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WO2018082090A1 - Biological tissue-reinforcing material and artificial dura mater - Google Patents

Biological tissue-reinforcing material and artificial dura mater Download PDF

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Publication number
WO2018082090A1
WO2018082090A1 PCT/CN2016/104877 CN2016104877W WO2018082090A1 WO 2018082090 A1 WO2018082090 A1 WO 2018082090A1 CN 2016104877 W CN2016104877 W CN 2016104877W WO 2018082090 A1 WO2018082090 A1 WO 2018082090A1
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WIPO (PCT)
Prior art keywords
cellulose
biological tissue
reinforcing material
film made
hydroxy groups
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Ceased
Application number
PCT/CN2016/104877
Other languages
French (fr)
Inventor
Chiaki Tanaka
Yoshinari Yui
Shojiro Matsuda
Hideki TAKAMORI
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Gunze Medical Devices (shenzhen) Ltd
Gunze Ltd
Original Assignee
Gunze Medical Devices (shenzhen) Ltd
Gunze Ltd
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Application filed by Gunze Medical Devices (shenzhen) Ltd, Gunze Ltd filed Critical Gunze Medical Devices (shenzhen) Ltd
Priority to JP2018567186A priority Critical patent/JP6678255B2/en
Priority to CN201680090628.2A priority patent/CN109937055A/en
Priority to PCT/CN2016/104877 priority patent/WO2018082090A1/en
Publication of WO2018082090A1 publication Critical patent/WO2018082090A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • D—TEXTILES; PAPER
    • D21—PAPER-MAKING; PRODUCTION OF CELLULOSE
    • D21H—PULP COMPOSITIONS; PREPARATION THEREOF NOT COVERED BY SUBCLASSES D21C OR D21D; IMPREGNATING OR COATING OF PAPER; TREATMENT OF FINISHED PAPER NOT COVERED BY CLASS B31 OR SUBCLASS D21G; PAPER NOT OTHERWISE PROVIDED FOR
    • D21H27/00—Special paper not otherwise provided for, e.g. made by multi-step processes
    • D21H27/30—Multi-ply
    • D21H27/38—Multi-ply at least one of the sheets having a fibrous composition differing from that of other sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/36—Surgical swabs, e.g. for absorbency or packing body cavities during surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses

Definitions

  • the present invention relates to a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue, which is a blood product, and also relates to an artificial dura mater including the biological tissue-reinforcing material.
  • the dura mater lying between the cranial bones and brain and covering the spinal cord, mainly protects the brain and spinal cord and inhibits leakage of cerebrospinal fluid.
  • a defect or contracture of the dura mater after opening the dura mater in a surgery needs to be filled, and lyophilized products of human dura mater were used for the filling.
  • lyophilized products of human dura mater have had drawbacks such as low homogeneity and short supply.
  • Non-Patent Literature 1 reports a possible transmission of Creutzfelt-Jacob disease infection through the use of human dura mater. Eventually, the Japanese Ministry of Health and Welfare banned the use of lyophilized products of human dura mater on April 7, 1997.
  • artificial dura maters made of biodegradable and bioabsorbable polymers which are decomposed and absorbed after a certain time period ofusage have been proposed.
  • artificial dura maters include those made of natural polymers such as collagen reported in Non-Patent Literature 3 and gelatin reported in Non-Patent Literature 4.
  • those artificial dura maters have not been practically usedbecause of various drawbacks including insufficient suture strength upon integral suturing with the dura mater of a living body and possible risk of infection due to the natural raw materials.
  • Patent Literature 1 discloses an artificial dura mater made of a biodegradable and bioabsorbable synthetic polymer, in particular, a lactide- ⁇ -caprolactone copolymer.
  • the artificial dura mater has almost no risk of infection and decomposes after a certain time period of usage, thereby preventing the harmful effects caused by long-term implantation.
  • fibrin glue which is a blood product, may lead to unknown virus infection, specialists in the field of neurosurgery hesitate to use fibrin glue.
  • Patent Literature 1 JP H8-80344 A
  • Non-Patent Literature 1 Neurosurgery, 21 (2) , 167-170, 1993
  • Non-Patent Literature 2 Japanese Journal of Neurosurgery, 16 (7) , 555-560 (2007)
  • Non-Patent Literature 3 Journal of Biomedical Materials Research, Vol. 25, 267-276, 1991
  • Non-Patent Literature 4 Brain and Nerve, 21, 1089-1098, 1969
  • the present invention aims to provide a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue, which is a blood product, and an artificial dura mater including the biological tissue-reinforcing material.
  • the present invention relates to a biological tissue-reinforcing material including a laminated structure, the laminated structure including: a film made of a bioabsorbable polymer; and a fiber structure, sponge body, or film made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose.
  • a biological tissue-reinforcing material including, instead of fibrin glue, etherified cellulose produced through etherification of hydroxy groups of cellulose (hereinafter, also referred to as ′′etherified cellulose′′ ) can more reliably reinforce weakened tissue, and in particular also found that the use of the etherified cellulose for attachment of artificial dura maters prevents fluid leakage.
  • the inventors completed the present invention based on the finding.
  • Etherified cellulose is a compound proven to be very safe, and gels in a short time to act as glue like fibrin glue. Further, since etherified cellulose has a certain level of adhesion even after it gels, if cohesive failure or interfacial peeling occurs due to high pressure, it can adhere again to prevent air leakage or fluid leakage. Etherified cellulose can be processed into various shapes. Thus, a biological tissue-reinforcing material with excellent handleability can be prepared from a laminated structure in which a fiber structure, sponge body, or film made of etherified cellulose is stacked on a film made of a bioabsorbable polymer.
  • the biological tissue-reinforcing material of the present invention includes a laminated structure that includes a film made of a bioabsorbable polymer and a fiber structure, sponge body, or film made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose.
  • the film made of a bioabsorbable polymer is designed to exhibit a tissue-reinforcing effect, an air leakage prevention effect, and a fluid leakage prevention effect when it is attached to a damaged or weakened organ.
  • the biological tissue-reinforcing material of the present invention is used as an artificial dura mater, the artificial dura mater plays an important role to protect the brain and spinal cord and prevents cerebrospinal fluid leakage.
  • the fiber structure, sponge body, film made of etherified cellulose absorbs moisture to gel, and acts as glue to attach the film made of a bioabsorbable polymer to biological tissue.
  • bioabsorbable polymer examples include synthetic absorbable polymers such as ⁇ -hydroxy acid polymers, for example, polyglycolide, polylactide (D, L, DL isomer) , glycolide-lactide(D, L, DL isomer) copolymers, glycolide- ⁇ -caprolactone copolymers, lactide (D, L, DL isomer) - ⁇ -caprolactone copolymers, poly (p-dioxanone) , or glycolide-lactide (D, L, DL isomer) - ⁇ -caprolactone copolymers; and natural absorbable polymers such as collagen, gelatin, chitosan, or chitin.
  • synthetic absorbable polymers such as ⁇ -hydroxy acid polymers, for example, polyglycolide, polylactide (D, L, DL isomer) , glycolide-lactide(D, L, DL isomer) copolymers, glycolide
  • a natural absorbable polymer may be used together therewith.
  • an ⁇ -hydroxy acid polymer which is a homopolymer or copolymer of at least one monomer selected from the group consisting of glycolide, lactide, ⁇ -caprolactone, dioxanone, and trimethylene carbonate is preferably used because of its high strength.
  • An ⁇ -hydroxy acid polymer which is a homopolymer or copolymer of a monomer containing glycolide is more preferably used because the polymer shows appropriate decomposition behavior.
  • the bioabsorbable material is preferably a lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer.
  • a film made of a lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer has such high flexibility and high strength that it can fit to the applied part along with the subtle curvature of the part, and is thus suitable for an artificial dura mater.
  • the material is decomposed after a certain time period of usage and can prevent problems which may occur after long-term implantation.
  • the lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer preferably contains at least 40 mol%and at most 60 mol%of lactide.
  • the lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer contains more than 60 mol%of lactide or ⁇ -caprolactone, a resulting biological tissue-reinforcing material may have a high crystallinity and become rigid so that it may fail to obtain sufficient flexibility.
  • the lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer contains at least 45 mol%and at most 55 mol%of lactide.
  • the lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer has a weight average molecular weight of preferably not less than 100,000 and not more than 500,000.
  • a lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer having a weight average molecular weight of less than 100,000 may not have sufficient strength.
  • the lactide (D, L, DL isomer) - ⁇ -caprolactone copolymer having a weight average molecular weight of more than 500,000 is used, the resulting film may be poor in moldability due to high melt viscosity.
  • the lactide (D, L, DL isomer) - ⁇ -caprotactone copolymer has a weight average molecular weight of preferably not less than 150,000 and not more than 450,000.
  • the thickness of the film made of the bioabsorbable polymer is not particularly limited, and the preferable lower limit is 10 ⁇ m, and the preferable upper limit is 800 ⁇ m.
  • a film made of the bioabsorbable polymer having a thickness of less than 10 ⁇ m is poor in strength and may not impart a sufficient tissue-reinforcing effect.
  • a film made of the bioabsorbable polymer having a thickness of more than 800 ⁇ m may not sufficiently adhere to and fix tissue.
  • the more preferable lower limit of the thickness of the film made of the bioabsorbable polymer is 20 ⁇ m, and the more preferable upper limit thereof is 300 ⁇ m.
  • the film made of the bioabsorbable polymer may be subjected to hydrophilization.
  • the film having been subjected to hydrophilization rapidly absorbs moisture such as physiological saline upon contact, and is therefore readily handled.
  • Non-limiting examples of the hydrophilization include plasma treatment, glow discharge treatment, corona discharge treatment, ozone treatment, surface graft treatment, and ultraviolet irradiation treatment.
  • plasma treatment is preferred because this treatment markedly increases the water absorption rate without changing the outward appearance of the film.
  • the etherified cellulose is produced through etherification of hydroxy groups of cellulose.
  • hydroxyalkylated cellulose represented by the formula (1) below such as hydroxyethylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxyethyl groups or hydroxypropylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxypropyl groups; and carboxyalkylated cellulose such as carboxymethylated cellulose in which hydroxy groups of the cellulose have been replaced with carboxymethyl groups.
  • hydroxyethylated cellulose which is proven to be very safe, is preferred.
  • n represents an integer
  • R represents hydrogen or -R′OH in which R′represents an alkylene group.
  • the molar ratio of a diethylene glycol group to an ethylene glycol group is preferably 0.1 to 1.0, and the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) is preferably 0.1 to 0.5 in the hydroxyethylated cellulose.
  • the etherified cellulose having molar ratios within such ranges imparts excellent initial adhesion when the film made of the bioabsorbable polymer adheres to biological tissue through the fiber structure, sponge body, or film made of the etherified cellulose, and the high adhesion is maintained after adhesion. Even if cohesive failure or interfacial peeling occurs due to high pressure, the film can adhere again to prevent air leakage or fluid leakage.
  • the numbers of moles of ethylene glycol groups, diethylene glycol groups, and triethylene glycol groups in the hydroxyethylatedcellulose can be measured, for example, byNMR or thermal decomposition GC-MS.
  • the preferable lower limit of the average number of molecules (molar substitution, MS) of alkylene oxides bonded to an anhydroglucose unit is 1.0, and the preferable upper limit thereof is 4.0.
  • the etherified cellulose having a MS within such a range can gel in a short time with high gel strength, and closely adhere to and fix tissue.
  • MS is less than 1.0, gelledhydroxyethylated cellulose tends to be less viscous.
  • the MS is more than 4.0, gelation tends to take a long time.
  • the more preferable lower limit of the MS is 1.3, and the more preferable upper limit thereof is 3.0.
  • the preferable lower limit of the average degree of substitution (DS) of alkylene oxides to hydroxy groups at positions 2, 3, and 6 of an anhydroglucose unit is 0.2, and the preferable upper limit thereof is 2.5.
  • the etherified cellulose having a DS within such a range can gel in a short time with high gel strength, and closely adhere to and fix tissue. When the DS is less than 0.2, gelationmay take a long time. When the DS is more than 2.5, the wet strength may decrease.
  • the more preferable lower limit of the DS is 0.3, and the more preferable upper limit thereof is 1.5.
  • the MS and DS can be calculated by determining the NMR spectrum of an aqueous solution of the hydroxyethylated cellulose, and measuring the intensities of signals belonging to carbon atoms of an anhydroglucose ring and carbon atoms of a substituent group in the spectrum (see, for example, JP H6-41926 B) .
  • 0.2 g of a sample, 30 mg of an enzyme (cellulase) , and an internal standard material are dissolved in 3 mL of heavy water.
  • the resulting solution is subjected to ultrasonication for 4 hours, and its NMR spectrum is determined using an NMR measuring device (e.g. JNM-ECX400P available from JEOL) under the conditions of the number of scanning of 700, pulse width of 45°, and observed frequency of 31, 500 Hz.
  • an NMR measuring device e.g. JNM-ECX400P available from JEOL
  • the etherified cellulose may be cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose so that part of unetherified hydroxy groups are carboxylated (hereinafter, also referred to as "etherified and carboxylated cellulose") .
  • etherified and carboxylated cellulose enables strong adhesion to damaged sites with particularly large surface irregularities.
  • the etherified and carboxylated cellulose is produced through etherification and carboxylation of hydroxy groups of cellulose.
  • hydroxyalkylated and carboxylated cellulose such as hydroxyethylated and carboxylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxyethyl groups and carboxyl groups, or hydroxypropylated and carboxylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxypropyl groups and carboxyl groups.
  • Particularly preferred is hydroxyethylated and carboxylated cellulose because it is proven to be very safe.
  • hydroxyalkylated and carboxylated cellulose represented by the following formula (2) :
  • R represents hydrogen or-R′ OH in which R′ represents an alkylene group.
  • the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) in the hydroxyethylated and carboxylated cellulose is preferably 0.1 to 1.5, and the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) is preferably 0.1 to 1.0.
  • the lower limit of the average number of molecules (molar substitution, MS) of alkylene oxide bonded to ananhydroglucose unit is preferably 1.0, and the upper limit thereof is preferably 4.0.
  • the lower limit of the average degree of substitution (DS) of alkylene oxides to hydroxy groups at positions 2, 3, and 6 of an anhydroglucose unit is preferably 0.2, and the upper limit thereof is preferably 2.5.
  • the average number of molecules (MS) , the average degree of substitution (DS) , and the numbers of moles of ethylene glycol groups, diethylene glycol groups, and triethylene glycol groups can be measured, for example, by NMR or thermal decomposition GC-MS.
  • the hydroxyethylated cellulose can be produced, for example, by the reaction of an ethylene oxide with alkali cellulose produced by treating cellulose with an aqueous solution of an alkali.
  • alkali cellulose is produced from a fiber structure made of cellulose as a raw material by treating the fiber structure with an aqueous solution of an alkali such as sodium hydroxide. To the resulting alkali cellulose are added a certain amount of an ethylene oxide and a reaction solvent, and a reaction is performed.
  • an alkali such as sodium hydroxide
  • the etherified and carboxylated cellulose can be produced by, for example, carboxylating and then etherifying cellulose.
  • the cellulose may be carboxylated as follows, for example. Through a reaction with 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPO) as an oxidant and sodium hypochlorite, hydroxy groups of the cellulose are oxidized to aldehyde (TEMPO oxidation step) . Subsequently, the cellulose is reacted with sodium chlorite so that the aldehyde is carboxylated (carboxylation step) .
  • TEMPO 2, 2, 6, 6-tetramethylpiperidine-1-oxyl
  • the resulting carboxylated cellulose is treated with an aqueous solution of an alkali such as sodium hydroxide (alkali treatment step) and then reacted with ethylene oxide to be etherified (hydroxyethylated) (hydroxyethylation step) .
  • alkali treatment step an alkali such as sodium hydroxide
  • ethylene oxide ethylene oxide
  • etherified and carboxylated cellulose can be prepared.
  • carboxyl groups are mainly introduced to position 6 of cellulose, and hydroxyethyl groups are mainly introduced to position 2 or 6.
  • the preferable lower limit of the water absorption rate of the fiber structure, sponge body, or film made of the etherified cellulose is 200%, and the preferable upper limit thereof is 1,000%.
  • the fiber structure, sponge body, or film made of the etherified cellulose having a water absorption rate within such a range can gel in a short time with high gel strength, and closely adhere to and fix tissue.
  • gelation may take a long time.
  • gel strength tends to be low.
  • the more preferable lower limit of the water absorption rate is 400%, and the more preferable upper limit thereof is 800%.
  • the water absorption rate herein can be measured by the following method.
  • the initial weight of a sample is measured, and the sample is placed in a petri dish. Distilled water is slowly dropped onto the sample.
  • the weight of the sample having absorbed distilled water to the maximum is determined as a maximum water absorption weight.
  • the water absorption rate can be determined based on the following equation from the initial weight and the maximum water absorption weight.
  • Water absorption rate (%) (maximum water absorption weight-initial weight) /initial weight ⁇ 100
  • the preferable lower limit of the moisture absorption rate of the fiber structure, sponge body, or film made of the etherified cellulose is 7%, and the preferable upper limit thereof is 50%.
  • the fiber structure, sponge body, or film made of the etherified cellulose having a moisture absorption rate within such a range can gel in a short time with high gel strength, and closely adhere to and fix tissue.
  • gelation maytake a long time.
  • the moisture absorption rate is higher than 50%, the gel strength tends to be low.
  • the more preferable lower limit of the moisture absorption rate is 10%, and the more preferable upper limit thereof is 35%.
  • the moisture absorption rate used herein can be measured by the following method.
  • a sample is heated at 105°C for 2 hours.
  • the weight of the resulting sample is determined as an absolute dry weight.
  • the absolute dry sample is allowed to stand in an atmosphere at 20°C and 65%Rh for 7 hours to control the moisture content of the sample.
  • the weight of the sample is determined as a weight after moisture control.
  • a moisture absorption rate can be calculated based on the following equation from the absolute dry weight and the weight after moisture control.
  • Moisture absorption rate (%) (weight after moisture control -absolute dry weight) /absolute dry weight ⁇ 100
  • the fiber structure made of the etherified cellulose may be in any form, including the form of a non-woven fabric, a knitted fabric, a woven fabric, gauze, or yarn, or a combination of these forms.
  • the form of a non-woven fabric is preferred.
  • the weight per unit area of the non-woven fabric is not particularly limited, and the preferable lower limit is 20 g/m 2 , and the preferable upper limit is 700 g/m 2 .
  • a non-woven fabric having a weight per unit area of less than 20 g/m 2 may fail to attach the biological tissue-reinforcing material to biological tissue with sufficient adhesion.
  • the etherified cellulose may take a long time to gel.
  • the more preferable lower limit of the weight per unit area of the non-woven fabric is 50 g/m 2
  • the more preferable upper limit thereof is 500 g/m 2 .
  • the non-woven fabric may be produced by any method, and examples of the method include conventionally known methods such as electrospinning deposition, melt blowing, needle punching, spun bonding, flash spinning, hydroentanglement, air laying, thermal bonding, resin bonding, or wet processing.
  • the weight per unit area of the sponge body made of the etherified cellulose is not particularly limited, and the preferable lower limit is 15 g/m 2 , and the preferable upper limit is 1,200 g/m 2 .
  • a sponge body having a weight per unit area of less than 15 g/m 2 has strength not enough for a biological tissue-reinforcing material, and may not reinforce weakened tissue.
  • a sponge body having a weight per unit area of more than 1,200 g/m 2 may result in poor adhesion to tissue.
  • the more preferable lower limit of the weight per unit area of the sponge body is 30 g/m 2 , and the more preferable upper limit thereof is 500 g/m 2 .
  • the thickness of the fiber structure or sponge body made of the etherified cellulose is not particularly limited, and the preferable lower limit is 50 ⁇ m, and the preferable upper limit is 10 mm.
  • a fiber structure or sponge body made of the etherified cellulose having a thickness of less than 50 ⁇ m may fail to attach the biological tissue-reinforcing material to biological tissue with sufficient adhesion.
  • a fiber structure or sponge body made of the etherified cellulose having a thickness of more than 10 mm is less likely to absorb water to have poor texture, thereby deteriorating the handleability.
  • the more preferable lower limit of the thickness of the fiber structure or sponge body made of the etherified cellulose is 50 ⁇ m, and the more preferable upper limit thereof is 5 mm.
  • the thickness of the film made of the etherified cellulose is not particularly limited, and the preferable lower limit is 10 ⁇ m, and the preferable upper limit is 800 ⁇ m.
  • a film made of the etherified cellulose having a thickness of less than 10 ⁇ m is poor in strength and may not impart a sufficient tissue-reinforcing effect.
  • a film made of the etherified cellulose having a thickness of more than 800 ⁇ m may not sufficiently adhere to and fix tissue.
  • the more preferable lower limit of the thickness of the film made of the etherified cellulose is 20 ⁇ m, and the more preferable upper limit thereof is 300 ⁇ m.
  • the film made of the bioabsorbable polymer and the fiber structure, sponge body, or film made of theetherifiedcellulose are preferably integrated to improve the handleability.
  • integrated herein means a state where two structures laminated to each other can be treated as one structure, and are not easily separated.
  • Non-limiting example of the mode of the integration include a mode in which a part of the fiber structure or sponge body made of the etherified cellulose has entered a part of the film made of the bioabsorbable polymer.
  • the biological tissue-reinforcing material of the present invention is used to stop bleeding from a damaged or weakened organ or tissue, or to prevent air leakage or fluid leakage in the field of surgery.
  • the biological tissue-reinforcing material is favorably used as an artificial dura mater in the neurosurgery field.
  • Another aspect of the present invention is an artificial dura mater including the biological tissue-reinforcing material.
  • the biological tissue-reinforcing material of the present invention can be readily attached to an affected area just by applying the material preliminary immersed into physiological saline to the affected area. Furthermore, the biological tissue-reinforcing material absorbs blood or fluid from an affected area so that it can exhibit adhesion.
  • Fig. 1 is a view schematically illustrating a water pressure resistance tester used in the water pressure resistance test performed in examples.
  • the present invention can provide a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue, which is a blood product, and an artificial dura mater including the biological tissue-reinforcing material.
  • a 280- ⁇ m-thick single knit made of No. 80 count cellulose yarn as a raw material was bleached by hydrogen peroxide bleaching.
  • the resulting knit was dried at 40°C for 24 hours to prepare a fiber structure made of hydroxyethylated cellulose.
  • a L-lactide/ ⁇ -caprolactone copolymer (molar ratio: 50/50, weight average molecular weight measured by GPC: 220,000, hereinafter also referred to as ′′P (L-LA/CL) (molar ratio: 50/50) ′′ ) was dissolved in chloroform and filtered to remove unmolten substances so that a 5 weight percent solution was prepared. The solution was casted on a glass plate, and air-dried and subsequently dried in vacuo at 50°C for 12 hours to give a 100- ⁇ m-thick film made of P (L-LA/CL) (molar ratio: 50/50) .
  • a fiber structure made of hydroxyethylated cellulose was immersed in 1, 4-dioxane to be partially dissolved.
  • the partially dissolved fiber structure made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) and uniformly pressed, followed by drying at 23°C for three hours.
  • a biological tissue-reinforcing material including a laminated structure in which the fiber structure made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) was prepared.
  • the biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
  • a water pressure resistance test was performed using a water pressure resistance tester 1 illustrated in Fig. 1.
  • a 20-mL syringe 3 (Terumo Syringe SS-20ESZ available from Terumo Corporation) containing a phosphate buffer and a pressure gauge 5 (digital manometer FUSO-8230 available from Fusorika Co., Ltd. ) were placed at the downstream of the filter holder via a three way cock 4. In this manner, a water pressure resistance tester was fabricated.
  • Purified water was dropped onto a face of the test sample on the side of the fiber structure made of hydroxyethylated cellulose.
  • the resulting test sample was placed at the center of the collagen film set in the filter holder such that the face was in contact with the collagen film.
  • a phosphate buffer was delivered from the syringe. The maximum pressure before the test sample was peeled was measured with a pressure gauge for evaluation of the water pressure resistance.
  • a 280- ⁇ m-thick single knit made of No. 80 count cellulose yarn as a raw material was bleached by hydrogen peroxide bleaching.
  • the bleached knit was immersed in a TEMPO oxidation solution (TEMPO concentration: 20%owf, 5%sodiumhypochlorite concentration: 180%owf, sodium bromide: 17.5%owf, pH 10 aqueous solution) at 25°C for 10 minutes at a bath ratio of 1 ⁇ 30 to be oxidized.
  • the oxidized knit was washed with water three times and subsequently immersed in a sodium chlorite solution (25%sodium chlorite concentration: 20%owf, CG1000 concentration: 1.0 g/L, pH 3.8 aqueous solution) at 80°C for 90 minutes at a bath ratio of 1 ⁇ 15 to be carboxylated.
  • the resulting knit was washed with hot water and then with water, and immersed in a hydrogen peroxide/sodium borohydride solution (30%hydrogen peroxide concentration: 1%owf, sodium borohydride concentration: 5%owf, PCL7000 concentration: 0.4 g/L, pH 10.5 aqueous solution) at 70°C for 20 minutes at a bath ratio of 1 ⁇ 20 for dechlorination and reduction of partially formed ketone to hydroxy groups.
  • the obtained knit was further washed with hot water, neutralized, and washed with water. A carboxylated knit was thus prepared.
  • the obtained carboxylated knit was immersed in a 20%sodium hydroxide aqueous solution at 15°C for 30 minutes at a bath ratio of 1 ⁇ 40 to be alkalized. To the resulting knit was applied a load of 2.5 to 3.0 kg for padding. The knit after padding was immersed in a 0.8 mol/L solution of ethylene oxide in hexane at 50°C for 30 minutes at a bath ratio of 1 ⁇ 15 to be hydroxyethylated.
  • a 100- ⁇ m-thick film made of P (L-LA/CL) (molar ratio: 50/50) was prepared as in Example 1.
  • a fiber structure made of hydroxyethylated and carboxylated cellulose was immersed in 1, 4-dioxane to be partially dissolved.
  • the partially dissolved fiber structure made of hydroxyethylated and carboxylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) and uniformly pressed, followed by drying at 23°C for three hours.
  • a biological tissue-reinforcing material including a laminated structure in which the fiber structure made of hydroxyethylated and carboxylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) was prepared.
  • the biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
  • test sample was subjected to a water pressure resistance test as in Example 1.
  • a sol solution of hydroxyethylated cellulose was prepared by dissolving a commercial hydroxyethylated cellulose (available from Wako Pure Chemical Industries, Ltd., the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) : 1.06, the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) : 4.01) in distilled water so that the solution had a solid content of 7.5%by weight.
  • a commercial hydroxyethylated cellulose available from Wako Pure Chemical Industries, Ltd., the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) : 1.06, the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) : 4.01) in distilled water so that the solution had a solid content of 7.
  • the sol solution of hydroxyethylated cellulose was casted on a petri dish and dried at 30°C for 24 hours, thereby obtaining a 50- ⁇ m-thick film made of a hydroxyethylated cellulose.
  • a 100- ⁇ m-thick film made of P (L-LA/CL) (molar ratio: 50/50) was prepared as in Example 1.
  • a film made of hydroxyethylated cellulose was immersed in 1, 4-dioxane to be partially dissolved.
  • the partially dissolved film made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50)and uniformly pressed, followed by drying at 23°C for three hours.
  • a biological tissue-reinforcing material including a laminated structure in which the film made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) was prepared.
  • the biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
  • the test sample was subjected to a water pressure resistance test as in Example 1.
  • a sol solution of carboxymethylated cellulose was prepared by dissolving a commercial carboxymethylated cellulose (available fromWako Pure Chemical Industries, Ltd. ) in distilled water so that the solution had a solid content of 7.5%by weight.
  • the sol solution of carboxymethylated cellulose was casted on a petri dish and dried at 30°C for 24 hours, thereby obtaining a 80- ⁇ m-thick film made of carboxymethylated cellulose.
  • a 100- ⁇ m-thick film made of P (L-LA/CL) (molar ratio: 50/50) was prepared as in Example 1.
  • a film made of carboxymethylated cellulose was immersed in 1, 4-dioxane to be partially dissolved.
  • the partially dissolved film made of carboxymethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) and uniformly pressed, followed by drying at 23°C for three hours.
  • a biological tissue-reinforcing material including a laminated structure in which the film made of carboxymethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio: 50/50) was prepared.
  • the biological tissue-reinforcing material was punched into a 11-mm-diameter circle to give a test sample for measurement.
  • the test sample was subjected to a water pressure resistance test as in Example 1.
  • a 11-mm-diameter circular piece was punched out from a 150- ⁇ m-thick nonwoven fabric made of polyglycolide (NEOVEIL Type NV-M015G, GUNZE LIMITED) .
  • a collagen film prepared as in Example 1 was set on the filter holder of the water pressure tester used in Example 1. Then, 20 ⁇ L of a solution A of fibrin glue (Beriplast P consisting of a solution A (mixture of fibrinogen powder and an aprotinin solution) and a solution B (mixture of thrombin powder and a calcium chloride solution) , available from CSL Behring K. K. ) was dropped onto the center of the collagen film in such a manner as to avoid the hole in the collagen film, and was spread into a shape with a diameter of approximately 11 mm. Next, the nonwoven fabric punched into a 11-mm-diameter circle was placed on the spread solution A and impregnated with the solution A. Subsequently, 20 ⁇ L of the solution A was dropped onto the nonwoven fabric, and the nonwoven fabric was sufficiently impregnated with the solution A. Thereafter, 20 ⁇ L of a solution B was dropped onto the nonwoven fabric.
  • fibrin glue Beriplast P consisting of
  • a biological tissue-reinforcing material was obtained in the same manner as in Example 1, except that a fiber structure made of oxidized cellulose (Surgicet available from Johnson & Johnson K. K. ) was used instead of the fiber structure made of hydroxyethylated cellulose.
  • the biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
  • the test sample was subjected to a water pressure resistance test as in Example 1.
  • a sol solution of oxidized cellulose was prepared by dissolving a fiber structure made of oxidized cellulose (Surgicel available from Johnson & Johnson K. K. ) in distilled water so that the solution had a solid content of 7.5%by weight.
  • the sol solution of oxidized cellulose was casted on a petri dish and dried at 30°C for 24 hours, thereby obtaining a 130- ⁇ m-thick film made of oxidized cellulose.
  • a film made of oxidized cellulose was immersed in 1, 4-dioxane to be partially dissolved.
  • the partially dissolved film made of oxidized cellulose was stacked on one surface of the film made of a lactide- ⁇ -caprolactone copolymer and was uniformly pressed, followed by drying at 23°C for three hours.
  • a biological tissue-reinforcing material including a laminated structure in which the film made of oxidized cellulose was stacked on one surface of the film made of a lactide- ⁇ -caprolactone copolymer was prepared.
  • the biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
  • the test sample was subjected to a water pressure resistance test as in Example 1.
  • the film was punched into a 11-mm-diameter circular shape to give a test sample.
  • a water pressure resistance test was performed using a water pressure resistance tester 1 illustrated in Fig. 1.
  • An about 130- ⁇ m-thick collagen film (available from Nippi. Inc. ) was punched into a rectangular shape with a length of 5.5 cm and a width of 5.0 cm, and the film was washed with 70%ethanol, and liquid was wiped off. The resulting film was set in a filter holder 2 (Swinnex (registered trademark) 25 available from Merck Millipore) . A 3-mm-diameter hole was formed with a punch in the center of the collagen film that was set in the filter holder 2. The test sample was placed on the collagen film in such a manner as to allow the center of the test sample to overlap the center of the hole of the collagen film.
  • test sample and the collagen film were sewn together using a suture (Monodiox (registered trademark) available fromAlfresa Pharma Corporation) made of polyglycolide with suture size No. 4-0.
  • the distance between the seams was 7.0 mm.
  • the 11-mm-diameter circular test sample for measurement had five seams of the suture.
  • a 20-mL syringe 3 (Terumo Syringe SS-20ESZ available from Terumo Corporation) containing a phosphate buffer and a pressure gauge 5 (digital manometer FUSO-8230 available from Fusorika Co., Ltd. ) were placed at the downstream of the filter holder via a three way cock 4. In this manner, a water pressure resistance tester was fabricated.
  • a phosphate buffer was delivered from the syringe.
  • the maximum pressure before the test sample was peeled was measured with a pressure gauge for evaluation of the water pressure resistance.
  • the present invention can provide a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue, which is a blood product, and can also provide an artificial dura mater including the biological tissue-reinforcing material.

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Abstract

Provided is a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue, which is a blood product, and an artificial dura mater including the biological tissue-reinforcing material. Provided is a biological tissue-reinforcing material including a laminated structure, the laminated structure including: a film made of a bioabsorbable polymer: and a fiber structure, sponge body, or film made of etherified cellulose that is produced through etherification of hydroxyl groups of cellulose.

Description

BIOLOGICAL TISSUE-REINFORCING MATERIAL AND ARTIFICIAL DURA MATER TECHNICAL FIELD
The present invention relates to a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product， and also relates to an artificial dura mater including the biological tissue-reinforcing material.
BACKGROUND ART
The most fundamental issue in the field of surgery is to repair a damaged or weakened organ or tissue.
The dura mater， lying between the cranial bones and brain and covering the spinal cord， mainly protects the brain and spinal cord and inhibits leakage of cerebrospinal fluid. In the field of neurosurgery， a defect or contracture of the dura mater after opening the dura mater in a surgery needs to be filled， and lyophilized products of human dura mater were used for the filling. However， lyophilized products of human dura mater have had drawbacks such as low homogeneity and short supply. Further， Non-Patent Literature 1 reports a possible transmission of Creutzfelt-Jacob disease infection through the use of human dura mater. Eventually， the Japanese Ministry of Health and Welfare banned the use of lyophilized products of human dura mater on April 7， 1997.
Artificial dura maters made of fluorine resin， for example， are available in the market as fillings replacing human dura mater. Unfortunately， however， fluorine resin artificial  dura maters may cause granulation or refractory skin fistula due to infection after long-term implantation， as reported in Non-Patent Literature 2.
Meanwhile， artificial dura maters made of biodegradable and bioabsorbable polymers which are decomposed and absorbed after a certain time period ofusage have been proposed. Examples of such artificial dura maters include those made of natural polymers such as collagen reported in Non-Patent Literature 3 and gelatin reported in Non-Patent Literature 4. However， those artificial dura maters have not been practically usedbecause of various drawbacks including insufficient suture strength upon integral suturing with the dura mater of a living body and possible risk of infection due to the natural raw materials.
In order to solve the above problems， Patent Literature 1 discloses an artificial dura mater made of a biodegradable and bioabsorbable synthetic polymer， in particular， a lactide-ε-caprolactone copolymer. The artificial dura mater has almost no risk of infection and decomposes after a certain time period of usage， thereby preventing the harmful effects caused by long-term implantation.
Artificial dura maters are usually fixed to the dura mater at the site where a defect or contracture occurs by suturing using sutures. However， small gaps are unavoidably formed in the periphery of sutures， and a portion of cerebrospinal fluid may leak from the gaps.
Use of fibrin glue together with artificial dura maters has been examined to enable sealing without suturing. However， since fibrin glue， which is a blood product， may lead to unknown virus infection， specialists in the field of neurosurgery hesitate to use fibrin glue.
CITATION LIST
- Patent Literature
Patent Literature 1： JP H8-80344 A
- Non-Patent Literature
Non-Patent Literature 1： Neurosurgery， 21 (2) ， 167-170， 1993 Non-Patent Literature 2： Japanese Journal of Neurosurgery， 16 (7) ， 555-560 (2007)
Non-Patent Literature 3： Journal of Biomedical Materials Research， Vol. 25， 267-276， 1991
Non-Patent Literature 4： Brain and Nerve， 21， 1089-1098， 1969
SUMMARY OF INVENTION
- Technical Problem
The present invention aims to provide a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product， and an artificial dura mater including the biological tissue-reinforcing material.
- Solution to Problem
The present invention relates to a biological tissue-reinforcing material including a laminated structure， the laminated structure including： a film made of a bioabsorbable polymer； and a fiber structure， sponge body， or film made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose.
The present invention is described in detail below.
As a result of various studies， the present inventors have found that a biological tissue-reinforcing material including， instead of fibrin glue， etherified cellulose produced through  etherification of hydroxy groups of cellulose (hereinafter， also referred to as ″etherified cellulose″ ) can more reliably reinforce weakened tissue， and in particular also found that the use of the etherified cellulose for attachment of artificial dura maters prevents fluid leakage. The inventors completed the present invention based on the finding.
Etherified cellulose is a compound proven to be very safe， and gels in a short time to act as glue like fibrin glue. Further， since etherified cellulose has a certain level of adhesion even after it gels， if cohesive failure or interfacial peeling occurs due to high pressure， it can adhere again to prevent air leakage or fluid leakage. Etherified cellulose can be processed into various shapes. Thus， a biological tissue-reinforcing material with excellent handleability can be prepared from a laminated structure in which a fiber structure， sponge body， or film made of etherified cellulose is stacked on a film made of a bioabsorbable polymer.
The biological tissue-reinforcing material of the present invention includes a laminated structure that includes a film made of a bioabsorbable polymer and a fiber structure， sponge body， or film made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose.
The film made of a bioabsorbable polymer is designed to exhibit a tissue-reinforcing effect， an air leakage prevention effect， and a fluid leakage prevention effect when it is attached to a damaged or weakened organ. In particular， when the biological tissue-reinforcing material of the present invention is used as an artificial dura mater， the artificial dura mater plays an important role to protect the brain and spinal cord and prevents cerebrospinal fluid leakage.
The fiber structure， sponge body， film made of etherified cellulose absorbs moisture to gel， and acts as glue to attach the film made of a bioabsorbable polymer to biological tissue.
Non-limiting examples of the bioabsorbable polymer include synthetic absorbable polymers such as α-hydroxy acid polymers， for example， polyglycolide， polylactide (D， L， DL isomer) ， glycolide-lactide(D， L， DL isomer) copolymers， glycolide-ε-caprolactone copolymers， lactide (D， L， DL isomer) -ε-caprolactone copolymers， poly (p-dioxanone) ， or glycolide-lactide (D， L， DL isomer) -ε-caprolactone copolymers； and natural absorbable polymers such as collagen， gelatin， chitosan， or chitin. Any of these may be used alone， or two or more of these may be used in combination. For example， in cases where the synthetic absorbable polymer is used as the bioabsorbable polymer， a natural absorbable polymer may be used together therewith. In particular， an α-hydroxy acid polymer which is a homopolymer or copolymer of at least one monomer selected from the group consisting of glycolide， lactide， ε-caprolactone， dioxanone， and trimethylene carbonate is preferably used because of its high strength. An α-hydroxy acid polymer which is a homopolymer or copolymer of a monomer containing glycolide is more preferably used because the polymer shows appropriate decomposition behavior.
In cases where the biological tissue-reinforcing material of the present invention is used as an artificial dura mater， the bioabsorbable material is preferably a lactide (D， L， DL isomer) -ε-caprolactone copolymer. A film made of a lactide (D， L， DL isomer) -ε-caprolactone copolymer has such high flexibility and high strength that it can fit to the applied part along with the subtle curvature of the part， and is thus suitable for an artificial dura mater. Moreover， the material is decomposed after a certain time period of usage and can prevent problems which may occur after long-term implantation.
The lactide (D， L， DL isomer) -ε-caprolactone copolymer preferably contains at least 40 mol％and at most 60 mol％of lactide. When the lactide (D， L， DL isomer) -ε-caprolactone  copolymer contains more than 60 mol％of lactide or ε-caprolactone， a resulting biological tissue-reinforcing material may have a high crystallinity and become rigid so that it may fail to obtain sufficient flexibility. More preferably， the lactide (D， L， DL isomer) -ε-caprolactone copolymer contains at least 45 mol％and at most 55 mol％of lactide.
The lactide (D， L， DL isomer) -ε-caprolactone copolymer has a weight average molecular weight of preferably not less than 100,000 and not more than 500,000. A lactide (D， L， DL isomer) -ε-caprolactone copolymer having a weight average molecular weight of less than 100,000 may not have sufficient strength. When a lactide (D， L， DL isomer) -ε-caprolactone copolymer having a weight average molecular weight of more than 500,000 is used， the resulting film may be poor in moldability due to high melt viscosity. More preferably， the lactide (D， L， DL isomer) -ε-caprotactone copolymer has a weight average molecular weight of preferably not less than 150,000 and not more than 450,000.
The thickness of the film made of the bioabsorbable polymer is not particularly limited， and the preferable lower limit is 10 μm， and the preferable upper limit is 800 μm. A film made of the bioabsorbable polymer having a thickness of less than 10 μm is poor in strength and may not impart a sufficient tissue-reinforcing effect. A film made of the bioabsorbable polymer having a thickness of more than 800 μm may not sufficiently adhere to and fix tissue. The more preferable lower limit of the thickness of the film made of the bioabsorbable polymer is 20 μm， and the more preferable upper limit thereof is 300 μm.
The film made of the bioabsorbable polymer may be subjected to hydrophilization. The film having been subjected to hydrophilization rapidly absorbs moisture such as  physiological saline upon contact， and is therefore readily handled.
Non-limiting examples of the hydrophilization include plasma treatment， glow discharge treatment， corona discharge treatment， ozone treatment， surface graft treatment， and ultraviolet irradiation treatment. In particular， plasma treatment is preferred because this treatment markedly increases the water absorption rate without changing the outward appearance of the film.
The etherified cellulose is produced through etherification of hydroxy groups of cellulose. Specific examples thereof include： hydroxyalkylated cellulose represented by the formula (1) below such as hydroxyethylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxyethyl groups or hydroxypropylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxypropyl groups； and carboxyalkylated cellulose such as carboxymethylated cellulose in which hydroxy groups of the cellulose have been replaced with carboxymethyl groups. In particular， hydroxyethylated cellulose， which is proven to be very safe， is preferred.
Figure PCTCN2016104877-appb-000001
In the formula (1) ， n represents an integer， and R represents hydrogen or -R′OH in which R′represents an alkylene group.
In cases where the etherified cellulose is hydroxyethylated cellulose， the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) is preferably 0.1 to 1.0， and the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) is preferably 0.1 to 0.5 in the hydroxyethylated cellulose. The etherified cellulose having molar ratios within such ranges imparts excellent initial adhesion when the film made of the bioabsorbable polymer adheres to biological tissue through the fiber structure， sponge body， or film made of the etherified cellulose， and the high adhesion is maintained after adhesion. Even if cohesive failure or interfacial peeling occurs due to high pressure， the film can adhere again to prevent air leakage or fluid leakage.
The numbers of moles of ethylene glycol groups， diethylene glycol groups， and triethylene glycol groups in the hydroxyethylatedcellulose can be measured， for example， byNMR or thermal decomposition GC-MS.
In cases where the etherified cellulose is hydroxyethylated cellulose， the preferable lower limit of the average number of molecules (molar substitution， MS) of alkylene oxides bonded to an anhydroglucose unit is 1.0， and the preferable upper limit thereof is 4.0. The etherified cellulose having a MS within such a range can gel in a short time with high gel strength， and closely adhere to and fix tissue. When the MS is less than 1.0， gelledhydroxyethylated cellulose tends to be less viscous. When the MS is more than 4.0， gelation tends to take a long time. The more preferable lower limit of the MS is 1.3， and the more preferable upper limit thereof is 3.0.
In cases where the etherified cellulose is hydroxyethylated cellulose， the preferable lower limit of the  average degree of substitution (DS) of alkylene oxides to hydroxy groups at  positions  2， 3， and 6 of an anhydroglucose unit is 0.2， and the preferable upper limit thereof is 2.5. The etherified cellulose having a DS within such a range can gel in a short time with high gel strength， and closely adhere to and fix tissue. When the DS is less than 0.2， gelationmay take a long time. When the DS is more than 2.5， the wet strength may decrease. The more preferable lower limit of the DS is 0.3， and the more preferable upper limit thereof is 1.5.
The MS and DS can be calculated by determining the NMR spectrum of an aqueous solution of the hydroxyethylated cellulose， and measuring the intensities of signals belonging to carbon atoms of an anhydroglucose ring and carbon atoms of a substituent group in the spectrum (see， for example， JP H6-41926 B) .
Specifically， for example， 0.2 g of a sample， 30 mg of an enzyme (cellulase) ， and an internal standard material are dissolved in 3 mL of heavy water. The resulting solution is subjected to ultrasonication for 4 hours， and its NMR spectrum is determined using an NMR measuring device (e.g. JNM-ECX400P available from JEOL) under the conditions of the number of scanning of 700， pulse width of 45°， and observed frequency of 31， 500 Hz.
The etherified cellulose may be cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose so that part of unetherified hydroxy groups are carboxylated (hereinafter， also referred to as "etherified and carboxylated cellulose") . The use of etherified and carboxylated cellulose enables strong adhesion to damaged sites with particularly large surface irregularities.
The etherified and carboxylated cellulose is produced through etherification and carboxylation of hydroxy groups of  cellulose. Specific examples thereof include hydroxyalkylated and carboxylated cellulose such as hydroxyethylated and carboxylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxyethyl groups and carboxyl groups， or hydroxypropylated and carboxylated cellulose in which hydroxy groups of the cellulose have been replaced with hydroxypropyl groups and carboxyl groups. Particularly preferred is hydroxyethylated and carboxylated cellulose because it is proven to be very safe.
Preferred is， for example， hydroxyalkylated and carboxylated cellulose represented by the following formula (2) ：
Figure PCTCN2016104877-appb-000002
Wherein n represents an integer， Rrepresents hydrogen or-R′ OH in which R′ represents an alkylene group.
In cases where the etherification for producing the etherified and carboxylated cellulose is hydroxyethylation， the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) in the hydroxyethylated and carboxylated cellulose is preferably 0.1 to 1.5， and the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) is preferably 0.1 to 1.0.
The lower limit of the average number of molecules (molar substitution， MS) of alkylene oxide bonded to ananhydroglucose unit is preferably 1.0， and the upper limit thereof is preferably 4.0. The lower limit of the average degree of  substitution (DS) of alkylene oxides to hydroxy groups at  positions  2， 3， and 6 of an anhydroglucose unit is preferably 0.2， and the upper limit thereof is preferably 2.5.
The average number of molecules (MS) ， the average degree of substitution (DS) ， and the numbers of moles of ethylene glycol groups， diethylene glycol groups， and triethylene glycol groups can be measured， for example， by NMR or thermal decomposition GC-MS.
The hydroxyethylated cellulose can be produced， for example， by the reaction of an ethylene oxide with alkali cellulose produced by treating cellulose with an aqueous solution of an alkali.
Specifically， for example， alkali cellulose is produced from a fiber structure made of cellulose as a raw material by treating the fiber structure with an aqueous solution of an alkali such as sodium hydroxide. To the resulting alkali cellulose are added a certain amount of an ethylene oxide and a reaction solvent， and a reaction is performed.
The etherified and carboxylated cellulose can be produced by， for example， carboxylating and then etherifying cellulose.
The cellulose may be carboxylated as follows， for example. Through a reaction with 2， 2， 6， 6-tetramethylpiperidine-1-oxyl (TEMPO) as an oxidant and sodium hypochlorite， hydroxy groups of the cellulose are oxidized to aldehyde (TEMPO oxidation step) . Subsequently， the cellulose is reacted with sodium chlorite so that the aldehyde is carboxylated (carboxylation step) .
The resulting carboxylated cellulose is treated with an aqueous solution of an alkali such as sodium hydroxide (alkali treatment step) and then reacted with ethylene oxide to be etherified (hydroxyethylated) (hydroxyethylation step) . In this manner， etherified and carboxylated cellulose (hydroxyethylated and carboxylated cellulose) can be prepared.
In hydroxyethylated and carboxylated cellulose obtained by such a method， carboxyl groups are mainly introduced to position 6 of cellulose， and hydroxyethyl groups are mainly introduced to  position  2 or 6.
The preferable lower limit of the water absorption rate of the fiber structure， sponge body， or film made of the etherified cellulose is 200％， and the preferable upper limit thereof is 1,000％. The fiber structure， sponge body， or film made of the etherified cellulose having a water absorption rate within such a range can gel in a short time with high gel strength， and closely adhere to and fix tissue. When the water absorption rate is lower than 200％， gelation may take a long time. When the water absorption rate is higher than 1,000％， gel strength tends to be low. The more preferable lower limit of the water absorption rate is 400％， and the more preferable upper limit thereof is 800％.
The water absorption rate herein can be measured by the following method.
Specifically， the initial weight of a sample is measured， and the sample is placed in a petri dish. Distilled water is slowly dropped onto the sample. The weight of the sample having absorbed distilled water to the maximum (in a condition the sample absorbs no more distilled water， and excess distilled water leaks from the sample if distilled water is further dropped) is determined as a maximum water absorption weight. The water absorption rate can be determined based on the following equation from the initial weight and the maximum water absorption weight.
Water absorption rate (％) ＝ (maximum water absorption weight-initial weight) /initial weight × 100
The preferable lower limit of the moisture absorption rate of the fiber structure， sponge body， or film made of the etherified cellulose is 7％， and the preferable upper limit  thereof is 50％. The fiber structure， sponge body， or film made of the etherified cellulose having a moisture absorption rate within such a range can gel in a short time with high gel strength， and closely adhere to and fix tissue. When the moisture absorption rate is lower than 7％， gelationmaytake a long time. When the moisture absorption rate is higher than 50％， the gel strength tends to be low. The more preferable lower limit of the moisture absorption rate is 10％， and the more preferable upper limit thereof is 35％.
The moisture absorption rate used herein can be measured by the following method.
Specifically， a sample is heated at 105℃ for 2 hours. The weight of the resulting sample is determined as an absolute dry weight. Next， the absolute dry sample is allowed to stand in an atmosphere at 20℃ and 65％Rh for 7 hours to control the moisture content of the sample. The weight of the sample is determined as a weight after moisture control. A moisture absorption rate can be calculated based on the following equation from the absolute dry weight and the weight after moisture control.
Moisture absorption rate (％) ＝ (weight after moisture control -absolute dry weight) /absolute dry weight × 100
The fiber structure made of the etherified cellulose may be in any form， including the form of a non-woven fabric， a knitted fabric， a woven fabric， gauze， or yarn， or a combination of these forms. In particular， the form of a non-woven fabric is preferred.
In cases where the fiber structure made of the etherified cellulose is in the form of a non-woven fabric， the weight per unit area of the non-woven fabric is not particularly limited， and the preferable lower limit is 20 g/m2， and the preferable upper limit is 700 g/m2. A non-woven fabric having a weight per unit area of less than 20 g/m2 may fail to attach the  biological tissue-reinforcing material to biological tissue with sufficient adhesion. When the non-woven fabric has a weight per unit area of more than 700 g/m2， the etherified cellulose may take a long time to gel. The more preferable lower limit of the weight per unit area of the non-woven fabric is 50 g/m2， and the more preferable upper limit thereof is 500 g/m2.
The non-woven fabric may be produced by any method， and examples of the method include conventionally known methods such as electrospinning deposition， melt blowing， needle punching， spun bonding， flash spinning， hydroentanglement， air laying， thermal bonding， resin bonding， or wet processing.
The weight per unit area of the sponge body made of the etherified cellulose is not particularly limited， and the preferable lower limit is 15 g/m2， and the preferable upper limit is 1,200 g/m2. A sponge body having a weight per unit area of less than 15 g/m2 has strength not enough for a biological tissue-reinforcing material， and may not reinforce weakened tissue. A sponge body having a weight per unit area of more than 1,200 g/m2 may result in poor adhesion to tissue. The more preferable lower limit of the weight per unit area of the sponge body is 30 g/m2， and the more preferable upper limit thereof is 500 g/m2.
The thickness of the fiber structure or sponge body made of the etherified cellulose is not particularly limited， and the preferable lower limit is 50 μm， and the preferable upper limit is 10 mm. A fiber structure or sponge body made of the etherified cellulose having a thickness of less than 50 μm may fail to attach the biological tissue-reinforcing material to biological tissue with sufficient adhesion. A fiber structure or sponge body made of the etherified cellulose having a thickness of more than 10 mm is less likely to absorb water to have poor texture， thereby deteriorating the handleability.  The more preferable lower limit of the thickness of the fiber structure or sponge body made of the etherified cellulose is 50 μm， and the more preferable upper limit thereof is 5 mm.
The thickness of the film made of the etherified cellulose is not particularly limited， and the preferable lower limit is 10 μm， and the preferable upper limit is 800 μm. A film made of the etherified cellulose having a thickness of less than 10 μm is poor in strength and may not impart a sufficient tissue-reinforcing effect. A film made of the etherified cellulose having a thickness of more than 800 μm may not sufficiently adhere to and fix tissue. The more preferable lower limit of the thickness of the film made of the etherified cellulose is 20 μm， and the more preferable upper limit thereof is 300 μm.
The film made of the bioabsorbable polymer and the fiber structure， sponge body， or film made of theetherifiedcellulose are preferably integrated to improve the handleability.
The expression "integrated" herein means a state where two structures laminated to each other can be treated as one structure， and are not easily separated.
Non-limiting example of the mode of the integration include a mode in which a part of the fiber structure or sponge body made of the etherified cellulose has entered a part of the film made of the bioabsorbable polymer.
The biological tissue-reinforcing material of the present invention is used to stop bleeding from a damaged or weakened organ or tissue， or to prevent air leakage or fluid leakage in the field of surgery. In particular， the biological tissue-reinforcing material is favorably used as an artificial dura mater in the neurosurgery field.
Another aspect of the present invention is an artificial dura mater including the biological tissue-reinforcing  material.
The biological tissue-reinforcing material of the present invention can be readily attached to an affected area just by applying the material preliminary immersed into physiological saline to the affected area. Furthermore， the biological tissue-reinforcing material absorbs blood or fluid from an affected area so that it can exhibit adhesion.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is a view schematically illustrating a water pressure resistance tester used in the water pressure resistance test performed in examples.
- Advantageous Effects of Invention
The present invention can provide a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product， and an artificial dura mater including the biological tissue-reinforcing material.
DESCRIPTION OF EMBODIMENTS
The following describes examples to more specifically illustrate embodiments of the present invention. The present invention is not limited only to these examples.
(Example 1)
(1) Preparation of fiber structure made of hydroxyethylated cellulose
A 280-μm-thick single knit made of No. 80 count cellulose yarn as a raw material was bleached by hydrogen peroxide  bleaching.
An amount of 3.55 g of the bleached knit was immersed in 140 mL of a 10％sodium hydroxide aqueous solution at 15℃ for 30 minutes so that the cellulose was alkalized. To the alkalized knit was applied a load of 2.5 to 3.0 kg for padding.
Next， 12.25 g of the resulting knit made of alkali cellulose was immersed in 50 mL of a 0.8 mol/L solution of ethylene oxide in hexane at 25℃， and reacted at 50℃ for three hours. The reacted knit was immersed in 70 mL of a mixture of methanol and methyl isobutyl ketone (methanol∶methyl isobutyl ketone ＝ 35∶35) at 25℃ for five minutes to be washed and subsequently immersed in 72.6 mL of a mixture of methanol， methyl isobutyl ketone， and acetic acid (methanol∶methyl isobutyl ketone∶acetic acid＝ 35∶35∶2.6) at 25℃ for 10 minutes to be neutralized. The neutralized knit was immersed in 70 mL of a mixture of isopropyl alcohol and water (isopropyl alcohol∶water ＝ 63∶7) at 25℃ for three minutes， and subsequently in 70 mL of acetone at 25℃ for five minutes. The resulting knit was dried at 40℃ for 24 hours to prepare a fiber structure made of hydroxyethylated cellulose.
An analysis of the hydroxyethylated cellulose of the resulting fiber structure using a thermal decomposition GC-MS revealed that the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) was 0.20， and the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) was 0.21.
(2) Production of biological tissue-reinforcing material
A L-lactide/ε-caprolactone copolymer (molar ratio： 50/50， weight average molecular weight measured by GPC： 220,000， hereinafter also referred to as ″P (L-LA/CL) (molar ratio： 50/50) ″ ) was dissolved in chloroform and filtered to remove unmolten substances so that a 5 weight percent solution was prepared. The solution was casted on a glass plate， and  air-dried and subsequently dried in vacuo at 50℃ for 12 hours to give a 100-μm-thick film made of P (L-LA/CL) (molar ratio： 50/50) .
A fiber structure made of hydroxyethylated cellulose was immersed in 1， 4-dioxane to be partially dissolved. The partially dissolved fiber structure made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) and uniformly pressed， followed by drying at 23℃ for three hours. In this manner， a biological tissue-reinforcing material including a laminated structure in which the fiber structure made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) was prepared.
The biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
(3) Water pressure resistance test
A water pressure resistance test was performed using a water pressure resistance tester 1 illustrated in Fig. 1.
An about 130-μm-thick collagen film (available fromNippi. Inc. ) was punched into a rectangular shape with a length of 5.5 cmandawidthof 5.0 cm， and the film was washed with 70％ethanol， and liquid was wiped off. The resulting film was set in a filter holder 2 (Swinnex (registered trademark) 25 available from Merck Millipore) . A 3-mm-diameter hole was formed with a punch in the center of the collagen film that was set in the filter holder 2. A 20-mL syringe 3 (Terumo Syringe SS-20ESZ available from Terumo Corporation) containing a phosphate buffer and a pressure gauge 5 (digital manometer FUSO-8230 available from Fusorika Co.， Ltd. ) were placed at the downstream of the filter holder via a three way cock 4. In this manner， a water pressure resistance tester was fabricated.
Purified water was dropped onto a face of the test sample on the side of the fiber structure made of hydroxyethylated cellulose. The resulting test sample was placed at the center of the collagen film set in the filter holder such that the face was in contact with the collagen film. After the test sample was allowed to stand for 1 minute， a phosphate buffer was delivered from the syringe. The maximum pressure before the test sample was peeled was measured with a pressure gauge for evaluation of the water pressure resistance.
Table 1 shows the result.
(Example 2)
(1) Preparation of fiber structure made of hydroxyethylated and carboxylated cellulose
A 280-μm-thick single knit made of No. 80 count cellulose yarn as a raw material was bleached by hydrogen peroxide bleaching.
The bleached knit was immersed in a TEMPO oxidation solution (TEMPO concentration： 20％owf， 5％sodiumhypochlorite concentration： 180％owf， sodium bromide： 17.5％owf， pH 10 aqueous solution) at 25℃ for 10 minutes at a bath ratio of 1∶30 to be oxidized. The oxidized knit was washed with water three times and subsequently immersed in a sodium chlorite solution (25％sodium chlorite concentration： 20％owf， CG1000 concentration： 1.0 g/L， pH 3.8 aqueous solution) at 80℃ for 90 minutes at a bath ratio of 1∶15 to be carboxylated. The resulting knit was washed with hot water and then with water， and immersed in a hydrogen peroxide/sodium borohydride solution (30％hydrogen peroxide concentration： 1％owf， sodium borohydride concentration： 5％owf， PCL7000 concentration： 0.4 g/L， pH 10.5 aqueous solution) at 70℃ for 20 minutes at a bath ratio of 1∶20 for dechlorination and reduction of partially formed ketone to hydroxy groups. The obtained knit was further washed with hot water， neutralized， and washed with water. A carboxylated knit was thus prepared.
The obtained carboxylated knit was immersed in a 20％sodium hydroxide aqueous solution at 15℃ for 30 minutes at a bath ratio of 1∶40 to be alkalized. To the resulting knit was applied a load of 2.5 to 3.0 kg for padding. The knit after padding was immersed in a 0.8 mol/L solution of ethylene oxide in hexane at 50℃ for 30 minutes at a bath ratio of 1∶15 to be hydroxyethylated. The knit after the reaction was immersed in 70 mL of a mixture of methanol and methyl isobutyl ketone (methanol： methyl isobutyl ketone ＝ 35∶35) at 25℃ for five minutes at a bath ratio of 1∶30 to be washed and subsequently immersed in 70 mL of a mixture of methanol， methyl isobutyl ketone， and acetic acid (methanol∶methyl isobutyl ketone∶acetic acid＝ 35∶35∶2.6) at 25℃ for 10 minutes at a bath ratio of 1∶30 to be neutralized. The neutralized knit was immersed (twice) in 70 mL of a mixture of isopropyl alcohol and water (isopropyl alcohol∶water＝ 63∶7) at 25℃ for three minutes at a bath ratio of 1∶30， then immersed in acetone at 25℃ for five minutesat a bath ratio of 1∶60， followed by drying at 40℃for 24 hours to give a medical fiber structure including a fiber structure made of hydroxyethylated and carboxylated cellulose.
An analysis of the hydroxyethylated and carboxylated cellulose of the resulting fiber structure using a thermal decomposition GC-MS revealed that the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) was 0.18， and the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) was 0.15.
(2) Production of biological tissue-reinforcing material
A 100-μm-thick film made of P (L-LA/CL) (molar ratio： 50/50) was prepared as in Example 1.
A fiber structure made of hydroxyethylated and carboxylated cellulose was immersed in 1， 4-dioxane to be partially dissolved. The partially dissolved fiber structure  made of hydroxyethylated and carboxylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) and uniformly pressed， followed by drying at 23℃ for three hours. In this manner， a biological tissue-reinforcing material including a laminated structure in which the fiber structure made of hydroxyethylated and carboxylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) was prepared.
The biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement.
The test sample was subjected to a water pressure resistance test as in Example 1.
(Example 3)
(1) Preparation of film made of hydroxyethylated cellulose
A sol solution of hydroxyethylated cellulose was prepared by dissolving a commercial hydroxyethylated cellulose (available from Wako Pure Chemical Industries， Ltd.， the molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) ： 1.06， the molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) ： 4.01) in distilled water so that the solution had a solid content of 7.5％by weight.
The sol solution of hydroxyethylated cellulose was casted on a petri dish and dried at 30℃ for 24 hours， thereby obtaining a 50-μm-thick film made of a hydroxyethylated cellulose.
(2) Production of biological tissue-reinforcing material
A 100-μm-thick film made of P (L-LA/CL) (molar ratio： 50/50) was prepared as in Example 1. A film made of hydroxyethylated cellulose was immersed in 1， 4-dioxane to be partially dissolved. The partially dissolved film made of hydroxyethylated cellulose was stacked on one surface of the  film made of P (L-LA/CL) (molar ratio： 50/50)and uniformly pressed， followed by drying at 23℃ for three hours. In this manner， a biological tissue-reinforcing material including a laminated structure in which the film made of hydroxyethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) was prepared.
The biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement. The test sample was subjected to a water pressure resistance test as in Example 1.
(Example 4)
(1) Preparation of film made of carboxymethylated cellulose
A sol solution of carboxymethylated cellulose was prepared by dissolving a commercial carboxymethylated cellulose (available fromWako Pure Chemical Industries， Ltd. ) in distilled water so that the solution had a solid content of 7.5％by weight.
The sol solution of carboxymethylated cellulose was casted on a petri dish and dried at 30℃ for 24 hours， thereby obtaining a 80-μm-thick film made of carboxymethylated cellulose.
(2) Production of biological tissue-reinforcing material
A 100-μm-thick film made of P (L-LA/CL) (molar ratio： 50/50) was prepared as in Example 1.
A film made of carboxymethylated cellulose was immersed in 1， 4-dioxane to be partially dissolved. The partially dissolved film made of carboxymethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) and uniformly pressed， followed by drying at 23℃ for three hours. In this manner， a biological tissue-reinforcing material including a laminated structure in which the film made of carboxymethylated cellulose was stacked on one surface of the film made of P (L-LA/CL) (molar ratio： 50/50) was prepared.
The biological tissue-reinforcing material was punched into a 11-mm-diameter circle to give a test sample for measurement. The test sample was subjected to a water pressure resistance test as in Example 1.
(Comparative Example 1)
Water pressure resistance in the case of using fibrin glue and a fiber structure made of a bioabsorbable polymer in combination was evaluated by the following method.
A 11-mm-diameter circular piece was punched out from a 150-μm-thick nonwoven fabric made of polyglycolide (NEOVEIL Type NV-M015G， GUNZE LIMITED) .
A collagen film prepared as in Example 1 was set on the filter holder of the water pressure tester used in Example 1. Then， 20μL of a solution A of fibrin glue (Beriplast P consisting of a solution A (mixture of fibrinogen powder and an aprotinin solution) and a solution B (mixture of thrombin powder and a calcium chloride solution) ， available from CSL Behring K. K. ) was dropped onto the center of the collagen film in such a manner as to avoid the hole in the collagen film， and was spread into a shape with a diameter of approximately 11 mm. Next， the nonwoven fabric punched into a 11-mm-diameter circle was placed on the spread solution A and impregnated with the solution A. Subsequently， 20 μL of the solution A was dropped onto the nonwoven fabric， and the nonwoven fabric was sufficiently impregnated with the solution A. Thereafter， 20 μL of a solution B was dropped onto the nonwoven fabric.
Five minutes after the dropping of the solution B， a phosphate buffer was delivered from the syringe. The maximum pressure before the test sample was peeled was measured with a pressure gauge for evaluation of the water pressure resistance. Table 1 shows the result.
(Comparative Example 2)
A biological tissue-reinforcing material was obtained in the same manner as in Example 1， except that a fiber structure made of oxidized cellulose (Surgicet available from Johnson & Johnson K. K. ) was used instead of the fiber structure made of hydroxyethylated cellulose.
The biological tissue-reinforcing material was punched into a 11-mm-diameter circular shape to give a test sample for measurement. The test sample was subjected to a water pressure resistance test as in Example 1.
(Comparative Example 3)
(1) Preparation of film made of oxidized cellulose
A sol solution of oxidized cellulose was prepared by dissolving a fiber structure made of oxidized cellulose (Surgicel available from Johnson & Johnson K. K. ) in distilled water so that the solution had a solid content of 7.5％by weight.
The sol solution of oxidized cellulose was casted on a petri dish and dried at 30℃ for 24 hours， thereby obtaining a 130-μm-thick film made of oxidized cellulose.
(2) Production of biological tissue-reinforcing material
A 100-μm-thick commercial film made of a lactide-ε-caprolactone copolymer (SEAMDURA available from GUNZE LIMITED) was used as a film made of a bioabsorbable polymer.
A film made of oxidized cellulose was immersed in 1， 4-dioxane to be partially dissolved. The partially dissolved film made of oxidized cellulose was stacked on one surface of the film made of a lactide-ε-caprolactone copolymer and was uniformly pressed， followed by drying at 23℃ for three hours. In this manner， a biological tissue-reinforcing material including a laminated structure in which the film made of oxidized cellulose was stacked on one surface of the film made of a lactide-ε-caprolactone copolymer was prepared.
The biological tissue-reinforcing material was punched  into a 11-mm-diameter circular shape to give a test sample for measurement. The test sample was subjected to a water pressure resistance test as in Example 1.
(Comparative Example 4)
A 100-μm-thick commercial film made of a lactide-ε-caprolactone copolymer (SEAMDURA available from GUNZE LIMITED) was used as a film made of a bioabsorbable polymer.
The film was punched into a 11-mm-diameter circular shape to give a test sample.
A water pressure resistance test was performed using a water pressure resistance tester 1 illustrated in Fig. 1.
An about 130-μm-thick collagen film (available from Nippi. Inc. ) was punched into a rectangular shape with a length of 5.5 cm and a width of 5.0 cm， and the film was washed with 70％ethanol， and liquid was wiped off. The resulting film was set in a filter holder 2 (Swinnex (registered trademark) 25 available from Merck Millipore) . A 3-mm-diameter hole was formed with a punch in the center of the collagen film that was set in the filter holder 2. The test sample was placed on the collagen film in such a manner as to allow the center of the test sample to overlap the center of the hole of the collagen film. The test sample and the collagen film were sewn together using a suture (Monodiox (registered trademark) available fromAlfresa Pharma Corporation) made of polyglycolide with suture size No. 4-0. The distance between the seams was 7.0 mm. The 11-mm-diameter circular test sample for measurement had five seams of the suture. A 20-mL syringe 3 (Terumo Syringe SS-20ESZ available from Terumo Corporation) containing a phosphate buffer and a pressure gauge 5 (digital manometer FUSO-8230 available from Fusorika Co.， Ltd. ) were placed at the downstream of the filter holder via a three way cock 4. In this manner， a water pressure resistance tester was fabricated.
A phosphate buffer was delivered from the syringe. The maximum pressure before the test sample was peeled was measured with a pressure gauge for evaluation of the water pressure resistance.
[Table 1]
  Pressure resistance (mmHg)
Example 1 53.6
Example 2 60.7
Example 3 146.5
Example 4 71.3
Comparative Example 1 52.1
Comparative Example 2 4.8
Comparative Example 3 6.2
Comparative Example 4 6.6
INDUSTRIAL APPLICABILITY
The present invention can provide a biological tissue-reinforcing material capable of more reliably reinforcing weakened tissue while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product， and can also provide an artificial dura mater including the biological tissue-reinforcing material.
REFERENCE SIGNS LIST
1 Water pressure resistance tester
2 Filter holder
3 Syringe
4 Three way cock
5 Pressure gauge
6 Collagen film with hole

Claims (9)

  1. A biological tissue-reinforcing material comprising a laminated structure， the laminated structure comprising：
    a film made of a bioabsorbable polymer； and
    a fiber structure， sponge body， or film made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose.
  2. The biological tissue-reinforcing material according to claim 1，
    wherein the etherified cellulose that is produced through etherification of hydroxy groups of cellulose is hydroxyalkylated cellulose represented by the following formula (1) ：
    Figure PCTCN2016104877-appb-100001
    wherein n represents an integer， and R represents hydrogen or -R′ OH in which R′ represents an alkylene group.
  3. The biological tissue-reinforcing material according to claim 1，
    wherein the etherified cellulose that is produced through etherification of hydroxy groups of cellulose is hydroxyethylated cellulose.
  4. The biological tissue-reinforcing material according to claim 1， 2， or 3，
    wherein the etherified cellulose that is produced through  etherification of hydroxy groups of cellulose is cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose so that part of unetherified hydroxy groups are carboxylated.
  5. The biological tissue-reinforcing material according to claim 4，
    wherein the cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose is cellulose that is produced through hydroxyalkylation and carboxylation of hydroxy groups of cellulose， represented by the following formula (2) ：
    Figure PCTCN2016104877-appb-100002
    wherein n represents an integer， and R represents hydrogen or -R′ OH in which R′ represents an alkylene group.
  6. The biological tissue-reinforcing material according to claim 1， 2， 3， 4， or 5，
    wherein the fiber structure made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose is in the form of anon-woven fabric， a knitted fabric， a woven fabric， gauze， or yarn.
  7. The biological tissue-reinforcing material according to claim 1， 2， 3， 4， or 5，
    wherein the bioabsorbable polymer is a lactide (D， L， DL isomer) -ε-caprolactone copolymer.
  8. The biological tissue-reinforcing material according to claim 7，
    wherein the lactide (D， L， DL isomer) -ε-caprolactone copolymer contains 40 to 60 mol％ of lactide and has a weight average molecular weight of 100,000 to 500,000.
  9. An artificial dura mater including the biological tissue-reinforcing material according to claim 1， 2， 3， 4， 5， 6， 7， or 8.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1799649A (en) * 2005-12-09 2006-07-12 清华大学 Blood compatible biological material and preparation method thereof
CN101137402A (en) * 2004-10-20 2008-03-05 伊西康公司 Reinforced absorbable multilayer fabric for medical devices and method of making same
CN101878048A (en) * 2007-11-29 2010-11-03 郡是株式会社 Lactide/ε-caprolactone copolymer for medical implant, method for producing same, medical implant, and artificial dura mater
CN102600013A (en) * 2012-03-21 2012-07-25 苏州博创同康生物工程有限公司 Medical flocking hemostasis material, preparation thereof and application
CN104207879A (en) * 2013-05-31 2014-12-17 天津法莫西医药科技有限公司 Medical dressing with sodium carboxymethylcellulose/polylactic acid sponge protection layer

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001309969A (en) * 2000-04-28 2001-11-06 Gunze Ltd Artificial dura mater
SA111320355B1 (en) * 2010-04-07 2015-01-08 Baxter Heathcare S A Hemostatic sponge
DE102010034782A1 (en) * 2010-08-18 2012-02-23 Carl Freudenberg Kg Process for the preparation of oxidized cellulose fibers, oxidized cellulose fiber sheets or oxidized cellulose nonwovens and their use
CN104874029B (en) * 2015-03-30 2018-04-27 陕西佰傲再生医学有限公司 A kind of bleeding stopping and adherence preventing material and preparation method thereof
WO2016169041A1 (en) * 2015-04-24 2016-10-27 Gunze Limited Biological tissue-reinforcing material
JP2019519619A (en) * 2016-06-02 2019-07-11 グンゼ株式会社 Medical fiber structure and medical laminate
JP6678256B2 (en) * 2016-11-07 2020-04-08 グンゼ株式会社 Biological tissue reinforcement material

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101137402A (en) * 2004-10-20 2008-03-05 伊西康公司 Reinforced absorbable multilayer fabric for medical devices and method of making same
CN1799649A (en) * 2005-12-09 2006-07-12 清华大学 Blood compatible biological material and preparation method thereof
CN101878048A (en) * 2007-11-29 2010-11-03 郡是株式会社 Lactide/ε-caprolactone copolymer for medical implant, method for producing same, medical implant, and artificial dura mater
CN102600013A (en) * 2012-03-21 2012-07-25 苏州博创同康生物工程有限公司 Medical flocking hemostasis material, preparation thereof and application
CN104207879A (en) * 2013-05-31 2014-12-17 天津法莫西医药科技有限公司 Medical dressing with sodium carboxymethylcellulose/polylactic acid sponge protection layer

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