WO2017206131A1 - Medical fiber structure and medical laminate - Google Patents

Medical fiber structure and medical laminate Download PDF

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Publication number
WO2017206131A1
WO2017206131A1 PCT/CN2016/084448 CN2016084448W WO2017206131A1 WO 2017206131 A1 WO2017206131 A1 WO 2017206131A1 CN 2016084448 W CN2016084448 W CN 2016084448W WO 2017206131 A1 WO2017206131 A1 WO 2017206131A1
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Prior art keywords
fiber structure
cellulose
medical
tissue
laminate
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Ceased
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PCT/CN2016/084448
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French (fr)
Inventor
Chiaki Tanaka
Yoshinari Yui
Shojiro Matsuda
Hideki TAKAMORI
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Gunze Medical Devices (shenzhen) Ltd
Gunze Ltd
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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 CN201680004190.1A priority Critical patent/CN107849154A/en
Priority to JP2018542185A priority patent/JP2019519619A/en
Priority to PCT/CN2016/084448 priority patent/WO2017206131A1/en
Publication of WO2017206131A1 publication Critical patent/WO2017206131A1/en
Anticipated expiration legal-status Critical
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    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B11/00—Preparation of cellulose ethers
    • C08B11/02—Alkyl or cycloalkyl ethers
    • C08B11/04—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals
    • C08B11/08—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals with hydroxylated hydrocarbon radicals; Esters, ethers, or acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/02—Oxycellulose; Hydrocellulose; Cellulosehydrate, e.g. microcrystalline cellulose
    • C08B15/04—Carboxycellulose, e.g. prepared by oxidation with nitrogen dioxide
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/26—Cellulose ethers
    • C08L1/28—Alkyl ethers
    • C08L1/286—Alkyl ethers substituted with acid radicals, e.g. carboxymethyl cellulose [CMC]
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/40—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties
    • D04H1/42—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres from fleeces or layers composed of fibres without existing or potential cohesive properties characterised by the use of certain kinds of fibres insofar as this use has no preponderant influence on the consolidation of the fleece
    • D04H1/425—Cellulose series
    • D04H1/4258—Regenerated cellulose series
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06L—DRY-CLEANING, WASHING OR BLEACHING FIBRES, FILAMENTS, THREADS, YARNS, FABRICS, FEATHERS OR MADE-UP FIBROUS GOODS; BLEACHING LEATHER OR FURS
    • D06L4/00—Bleaching fibres, filaments, threads, yarns, fabrics, feathers or made-up fibrous goods; Bleaching leather or furs
    • D06L4/10—Bleaching fibres, filaments, threads, yarns, fabrics, feathers or made-up fibrous goods; Bleaching leather or furs using agents which develop oxygen
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M11/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising
    • D06M11/07—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with halogens; with halogen acids or salts thereof; with oxides or oxyacids of halogens or salts thereof
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M11/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising
    • D06M11/07—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with halogens; with halogen acids or salts thereof; with oxides or oxyacids of halogens or salts thereof
    • D06M11/11—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with halogens; with halogen acids or salts thereof; with oxides or oxyacids of halogens or salts thereof with halogen acids or salts thereof
    • D06M11/155—Halides of elements of Groups 2 or 12 of the Periodic Table
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M11/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising
    • D06M11/32—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with oxygen, ozone, ozonides, oxides, hydroxides or percompounds; Salts derived from anions with an amphoteric element-oxygen bond
    • D06M11/36—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with oxygen, ozone, ozonides, oxides, hydroxides or percompounds; Salts derived from anions with an amphoteric element-oxygen bond with oxides, hydroxides or mixed oxides; with salts derived from anions with an amphoteric element-oxygen bond
    • D06M11/38—Oxides or hydroxides of elements of Groups 1 or 11 of the Periodic Table
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M11/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising
    • D06M11/32—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with oxygen, ozone, ozonides, oxides, hydroxides or percompounds; Salts derived from anions with an amphoteric element-oxygen bond
    • D06M11/50—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with oxygen, ozone, ozonides, oxides, hydroxides or percompounds; Salts derived from anions with an amphoteric element-oxygen bond with hydrogen peroxide or peroxides of metals; with persulfuric, permanganic, pernitric, percarbonic acids or their salts
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M11/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising
    • D06M11/80—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with inorganic substances or complexes thereof; Such treatment combined with mechanical treatment, e.g. mercerising with boron or compounds thereof, e.g. borides
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M13/00—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment
    • D06M13/10—Treating fibres, threads, yarns, fabrics or fibrous goods made from such materials, with non-macromolecular organic compounds; Such treatment combined with mechanical treatment with compounds containing oxygen
    • D06M13/11—Compounds containing epoxy groups or precursors thereof
    • D—TEXTILES; PAPER
    • D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
    • D06M—TREATMENT, NOT PROVIDED FOR ELSEWHERE IN CLASS D06, OF FIBRES, THREADS, YARNS, FABRICS, FEATHERS OR FIBROUS GOODS MADE FROM SUCH MATERIALS
    • D06M2101/00—Chemical constitution of the fibres, threads, yarns, fabrics or fibrous goods made from such materials, to be treated
    • D06M2101/02—Natural fibres, other than mineral fibres
    • D06M2101/04—Vegetal fibres
    • D06M2101/06—Vegetal fibres cellulosic
    • D06M2101/08—Esters or ethers of cellulose

Definitions

  • the present invention relates to a medical fiber structure and a medical laminate, which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
  • the most fundamental issue in the field of surgery is to stop bleeding of a damaged or weakened organ or tissue and repair it. For example, bleeding of a damaged organ is still treated by stopping bleeding and suturing the wound, which is the most commonly used surgical procedure to stop bleeding even now.
  • Another important issue in the surgical treatment is to prevent fluid leakage or air leakage from weakened or damaged tissue. Particularly in the field of chest surgery, it is important to prevent air leakage due to pneumothorax or after resection of lung cancer.
  • pneumothorax is a disease that is difficult to treat because the recurrence rate is increased without appropriate treatment.
  • Pneumothorax often occurs due to air leakage into a thoracic cavity from a stump or suture site of the lung after resection, a site of the lung after partial resection to remove lung cancer, or a damaged site of lung tissue due to injury; or air leakage into a thoracic cavity from a tear of cysts (referred to bullae) which are transformed from some alveoli.
  • Such leakage has been treated by pleurodesis in which lung tissue is allowed to adhere to pleura with drugs or by artificial chemical burns.
  • Pleurodesis can prevent recurrence of pneumothorax to some extent. However, if lung tissue does not tightly adhere to pleura, the recurrence rate is increased. If further surgery is needed, adhesion between lung tissue and parietal pleura needs to be removed, which prolongs a surgical time or causes bleeding during removal of the adhesion. Therefore, new treatment alternative to pleurodesis has been investigated.
  • pancreatic juice dissolves granulation tissue that is responsible for wound healing, and prevents the growth of the tissue, leading to difficulty in regeneration of pancreatic tissue. Furthermore, it is concerned that leakage of pancreatic juice digests blood vessels to possibly cause postoperative hemorrhage, which is a life-threatening complication.
  • Non-Patent Literatures 1 to 4 suggest that this method more reduces the recurrence rate of pneumothorax than usual pleurodesis.
  • Non-Patent Literature 5 suggests that such a method is also used to prevent bleeding after liver resection in the field of digestive surgery.
  • fibrin glue and a fiber structure made of a bioabsorbable polymer in combination is remarkably effective to stop bleeding of damaged tissue and reinforce weakened tissue.
  • hemostasis may be insufficient or air leakage or fluid leakage may occur at a reinforced area, which may give rise to the need of further surgery. The incidence of such a case is not high, but leakage may become a risk factor to cause severe symptoms. Therefore, a reliable method of reinforcement has been needed.
  • fibrin glue which is a blood product, may lead to unknown viral infection.
  • Absorbable hemostatic agents prepared from regenerated oxidized cellulose are commercially available as hemostatic agents excellent in bioabsorbability.
  • the absorbable hemostatic agents prepared from regenerated oxidized cellulose are considered to be highly safe as they are originated from plants and provide a hemostatic effect by forming a salt together with erythrocyte.
  • the absorbable hemostatic agents prepared from regenerated oxidized cellulose are, however, highly acidic, which may inhibit wound healing.
  • hemostasis may be insufficient or air leakage or fluid leakage may occur at a reinforced area.
  • Non-Patent Literature 1 J. Pediatric Surg, 42, 1225-1230 (2007)
  • Non-Patent Literature 2 Interact. Cardiovasc. Thorac. Surg, 6, 12-15 (2007)
  • Non-Patent Literature 3 The Journal of the Japanese Association for Chest Surgery, 19 (4) , 628-630 (2005)
  • Non-Patent Literature 4 The Journal of the Japanese Association for Chest Surgery, 22 (2) , 142-145 (2008)
  • Non-Patent Literature 5 The Japanese Journal of Clinical and Experimental Medicine, 84, 148 (2007)
  • the present invention aims to provide a medical fiber structure and a medical laminate, which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
  • the present invention relates to a medical fiber structure including a fiber structure made of cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose.
  • the present inventors have researched the cause of insufficient hemostasis or air leakage or fluid leakage from a reinforced area of wounded tissue subjected to hemostasis or reinforcement using fibrin glue and a fiber structure made of abioabsorbablepolymer in combination, and found that the cause of the leakage is in an adhesion area with fibrin glue.
  • Fibrin glue which gels in a short time, is very useful as biological glue.
  • fibrin glue in the form of a gel is relatively hard, cohesive failure or interfacial peeling is likely to occur due to impact.
  • cohesive failure or interracial peeling presumably occurs by a very high pressure applied to lung tissue by coughing or sneezing.
  • Gelled fibrin glue once separated cannot adhere again because it has almost no adhesiveness. Air leakage or fluid leakage presumably occurs at such a separation area.
  • the present inventors have also researched the cause of insufficient hemostasis or air leakage or fluid leakage from a reinforced area of wounded tissue subjected to hemostasis or reinforcement using a conventional absorbable hemostatic agent prepared from regenerated oxidized cellulose, and found out that the absorbable hemostatic agent prepared from regenerated oxidized cellulose is less likely to adhere to wounded tissue if the wounded part has significant surface roughness.
  • a fiber structure including cellulose produced through etherification and carboxylation of hydroxy groups of cellulose can sufficiently adhere to wounded tissue even if the wounded part has significant surface roughness to surely stop bleeding. Moreover, such a fiber structure causes neither cohesive failure nor interfacial peeling even under a high pressure, which allows more reliable reinforcement of weakened tissue to prevent air leakage or fluid leakage. The present invention was thus completed.
  • the medical fiber structure of the present invention includes a fiber structure made of cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose (hereafter, also simply referred to as ′′etherified and carboxylated cellulose′′ ) .
  • Etherified and carboxylated cellulose is a compound proven to be highly safe, and gels in a short time like fibrin glue to be attached to biological tissue.
  • the medical fiber structure of the present invention including a fiber structure made of such etherified and carboxylated cellulose is attached to wounded tissue, the medical fiber structure can sufficiently adhere to the wounded tissue to surely stop bleeding even if the wounded part has significant surface roughness.
  • gelled etherified and carboxylated cellulose has a certain level of adhesive force, even if cohesive failure or interfacial peeling occurs due to high pressure, the etherified and carboxylated cellulose can adhere again to the wounded tissue to prevent air leakage or fluid leakage.
  • 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 cellulose are replaced with hydroxyethyl groups and carboxyl groups, and hydroxypropylated and carboxylated cellulose in which hydroxy groups of cellulose are replaced with hydroxypropyl groups and carboxyl groups.
  • Particularly preferred is hydroxyethylated and carboxylated cellulose because it is proven to be highly safe.
  • Preferred hydroxyalkylated and carboxylated cellulose is, for example, represented by the following formula (1) .
  • n represents an integer
  • R represents hydrogen or a -R′OH group
  • R′ represents an alkylene group
  • the molar ratio of a diethylene glycol group and 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 and 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 one anhydroglucose 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 etherified and carboxylated cellulose can be prepared by, for example, carboxylating and then etherifying cellulose.
  • the cellulose may be carboxylated as follows, for example.
  • TEMPO 2, 2, 6, 6-tetramethylpiperidine-l-oxyl
  • hydroxy groups of the cellulose is oxidized to produce aldehyde (TEMPO oxidation step) .
  • sodium chlorite the aldehyde is carboxylated (carboxylation step) .
  • carboxylated cellulose is treated with an alkaline aqueous solution such as an aqueous solution of sodium hydroxide (alkali treatment step) , and then reacted with ethylene oxide to be etherified (hydroxyethylated) (hydroxyethylation step) .
  • alkali treatment step an alkaline aqueous solution such as an aqueous solution of sodium hydroxide
  • ethylene oxide ethylene oxide
  • etherified and carboxylated cellulose hydroxyethylated carboxylated cellulose
  • carboxyl groups are mainly introduced to position 6 of cellulose and hydroxyethyl groups are mainly introduced to position 2 or 6.
  • the lower limit of a water absorption rate of the fiber structure made of the etherified and carboxylated cellulose is preferably 200%, and the upper limit thereof is preferably 1000%.
  • the fiber structure made of the etherified and carboxylated cellulose having a water absorption rate within such a range can gel ina short time with high gel strength, and tightly adhere to damaged tissue to stop bleeding. If the water absorption rate is lower than 200%, gelation may need a long time. If the water absorption rate is higher than 1000%, gel strength tends to be lowered.
  • 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 as used 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 added dropwise to the sample.
  • the weight of the sample containing absorbed distilled water to the maximum is determined as a maximum water absorption weight.
  • the lower limit of a moisture absorption rate of the fiber structure made of the etherified and carboxylated cellulose is preferably 7%, and the upper limit thereof is preferably 50%.
  • the fiber structure made of the etherified and carboxylated cellulose having the moisture absorption rate within such a range can gel in a short time with high gel strength, and tightly adhere to damaged tissue to stop bleeding. If the moisture absorption rate is lower than 7%, gelation may need a long time. If the moisture absorption rate is higher than 50%, the gel strength tends to be lowered.
  • 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.
  • Moisture absorption rate (%) (Weight after moisture control -absolute dry weight) /absolute dry weight ⁇ 100.
  • the fiber structure made of the etherified and carboxylated cellulose may be in any form, and may be in the form of a non-woven fabric, a knitted fabric, a woven fabric, gauze, or yarn.
  • the fiber structures having such forms may be combined one another.
  • a non-woven fabric is preferred.
  • the weight per unit area of the non-woven fabric is not particularly limited, and the lower limit is preferably 20 g/m 2 , and the upper limit is preferably 700 g/m 2 . If the non-woven fabric has a weight per unit area of less than 20 g/m 2 , the fiber structure may fail to sufficiently adhere to damaged tissue. If the non-woven fabric has the weight per unit area of more than 700 g/m 2 , gelation of etherified and carboxylated cellulose may need a long time.
  • the lower limit of the weight per unit area of the non-woven fabric is more preferably 50 g/m 2 , and the upper limit thereof is more preferably 500 g/m 2 .
  • the thickness of the fiber structure made of the etherified and carboxylated cellulose is not particularly limited, and the lower limit is preferably 50 ⁇ m, and the upper limit is preferably 10 mm. If the fiber structure made of the etherified and carboxylated cellulose has a thickness of less than 50 ⁇ m, the fiber structure may fail to sufficiently adhere to damaged tissue. If the fiber structure made of the etherified and carboxylated cellulose has a thickness of more than 10 mm, the fiber structure is less likely to absorb water to have an impaired texture, and have poor handleability.
  • the lower limit of the thickness of the fiber structure made of the etherified and carboxylated cellulose is more preferably 50 ⁇ m, and the upper limit thereof is more preferably 5 mm.
  • the medical fiber structure of the present invention can sufficiently adhere to damaged tissue to stop bleeding, without containing fibrin glue that is a blood product, and more reliably reinforce weakened tissue by preventing air leakage or fluid leakage.
  • the medical fiber structure of the present invention is almost neutral and therefore does not disturb wound healing.
  • the medical fiber structure of the present invention can be used for hemostasis of damaged or wounded organs or tissues and for prevention of air leakage or fluid leakage therefrom in the field of surgery.
  • the medical fiber structure of the present invention may be used alone or in the form of a laminate in combination with other film (s) or fiber structure (s) made of bioabsorbable polymer (s) .
  • the medical fiber structure of the present invention serves as an adhesive between the film (s) or fiber structure (s) made of bioabsorbable polymers and damaged tissue.
  • the present invention also encompasses a laminate including the medical fiber structure of the present invention and the film (s) or fiber structure (s) made of bioabsorbable polymer (s) .
  • the medical fiber structure of the present invention and the film (s) or fiber structure (s) of bioabsorbable polymer (s) are preferably integrated.
  • An integrated structure shows more enhanced handleability.
  • the integration may be performed by any method, and examples of the method include needle punch entanglement, hydroentanglement, air entanglement, interknitting, weaving, and spray spinning (melt blowing, electrospinning) .
  • phrase ′′integrated′′ as used herein means a state where the laminate of the medical fiber structure of the present invention and the film (s) or fiber structure (s) of bioabsorbable polymer (s) can be treated as one structure, and are not easily separated.
  • the bioabsorbable polymer is not particularly limited, and examples thereof include synthetic absorbable polymers such as ⁇ -hydroxy acid polymers (e.g., 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) , glycolide-lactide (D, L, DL isomer) - ⁇ -caprolactone copolymers) and natural absorbable polymers such as collagen, gelatin, chitosan, and chitin.
  • synthetic absorbable polymers such as ⁇ -hydroxy acid polymers (e.g., polyglycolide, polylactide (D, L, DL isomer) , glycolide-lactide (D, L, DL is
  • a natural absorbable polymer may be used together.
  • a ⁇ -hydroxy acid polymer that is a homopolymer or copolymer prepared by polymerizing at least one monomer selected from the group consisting of glycolide, lactide, ⁇ -caprolactone, dioxanone, and trimethylene carbonate because of its high strength.
  • a ⁇ -hydroxy acid polymer that is a homopolymer or copolymer prepared by polymerizing a monomer containing glycolide because the polymer shows appropriate decomposition behavior.
  • the lower limit of the weight average molecular weight of the polyglycolide is preferably 30,000, and the upper limit thereof is preferably 1,000,000.
  • Polyglycolide having a weight average molecular weight of less than 30,000 is poor in strength and may not impart a sufficient tissue reinforcement effect.
  • Polyglycolide having a weight average molecular weight of more than 1,000,000 slowly decomposes in the body and therefore may lead to a foreign-body reaction.
  • the lower limit of the weight average molecular weight of the polyglycolide is more preferably 50,000, and the upper limit thereof is more preferably 300,000.
  • the film (s) or fiber structure (s) made of bioabsorbable polymer (s) may be in any form, and may be a nonwoven fabric, a knitted fabric, a woven fabric, gauze, or yarn. Moreover, these forms may be combined.
  • the film (s) or fiber structure (s) made of bioabsorbable polymer (s) may be subjected to hydrophilization.
  • the hydrophilization may be performed by any method, and examples thereof include plasma treatment, glow discharge treatment, corona discharge treatment, ozone treatment, surface graft treatment, and irradiation with ultraviolet light.
  • plasma treatment is preferred for significant improvement of the water absorption rate without changing the external appearance of the nonwoven fabric.
  • the present invention can provide a medical fiber structure and a medical laminate, which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
  • Fig. 1 is a view schematically illustrating a pressure tester used in the pressure test performed in examples.
  • 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%sodium hypochlorite 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 then 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: l%owf, sodiumborohydride 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 treatment and treatment of reducing 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.
  • methanol: methyl isobutyl ketone 35: 35
  • acetic acid 35: 35: 2.6
  • the molar ratio of a diethylene glycol group and an ethylene glycol group was 0.18
  • the molar ratio of a triethylene glycol group and an ethylene glycol group was 0.15.
  • a grilled chicken liver was used as a model of damaged tissue.
  • purified water was dropped.
  • the medical fiber structure was then placed on the center of the damaged-tissue model in such a manner that the surface on which purified water was dropped was in contact with the liver. After standing for 15 minutes, the state of the medical fiber structure was evaluated based on the following criteria.
  • a 150- ⁇ m-thick nonwoven fabric made of polyglycolide (NEOVEIL Type NV-M015G, Gunze Limited) was prepared as a fiber structure made of a bioabsorbable polymer.
  • Two sheets of the obtained fiber structure made of hydroxyethylated and carboxylated cellulose, a nonwoven fabric made of polyglycolide, and one sheet of the fiber structure made of hydroxyethylated and carboxylated cellulose were stacked in the stated order and integrated to one another by needle punch entanglement to give a medical laminate.
  • a 9-mm circle piece was punched out from the obtained medical laminate and used as a test sample.
  • the pressure test was performed using a pressure tester 1 illustrated in Fig. 1.
  • a 24-mm circle piece was punched out from a collagen film (about 130 ⁇ m in thickness, Nippi. Inc. ) , washed with 70%ethanol, wiped to remove moisture, and set on a filter holder 2 (EMD Millipore Corporation, Swinnex 25) .
  • a 3-mm hole was punched at the center of the collagen film set on the filter holder 2.
  • a 20-ml syringe 3 (Terumo syringe SS-20ESZ, Terumo Corporation) and a pressure gauge 5 (Digital Manometer FUSO-8230, Fusorika Co., Ltd. ) were set through a three-way cock 4. A pressure tester was thus prepared.
  • Purified water was dropped onto a surface of the obtained test sample on the side where two sheets of the fiber structure made of hydroxyethylated and carboxylated cellulose were positioned.
  • the test sample was then placed on the center of the collagen film set on the filter holder in such a manner that the surface where purified water was dropped was in contact with the collagen film.
  • air was delivered from the syringe until the test sample was peeled.
  • the maximum pressure before the test sample was peeled was measured with the pressure gauge for evaluation of the pressure resistance (initial pressure resistance) .
  • TEMPO oxidation solution used in the TEMPO oxidation step was a TEMPO oxidation solution (TEMPO concentration: 20%owf, 5%sodium hypochlorite concentration: 350%owf, sodium bromide: 17.5%owf, pH 10 aqueous solution) .
  • a 9-mm circle piece was punched out from a 150- ⁇ m-thick nonwoven fabric made of polyglycolide (NEOVEIL TypeNV-M015G, Gunze Limited) .
  • a collagen film was set on the filter holder of the pressure tester prepared in Example 1. Then, 20 ⁇ L of liquid A of fibrin glue (CSL Behring K.K., Beriplast P) was dropped onto the center of the collagen film in such a manner as to avoid the hole in the collagen film and spread in an approximately 9-mm-diameter shape. Next, the nonwoven fabric in the shape of a 9-mm circle was placed on the spread liquid A, and was impregnated with the liquid A. Then, 40 ⁇ L of the liquid A was dropped onto the nonwoven fabric, and the nonwoven fabric was sufficiently impregnated with the liquid A. Then, 40 ⁇ L of liquid B was dropped onto the nonwoven fabric.
  • fibrin glue CSL Behring K.K., Beriplast P
  • 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%sodium hypochlorite 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 then 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: l%owf, sodiumborohydride 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 treatment and treatment of reducing partially formed ketone to hydroxy groups.
  • the obtained knit was further washed with hot water, neutralized, and washed with water.
  • a medical fiber structure including a fiber structure made of carboxylated cellulose was thus prepared.
  • a 280- ⁇ m-thick single knit made of No. 80 count cellulose yarn as a raw material was bleached by hydrogen peroxide bleaching.
  • the molar ratio of a diethylene glycol group and an ethylene glycol group was 0.20
  • the molar ratio of a triethylene glycol group and an ethylene glycol group was 0.21.
  • the present invention can provide a medical fiber structure and a medical laminate, which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.

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Abstract

The medical fiber structure and the medical laminate provided herein are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage. The medical fiber structure includes a fiber structure made of cellulose which is produced through etherification and carboxylation of hydroxy groups of cellulose.

Description

MEDICAL FIBER STRUCTURE AND MEDICAL LAMINATE TECHNICAL FIELD
The present invention relates to a medical fiber structure and a medical laminate， which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
BACKGROUND ART
The most fundamental issue in the field of surgery is to stop bleeding of a damaged or weakened organ or tissue and repair it. For example， bleeding of a damaged organ is still treated by stopping bleeding and suturing the wound， which is the most commonly used surgical procedure to stop bleeding even now. Furthermore， another important issue in the surgical treatment is to prevent fluid leakage or air leakage from weakened or damaged tissue. Particularly in the field of chest surgery， it is important to prevent air leakage due to pneumothorax or after resection of lung cancer. In particular， pneumothorax is a disease that is difficult to treat because the recurrence rate is increased without appropriate treatment.
Pneumothorax often occurs due to air leakage into a thoracic cavity from a stump or suture site of the lung after resection， a site of the lung after partial resection to remove lung cancer， or a damaged site of lung tissue due to injury； or air leakage into a thoracic cavity from a tear of cysts (referred to bullae) which are transformed from some alveoli. Such leakage has been treated by pleurodesis in which lung tissue is allowed to adhere to pleura with drugs or by artificial  chemical burns. Pleurodesis can prevent recurrence of pneumothorax to some extent. However， if lung tissue does not tightly adhere to pleura， the recurrence rate is increased. If further surgery is needed， adhesion between lung tissue and parietal pleura needs to be removed， which prolongs a surgical time or causes bleeding during removal of the adhesion. Therefore， new treatment alternative to pleurodesis has been investigated.
Furthermore， an important issue in the field of digestive surgery is to prevent leakage of pancreatic juice from a stump of the pancreas after partial pancreatectomy. Pancreatic juice dissolves granulation tissue that is responsible for wound healing， and prevents the growth of the tissue， leading to difficulty in regeneration of pancreatic tissue. Furthermore， it is concerned that leakage of pancreatic juice digests blood vessels to possibly cause postoperative hemorrhage， which is a life-threatening complication.
For such a situation， fibrin glue and a fiber structure made of a bioabsorbable polymer have been used in combination to reinforce lung tissue and seal the surface of the lung. Non-Patent Literatures 1 to 4 suggest that this method more reduces the recurrence rate of pneumothorax than usual pleurodesis. Non-Patent Literature 5 suggests that such a method is also used to prevent bleeding after liver resection in the field of digestive surgery.
Use of fibrin glue and a fiber structure made of a bioabsorbable polymer in combination is remarkably effective to stop bleeding of damaged tissue and reinforce weakened tissue. However， hemostasis may be insufficient or air leakage or fluid leakage may occur at a reinforced area， which may give rise to the need of further surgery. The incidence of such a case is not high， but leakage may become a risk factor to cause severe symptoms. Therefore， a reliable method of reinforcement has  been needed. Further， fibrin glue， which is a blood product， may lead to unknown viral infection.
Absorbable hemostatic agents prepared from regenerated oxidized cellulose are commercially available as hemostatic agents excellent in bioabsorbability. The absorbable hemostatic agents prepared from regenerated oxidized cellulose are considered to be highly safe as they are originated from plants and provide a hemostatic effect by forming a salt together with erythrocyte. The absorbable hemostatic agents prepared from regenerated oxidized cellulose are， however， highly acidic， which may inhibit wound healing. Moreover， even in the case of using an absorbable hemostatic agent prepared from regenerated oxidized cellulose， hemostasis may be insufficient or air leakage or fluid leakage may occur at a reinforced area.
CITATION LIST
-Non-Patent Literature
Non-Patent Literature 1： J. Pediatric Surg， 42， 1225-1230 (2007)
Non-Patent Literature 2： Interact. Cardiovasc. Thorac. Surg， 6， 12-15 (2007)
Non-Patent Literature 3： The Journal of the Japanese Association for Chest Surgery， 19 (4) ， 628-630 (2005)
Non-Patent Literature 4： The Journal of the Japanese Association for Chest Surgery， 22 (2) ， 142-145 (2008)
Non-Patent Literature 5： The Japanese Journal of Clinical and Experimental Medicine， 84， 148 (2007)
SUMMARY OF INVENTION
-Technical Problem
In consideration of the state of the art， the present invention aims to provide a medical fiber structure and a medical laminate， which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
-Solution to problem
The present invention relates to a medical fiber structure including a fiber structure made of cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose.
The present invention is specifically described in the followings.
The present inventors have researched the cause of insufficient hemostasis or air leakage or fluid leakage from a reinforced area of wounded tissue subjected to hemostasis or reinforcement using fibrin glue and a fiber structure made of abioabsorbablepolymer in combination， and found that the cause of the leakage is in an adhesion area with fibrin glue.
Fibrin glue， which gels in a short time， is very useful as biological glue. However， since fibrin glue in the form of a gel is relatively hard， cohesive failure or interfacial peeling is likely to occur due to impact. In particular， in cases where fibrin glue is used to reinforce lung tissue， cohesive failure or interracial peeling presumably occurs by a very high pressure applied to lung tissue by coughing or sneezing. Gelled fibrin glue once separated cannot adhere again because it has almost no adhesiveness. Air leakage or fluid leakage presumably occurs at such a separation area.
The present inventors have also researched the cause of insufficient hemostasis or air leakage or fluid leakage from a reinforced area of wounded tissue subjected to hemostasis or  reinforcement using a conventional absorbable hemostatic agent prepared from regenerated oxidized cellulose， and found out that the absorbable hemostatic agent prepared from regenerated oxidized cellulose is less likely to adhere to wounded tissue if the wounded part has significant surface roughness.
As a result of further intensive studies， the present inventors have found that a fiber structure including cellulose produced through etherification and carboxylation of hydroxy groups of cellulose can sufficiently adhere to wounded tissue even if the wounded part has significant surface roughness to surely stop bleeding. Moreover， such a fiber structure causes neither cohesive failure nor interfacial peeling even under a high pressure， which allows more reliable reinforcement of weakened tissue to prevent air leakage or fluid leakage. The present invention was thus completed.
The medical fiber structure of the present invention includes a fiber structure made of cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose (hereafter， also simply referred to as ″etherified and carboxylated cellulose″ ) .
Etherified and carboxylated cellulose is a compound proven to be highly safe， and gels in a short time like fibrin glue to be attached to biological tissue. In a case where the medical fiber structure of the present invention including a fiber structure made of such etherified and carboxylated cellulose is attached to wounded tissue， the medical fiber structure can sufficiently adhere to the wounded tissue to surely stop bleeding even if the wounded part has significant surface roughness. Further， since gelled etherified and carboxylated cellulose has a certain level of adhesive force， even if cohesive failure or interfacial peeling occurs due to high pressure， the etherified and carboxylated cellulose can  adhere again to the wounded tissue to prevent air leakage or fluid leakage.
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 cellulose are replaced with hydroxyethyl groups and carboxyl groups， and hydroxypropylated and carboxylated cellulose in which hydroxy groups of cellulose are replaced with hydroxypropyl groups and carboxyl groups. Particularly preferred is hydroxyethylated and carboxylated cellulose because it is proven to be highly safe.
Preferred hydroxyalkylated and carboxylated cellulose is， for example， represented by the following formula (1) .
Figure PCTCN2016084448-appb-000001
In the formula (1) ， n represents an integer， R represents hydrogen or a -R′OH group， and 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 and 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 and 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 one anhydroglucose 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 etherified and carboxylated cellulose can be prepared by， for example， carboxylating and then etherifying cellulose.
The cellulose may be carboxylated as follows， for example. In the reaction with 2， 2， 6， 6-tetramethylpiperidine-l-oxyl (TEMPO) as an oxidant and sodium hypochlorite， hydroxy groups of the cellulose is oxidized to produce aldehyde (TEMPO oxidation step) . Then， in the reaction with sodium chlorite， the aldehyde is carboxylated (carboxylation step) .
Thus obtained carboxylated cellulose is treated with an alkaline aqueous solution such as an aqueous solution of 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 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 lower limit of a water absorption rate of the fiber structure made of the etherified and carboxylated cellulose is  preferably 200％， and the upper limit thereof is preferably 1000％. The fiber structure made of the etherified and carboxylated cellulose having a water absorption rate within such a range can gel ina short time with high gel strength， and tightly adhere to damaged tissue to stop bleeding. If the water absorption rate is lower than 200％， gelation may need a long time. If the water absorption rate is higher than 1000％， gel strength tends to be lowered. 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 as used 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 added dropwise to the sample. The weight of the sample containing absorbed distilled water to the maximum (the sample in a condition that any more distilled water cannot be absorbed， and if distilled water is further added dropwise to the sample， excess water leaks) is determined as a maximum water absorption weight. The water absorption rate can be determined from the following equation using the resulting initial weight and the maximum water absorption weight： Water absorption rate (％) ＝ (Maximum water absorption weight -initial weight) ) /initial weight × 100.
The lower limit of a moisture absorption rate of the fiber structure made of the etherified and carboxylated cellulose is preferably 7％， and the upper limit thereof is preferably 50％. The fiber structure made of the etherified and carboxylated cellulose having the moisture absorption rate within such a range can gel in a short time with high gel strength， and tightly adhere to damaged tissue to stop bleeding. If the moisture absorption rate is lower than 7％， gelation may need a long time. If the moisture absorption rate is higher than 50％， the gel strength tends to be lowered. 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 two 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 environment at 20℃ and 65％Rh for seven hours to control the moisture content thereof. The weight of the resulting sample is determined as a weight after moisture control. A moisture absorption rate can be calculated from the following equation using the obtained 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 and carboxylated cellulose may be in any form， and may be in the form of a non-woven fabric， a knitted fabric， a woven fabric， gauze， or yarn. In addition， the fiber structures having such forms may be combined one another. In particular， a non-woven fabric is preferred.
In cases where the fiber structure made of the etherified and carboxylated 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 lower limit is preferably 20 g/m2， and the upper limit is preferably 700 g/m2. If the non-woven fabric has a weight per unit area of less than 20 g/m2， the fiber structure may fail to sufficiently adhere to damaged tissue. If the non-woven fabric has the weight per unit area of more than 700 g/m2， gelation of etherified and carboxylated cellulose may need a long time. The lower limit of the weight per unit area of the non-woven fabric is more preferably 50 g/m2， and the upper limit thereof is more preferably 500 g/m2.
The thickness of the fiber structure made of the etherified and carboxylated cellulose is not particularly limited， and the lower limit is preferably 50 μm， and the upper limit is preferably 10 mm. If the fiber structure made of the etherified and carboxylated cellulose has a thickness of less than 50 μm， the fiber structure may fail to sufficiently adhere to damaged tissue. If the fiber structure made of the etherified and carboxylated cellulose has a thickness of more than 10 mm， the fiber structure is less likely to absorb water to have an impaired texture， and have poor handleability. The lower limit of the thickness of the fiber structure made of the etherified and carboxylated cellulose is more preferably 50 μm， and the upper limit thereof is more preferably 5 mm.
The medical fiber structure of the present invention can sufficiently adhere to damaged tissue to stop bleeding， without containing fibrin glue that is a blood product， and more reliably reinforce weakened tissue by preventing air leakage or fluid leakage. The medical fiber structure of the present invention is almost neutral and therefore does not disturb wound healing.
The medical fiber structure of the present invention can be used for hemostasis of damaged or wounded organs or tissues and for prevention of air leakage or fluid leakage therefrom in the field of surgery.
The medical fiber structure of the present invention may be used alone or in the form of a laminate in combination with other film (s) or fiber structure (s) made of bioabsorbable polymer (s) . In the case of such a laminate， while the film (s) or fiber structure (s) made of bioabsorbable polymer (s) enable (s) more certain hemostasis and reinforcement of tissue， the medical fiber structure of the present invention serves as  an adhesive between the film (s) or fiber structure (s) made of bioabsorbable polymers and damaged tissue.
The present invention also encompasses a laminate including the medical fiber structure of the present invention and the film (s) or fiber structure (s) made of bioabsorbable polymer (s) .
In the medical laminate of the present invention， the medical fiber structure of the present invention and the film (s) or fiber structure (s) of bioabsorbable polymer (s) are preferably integrated. An integrated structure shows more enhanced handleability.
The integration may be performed by any method， and examples of the method include needle punch entanglement， hydroentanglement， air entanglement， interknitting， weaving， and spray spinning (melt blowing， electrospinning) .
The phrase ″integrated″ as used herein means a state where the laminate of the medical fiber structure of the present invention and the film (s) or fiber structure (s) of bioabsorbable polymer (s) can be treated as one structure， and are not easily separated.
The bioabsorbable polymer is not particularly limited， and examples thereof include synthetic absorbable polymers such as α-hydroxy acid polymers (e.g.， 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) ， glycolide-lactide (D， L， DL isomer) -ε-caprolactone copolymers) and natural absorbable polymers such as collagen， gelatin， chitosan， and chitin. These may be used alone， or in combination of two or more thereof. For example， in cases where the synthetic absorbable polymer is used as the bioabsorbable polymer， a natural absorbable polymer may be used together. In particular， preferred is a α-hydroxy acid polymer that is a  homopolymer or copolymer prepared by polymerizing at least one monomer selected from the group consisting of glycolide， lactide， ε-caprolactone， dioxanone， and trimethylene carbonate because of its high strength. More preferred is a α-hydroxy acid polymer that is a homopolymer or copolymer prepared by polymerizing a monomer containing glycolide because the polymer shows appropriate decomposition behavior.
If polyglycolide (homopolymer or copolymer of glycolide) is used as the bioabsorbable polymer， the lower limit of the weight average molecular weight of the polyglycolide is preferably 30,000， and the upper limit thereof is preferably 1,000,000. Polyglycolide having a weight average molecular weight of less than 30,000 is poor in strength and may not impart a sufficient tissue reinforcement effect. Polyglycolide having a weight average molecular weight of more than 1,000,000 slowly decomposes in the body and therefore may lead to a foreign-body reaction. The lower limit of the weight average molecular weight of the polyglycolide is more preferably 50,000， and the upper limit thereof is more preferably 300,000.
The film (s) or fiber structure (s) made of bioabsorbable polymer (s) may be in any form， and may be a nonwoven fabric， a knitted fabric， a woven fabric， gauze， or yarn. Moreover， these forms may be combined.
The film (s) or fiber structure (s) made of bioabsorbable polymer (s) may be subjected to hydrophilization.
The hydrophilization may be performed by any method， and examples thereof include plasma treatment， glow discharge treatment， corona discharge treatment， ozone treatment， surface graft treatment， and irradiation with ultraviolet light. In particular， plasma treatment is preferred for significant improvement of the water absorption rate without changing the external appearance of the nonwoven fabric.
-Advantageous Effects of Invention
The present invention can provide a medical fiber structure and a medical laminate， which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is a view schematically illustrating a pressure tester used in the pressure test performed in examples.
DESCRIPTION OF EMBODIMENTS
The following describes examples to more specifically illustrate embodiments of the present invention. It should be noted that the present invention is not limited only to these examples.
(Example 1)
(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％sodium hypochlorite 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 then 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： l％owf， sodiumborohydride 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 treatment and treatment of reducing 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 then immersed in 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 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 minutes at a bath ratio of 1： 60， and dried at 40℃ for 24 hours to give a medical fiber structure including a fiber structure made of hydroxyethylated and carboxylated cellulose.
As a result of analysis of the hydroxyethylated and carboxylated cellulose of the resulting fiber structure using a thermal decomposition GC-MS， the molar ratio of a diethylene glycol group and an ethylene glycol group (diethylene glycol  group/ethylene glycol group) was 0.18， and the molar ratio of a triethylene glycol group and an ethylene glycol group (triethylene glycol group/ethylene glycol group) was 0.15.
(2) Evaluation of adhesion to damaged tissue
A grilled chicken liver was used as a model of damaged tissue. To the surface of the obtained medical fiber structure， purified water was dropped. The medical fiber structure was then placed on the center of the damaged-tissue model in such a manner that the surface on which purified water was dropped was in contact with the liver. After standing for 15 minutes， the state of the medical fiber structure was evaluated based on the following criteria.
″oo (excellent) ″ ： The fiber structure pulled by a hand was not at all peeled.
″o (good) ″ ： The fiber structure pulled strongly by a hand was peeled.
″Δ (not good) ″ ： The fiber structure was seemed to tightly adhere to the model but easily peeled when pulled by a hand.
″× (poor) ″ ： The fiber structure was not seemed to tightly adhere to the model and was easily peeled when pulled by a hand.
Table 1 shows the results.
(3) Preparation of medical laminate and pressure test
A 150-μm-thick nonwoven fabric made of polyglycolide (NEOVEIL Type NV-M015G， Gunze Limited) was prepared as a fiber structure made of a bioabsorbable polymer.
Two sheets of the obtained fiber structure made of hydroxyethylated and carboxylated cellulose， a nonwoven fabric made of polyglycolide， and one sheet of the fiber structure made of hydroxyethylated and carboxylated cellulose were stacked in the stated order and integrated to one another by needle punch entanglement to give a medical laminate. A 9-mm circle piece was punched out from the obtained medical laminate and used as a test sample.
The pressure test was performed using a pressure tester 1 illustrated in Fig. 1.
A 24-mm circle piece was punched out from a collagen film (about 130 μm in thickness， Nippi. Inc. ) ， washed with 70％ethanol， wiped to remove moisture， and set on a filter holder 2 (EMD Millipore Corporation， Swinnex
Figure PCTCN2016084448-appb-000002
25) . A 3-mm hole was punched at the center of the collagen film set on the filter holder 2. At a downstream side of the filter holder， a 20-ml syringe 3 (Terumo syringe SS-20ESZ， Terumo Corporation) and a pressure gauge 5 (Digital Manometer FUSO-8230， Fusorika Co.， Ltd. ) were set through a three-way cock 4. A pressure tester was thus prepared.
Purified water was dropped onto a surface of the obtained test sample on the side where two sheets of the fiber structure made of hydroxyethylated and carboxylated cellulose were positioned. The test sample was then placed on the center of the collagen film set on the filter holder in such a manner that the surface where purified water was dropped was in contact with the collagen film. After standing for 15 minutes， air was delivered from the syringe until the test sample was peeled. The maximum pressure before the test sample was peeled was measured with the pressure gauge for evaluation of the pressure resistance (initial pressure resistance) .
After evaluation of the initial pressure resistance， air was delivered from the syringe five times every five minutes for measurement of the maximum pressure before the test sample was peeled with the pressure gauge. Based on the results， the repeated pressure resistance was evaluated.
Table 2 shows the results.
(Example 2)
Preparation of a medical fiber structure and a medical laminate， evaluation of the adhesion to damaged tissue， and the  pressure test were performed in the same manner as in Example 1， except that the TEMPO oxidation solution used in the TEMPO oxidation step was a TEMPO oxidation solution (TEMPO concentration： 20％owf， 5％sodium hypochlorite concentration： 350％owf， sodium bromide： 17.5％owf， pH 10 aqueous solution) .
Tables 1 and 2 show the results.
(Comparative Example 1)
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 9-mm circle piece was punched out from a 150-μm-thick nonwoven fabric made of polyglycolide (NEOVEIL TypeNV-M015G， Gunze Limited) .
A collagen film was set on the filter holder of the pressure tester prepared in Example 1. Then， 20 μL of liquid A of fibrin glue (CSL Behring K.K.， Beriplast P) was dropped onto the center of the collagen film in such a manner as to avoid the hole in the collagen film and spread in an approximately 9-mm-diameter shape. Next， the nonwoven fabric in the shape of a 9-mm circle was placed on the spread liquid A， and was impregnated with the liquid A. Then， 40 μL of the liquid A was dropped onto the nonwoven fabric， and the nonwoven fabric was sufficiently impregnated with the liquid A. Then， 40 μL of liquid B was dropped onto the nonwoven fabric.
After 15 minutes from dropping of the liquid B， air was delivered through the syringe， and the maximum pressure before the test sample was peeled was measured with the pressure gauge for evaluation of the pressure resistance (initial pressure resistance) .
After evaluation of the initial pressure resistance， air was delivered through the syringe four times every five minutes， and the maximum pressure before the test sample was peeled was measured with the pressure gauge for evaluation of the repeated pressure resistance.
Table 1 shows the results.
(Comparative Example 2)
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％sodium hypochlorite 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 then 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： l％owf， sodiumborohydride 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 treatment and treatment of reducing partially formed ketone to hydroxy groups. The obtained knit was further washed with hot water， neutralized， and washed with water. A medical fiber structure including a fiber structure made of carboxylated cellulose was thus prepared.
The evaluation of the adhesion to damaged tissue， production of a medical laminate， and the pressure test were performed in the same manner as in Example 1， except that the obtained medical fiber structure was used.
Tables 1 and 2 show the results.
(Comparative Example 3)
The evaluation of the adhesion to damaged tissue， production of a medical laminate， and the pressure test were performed in the same manner as in Example 1， except that the  fiber structure used was a commercially available absorbable hemostatic agent prepared from regenerated oxidized cellulose (Johnson &Johnson K.K.， Surgicel) .
Tables 1 and 2 show the results.
(Comparative Example 4)
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 obtained 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 then 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 then 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 then in 70 mL of acetone at 25℃ for five minutes. The resulting knit was then dried at 40℃ for 24 hours to prepare a fiber structure made of hydroxyethylated cellulose.
As a result of analysis of the hydroxyethylated cellulose of the resulting fiber structure using a thermal decomposition GC-MS， the molar ratio of a diethylene glycol group and an ethylene glycol group (diethylene glycol group/ethylene glycol group) was 0.20， and the molar ratio of a triethylene glycol group and an ethylene glycol group (triethylene glycol group/ethylene glycol group) was 0.21.
[Table 1]
Figure PCTCN2016084448-appb-000003
[Table 2]
Figure PCTCN2016084448-appb-000004
INDUSTRIAL APPLICABILITY
The present invention can provide a medical fiber structure and a medical laminate， which are capable of sufficiently adhering to damaged tissue to stop bleeding and more reliably reinforcing weakened tissue by preventing air leakage or fluid leakage.
REFERENCE SIGNS LIST
1. Pressure tester
2. Filter holder
3. Syringe
4. Three-way cock
5. Pressure gauge
6. Collagen film with a hole

Claims (6)

  1. A medical fiber structure comprising
    a fiber structure made of cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose.
  2. The medical fiber structure according to claim 1，
    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 (1) ：
    Figure PCTCN2016084448-appb-100001
    wherein n represents an integer， and R represents hydrogen or a —R′ OH group， wherein R′ represents an alkylene group.
  3. The medical fiber structure according to claim 1 or 2，
    wherein the fiber structure made of the cellulose that is produced through etherification and carboxylation of hydroxy groups of cellulose is in the form of a non—woven fabric， a knitted fabric， a woven fabric， gauze， or yarn.
  4. A medical laminate comprising
    a laminate that includes the medical fiber structure according to claim 1， 2， or 3 and a film or a fiber structure made of a bioabsorbable polymer.
  5. The medical laminate according to claim 4，
    wherein the bioabsorbable polymer is a α-hydroxy acid polymer.
  6. The medical laminate according to claim 5，
    wherein the α-hydroxy acid polymer is a homopolymer or a copolymer prepared by polymerization of at least one monomer selected from the group consisting of glycolide， lactide， ε-caprolactone， dioxanone， and trimethylene carbonate.
PCT/CN2016/084448 2016-06-02 2016-06-02 Medical fiber structure and medical laminate Ceased WO2017206131A1 (en)

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