistance to high-pressure steam treatment. It is not limited to. Examples of film materials include polyester, nylon, polyurethane, polypropylene, polyvinyl alcohol, polytetrafluoroethylene, and a laminate film of two or more of these. Moreover, about the thickness of these films, it is possible to use a film of arbitrary thickness in the range which does not interfere with handling. Moreover, those obtained by surface-treating these films with plasma, ozone or the like are preferably used.

  As the sterilization bag used in the high-pressure steam sterilization treatment of the present invention, a commercially available sterilization bag for autoclave can be used. The sterilization bag for autoclave is usually a bag made by laminating two different films, and one side is polyester, nylon, polyurethane, polypropylene, polyvinyl alcohol, polytetrafluoroethylene, and 2 of these. A gas barrier film such as a laminate film of more than one kind is used. On the other side, a gas and water vapor permeable film such as paper or nonwoven fabric is used.

  In the polymer hydrogel used in the present invention, when at least a part is covered with a film, at the time of high-pressure steam sterilization, the part covered with the film of the polymer hydrogel is brought into contact with the paper and the nonwoven fabric side of the sterilization bag. By putting in, the influence which the high temperature vapor | steam which passes the paper and nonwoven fabric surface of a sterilization bag has on a polymer hydrogel is reduced.

[Biocompatible material]
The polymer hydrogel sterilized by the polymer hydrogel sterilization method of the present invention is excellent in flexibility and toughness, and is sufficiently sterilized, and thus has high safety to living bodies.

  Further, the polymer hydrogel can be prepared in various sizes and shapes by changing the shape of the polymerization vessel during polymerization or by cutting the polymerized gel, for example, fibrous, rod-like, flat plate, The shape may be any shape such as a columnar shape, a hollow shape, a spiral shape, or a spherical shape. It is also possible to form fine particles by a method of coexisting a conventional surfactant during the polymerization reaction.

  Thus, the polymer hydrogel sterilized by the sterilization method of the present invention is extremely useful as a biocompatible material because it has high safety to living bodies, flexible and tough physical properties, and excellent processability. Material.

  EXAMPLES Next, although an Example demonstrates this invention more concretely, naturally this invention is not limited only to the Example shown below.

Example 1
For the clay mineral, water-swellable synthetic hectorite (“Laponite XLG” manufactured by Rockwood Ltd.) having a composition of [Mg _5.34 Li _0.66 Si ₈ O ₂₀ (OH) ₄ ] Na ⁺ _0.66 is vacuumed. Used after drying. As the organic monomer, N, N-dimethylacrylamide (manufactured by Kojin Co., Ltd .: hereinafter abbreviated as DMAA) was purified by a known method and used after removing the polymerization inhibitor. As a polymerization initiator, potassium peroxodisulfate (manufactured by Kanto Chemical Co., Inc .: hereinafter abbreviated as KPS) was dissolved in deoxygenated ultrapure water and used as an aqueous solution. As the polymerization accelerator, N, N, N ′, N′-tetramethylethylenediamine (manufactured by Wako Pure Chemical Industries, Ltd .: hereinafter abbreviated as TEMED) was used. The ultrapure water was used after thoroughly bubbling high-purity nitrogen through a particulate removal filter in advance to remove the oxygen contained therein.

  In a constant temperature room at 20 ° C., 57.06 g of ultrapure water and a Teflon (registered trademark) stirrer were placed in a flat bottom glass container purged with nitrogen, and 1.44 g of Laponite XLG was added while stirring, A solution was prepared. DMAA 5.94g was added to this, and it stirred in nitrogen atmosphere, and obtained the colorless and transparent solution (a). Furthermore, KPS aqueous solution and TEMED were added. This solution was placed in a nitrogen atmosphere in advance and transferred to three polystyrene containers (9 cm × 15 cm) with lids from which oxygen in the container had been removed. Then, the polymerization was carried out by standing in a constant temperature water bath at 20 ° C. for 20 hours. The operations from preparation of the solution to polymerization were all performed in a nitrogen atmosphere in which oxygen was blocked. 20 hours after the start of polymerization, a substantially colorless and transparent uniform sheet-like hydrogel (A) was obtained in a polystyrene container.

  Next, this sheet-like hydrogel (A) was cut into a size of 5 cm × 5 cm, put into a sterilization bag for autoclave (trade name: roll bag for autoclave, manufactured by Hogi Medical Co., Ltd.), and sealed with a heat sealer. . The sterilized bag containing the hydrogel (A) was set in an autoclave apparatus (apparatus name: Autoclave SX-700, manufactured by Tommy Seiko Co., Ltd.) and subjected to high-pressure steam treatment. The treatment conditions were 121 ° C. for 20 minutes. Further, in the sterilization bag, a biological indicator product (Raven Biological Laboratories, Inc., hereinafter referred to as BI) containing spores of Bacillus stearothermophilus which is a sterilization indicator bacterium was enclosed with hydrogel.

  After the treatment, the sterilized hydrogel (A ′) contained in the sterilization bag was taken out from the apparatus, and when the viable bacteria in the BI were confirmed, it was confirmed that the bacteria were dead.

  Further, when the appearance of the hydrogel (A ′) was observed, no particular deformation or generation of bubbles was observed in the hydrogel (A ′). The hydrogel (A) before the high-pressure steam treatment and the hydrogel (A ′) after the treatment were subjected to a tensile test using a tensile test device (manufactured by Shimadzu Corporation, tabletop universal testing machine AGS-H) to compare mechanical properties. As a result, it was confirmed that both the elongation at break and the strength at break were almost unchanged, and the flexibility and toughness of the hydrogel were not changed and maintained by the high-pressure steam treatment.

(Example 2)
In Example 1, the same procedure as in Example 1 was conducted except that 0.84 mg of N, N′-methylenebisacrylamide (Wako Pure Chemical Industries, Ltd .: hereinafter abbreviated as BIS) was added to the colorless transparent solution (a). Thus, a colorless and transparent sheet-like hydrogel (B) was obtained.

  Next, this sheet-like hydrogel (B) was cut into a size of 5 cm × 5 cm, placed in a sterilization bag for autoclave together with the same BI used in Example 1, and sealed with a heat sealer. The hydrogel (B) contained in the sterilized bag was subjected to high-pressure steam treatment in the same manner as in Example 1.

  After the treatment, the sterilized hydrogel (B ′) contained in the sterilization bag was taken out from the apparatus, and when the viable bacteria in the BI were confirmed, it was confirmed that the bacteria were dead.

  Further, when the appearance of the hydrogel (B ′) was observed, no deformation or generation of bubbles was observed in the hydrogel (B ′). When the hydrogel (B) before the high-pressure steam treatment and the hydrogel (B ′) after the treatment were subjected to the same tensile test as in Example 1 and the mechanical properties were compared, both the breaking elongation and breaking strength were almost the same. It was confirmed that the flexibility and toughness of the hydrogel were not changed and maintained by the high-pressure steam treatment.

(Example 3)
The sheet-like hydrogel (C) obtained by the same method as in Example 1 was sealed in a gas-blocking plastic bag and irradiated with gamma rays. Cobalt 60 was used as the radiation source, and the irradiation dose was 5 kGy. The sheet-like hydrogel (C) after irradiation was not particularly discolored, deformed, or contracted.

  Next, this sheet-like gamma-irradiated hydrogel (C) was cut into a size of 5 cm × 5 cm, placed in a sterilization bag for autoclave together with the same BI used in Example 1, and sealed with a heat sealer. The hydrogel (C) contained in the sterilized bag was subjected to high-pressure steam treatment in the same manner as in Example 1.

  After the treatment, the sterilized hydrogel (C ′) contained in the sterilization bag was taken out from the apparatus, and when the viable bacteria in the BI were confirmed, it was confirmed that the bacteria were dead.

  Further, when the appearance of the hydrogel (C ′) was observed, no deformation or generation of bubbles was observed in the hydrogel (C ′). The gamma-irradiated hydrogel (C) before the high-pressure steam treatment and the hydrogel (C ′) after the treatment were subjected to the same tensile test as in Example 1, and the mechanical properties were compared. In both cases, it was confirmed that the hydrogel flexibility and toughness were not changed by the high-pressure steam treatment and maintained.

Example 4
A sheet-like hydrogel (D) obtained by the same method as in Example 1 was cut into a size of 5 cm × 5 cm, and a 7 cm × 7 cm polyester film (trade name: Lumirror S10, manufactured by Toray Industries, Inc.) And placed on top of each other. The other side was left untouched. The hydrogel (D) placed on the polyester film was placed in a sterilization bag for autoclave and sealed with a heat sealer. At this time, the polyester film was placed on the paper side surface of the sterilization bag. Further, the same BI as that used in Example 1 was enclosed in the sterilization bag. The hydrogel (D) contained in the sterilized bag was subjected to high-pressure steam treatment in the same manner as in Example 1.

  After the treatment, the sterilized hydrogel (D ') contained in the sterilization bag was taken out from the apparatus, and when the viable bacteria in the BI were confirmed, it was confirmed that the bacteria were dead.

  Further, when the appearance of the hydrogel (D ′) was observed, no deformation or generation of bubbles was observed in the hydrogel (D ′). When the hydrogel (D) before the high-pressure steam treatment and the hydrogel (D ′) after the treatment were subjected to the same tensile test as in Example 1 and the mechanical properties were compared, both the breaking elongation and breaking strength were almost the same. It was confirmed that the flexibility and toughness of the hydrogel were not changed and maintained by the high-pressure steam treatment.

(Example 5)
The sheet-like hydrogel (E) obtained by the same method as in Example 2 was cut into a size of 5 cm × 5 cm, and placed on and adhered to a 7 cm × 7 cm polyester film. The other side was left untouched. The hydrogel (E) placed on the polyester film was placed in a sterilization bag for autoclave together with the same BI used in Example 1, and sealed with a heat sealer. At this time, the polyester film was placed on the paper side surface of the sterilization bag. The hydrogel (E) contained in the sterilized bag was subjected to high-pressure steam treatment in the same manner as in Example 1.

  After the treatment, the sterilized hydrogel (E ') contained in the sterilization bag was taken out from the apparatus, and when the viable bacteria in the BI were confirmed, it was confirmed that the bacteria were dead.

  Further, when the appearance of the hydrogel (E ′) was observed, no deformation or generation of bubbles was observed in the hydrogel (E ′). When the hydrogel (E) before the high-pressure steam treatment and the hydrogel (E ′) after the treatment were subjected to the same tensile test as in Example 1 and the mechanical properties were compared, both the elongation at break and the strength at break were almost the same. It was confirmed that the flexibility and toughness of the hydrogel were not changed and maintained by the high-pressure steam treatment.

(Example 6)
A short-term implantation test on rabbits was performed using a sterilized hydrogel (F) obtained by the same method as in Example 1. In a Class 100 clean booth, the sterilized hydrogel (F) was cut into a size of 1 mm × 3 cm and filled into a stainless steel stylet. Four of these were prepared and used as an implantation test sample (F ′). Next, a Japanese white male healthy male rabbit was fixed on a fixed base in a prone position, and after shaving with an electric clipper, a midline incision was made about 5 cm in length with an electric knife to expose the muscle layer. It was. A test sample (F ′) is embedded in a sterile 15-gauge transplant needle, and placed on one side of the rabbit into the dorsal muscle of the four test samples (approximately 3.5 cm apart from the spinal column at about 2.5 cm intervals). F ′) was implanted from the stylet. In the same manner, two control samples (high density polyethylene) of the same size were implanted in the dorsal muscle on the opposite side of the spinal column. After 72 hours of implantation, the rabbit was sacrificed and the muscle tissue surrounding the test sample (F ′) and the control sample was observed. As a result, bleeding and encapsulated formation were observed in the muscle tissue surrounding the test sample (F ′). It was confirmed that the hydrogel was highly biocompatible.

(Comparative example)
The sheet-like hydrogel (F) obtained by the same method as in Example 1 was sealed in a gas-blocking plastic bag and sterilized by gamma irradiation. The radiation dose was 50 kGy. When the same tensile test as in Example 1 was performed on the hydrogel (F ′) subjected to gamma irradiation and the hydrogel (F) before irradiation, the gamma-irradiated hydrogel (F ′) was compared with the hydrogel (F) before irradiation. Thus, the elongation at break became 1/10 and the break strength became 1/8, and both the flexibility and toughness were greatly reduced.

Claims (7)

A hydrogel sterilization method comprising sterilizing a polymer hydrogel having a three-dimensional network structure composed of a polymer of a water-soluble organic monomer and a water-swellable clay mineral by high-pressure steam treatment. The hydrogel sterilization method according to claim 1, wherein the high-pressure steam treatment is treatment under conditions of 100 ° C to 150 ° C. The method for sterilizing a hydrogel according to claim 1 or 2, wherein 0.001 to 10 mol% of the polymer of the organic monomer in the polymer hydrogel is crosslinked by a covalent bond. The hydrogel sterilization method according to claim 3, wherein the covalent bond is due to an organic crosslinking agent. The method for sterilizing a hydrogel according to claim 3, wherein the covalent bond is a covalent bond between polymers of organic monomers by irradiation with active energy rays. The hydrogel sterilization method according to claim 1, wherein at least a part of the polymer hydrogel is coated with a film. A biocompatible material comprising a polymer hydrogel sterilized by the hydrogel sterilization method according to claim 1.