WO2019071587A1

WO2019071587A1 - Biological tissue-reinforcing material kit and biological tissue-reinforcing material

Info

Publication number: WO2019071587A1
Application number: PCT/CN2017/106126
Authority: WO
Inventors: Chiaki Tanaka; Yoshinari Yui; Shojiro Matsuda; Hideki TAKAMORI
Original assignee: Gunze Medical Devices (shenzhen) Ltd; Gunze Ltd
Current assignee: Gunze Medical Devices (shenzhen) Ltd; Gunze Ltd
Priority date: 2017-10-13
Filing date: 2017-10-13
Publication date: 2019-04-18
Anticipated expiration: 2020-04-13
Also published as: JP6868129B2; JP2020526258A; CN111050812A; CN111050812B

Abstract

Provided is a biological tissue-reinforcing material kit and a biological tissue-reinforcing material which are capable of more reliably reinforcing weakened tissues while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product. And provided is a biological tissue-reinforcing material kit including： a fiber structure， sponge body， or film made of a bioabsorbable polymer; and a powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose.

Description

BIOLOGICAL TISSUE-REINFORCING MATERIAL KIT AND BIOLOGICAL TISSUE-REINFORCING MATERIAL

TECHNICAL FIELD

The present invention relates to a biological tissue-reinforcing material kit and a biological tissue-reinforcing material which are capable of more reliably reinforcing weakened tissues while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product.

BACKGROUND ART

The most fundamental issue in the field of surgery is to repair damaged or weakened organs or tissues. For example， bleeding of a damaged organ is still treated by stopping bleeding and suturing the wound， which is even now the most common surgical technique to treat bleeding. Another important issue in the surgical treatment is to prevent fluid leakage or air leakage from weakened or damaged tissues. 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 of the high recurrence rate unless properly treated.

Pneumothorax occurs mainly 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 area of lung tissue due to injury； or air leakage into a thoracic cavity from a tear of cysts (called bullae) which are transformed from some alveoli. Such leakage has been treated by pleurodesis in which lung tissue is allowed to adhere to pleura using drugs or through 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 increases. If further surgery is necessary， the adhesion between lung tissue and parietal pleura needs to be removed， which unfortunately prolongs a surgical time or causes bleeding during removal of the adhesion. Therefore， new treatment alternative to pleurodesis has been sought.

Meanwhile， 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 granulation tissue， leading to difficulty in regeneration of pancreatic tissue. Another concern is that leaked pancreatic juice may digest blood vessels to cause postoperative hemorrhage， 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 reduces the recurrence rate of pneumothorax more 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 a combination of fibrin glue and a fiber structure made of a bioabsorbable polymer is remarkably effective to reinforce weakened tissues. However， air leakage or fluid leakage may occur even at a reinforced area to necessitate further surgery. Although the incidence of such a condition is not high， leakage may become a risk factor to cause severe symptoms. Therefore， a reliable method of reinforcement has been needed. Furthermore， fibrin glue， which is a blood product， unfortunately may lead to unknown viral infection.

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

It is an object of the present invention to provide a biological tissue-reinforcing material kit and a biological tissue-reinforcing material which are capable of more reliably reinforcing weakened tissues while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product.

- Solution to Problem

The present invention is a biological tissue-reinforcing material kit including： a fiber structure， sponge body， or film made of a bioabsorbable polymer； and a powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose.

The present invention is described in detail below.

The present inventors have investigated the cause of air leakage or fluid leakage from a reinforced area of biological tissue having been reinforced using fibrin glue and a fiber structure or the like made of a bioabsorbable polymer in combination， and found that the problem occurs at an adhesion area attached 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 interfacial peeling may be caused by a very high pressure applied to lung tissue when the patient coughs or sneezes. Since gelled fibrin glue has almost no adhesion， once separated， it cannot adhere again. Air leakage or fluid leakage is considered to occur at such a separation area.

As a result of further various studies， the present inventors have found that weakened tissues can be more reliably reinforced by using a powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose (hereinafter， also referred to simply as ″etherified cellulose″ ) or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose (hereinafter， also referred to simply as ″esterified cellulose″ ) instead of fibrin glue， and the use of such a powder enables production of a biological tissue-reinforcing material causing no air leakage or fluid leakage. Accordingly， the inventors completed the present invention.

Etherified cellulose or esterified cellulose is a compound proven to be very safe， and gels in a short time like fibrin glue to act as glue to attach a fiber structure made of a bioabsorbable polymer to biological tissues. Furthermore， since such a powder 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. In addition， in the application to damaged areas with large surface irregularities， the etherified cellulose or esterified cellulose in the form of powder can enter between the irregularities and gels to be closely attached to the surfaces. Thus， air leakage or fluid leakage can be prevented.

The biological tissue-reinforcing material kit of the present invention includes： a fiber structure， sponge body， or film made of a bioabsorbable polymer； and a powder made of etherified cellulose.

The fiber structure， sponge body， or 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 powder made of etherified cellulose absorbs moisture to become a gel， and acts as glue to attach the film， fiber structure， or sponge body made of a bioabsorbable polymer to biological tissues.

In the biological tissue-reinforcing material kit of the present invention， the fiber structure， sponge body， or film made of a bioabsorbable polymer and the powder made of etherified cellulose may be combined at the time of use or may be combined in advance as a composite.

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 polyglycolide (homopolymer or copolymer of glycolide) is used as the bioabsorbable polymer， the preferable lower limit of the weight average molecular weight of the polyglycolide is 30,000， and the preferable upper limit is 1,000,000. Polyglycolide having a weight average molecular weight of less than 30,000 has insufficient strength and may not impart a sufficient tissue-reinforcing effect. Polyglycolide having a weight average molecular weight of more than 1,000,000 slowly decomposes in the body and therefore may cause a foreign-body reaction. The more preferable lower limit of the weight average molecular weight of the polyglycolide is 50,000， and the more preferable upper limit is 300,000.

The fiber structure made of a bioabsorbable polymer 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 a bioabsorbable polymer 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 5 g/m²， and the preferable upper limit is 300 g/m². A non-woven fabric having a weight per unit area of less than 5 g/m² has insufficient strength for a biological tissue-reinforcing material， and may not reinforce weakened tissues. A non-woven fabric having a weight per unit area of more than 300 g/m² may be poor in adhesion to tissues. The more preferable lower limit of the weight per unit area of the non-woven fabric is 10 g/m²， and the more preferable upper limit is 100 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 a bioabsorbable polymer is not particularly limited， and the preferable lower limit is 5 g/m²， and the preferable upper limit is 1,000 g/m². A sponge body made of a bioabsorbable polymer having a weight per unit area of less than 5 g/m² has insufficient strength for a biological tissue-reinforcing material， and may not reinforce weakened tissues. A sponge body made of a bioabsorbable polymer having a weight per unit area of more than 1,000 g/m² may be poor in adhesion to tissues. The more preferable lower limit of the weight per unit area of the sponge body made of a bioabsorbable polymer is 30 g/m²， and the more preferable upper limit is 500 g/m².

The thickness of the fiber structure or sponge body made of a bioabsorbable polymer is not particularly limited， and the preferable lower limit is 5 μm， and the preferable upper limit is 1 mm. A fiber structure or sponge body made of a bioabsorbable polymer having a thickness of less than 5 μm has insufficient strength and may not impart a sufficient tissue-reinforcing effect. A fiber structure or sponge body made of a bioabsorbable polymer having a thickness of more than lmm may not closely adhere to tissues to be insufficiently fixed. The more preferable lower limit of the thickness of the fiber structure or sponge body made of a bioabsorbable polymer is 10 μm， and the more preferable upper limit is 0.5 mm.

The thickness of the film made of a 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 a bioabsorbable polymer having a thickness of less than 10 μm has insufficient strength and may not impart a sufficient tissue-reinforcing effect. A film made of a bioabsorbable polymer having a thickness of more than 800 μm may not closely adhere to tissues to be insufficiently fixed. The more preferable lower limit of the thickness of the film made of a bioabsorbable polymer is 20 μm， and the more preferable upper limit is 300 μm.

The fiber structure， sponge body， or film made of a bioabsorbable polymer may be subjected to hydrophilization. The fiber structure 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 non-woven fabric.

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. In particular， hydroxyethylated cellulose is preferred because it is proven to be very safe.

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 fiber structure， sponge body， or film made of a bioabsorbable polymer adheres to biological tissue through the powder 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 fiber structure， sponge body， or 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 hydroxyethylated cellulose can be measured， for example， by NMR or thermal decomposition GC-MS.

In cases where the etherified cellulose is hydroxyethylated cellulose， the preferable lower limit of the average number of molecules (MS) of alkylene oxides bonded to an anhydroglucose unit is 1.0， and the preferable upper limit is 4.0. The etherified cellulose having a MS within such a range can gel in a short time with high gel strength， enabling closer adhesion and fixation to tissues. When the MS is less than 1.0， gelled hydroxyethylated cellulose tends to be less viscous. When the MS is more than 4.0， gelationtends to take a long time. The more preferable lower limit of the MS is 1.3， and the more preferable upper limit 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 is 2.5. The etherified cellulose having a DS within such a range can gel in a short time with high gel strength， enabling closer adhesion and fixation to tissues. When the DS is less than 0.2， gelation may take a long time. When the DS is more than 2.5， the strength may decrease. The more preferable lower limit of the DS is 0.3， and the more preferable upper limit 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 areas 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) ：

wherein n represents an integer， and R represents 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) 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 in the hydroxyethylated and carboxylated cellulose.

The lower limit of the average number of molecules (MS) of alkylene oxide bonded to an anhydroglucose unit is preferably 1.0， and the upper limit 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 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 in the hydroxyethylated and carboxylated cellulose can be measured， for example， by NMR or thermal decomposition GC-MS.

The hydroxyethylated cellulose can be produced， for example， by reacting an ethylene oxide with alkali cellulose which is 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 to carry out a reaction.

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-l-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 is then reacted with an 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 esterified cellulose is produced through esterification of hydroxy groups of cellulose.

Specific examples include phosphorylated cellulose produced through phosphorylation of hydroxy groups of cellulose， nitrocellulose produced through nitration of hydroxy groups of cellulose， cellulose sulfate produced through sulfation of hydroxy groups of cellulose， and cellulose acetate produced through acetylation of hydroxy groups of cellulose. Preferred of these is phosphorylated cellulose because it is proven to be very safe.

The shape of the powder made of etherified cellulose or esterified cellulose is not particularly limited.

The average particle size of the powder made of etherified cellulose or esterified cellulose is not particularly limited， and the preferable lower limit is 1 μm， and the preferable upper limit is 100 μm. A powder made of etherified cellulose or esterified cellulose having an average particle size of less than 1 μm may be difficult to treat. A powder made of etherified cellulose or esterified cellulose having an average particle size of more than 100 μm is less likely to absorb water， takes a long time to gel， and may not be readily handled. The more preferable lower limit of the average particle size of the powder made of etherified cellulose or esterified cellulose is 5 μm， and the more preferable upper limit is 50 μm. For application to damaged areas with large surface irregularities， the powder made of etherified cellulose or esterified cellulose having an average particle size within the more preferable range can readily enter between the irregularities， thereby better preventing air leakage or fluid leakage.

The powder made of etherified cellulose or esterified cellulose may be used as it is in the form of powder but may be used as a dispersion (or paste) in an amphiphilic medium. The powder in the form of a dispersion can be more readily treated and also can better enter between the irregularities upon application to damaged areas with large surface irregularities. Damaged areas may repel a hydrophilic medium. Thus， an amphiphilic medium is used to allow the powder to enter between the irregularities.

Any amphiphilic medium may be used as long as it allows the powder made of etherified cellulose or esterified cellulose to be uniformly dispersed therein without causing gel formation. Examples include polyethylene glycol， methanol， ethanol， 2-propanol， polypropylene glycol， and glycerol. Preferred of these is polyethylene glycol because of its ability to excellently disperse the powder made of etherified cellulose or esterified cellulose， easy control of the viscosity， and high safety.

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 to prevent air leakage due to pneumothorax or after resection of lung cancer in the field of chest surgery.

In the biological tissue-reinforcing material kit of the present invention， the film， fiber structure， or sponge body made of a bioabsorbable polymer and the powder made of etherified cellulose or esterified cellulose may be combined at the time of use. For example， after a phosphate buffer or physiological saline is dropped onto the film， fiber structure， or sponge body made of a bioabsorbable polymer， the powder made of etherified cellulose or esterified cellulose is sprinkled thereon so that the powder absorbs moisture to become a gel. The resulting composite can be readily attached to an affected area. Alternatively， a dispersion prepared by dispersing the powder made of etherified cellulose or esterified cellulose in an amphiphilic medium is applied to an affected area， a phosphate buffer or physiological saline is dropped to cause gel formation， and the film， fiber structure， or sponge body made of a bioabsorbable polymer is attached to the gel.

In the biological tissue-reinforcing material kit of the present invention， the film， fiber structure， or sponge body made of a bioabsorbable polymer may be combined with the powder made of etherified cellulose or esterified cellulose in advance. For example， a phosphate buffer or physiological saline is dropped onto the film， fiber structure， or sponge body made of a bioabsorbable polymer， and the powder made of etherified cellulose or esterified cellulose is sprinkled thereon so that the powder absorbs moisture to become a gel， followed by drying. Thus， a biological tissue-reinforcing material in which the film， fiber structure， or sponge body made of a bioabsorbable polymer is partly or entirely coated with the powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose can be produced. Such a biological tissue-reinforcing material can be readily attached to an affected area， for example， just by applying the material preliminary immersed into a phosphate buffer or physiological saline to the affected area. Furthermore， for an affected area with blood or fluid， the biological tissue-reinforcing material absorbs blood or fluid to thereby exhibit adhesion.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 is a view schematically illustrating a pressure tester used in the pressure test performed in examples.

Fig. 2 is a cross-sectional view of a filter holder 2 on which an urethane sponge 7 and a collagen film 8 are mounted.

- Advantageous Effects of Invention

The present invention can provide a biological tissue-reinforcing material kit and a biological tissue-reinforcing material which are capable of more reliably reinforcing weakened tissues while preventing air leakage or fluid leakage without using fibrin glue， which is a blood product.

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) Production of biological tissue-reinforcing material kit

A powder made of a commercial hydroxyethylated cellulose (available from Wako Pure Chemical Industries， Ltd.， average particle size： 20 μm， molar ratio of a diethylene glycol group to an ethylene glycol group (diethylene glycol group/ethylene glycol group) ： 1.06， molar ratio of a triethylene glycol group to an ethylene glycol group (triethylene glycol group/ethylene glycol group) ： 4.01) was prepared.

An amount of 25 parts by weight of the powder made of the hydroxyethylated cellulose was added to 75 parts by weight of polyethylene glycol (available from Nacalai Tesque， Inc.， PEG400) ， and the mixture was sufficiently stirred to prepare a dispersion.

A 150-μm-thick non-woven fabric made of polyglycolide (NEOVEIL Type NV-M015G available from Gunze Limited) was cut to have a length of 5.0 cm and a width of 5.0 cm to prepare a fiber structure made of a bioabsorbable polymer.

2) Pressure test

A pressure test was performed using a pressure tester 1 illustrated in Fig. 1.

An about 130-μm-thick collagen film (available from Nippi. Inc. ) was punched out 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 (collagen film 8) . An about 2-mm-thick urethane sponge 7 (available from Inoac Corporation， ST15， cell diameter： 50 μm， porosity： 85％) was punched out to have a diameter of 20 mm using a puncher. The collagen film 8 was placed on the urethane sponge. The urethane sponge 7 represents a damaged area with large surface irregularities. A 3-mm-diameter hole 6 was formed in the center of the collagen film 8 using a puncher. Fig. 2 shows a cross-sectional view of the filter holder 2 on which the urethane sponge 7 and the collagen film 8 were mounted. A 20-mL syringe 3 (Terumo Syringe SS-20ESZ available from Terumo Corporation) and a pressure gauge 5 (digital manometer FUSO-8230 available from Fusorika Co.， Ltd. ) were placed at the downstream of the filter holder 2 via a three way cock 4， thereby preparing a pressure tester.

The pressure tester 1 illustrated in Fig. 1 can measure pressures up to 200 mmHg.

(Pressure test A)

A small amount of a 70％ethanol solution was sprayed to one surface of the non-woven fabric made of polyglycolide using a spray to wet the surface of the non-woven fabric. Subsequently， 0.2 g of the powder made of hydroxyethylated cellulose was uniformly sprayed over the surface of the non-woven fabric made of polyglycolide. The resulting non-woven fabric was dried at 60℃ for two hours， thereby providing a biological tissue-reinforcing material in which one surface of the non-woven fabric made of polyglycolide was coated with the powder 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.

An amount of 20 μL of phosphate buffer was dropped onto the surface of the test sample for measurement on the side coated with the powder made of hydroxyethylated cellulose. The resulting test sample was placed at the center of the collagen film mounted on the filter holder such that the surface was in contact with the collagen film. After the test sample was allowed to stand for five minutes， air was delivered through the syringe. The maximum pressure before the test sample for measurement was peeled was measured with a pressure gauge to evaluate the pressure resistance.

Table 1 shows the result.

(Pressure test B)

An amount of 20 μL of the dispersion of the powder made of hydroxyethylated cellulose in polyethylene glycol was applied to the brim of the hole in the collagen film mounted on the filter holder and to the urethane film via the hole. Onto the applied dispersion was dropped 20 μL of a phosphate buffer， and the non-woven fabric made of polyglycolide was placed thereon. After the test sample was allowed to stand for 5 minutes， air was delivered through the syringe. The maximum pressure before the test sample for measurement was peeled was measured with a pressure gauge to evaluate the pressure resistance.

Table 1 shows the result.

(Example 2)

A 100 μm-thick film made of polyglycolide was prepared by a heat press molding method. The film was cut to have a length of 5.0 cm and a width of 5.0 cm to prepare a film made of a bioabsorbable polymer.

A biological tissue-reinforcing material kit prepared using the film made of a bioabsorbable polymer instead of the fiber structure made of a bioabsorbable polymer was subject to the pressure tests as in Example 1.

Table 1 shows the result.

(Example 3)

An amount of 0.2 g of phosphoric acid (available from Wako Pure Chemical Industries， Ltd. ) was mixed with 6.0 g of urea (available from Wako Pure Chemical Industries， Ltd. ) . Next， 0.2 g of KC Flock (available from Nippon Paper Industries Co.， Ltd. ) as a cellulose raw material was added to the mixture and they were reacted at 145℃ for 10 minutes. The reaction product was cooled and subsequently washed with an ethanol/water mixture (ethanol： water ＝ 90 parts by weight： 10 parts by weight) and then with an ethanol/sodium hydroxide aqueous solution mixture (ethanol： sodium hydroxide aqueous solution ＝ 90 parts by weight： 10 parts by weight) . After further washing with an ethanol/hydrochloric acid aqueous solution mixture (ethanol： hydrochloric acid aqueous solution ＝ 90 parts by weight： 10 parts by weight) ， the resulting reaction product was washed twice with an ethanol/water mixture (ethanol： water ＝ 90 parts by weight： 10 parts by weight) ， thereby obtaining a powder made of phosphorylated cellulose having an average particle size of about 20 μm.

Separately， 25 parts by weight of the powder made of phosphorylated cellulose was added to 75 parts by weight of polyethylene glycol (available from Nacalai Tesque， Inc.， PEG400) ， and the mixture was sufficiently stirred to prepare a dispersion.

A biological tissue-reinforcing material kit prepared using the powder or the dispersion was subject to the pressure tests as in Example 1.

Table 1 shows the result.

(Example 4)

A powder made of phosphorylated cellulose was prepared as in Example 3.

A biological tissue-reinforcing material kit prepared using the powder or the dispersion was subject to the pressure tests as in Example 2.

Table 1 shows the result.

(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 11-mm-diameter circular piece was punched out from a 150-μm-thick non-woven fabric made of polyglycolide (NEOVEIL Type NV-M015G， available from Gunze Limited) .

A collagen film prepared as in Example 1 was set on the filter holder of the pressure tester used in Example 1. Then， 20 μL of a solutionA of fibrin glue (available fromCSL 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 was spread into a shape with a diameter of approximately ll mm. Next， the non-woven 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 non-woven fabric， and the non-woven fabric was sufficiently impregnated with the solution A. Thereafter， 20 μL of a solution B was dropped onto the non-woven fabric.

Five minutes after the dropping of the solution B， air was delivered from the syringe. The maximum pressure before the test sample was peeled was measured with a pressure gauge to evaluate the pressure resistance.

Table 1 shows the result.

(Comparative Example 2)

Separately， a 320-μm-thick fiber structure made of oxidized cellulose (available from Johnson & Johnson K.K.， Surgicel) was cut to have a length of 5.0 cm and a width of 5.0 cm.

The fiber structure made of oxidized cellulose， the non-woven fabric made of polyglycolide， and the fiber structure made of oxidized cellulose were stacked in the stated order， and they were integrated by needle punching， thereby providing a biological tissue-reinforcing material.

The biological tissue-reinforcing material was subjected to the pressure tests as in Example 1.

Table 1 shows the result.

[Table 1]

INDUSTRIAL APPLICABILITY

REFERENCE SIGNS LIST

1 Pressure tester

2 Filter holder

3 Syringe

4 Three way cock

5 Pressure gauge

6 Hole formed in collagen film

7 Urethane sponge

8 Collagen film

Claims

A biological tissue-reinforcing material kit comprising：

a fiber structure， sponge body， or film made of a bioabsorbable polymer； and

a powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose.
The biological tissue-reinforcing material kit according to claim 1，

wherein the powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose is dispersed in an amphiphilic medium.
The biological tissue-reinforcing material kit according to claim 2，

wherein the amphiphilic medium is polyethylene glycol.
The biological tissue-reinforcing material kit according to claim 1， 2， or 3，

wherein the etherified cellulose that is produced through etherification of hydroxy groups of cellulose is hydroxyalkylated cellulose represented by the following formula (1) ：

wherein n represents an integer， and R represents hydrogen or -R′OH in which R′ represents an alkylene group.
The biological tissue-reinforcing material kit according to claim 1， 2， or 3，

wherein the etherified cellulose that is produced through etherification of hydroxy groups of cellulose is hydroxyethylated cellulose.
The biological tissue-reinforcing material kit according to claim 1， 2， 3， 4， or 5，

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.
The biological tissue-reinforcing material kit according to claim 6，

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) ：

wherein n represents an integer， and R represents hydrogen or -R′OH in which R′ represents an alkylene group.
The biological tissue-reinforcing material kit according to claim 1， 2， or 3，

wherein the esterified cellulose that is produced through esterification of hydroxy groups of cellulose is phosphorylated cellulose.
The biological tissue-reinforcing material kit according to claim 1， 2， 3， 4， 5， 6， 7， or 8，

wherein the bioabsorbable polymer is an α-hydroxy acid polymer.
The biological tissue-reinforcing material kit according to claim 9，

wherein the α-hydroxy acid polymer is a homopolymer or copolymer of at least one monomer selected from the group consisting of glycolide， lactide， ε-caprolactone， dioxanone， and trimethylene carbonate.
The biological tissue-reinforcing material kit according to claim 1， 2， 3， 4， 5， 6， 7， 8， 9， or 10，

wherein the fiber structure made of a bioabsorbable polymer is in the form of a non-woven fabric， a knitted fabric， a woven fabric， gauze， or yarn.
A biological tissue-reinforcing material comprising：

a film， fiber structure， or sponge body made of a bioabsorbable polymer； and

a powder made of etherified cellulose that is produced through etherification of hydroxy groups of cellulose or made of esterified cellulose that is produced through esterification of hydroxy groups of cellulose，

the film， fiber structure， or sponge body being partly or entirely coated with the powder.