JP2007143833A - In vivo implanting member, and artificial tissue - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an artificial tissue in which the living tissue infiltrates to the deep section even when being enlarged, and to provide an in vivo implanting member for manufacturing the artificial tissue. <P>SOLUTION: This in vivo implanting member is constituted by having a porous body consisting of a synthetic resin of a porous three-dimensional mesh structure having communicating property, and gel of a water-soluble polymer such as gelatin containing 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-il)methyl piperidine and/or its salt, which is held by the porous body. The in vivo implanting member is implanted in the living body, and is made to perform its organization. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a living body implant member that is embedded in a living body and organized into an artificial tissue, and an artificial tissue manufactured using the living body implant member.

  There are cases in which biological tissue is lost due to sports injury, traffic accident, malignant tumor, necrosis, poor limb blood flow, etc., but if the affected part affects the individual's appearance such as face, ear, etc. Plastic surgery has been performed by excising the autologous tissue from the area that can be concealed and filling and transplanting it to the defect site, or by using a plastic artifact.

  It should be noted that filling with plastic artifacts has been on the decline since the unfortunate accident (breast cancer) when transplanting silicone moldings in breast augmentation.

  In addition, excision of autologous tissue such as the large buttocks is highly invasive and the amount that can be removed is limited. Even if it is concealed with clothing, the function of the buttocks (sitting position stability, etc.) is impaired because the tissue of the large buttocks is lost.

  In recent years, a technique has been developed in which a porous body made of a thermoplastic resin having a porous three-dimensional network structure is embedded in a living body, cells are invaded and engrafted, and capillaries are built inside the porous body.

1-Benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine is known as a therapeutic / preventive agent for various senile dementias such as Alzheimer-type senile dementia (described below). Patent Document 1).
Japanese Patent No. 2578475

  In the above technique in which a porous body is embedded in a living body to infiltrate the tissue, the host tissue only infiltrates the inside of the porous body and does not grow in a lump to the outer periphery. Moreover, the degree of tissue infiltration into the porous body is only up to a depth of about 10 mm. For example, a large tissue body of about 50 mm × 50 mm × 50 mm or more cannot be created.

  An object of the present invention is to provide an artificial tissue in which a living tissue is infiltrated into a deep part even when the size is increased, and a living body implanting member for manufacturing the artificial tissue.

  The living body implant member of the present invention (Claim 1) includes a porous body made of a synthetic resin having a porous three-dimensional network structure, and 1-benzyl-4-[(5 , 6-Dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a water-soluble polymer gel containing a salt thereof.

  The living body implant member according to claim 2, wherein the water-soluble polymer gel is 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine according to claim 1, It is obtained by carrying out the crosslinking process of the aqueous solution containing / and its salt and water-soluble polymer.

  The biological implant member according to claim 3 is characterized in that in claim 2, the water-soluble polymer is modified with a molecular group having a photosensitive group.

  The biological implantable member according to claim 4, wherein the molecular group having the photosensitive group is xanthene dye, azine dye, thiazine dye, oxazine dye, quinoline dye, pyrazolone dye, stilsen dye. Azo dyes, diazo dyes, anthraquinone dyes, indigo dyes, thiazole dyes, phenylmethane dyes, acridine dyes, cyanine dyes, indophenol dyes, naphthalamide dyes and perylene dyes It is characterized by being at least one selected.

  The biological implantable member according to claim 5, wherein the molecular group having the photosensitive group is eosin, fluorescein, rose bengal, benzophenone, camphorquinone, olefin, benzalacetophenone, cinnamylideneacetyl, cinnamoyl, Styrylpyridine, α-phenylmaleimide, phenyl azide, sulfonyl azide, carbonyl azide, o-quinonediazide, furylacryloyl, coumarin, pyrone, anthracene, benzoyl, stilbene, dithiocarbamate, xanthate, cyclopropene, 1,2,3-thiadiazole, It is at least one selected from the group consisting of aza-dioxabicyclo, halogenated alkyls, ketones and diazos and substances modified with these.

  A living body implanting member according to a sixth aspect is characterized in that, in any one of the second to fifth aspects, the crosslinking treatment is light irradiation.

  The biological implant member according to claim 7 is the biological implant member according to any one of claims 2 to 6, wherein the aqueous solution further contains at least one selected from the group consisting of thiol, alcohol, reducing sugar, and polyphenol. It is a feature.

  The biological implant member according to claim 8 is the biological implant member according to any one of claims 2 to 7, wherein the aqueous solution is further selected from the group consisting of an amino group, an N-alkylamino group, and an N, N-dialkylamino group. And an amino compound having at least one group.

  The living body implant member according to claim 9, wherein the water-soluble polymer is gelatin, collagen, fibronectin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, Laminin, thrombospondin, vitronectin, osteonectin, entactin, casein, polyethylene glycol, polypropylene glycol, polyglycidol, side chain esterified product of polyglycidol, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, hydroxy Selected from the group consisting of copolymers of ethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide and polyvinylpyrrolidone Even without is characterized in that it is one.

The biological implantable member according to claim 10 is the communication device according to any one of claims 1 to 9, wherein the porous body has an average pore diameter of 10 to 650 μm and an apparent density of 0.01 to 0.5 g / cm ³ . It is made of a thermoplastic resin having a certain porous three-dimensional network structure.

  The biological implant member according to claim 11 is the biological implant member according to claim 10, wherein the thermoplastic resin is a polyurethane resin, a polyamide resin, a polylactic acid resin, a polyolefin resin, a polyester resin, a fluororesin, a silicon resin, an acrylic resin and a methacrylic resin, and these It is at least one selected from the group consisting of derivatives.

  According to a twelfth aspect of the present invention, in the biological implantable member according to the eleventh aspect, the thermoplastic resin is a polyurethane resin.

  The biological implant member according to claim 13 is characterized in that, in claim 12, the polyurethane resin is a segmented polyurethane resin.

  The artificial tissue of the present invention (Claim 14) is characterized in that the living body implant member according to any one of Claims 1 to 13 is embedded in a living body and organized.

  When the living body implant member of the present invention is embedded in the living body, the tissue infiltrates into the porous body and is organized by the host cells. In the living body implant member of the present invention, 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof is formed in the pore portion of the porous body. A water-soluble polymer gel containing is retained. This gel gradually decomposed in vivo and continued for more than 2 weeks, and 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or its salt was released slowly. Thus, the tissue can be infiltrated to the deep part of the porous body of the living body implant member.

  In order to retain a water-soluble polymer gel containing 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof in the porous body, Porous aqueous solution containing a water-soluble polymer such as benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof, gelatin modified with a photosensitive group, and a hydrogen donor It is preferable to saturate and irradiate light.

  In the present invention, the effects of 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof are as follows. That is, conventionally known donepezil (onepezil: 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine) is known as a therapeutic / preventive agent for various senile dementias. It has been found by the present inventors that renewal can be promoted remarkably and is effective as a tissue formation promoting component.

1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine: donepezil is an acetylcholinesterase inhibitor;
(1) Long plasma elimination half-life,
(2) Less peripheral side effects,
(3) High bioavailability and good brain migration,
These results were discovered as a result of an exploratory study as a compound that satisfies the above three items and has the effect of suppressing the progression of dementia symptoms in mild and moderate Alzheimer-type dementia.

  However, 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or its salt is easily soluble in water, and even if impregnated in a porous body as it is, it is embedded in the living body. If it enters, it quickly diffuses from the porous body, and the effect cannot be obtained. In the present invention, 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof is embedded in a water-soluble polymer gel such as gelatin gel. Thus, 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof can be gradually released over a long period of time, for example, over 2 weeks. Thus, it is possible to obtain angiogenesis with a higher density than before, tens of times the thickness of a tissue body, and a high degree of tissue maturation.

  In the existing technology, the depth of the tissue infiltrating into the porous body is about 1 to 15 mm from the outer surface of the porous body. In the present invention, the infiltration can be up to about 50 mm. For example, when the tissue is infiltrated from the whole surface of the true spherical porous body, the tissue can be infiltrated to the core of the spherical porous body having a diameter of 100 mm.

  The artificial tissue obtained by implanting the living body implant member of the present invention into a living body is constructed of living cells including a large number of blood vessels, and can itself be used as a medical material. .

  The porous body remaining as a skeleton in the artificial tissue itself has a shape retaining property, and has a function of reinforcing the strength to maintain the three-dimensional structure of the tissue body. For example, a hybrid-type artificial tissue created using a porous body molded into an ear shape retains the shape of the ear, and can be easily sutured with an autologous tissue and can be fixed to a transplant site. . For this reason, it is thought that it is useful as a filling material of an ear defect part.

  This artificial tissue body can be cut after production, and can be used for replenishing a defective tissue after the tissue body is made into a target shape. This artificial tissue body is a living tissue and has a function of growing after transplantation. Even if it is largely missing, it can be used for compensation. Further, if it is molded into a tubular shape, it can be used as an artificial blood vessel.

When the porous body is made of a thermoplastic resin having a porous three-dimensional network structure having an average pore diameter of 10 to 650 μm and an apparent density of 0.01 to 0.5 g / cm ³ , It becomes easy to uniformly impregnate an extracellular matrix such as collagen into the pores of the porous three-dimensional network structure part to the deep part, and it is advantageous for invasion of cells from the tissue and construction of capillaries. Become.

  There is a possibility that the inner wall of this porous body can be induced to differentiate into endothelial cells using vascular endothelial growth factor, etc. In that case, since it has antithrombogenicity equivalent to that of living blood vessels, continuous administration of anticoagulant is unnecessary. (Or the dose can be reduced).

  This porous body has a function of growing because it is organized as a whole. Therefore, there is no problem in durability, and there are few dangers such as calcification and thrombus generation.

  Hereinafter, the present invention will be described in more detail.

  The living body implant member of the present invention comprises a porous body having 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine represented by the following structural formula (I) and / or Alternatively, a water-soluble polymer gel containing a pharmacologically acceptable salt thereof is retained. Hereinafter, this salt is also referred to as donepezil.

  In the present invention, pharmacologically acceptable salts include, for example, inorganic acid salts such as hydrochloride, sulfate, hydrobromide, phosphate, formate, acetate, trifluoroacetate, maleate, Mention may be made of organic acid salts such as tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate.

  Further, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-di In some cases, organic amine salts such as benzylethylenediamine salts, ammonium salts, and the like are formed.

  Donepezil may include geometrical isomers, optical isomers, diastereomers, and the like, all of which are included in the scope of the present invention.

  The method for producing donepezil is described in Patent Document 1 above.

  Donepezil is easily soluble in water, so it is embedded in a water-soluble polymer gel.

  The gel-like product can be produced by a method in which an aqueous solution of donepezil and a water-soluble polymer is crosslinked with a chemical crosslinking agent such as glutaraldehyde, ethylenediamine, hexamethylene diisocyanate, or diglycidylaniline, or a radical is generated by heat. Although there is a method of cross-linking, it is preferable to use a water-soluble polymer modified with a molecular group having a photosensitive group and cross-linking by light irradiation. In the case of crosslinking by irradiation with light, it is preferable to use a water-soluble polymer modified with a molecular group having a photosensitive group.

  The concentration of the water-soluble polymer in this aqueous solution is preferably about 0.1 to 50% by weight, and the concentration of donepezil is preferably about 0.001 to 10% by weight. It is preferable to dissolve about 0.1 to 20% by weight of an amino compound described later in this aqueous solution.

  The molecular groups having this photosensitive group include xanthene dyes, azine dyes, thiazine dyes, oxazine dyes, quinoline dyes, pyrazolone dyes, stilsen dyes, azo dyes, diazo dyes, anthraquinone dyes, indigo dyes. At least one selected from the group consisting of a dye, a thiazole dye, a phenylmethane dye, an acridine dye, a cyanine dye, an indophenol dye, a naphthalamide dye, and a perylene dye is more preferable. And eosin, benzophenone, camphorquinone, olefin, benzalacetophenone, cinnamylideneacetyl, cinnamoyl, styrylpyridine, α-phenylmaleimide, phenylazide, sulfonylazide, carbonylazide, o-quinonediazide, furylacryloyl , Coumarin, pyrone, anthracene, benzoyl, stilbene, dithiocarbamate, xanthate, cyclopropene, 1,2,3-thiadiazole, aza-dioxabicyclo, alkyl halides, ketones and diazo, and substances modified with these At least one selected from the group consisting of eosin is preferred.

  Examples of water-soluble polymers include gelatin, collagen, fibronectin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin, entactin, gazein, polyethylene glycol, polypropylene glycol, Polyglycidol, side chain esterified product of polyglycidol, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, alginic acid, polyacrylamide, polydimethylacrylamide and polyvinylpyrrolidone At least one selected from the group consisting of is preferable, and gelatin is particularly preferable.

  Therefore, eosinized gelatin is suitable as the water-soluble polymer modified with the above molecular group.

  In the present invention, the aqueous solution is further selected from the group consisting of thiols, alcohols, reducing sugars, polyphenols, amino groups, N-alkylamino groups, and N, N-dialkylamino groups as proton donors that are radical counters. It is preferable to contain about 5% by weight of an amino compound having at least one group, particularly aminoacrylamide, specifically, polydimethylaminopropylacrylamide. By including this amino compound, etc., it is possible to cut the intermolecular bond and generate a decomposed product. Depending on the conditions within the scope of the present invention, light can be insolubilized with light at a level used in daily life such as a fluorescent lamp.

  Next, eosinized gelatin suitable for use in the present invention will be described.

  Here, the gelatin may be a normal gelatin having a molecular weight of 5,000 to 100,000 and an amino group of about 10 to 100 per molecule.

  Eosinized gelatin is prepared by introducing eosin into the side chain of gelatin according to the following reaction.

The number of eosin introduced into the gelatin molecule is determined, for example, by measuring the absorbance of an aqueous solution of eosinized gelatin at the maximum absorption wavelength of eosin at 522 nm and calculating the molar extinction coefficient of eosin (ε = 990,000 mol ⁻¹ dm ³ cm ⁻¹ ). It can be calculated on the basis of 1 to 10 and especially 2 to 5 is preferable for one molecule of gelatin. If the number of compounds having a photosensitive group such as eosin is small, the gelation rate is lowered, and if it is more than necessary, the flexibility inherent to gelatin may be impaired, and it becomes hardly soluble in water. End up.

  This eosinized gelatin is solid but easily dissolves in water to form a viscous liquid. When this is made into an aqueous solution having a concentration of 1 to 10% by weight, for example, it is irradiated with visible light for about 0.1 to 30 minutes at a relatively low illuminance of about 300 to 30,000 lx, particularly about 300 to 15,000 lx. And can be cured into a gel.

The porous body used in the present invention preferably has an average pore diameter of 10 to 650 μm and an apparent density of 0.01 to 0.5 g / cm ³ , that is, a continuous, ie, porous, porous three-dimensional network structure. It consists of a synthetic resin, particularly preferably a thermoplastic resin.

The average pore diameter of the porous three-dimensional network structure made of this thermoplastic resin is 10 to 650 μm and the apparent density is 0.01 to 0.5 g / cm ³ , but the preferable average pore diameter is 10 to 400 μm, more preferably 10 ˜300 μm. If the apparent density is in the range of 0.01 to 0.5 g / cm ³ , cell engraftment is good, excellent physical strength is maintained, and elastic properties approximate to a living body are obtained. 0.01 to 0.3 g / cm ³ , more preferably 0.01 to 0.2 g / cm ³ .

  Moreover, in the concept of average pore diameter, the distribution of the pore diameter is preferably monodispersed, and it is desirable that the contribution ratio of pores having a pore diameter of 10 to 200 μm, which is an important pore diameter size for cell invasion, is high. When the contribution ratio of pores having a pore diameter of 10 to 200 μm is 10% or more, preferably 20% or more, more preferably 30% or more, still more preferably 40% or more, and particularly preferably 50% or more, cells easily invade, Since the invading cells are easy to adhere and grow, it is effective for use as a vascular substitute such as an artificial blood vessel or an artificial esophagus.

  With such a porous three-dimensional network structure having an average pore size, apparent density, and pore size distribution, cells can easily penetrate into the pores, and the cells can easily adhere to and grow in the porous structure layer.

  Examples of the thermoplastic resin include polyurethane resin, polyamide resin, polylactic acid resin, polyolefin resin, polyester resin, fluororesin, silicon resin, acrylic resin, methacrylic resin and derivatives thereof. Although it may be used alone or in combination of two or more, it is preferably a polyurethane resin, and among them, a segmented polyurethane resin obtains an artificial blood vessel excellent in antithrombogenicity and physical properties. This is preferable.

  The segmented polyurethane resin is synthesized from three components of a polyol, a diisocyanate and a chain extender, and has an elastomeric property due to a block polymer structure having a so-called hard segment portion and soft segment portion in the molecule. An artificial blood vessel obtained by using an S-S curve that is elastodynamically approximate to a biological blood vessel (high elasticity in a low blood pressure region and low elasticity, and high elasticity in a high blood pressure region with lower compliance than a low blood pressure region) It is also possible to form into a tubular structure exhibiting a characteristic that is excellent in antithrombogenicity and physical characteristics.

  Also, if the thermoplastic resin is hydrolyzable or biodegradable, it is gradually decomposed and absorbed after living transplantation, and finally the resin-made skeletal substrate itself is left leaving the engrafted cells. It is also possible to exclude it from the living body.

  The porous three-dimensional network structure composed of such thermoplastic resin includes argatropane, pyridine, nicotine, nicotinic acid, nicotinic acid ester, nicotinic acid amide, collagen type I, collagen type II, collagen type III, collagen Type IV, atelo-type collagen, fibronectin, gelatin, hyaluronic acid, heparin, keratanic acid, chondroitin, chondroitin sulfate, chondroitin sulfate B, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, co-polymerization of hydroxyethyl methacrylate and methacrylic acid One or more selected from the group consisting of coalescence, alginic acid, polyacrylamide, polydimethylacrylamide and polyvinylpyrrolidone may be retained or simply impregnated, One or more cytokines selected from the group consisting of fibroblast growth factor, interleukin-1, tumor growth factor β, epidermal growth factor and diploid fibroblast growth factor may be retained. .

  Fine holes may also be provided in the skeleton base material itself made of a thermoplastic resin for constructing the porous three-dimensional network structure layer. Such micropores make the skeletal surface not a smooth surface but a complex uneven surface, and are also effective in retaining collagen and cell growth factors, and as a result, it is possible to increase cell engraftment. is there. However, the micropores in this case are not introduced into the concept of calculating the average pore diameter of the porous three-dimensional network structure referred to in the present invention.

  The animal in which the living body implant member is implanted may be a self (patient) or another person, but may be a heterogeneous animal, but is preferably a self that cannot induce an immune reaction or the like. However, in an emergency, it is possible to use a product prepared from a heterologous animal as it is (use of an immunosuppressive agent) or a product obtained by decellularization treatment.

  When the tissue body obtained by organizing and organizing in this way is grown in its own body, it can be used as it is, but it can be used immediately after production. If not, it can be stored frozen or lyophilized. When grown in other animals, the tissue is decellularized. Methods for decellularization include elution of extracellular matrix by enzyme treatment such as collagenase and washing with a water-soluble organic solvent such as alcohol, but aldehyde compounds such as glutaraldehyde and formaldehyde and / or Alternatively, there is a method of treating with a water-soluble organic solvent such as methanol, ethanol or isopropyl alcohol. Specifically, a method in which the aldehyde compound is adjusted so as to have a final concentration of about 1 to 3%, and the tissue body is immersed in a fixative having a volume of about 50 times the volume of the tissue body for 2 hours or more is preferable. By cross-linking lysine residues and the like of protein chains in this way, it becomes possible to maintain the structure of the tissue body, and it can be well preserved by combining freezing or freeze-drying techniques after the treatment.

  Furthermore, when these self-organized bodies are used as artificial blood vessels, it is possible to retain anti-thrombotic substances such as argatropan, hirudin, heparin, etc. with a coating before transplantation regardless of their origin. Thrombus generation can be suppressed.

  The tissue body after the decellularization treatment can be stably controlled in density and the like by further freeze-drying. It can be stored in water-soluble organic solvents such as alcohol, phosphate buffered saline, and physiological saline without lyophilization after decellularization treatment, but it is also stored frozen in order to suppress changes in physical properties during storage. However, it is preferable to freeze-dry, but it is more preferable to store only by freezing because the porous structure generated by decellularization is less likely to be destroyed. In the case of drying, there is a possibility that pores may be blocked and fiber association may occur in the shrinkage phenomenon during drying, and it may not be possible to obtain a tissue having useful physical properties before drying with good reproducibility. Freeze drying is preferred.

  Hereinafter, the present invention will be described more specifically with reference to examples.

  First, a porous body was produced as follows.

[Manufacture of porous material]
Dissolve thermoplastic polyurethane resin (Nippon Miractran, Milactolan E980PNAT) in N-methyl-2-pyrrolidinone (Kanto Chemical Co., Peptide Synthesis Reagent, NMP) at room temperature using a dissolver (about 2,000 rpm) A 5.0% solution (weight / weight) was obtained. About 1.0 kg of this NMP solution was weighed into a planetary mixer (Inoue Seisakusho, 2.0 L, PLM-2 type), and methyl cellulose equivalent to the weight of polyurethane resin (Kanto Chemical Co., Reagent, 25 cp grade) ) Was mixed at 40 ° C. for 20 minutes, and then defoamed under reduced pressure to 20 mmHg (2.7 kPa) for 10 minutes with continued stirring to obtain a polymer dope.

  A cylindrical paper tube with an inner diameter of 4 mmφ, an outer diameter of 6 mmφ, and a length of 60 mm made with a filter paper for chemical experiments (manufactured by Toyo Roshi Kaisha, No. 2), a core rod made of SUS440 with a diameter of 2 mmφ, and this core The polymer dope was injected and injected using a 23 gauge needle into a tube forming jig composed of a cylindrical seal plug made of medical polypropylene resin capable of fixing the rod to the center of the paper tube, and then sealed after being sealed. The polyurethane resin was coagulated by throwing it into methanol in a state and continuing to reflux for 72 hours to extract and remove the internal NMP solvent from the paper tube surface. At this time, methanol was replaced with a new solution as needed while maintaining the reflux state. After 72 hours, the tube forming jig is transferred from the refluxed methanol to a methanol bath at room temperature without drying, and the contents are taken out from the tube forming jig in the bath and washed in Japanese Pharmacopoeia purified water for 72 hours. As a result, methylcellulose, methanol and remaining NMP were extracted and removed. Water for cleaning was supplied with new solution as needed. This was dried under reduced pressure (20 mmHg (2.7 kPa)) at room temperature for 24 hours to produce a tubular porous three-dimensional network structure. This was cut into a soft polyurethane porous body (hereinafter sometimes referred to as SPU sponge).

  About the obtained SPU sponge, the average pore diameter and the apparent density were measured by the following method. In the measurement of the average pore diameter and the apparent density, the sample was cut at room temperature using a double-edged razor (manufactured by Feather, high stainless steel).

(1) Measurement of average pore diameter Using a photograph taken with a stereomicroscope (VH-6300, manufactured by Keyence Corporation) of a plane (cut surface) of a sample cut with a double-blade razor, individual holes on the same plane are tertiary. Image processing (image processing device using Nireco's LUZEX AP and image capturing CCD camera using Sony's LE N50) as a figure surrounded by the original network structure skeleton, and measuring the area of each figure did. This was defined as the perfect circle area, and the diameter of the corresponding circle was determined as the hole diameter. As a result of ignoring the fine holes drilled in the skeleton portion of the porous body and measuring only the communicating holes on the same plane, the average pore diameter was measured to be 169 ± 55 μm. At the same time, the contribution ratio of the pore size of 150 to 300 μm in the pore size distribution was measured to be 71.2%, and it was confirmed that the porous body was mainly composed of pores having a size effective for cell adhesion.

(2) Measurement of apparent density Volume is obtained from the dimension obtained by measuring a sample cut with a double-blade razor to a length of about 10 mm with a projector (Nikon, V-12), and the value obtained by dividing the weight by the volume. As a result, it was calculated as 0.077 ± 0.002 g / cm ³ .

[Example 1]
<Manufacture of donepezil sustained release SPU sponge>
An aqueous solution containing 20% by weight of eosinized gelatin, 5% by weight of polydimethylaminopropylacrylamide, and 0.1% by weight of donepezil was impregnated into the above SPU sponge having an inner diameter of 2 mm, an outer diameter of 4 mm and a length of 30 mm, and 7700 Lux visible Irradiated with light for 1 minute to insolubilize and carry it on the inside and outer peripheral surfaces of the SPU porous body to obtain donepezil sustained-release SPU sponge.

<Embedding and extraction>
The epidermis of the back of the rabbit that was locally anesthetized and shaved by a normal procedure was incised about 30 mm immediately after disinfecting isodine, and this donepezil sustained-release SPU sponge was implanted under the subcutaneous tissue and sutured. The suture site was disinfected with isodine twice a day, water was freely supplied, and an appropriate amount of ORC4 manufactured by Oriental Yeast Co., Ltd. was fed as feed.

  During the implantation period, there was no evidence of infection in the sutured area, and no antibiotics were required. It was removed 2 weeks after implantation. There was no adhesion with surrounding tissues, and it was easy to peel off. A thick tissue body was formed so as to cover the entire outer peripheral portion (FIG. 1), and the inside of the SPU sponge was infiltrated and organized (FIG. 2).

  The tissue body and SPU porous body formed on the outer peripheral part could be peeled off within a few days after transplantation because the eosinated gelatin remained without being fully biodegraded. The tissue body infiltrated in the SPU sponge and the tissue body in the outer peripheral part were integrated, and a hybrid type artificial tissue could be obtained. The adhesion between the tissue and the surrounding tissue of the host was not confirmed, and the extraction was easy.

[Comparative Example 1]
The same SPU sponge as used in Example 1 was impregnated with an aqueous solution containing 20% by weight of eosinized gelatin and 5% polydimethylaminopropylacrylamide (the same aqueous solution as Example 1 except that it did not contain donepezil). 7700Lux visible light was irradiated for 1 minute to insolubilize, and eosinized gelatin was supported on the inner and outer peripheral surfaces of the porous body. As in Example 1, the tissue was infiltrated into the SPU sponge when implanted in the back of the rabbit and removed 2 weeks later. However, the neoplastic density of the blood vessels and the maturity of the infiltrated tissue were higher in Example 1. Was good.

[Comparative Example 2]
The same SPU sponge as used in Example 1 was impregnated with a 0.01% by weight aqueous solution of donepezil hydrochloride. It was embedded in the back of the rabbit as it was and removed 2 weeks later. The result was almost the same as Comparative Example 1.

  As described above, as shown in Example 1, it was confirmed that a mature and thick artificial tissue body could be produced by using an SPU sponge that slowly releases donepezil for about 2 weeks or more. This artificial tissue body could be easily sutured with the living tissue by the SPU sponge located inside. This tissue retained the shape of the SPU sponge.

2 is an enlarged photograph of a tissue body formed in Example 1. 2 is an enlarged photograph in which the magnification of the tissue body formed in Example 1 is increased.

Claims (14)

  A porous body made of a synthetic resin having a porous three-dimensional network structure, and 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] retained in the porous body A bioimplantable member comprising a water-soluble polymer gel containing methylpiperidine and / or a salt thereof.   The water-soluble polymer gel according to claim 1, wherein the water-soluble polymer gel comprises 1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine and / or a salt thereof and the water-soluble polymer. A living body-implanted member obtained by crosslinking an aqueous solution containing the aqueous solution.   The biological implant member according to claim 2, wherein the water-soluble polymer is modified with a molecular group having a photosensitive group.   4. The molecular group having a photosensitive group according to claim 3, wherein the molecular group having xanthene dye, azine dye, thiazine dye, oxazine dye, quinoline dye, pyrazolone dye, stilsen dye, azo dye, diazo dye, anthraquinone. A dye, an indigo dye, a thiazole dye, a phenylmethane dye, an acridine dye, a cyanine dye, an indophenol dye, a naphthalamide dye, and a perylene dye. A bio-implanting member as a feature.   5. The molecular group having a photosensitive group according to claim 4, wherein eosin, fluorescein, rose bengal, benzophenone, camphorquinone, olefin, benzalacetophenone, cinnamylideneacetyl, cinnamoyl, styrylpyridine, α-phenylmaleimide, phenylazide , Sulfonyl azide, carbonyl azide, o-quinonediazide, furylacryloyl, coumarin, pyrone, anthracene, benzoyl, stilbene, dithiocarbamate, xanthate, cyclopropene, 1,2,3-thiadiazole, aza-dioxabicyclo, alkyl halide, A living body implanting member characterized by being at least one selected from the group consisting of ketones and diazos and substances modified with these.   The living body implanting member according to any one of claims 2 to 5, wherein the crosslinking treatment is light irradiation.   The living body implant member according to any one of claims 2 to 6, wherein the aqueous solution further contains at least one selected from the group consisting of thiol, alcohol, reducing sugar, and polyphenol.   8. The amino acid according to claim 2, wherein the aqueous solution further has at least one group selected from the group consisting of an amino group, an N-alkylamino group, and an N, N-dialkylamino group. A biological implant member comprising a compound.   The water-soluble polymer according to any one of claims 1 to 8, wherein the water-soluble polymer is gelatin, collagen, fibronectin, hyaluronic acid, keratanic acid, chondroitin, chondroitin sulfate, elastin, heparan sulfate, laminin, thrombospondin, vitronectin, osteonectin , Enteractin, casein, polyethylene glycol, polypropylene glycol, polyglycidol, polyglycidol side chain esterified product, polyvinyl alcohol, copolymer of hydroxyethyl methacrylate and dimethylaminoethyl methacrylate, copolymer of hydroxyethyl methacrylate and methacrylic acid, It is at least one selected from the group consisting of alginic acid, polyacrylamide, polydimethylacrylamide and polyvinylpyrrolidone. Biological embedded members to butterflies. The thermoplastic material according to any one of claims 1 to 9, wherein the porous body has a communicating porous three-dimensional network structure having an average pore diameter of 10 to 650 µm and an apparent density of 0.01 to 0.5 g / cm ³ . A living body implanting member comprising a resin.   11. The thermoplastic resin according to claim 10, wherein the thermoplastic resin is selected from the group consisting of polyurethane resin, polyamide resin, polylactic acid resin, polyolefin resin, polyester resin, fluororesin, silicon resin, acrylic resin, methacrylic resin, and derivatives thereof. A biological implant member characterized by being a seed.   The living body implanting member according to claim 11, wherein the thermoplastic resin is a polyurethane resin.   The living body implanting member according to claim 12, wherein the polyurethane resin is a segmented polyurethane resin.   An artificial tissue obtained by embedding and organizing the living body implant member according to any one of claims 1 to 13.

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