JP6678256B2 - Biological tissue reinforcement material - Google Patents

Description

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

In the field of surgery, repair of damaged or weakened organs and tissues is the most fundamental problem. For example, for bleeding due to organ damage, hemostasis and suturing is still the most commonly used surgical technique. Also, prevention of body fluid leakage and air leakage due to tissue weakness or damage has become a major issue in surgical treatment. Above all, in the field of respiratory surgery, prevention of air leakage after pneumothorax or lung cancer resection is a major issue. In particular, pneumothorax is a disease that has a high recurrence rate without proper treatment and is difficult to treat.

Pneumothorax is a problem in which air leaks into the thoracic cavity from a stump or suture site when the lung is removed, a partial lung resection site for lung cancer, or a site where lung tissue is damaged due to trauma, or a part of the alveoli becomes cystic. (Referred to as a bra), which is often caused by tearing and air leaking into the thoracic cavity from the breach. A method called pleurodesis has been used in which the leaked portion is treated with a drug or the like or artificially causing a chemical burn to adhere the lung tissue to the pleura. With pleurodesis, recurrence of pneumothorax can be prevented to a certain extent. However, if adhesion to the pleura is insufficient, there is a high probability of recurrence. If surgery is needed again, lung tissue has adhered to the parietal pleura, so it is necessary to remove the adhesion, resulting in longer operation time and bleeding when removing the adhesion. Occurs. Therefore, a new treatment alternative to pleurodesis was sought.
In the field of gastrointestinal surgery, prevention of pancreatic juice leakage from a stump after partial resection of the pancreas has become a major issue. Pancreatic juice dissolves the granulation tissue responsible for wound healing and prevents its growth. As a result, tissue regeneration of the pancreas becomes difficult. In addition, there is a concern that there is a risk of a fatal complication in which the leaked pancreatic juice digests the blood vessels and causes major bleeding after surgery.

On the other hand, a method of reinforcing lung tissue and sealing the lung surface by using a fibrin glue and a fibrous structure made of a bioabsorbable polymer has come to be used. According to this method, it has been reported that the pneumothorax recurrence rate was reduced as compared with the conventional pleurodesis (Non-patent Documents 1 to 4). A similar method has also been used in the field of gastrointestinal surgery for preventing bleeding after liver resection (Non-Patent Document 5).

The method of using such a fibrous structure composed of a bioabsorbable polymer in combination with fibrin glue is extremely effective for reinforcing fragile tissues. However, air leakage or body fluid leakage may occur from the supposedly reinforced part, and a reoperation may be required. Although the probability of occurrence of such cases is not high, there is a risk of causing serious symptoms, and thus a more reliable reinforcing method has been required. In addition, there is also a problem that fibrin glue, which is a blood product, may cause unknown virus infection.

J. Pediatric Surg, 42, 1225-1230 (2007) Interact. Cardiovasc. Thorac. Surg, 6, 12-15 (2007) Journal of the Japanese Society of Respiratory Surgery, 19 (4), 628-630 (2005) Journal of the Japanese Society of Respiratory Surgery, 22 (2), 142-145 (2008) Clinical and research, 84, 148 (2007)

An object of the present invention is to provide a biological tissue reinforcing material that can prevent air leakage and body fluid leakage without using fibrin glue, which is a blood product, and can more reliably reinforce weakened tissue.

The present invention is a biological tissue reinforcing material comprising a laminated structure of a fibrous structure, a sponge-like body or a film made of a bioabsorbable polymer, and a film made of etherified cellulose in which a hydroxy group of cellulose is etherified. .
Hereinafter, the present invention will be described in detail.

The inventors of the present application have found that when a living tissue is reinforced using a fibrin glue in combination with a fibrous structure or the like made of a bioabsorbable polymer, air leakage or body fluid leakage occurs from the supposed reinforced site. We considered the cause. As a result, it was found that there was a cause in the bonded portion due to the fibrin glue.
Fibrin glue has a property of gelling in a very short time, and is extremely useful as a glue for living organisms. However, since the gelled fibrin glue is a relatively hard gel, it is liable to undergo cohesive failure by impact or peel off at the interface. In particular, when used for reinforcing lung tissue, an extremely large pressure is applied during coughing and sneezing, and the pressure may cause cohesive failure and interface separation. Since the gelled fibrin glue had little tackiness, once it was peeled, it was not possible to adhere again, and it was considered that air leakage and body fluid leakage had occurred from the peeled portion.

The inventors of the present application have conducted further intensive studies. As a result, instead of using fibrin glue, a film made of etherified cellulose in which a hydroxy group of cellulose is etherified (hereinafter, also simply referred to as “etherified cellulose”) is used. The present inventors have found that a biological tissue reinforcing material which can more reliably reinforce weakened tissues and does not cause air leakage or body fluid leakage can be obtained, and completed the present invention.
Etherified cellulose is a compound that has been confirmed to be highly safe, and, like fibrin glue, gels in a short time and plays a role as a glue for adhering a fibrous structure made of a bioabsorbable polymer to living tissue. Can be fulfilled. In particular, a film made of etherified cellulose absorbs moisture to form a gel, and can adhere to living tissue to exhibit an extremely high adhesive force.Even when a very large pressure is applied during coughing or sneezing, the It is possible to prevent cohesive failure and interface separation due to pressure. In addition, since it has a constant adhesive force even after gelation, even if cohesive failure or interfacial separation occurs due to a large pressure, it can re-adhere to prevent air leakage and body fluid leakage. Furthermore, by forming a film made of etherified cellulose into a fibrous structure made of a bioabsorbable polymer, a sponge-like material or a laminated structure laminated on the film, a biological tissue reinforcing material having extremely excellent handleability can be obtained. Can be.

The biological tissue reinforcing material of the present invention has a laminated structure of a fibrous structure, sponge-like body or film made of a bioabsorbable polymer and a film made of etherified cellulose.
The fibrous structure, sponge-like body or film made of the bioabsorbable polymer exhibits a tissue reinforcing effect, an air leak preventing effect, and a body fluid leak preventing effect by being attached to a damaged or weakened organ. . The film made of the etherified cellulose gels by absorbing moisture, and plays a role as a glue for attaching a fiber structure or the like made of the bioabsorbable polymer to living tissue.
In addition, the film made of the etherified cellulose may be laminated on only one surface of the fibrous structure made of the bioabsorbable polymer, the sponge or the film, or made of the bioabsorbable polymer. It may be laminated on both sides of the fibrous structure, sponge-like body or film. When the film made of the etherified cellulose is laminated on both surfaces of the fibrous structure made of the bioabsorbable polymer, the sponge-like body or the film, it can exhibit a particularly high adhesive force to living tissue. it can.

The bioabsorbable polymer is not particularly limited. For example, polyglycolide, polylactide (D, L, DL), glycolide-lactide (D, L, DL) copolymer, glycolide-ε-caprolactone copolymer Α-hydroxy acids such as union, lactide (D, L, DL form) -ε-caprolactone copolymer, poly (p-dioxanone), glycolide-lactide (D, L, DL form) -ε-caprolactone copolymer Examples include synthetic absorbent polymers such as polymer polymers and natural absorbent polymers such as collagen, gelatin, chitosan and chitin. These may be used alone or in combination of two or more. For example, when the above synthetic absorbent polymer is used as the above bioabsorbable polymer, a natural absorbent polymer may be used in combination. Among them, α-hydroxy acids, which are homopolymers or copolymers obtained by polymerizing at least one monomer selected from the group consisting of glycolide, lactide, ε-caprolactone, dioxanone and trimethylene carbonate, because they exhibit high strength. Since a polymer polymer is preferable and exhibits an appropriate decomposition behavior, an α-hydroxy acid polymer polymer which is a homopolymer or a copolymer obtained by polymerizing a monomer containing glycolide is more preferable.

When polyglycolide (a homopolymer or copolymer of glycolide) is used as the bioabsorbable polymer, a preferred lower limit of the weight average molecular weight of the polyglycolide is 30,000, and a preferred upper limit is 1,000,000. When the weight average molecular weight of the polyglycolide is less than 30,000, the strength may be insufficient and a sufficient tissue reinforcing effect may not be obtained. is there. A more preferred lower limit of the weight average molecular weight of the polyglycolide is 50,000, and a more preferred upper limit is 300,000.

The form of the fiber structure made of the bioabsorbable polymer is not particularly limited, and examples thereof include a nonwoven fabric, a knitted fabric, a woven fabric, a gauze, and a yarn. Further, these forms may be combined. Among them, a nonwoven fabric is preferred.

When the fibrous structure comprising the bioabsorbable polymer is a nonwoven fabric, the basis weight of the nonwoven fabric is not particularly limited, but a preferred lower limit is 5 g / m ² and a preferred upper limit is 300 g / m ² . If the basis weight of the nonwoven fabric is less than 5 g / m ² , the strength as a biological tissue reinforcing material may be insufficient, and a fragile tissue may not be reinforced. If it exceeds 300 g / m ² , adhesion to the tissue is poor. May be. A more preferred lower limit of the basis weight of the nonwoven fabric is 10 g / m ² , and a more preferred upper limit is 100 g / m ² .

The method for producing the nonwoven fabric is not particularly limited, for example, electrospinning deposition method, melt blow method, needle punch method, spun bond method, flash spinning method, hydroentanglement method, air laid method, thermal bond method, resin bond method, A conventionally known method such as a wet method can be used.

The basis weight of the sponge-like body made of the bioabsorbable polymer is not particularly limited, but a preferable lower limit is 5 g / m ² and a preferable upper limit is 1000 g / m ² . When the basis weight of the sponge-like body is less than 5 g / m ^2, the strength of the body tissue reinforcement is insufficient, it may not be reinforced tissue fragile, exceeds 1000 g / m ^2, adhesion to tissue May worsen. A more preferred lower limit of the basis weight of the sponge-like body is 30 g / m ² , and a more preferred upper limit is 500 g / m ² .

Although the thickness of the fibrous structure or the sponge-like body made of the bioabsorbable polymer is not particularly limited, a preferable lower limit is 5 μm and a preferable upper limit is 1 mm. When the thickness of the fibrous structure or the sponge-like body made of the bioabsorbable polymer is less than 5 μm, the strength may be insufficient and a sufficient tissue reinforcing effect may not be obtained. In some cases, it cannot be fixed so that it adheres sufficiently. A more preferred lower limit of the thickness of the fibrous structure or the sponge-like body made of the bioabsorbable polymer is 10 μm, and a more preferred upper limit is 0.5 mm.

The thickness of the film made of the bioabsorbable polymer is not particularly limited, but a preferable lower limit is 10 μm and a preferable upper limit is 800 μm. If the thickness of the film made of the bioabsorbable polymer is less than 10 μm, the strength may be insufficient and a sufficient tissue reinforcing effect may not be obtained. If the thickness exceeds 800 μm, the film may be sufficiently adhered to the tissue. Sometimes it cannot be fixed. A more preferred lower limit of the thickness of the film made of the bioabsorbable polymer is 20 μm, and a more preferred upper limit is 300 μm.

The fibrous structure, sponge-like body, or film made of the bioabsorbable polymer may be subjected to a hydrophilic treatment. By performing the hydrophilization treatment, when it is brought into contact with water such as physiological saline, it can be absorbed quickly, and the handleability is excellent.
The hydrophilic treatment is not particularly limited, and examples thereof include a plasma treatment, a glow discharge treatment, a corona discharge treatment, an ozone treatment, a surface graft treatment, and an ultraviolet irradiation treatment. Among them, plasma treatment is preferable because the water absorption can be dramatically improved without changing the appearance of the nonwoven fabric.

The etherified cellulose is obtained by etherifying a hydroxy group of cellulose. Specifically, for example, hydroxyethylated cellulose in which the hydroxy group of cellulose is replaced by a hydroxyethyl group, hydroxypropylated cellulose in which the hydroxy group of cellulose is replaced by a hydroxypropyl group, and the like are represented by the following general formula (1). Examples include alkylated cellulose and carboxyalkylated cellulose having a carboxymethylated cellulose in which the hydroxy group of the cellulose is replaced by a carboxymethyl group. Among them, hydroxyethylated cellulose is preferred because high safety has been confirmed.

In the formula (1), n represents an integer, and R represents hydrogen or a -R'OH group. R 'represents an alkylene group.

When the etherified cellulose is hydroxyethylated cellulose, the molar ratio of diethylene glycol groups to ethylene glycol groups (diethylene glycol groups / ethylene glycol groups) in the hydroxyethylated cellulose may be 0.1 to 1.0. Preferably, the molar ratio of triethylene glycol groups to ethylene glycol groups (triethylene glycol groups / ethylene glycol groups) is preferably from 0.1 to 0.5. When it is within this range, when the fiber structure, the sponge-like body or the film made of the bioabsorbable polymer is adhered to the living tissue through the film made of the etherified cellulose, excellent initial adhesive strength is obtained. In addition to being able to demonstrate, it can maintain high adhesive strength even after bonding, and even if cohesive failure or interface peeling occurs due to a large pressure, it can re-adhere to prevent air leakage and body fluid leakage.
In addition, the mole number of the ethylene glycol group, the diethylene glycol group, and the triethylene glycol group in the hydroxyethylated cellulose can be measured, for example, by using NMR or pyrolysis GC-MS.

When the above-mentioned etherified cellulose is hydroxyethylated cellulose, the preferred lower limit of the average number of molecules of the alkylene oxide bound per anhydrous glucose unit (molar substitution, MS) is 1.0, and the preferred upper limit is 4.0. . When the MS is within this range, both gelation in a short time and high gel strength can be achieved, and the MS can be more closely adhered to the tissue and fixed. If the MS is less than 1.0, the viscosity after gelation tends to be low, and if it exceeds 4.0, the gelation tends to take a long time. The more preferable lower limit of the above MS is 1.3, and the more preferable upper limit is 3.0.

When the etherified cellulose is hydroxyethylated cellulose, the lower limit of the average substitution degree (DS) of the alkylene oxide to the hydroxyl groups at the 2, 3, and 6-positions of the anhydrous glucose unit is preferably 0.2, and the upper limit is preferably 2.5. It is. When the above-mentioned DS is within this range, gelation in a short time and high gel strength can be achieved at the same time, and the tissue can be more closely adhered and fixed. When the above DS is less than 0.2, gelation may take a long time, and when it exceeds 2.5, the strength may be reduced. A more preferred lower limit of DS is 0.3, and a more preferred upper limit is 1.5.

The MS and DS can be calculated by measuring the NMR spectrum of an aqueous solution of hydroxyethylated cellulose and quantifying the intensity of the signal attributed to the anhydrous glucose ring carbon and substituent carbon of the spectrum. . (For example, see Japanese Patent Publication No. 6-41926.)
More specifically, for example, 0.2 g of a sample, 30 mg of an enzyme (cellulase) and an internal standard are dissolved in 3 ml of heavy water and subjected to ultrasonic treatment for 4 hours, and then an NMR measurement apparatus (for example, JNM manufactured by JEOL Ltd.) -ECX400P), the NMR spectrum is measured under the conditions of 700 scans, a pulse width of 45 °, and an observation frequency of 31,500 Hz.

The above-mentioned etherified cellulose is cellulose in which a part of the hydroxy groups of unetherified cellulose is carboxylated, and the hydroxy groups of cellulose are etherified and carboxylated (hereinafter, also simply referred to as “etherified carboxylated cellulose”). .). By using the above-mentioned etherified carboxylated cellulose, high adhesion can be exerted particularly on a damaged portion having a large unevenness on the surface.

The etherified carboxylated cellulose is obtained by etherifying and carboxylating a hydroxy group of cellulose. Specifically, for example, hydroxyethylated carboxylated cellulose in which the hydroxy group of cellulose is replaced by hydroxyethyl group and carboxyl group, and hydroxypropylated carboxylated cellulose in which the hydroxy group of cellulose is replaced by hydroxypropyl group and carboxyl group, etc. Alkylated carboxylated cellulose is mentioned. Among them, hydroxyethylated carboxylated cellulose is preferred because high safety has been confirmed.
A preferred example of the hydroxyalkylated carboxylated cellulose is shown in the following general formula (2).

In the formula (2), n represents an integer, and R represents hydrogen or a -R'OH group. R 'represents an alkylene group.

In the above etherified carboxylated cellulose, when the etherification is hydroxyethylation, the molar ratio of diethylene glycol groups to ethylene glycol groups (diethylene glycol groups / ethylene glycol groups) in the hydroxyethylated carboxylated cellulose is 0.1. The molar ratio of triethylene glycol groups to ethylene glycol groups (triethylene glycol groups / ethylene glycol groups) is preferably 0.1 to 1.0.
Further, the preferred lower limit of the average molecular number (molecular substitution, MS) of the alkylene oxide bonded per anhydroglucose unit is 1.0, and the preferable upper limit is 4.0. The preferred lower limit of the average degree of substitution (DS) of the alkylene oxide to the hydroxyl group is 0.2, and the preferred upper limit is 2.5.
The number of moles, the average number of molecules (MS), and the average degree of substitution (DS) of the ethylene glycol group, diethylene glycol group, and triethylene glycol group in the hydroxyethylated carboxylated cellulose are determined by, for example, NMR or pyrolysis GC-MS. It can be measured using:

The hydroxyethylated cellulose can be produced, for example, by reacting alkali cellulose obtained by treating cellulose with an aqueous alkali solution and ethylene oxide.
Specifically, for example, using a fibrous structure made of cellulose as a raw material, the raw fibrous structure is treated with an aqueous alkali solution such as sodium hydroxide to convert the cellulose into alkali cellulose, and a certain amount of ethylene is added to the obtained alkali cellulose. A method in which an oxide and a reaction solvent are added and reacted is exemplified.

The above-mentioned etherified carboxylated cellulose can be produced, for example, by carboxylating cellulose and then further etherifying it.
As a method for carboxylating the cellulose, for example, a hydroxyl group in the cellulose is converted to an aldehyde by reacting sodium hypochlorite using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as an oxidizing agent. (Tempo oxidation step), and then the aldehyde is carboxylated (carboxylation step) by reacting with sodium chlorite.
The carboxylated cellulose thus obtained is treated with an aqueous alkali solution such as sodium hydroxide (alkali treatment step), and then etherified (hydroxyethylated) by reacting with ethylene oxide (hydroxyethylated step). Thereby, etherified carboxylated cellulose (hydroxyethylated carboxylated cellulose) can be obtained.
In the hydroxyethylated carboxylated cellulose obtained by such a method, a carboxyl group is introduced mainly at the 6-position of the cellulose, and a hydroxyethyl group is introduced mainly at the 2- or 6-position.

In the film made of the etherified cellulose, the lower limit of the water absorption is preferably 200%, and the upper limit is preferably 1000%. When the water absorption is within this range, the gelation in a short time and the high gel strength are compatible, and the tissue can be more closely adhered to the tissue and fixed. If the water absorption is less than 200%, gelation may take a long time, and if it exceeds 1000%, the gel strength tends to decrease. A more preferred lower limit of the water absorption is 400%, and a more preferred upper limit is 800%.
In this specification, the water absorption can be measured by the following method.
That is, a sample whose initial weight is measured is placed on a petri dish, and distilled water is slowly dropped on the sample. The weight of the sample when it absorbs the maximum amount of distilled water (when the distilled water is dripped any more and the distilled water that cannot be absorbed overflows from the sample) is measured and the weight is determined as the maximum water absorption weight. Using the obtained initial weight and maximum water absorption weight, the water absorption can be calculated by the following equation.
Water absorption (%) = (maximum water absorption−initial weight) / initial weight × 100

In the film made of the etherified cellulose, a preferable lower limit of the moisture absorption is 7%, and a preferable upper limit is 50%. When the moisture absorption is within this range, both gelation in a short time and high gel strength can be achieved, and the tissue can be more closely adhered and fixed to the tissue. If the moisture absorption is less than 7%, it may take a long time to gel, and if it exceeds 50%, the gel strength tends to decrease. A more preferred lower limit of the moisture absorption rate is 10%, and a more preferred upper limit is 35%.
In addition, in this specification, a moisture absorption rate can be measured by the following method.
That is, after heating the sample at 105 ° C. for 2 hours, the weight is measured and determined as the absolute dry weight. Next, the sample in the absolutely dry state is allowed to stand for 7 hours in an environment of 20 ° C. and 65% Rh to adjust the humidity, and the weight is measured, and the measured weight is defined as the weight after humidity adjustment. Using the obtained absolute dry weight and the weight after humidity control, the moisture absorption can be calculated by the following equation.
Moisture absorption (%) = (weight after humidity control-absolute dry weight) / absolute dry weight × 100

Although the thickness of the film made of the etherified cellulose is not particularly limited, a preferable lower limit is 10 μm and a preferable upper limit is 1500 μm. When the thickness of the film made of the etherified cellulose is less than 10 μm, it may not be possible to attach the biological tissue reinforcing material to the biological tissue with a sufficient adhesive force. It takes time and the operability may deteriorate. A more preferred lower limit of the thickness of the film made of the etherified cellulose is 20 μm, and a more preferred upper limit is 1000 μm.

It is preferable that the fibrous structure, sponge-like body or film made of the bioabsorbable polymer and the film made of the etherified cellulose are combined and integrated. By being combined and integrated, handleability is further improved.
Note that, in this specification, composite integration means that two stacked structures can be handled as one, and a state in which the two structures are not easily separated is used.
The mode of the composite integration is not particularly limited. For example, a part of the fibrous structure or the sponge-like body made of the bioabsorbable polymer has invaded a part of the film made of the etherified cellulose. Aspects and the like are given.

The biological tissue reinforcing material of the present invention is used in the field of surgery for preventing hemostasis, preventing air leakage, and preventing body fluid leakage of damaged or weakened organs and tissues. In particular, it can be suitably used in the field of respiratory surgery to prevent air leakage after pneumothorax or lung cancer resection.
The living tissue reinforcing material of the present invention can be easily applied, for example, only by immersing the living tissue reinforcing material in physiological saline and then applying it to the affected part. In addition, when blood or body fluid is present in the affected area, the adhesive strength can be exhibited by absorbing these.

ADVANTAGE OF THE INVENTION According to this invention, the living tissue reinforcement material which can prevent air leak and a bodily fluid leak and can reinforce weakened tissue more reliably without using fibrin glue which is a blood product can be provided.

It is a schematic diagram of the withstand voltage test apparatus used for the withstand voltage test performed in the Example.

Hereinafter, embodiments of the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

(Example 1)
(1) Production of Biological Tissue Reinforcement Material Commercially available hydroxyethylated cellulose (manufactured by Wako Pure Chemical Industries, Ltd .: molar ratio of diethylene glycol group to ethylene glycol group (diethylene glycol group / ethylene glycol group) is 1.06; A sol-like hydroxyethylated cellulose solution is prepared by dissolving a molar ratio to ethylene glycol groups (triethylene glycol groups / ethylene glycol groups) of 4.01) in distilled water so as to have a solid content of 7.5% by weight. Was prepared.

A 150 μm-thick non-woven fabric made of polyglycolide (Neovail Type NV-M015G, manufactured by Gunze) is cut into a size of 5.0 cm long and 5.0 cm wide to prepare a fiber structure made of a bioabsorbable polymer. did.
A small amount of a 70% ethanol solution was sprayed on one surface of the nonwoven fabric made of the polyglycolide using a spray to moisten the surface of the nonwoven fabric. 6.8 g of a sol hydroxyethylated cellulose solution was cast on the surface of the non-woven fabric made of polyglycolide. Air bubbles generated after casting were removed as much as possible by piercing with a needle whose tip was wetted with ethanol.
By drying at 60 ° C. for 2 hours, a biological tissue reinforcing material comprising a laminated structure in which a film made of hydroxyethylated cellulose was laminated on one surface of a non-woven fabric made of polyglycolide.
The obtained biological tissue reinforcing material was punched out into a circular shape having a diameter of 11 mm, which was used as a measurement sample.

(2) Withstand voltage test A withstand voltage test was performed using the withstand voltage test apparatus 1 shown in FIG.
A collagen film (manufactured by Nippi) having a thickness of about 130 μm is punched into a rectangle having a length of 5.5 cm and a width of 5.0 cm, washed with 70% ethanol, wiped off water, and then filtered with a filter holder 2 (manufactured by Merck Millipore, Swinex). (Registered trademark) 25). A hole having a diameter of 3 mm was formed in the center of the collagen film set in the filter holder 2 using a punch. At the downstream side of the filter holder, a 20 ml syringe 3 (Termo Syringe SS-20ESZ, manufactured by Terumo Corporation) and a pressure gauge 5 (Digital Manometer FUSO-8230, manufactured by Fuso Rika Co., Ltd.) are set via a three-way cock 4, and a pressure test is performed. The device.

After dropping 20 μL of a phosphate buffer solution onto the surface of the obtained sample on the side of two fibrous structures made of hydroxyethylated cellulose, the sample was placed at the center of a collagen film set in a filter holder such that the surface was in contact with the surface. Five minutes after standing, air was sent from the syringe, and the maximum pressure until the sample for measurement was peeled was measured with a pressure gauge to evaluate the pressure resistance.
The results are shown in Table 1.

(Example 2)
A 150 μm-thick non-woven fabric made of polyglycolide (Neovail Type NV-M015G, manufactured by Gunze) is cut into a size of 5.0 cm long and 5.0 cm wide to prepare a fiber structure made of a bioabsorbable polymer. did.
A small amount of a 70% ethanol solution was sprayed on one surface of the nonwoven fabric made of the polyglycolide using a spray to moisten the surface of the nonwoven fabric. 3.4 g of a sol-form hydroxyethylated cellulose solution prepared by the same method as in Example 1 was cast on the surface of the nonwoven fabric made of polyglycolide. Air bubbles generated after casting were pierced with a needle whose tip was wet with ethanol to remove as much as possible, and then dried at 60 ° C. for 2 hours.
Next, a small amount of a 70% ethanol solution was sprayed on the other surface of the nonwoven fabric made of polyglycolide using a spray to moisten the surface of the nonwoven fabric. 3.4 g of a sol-form hydroxyethylated cellulose solution prepared by the same method as in Example 1 was cast on the surface of the nonwoven fabric made of polyglycolide. Air bubbles generated after casting were pierced with a needle whose tip was wet with ethanol to remove as much as possible, and then dried at 60 ° C. for 2 hours.
As a result, a biological tissue reinforcing material comprising a laminated structure in which a film composed of hydroxyethylated cellulose was laminated on both sides of a nonwoven fabric composed of polyglycolide was obtained.
With respect to the obtained biological tissue reinforcing material, a pressure resistance test was performed in the same manner as in Example 1. The results are shown in Table 1.

(Example 3)
A commercially available carboxymethylated cellulose solution (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in distilled water so as to have a solid content of 7.5% by weight to prepare a carboxymethylated cellulose solution in the form of a sol.
A 150 μm-thick non-woven fabric made of polyglycolide (Neovail Type NV-M015G, manufactured by Gunze) is cut into a size of 5.0 cm long and 5.0 cm wide to prepare a fiber structure made of a bioabsorbable polymer. did.
A small amount of a 70% ethanol solution was sprayed on one surface of the nonwoven fabric made of the polyglycolide using a spray to moisten the surface of the nonwoven fabric. 3.4 g of the prepared sol-like carboxymethylated cellulose solution was cast on the surface of the nonwoven fabric made of polyglycolide. Air bubbles generated after casting were pierced with a needle whose tip was wet with ethanol to remove as much as possible, and then dried at 60 ° C. for 2 hours.
Next, a small amount of a 70% ethanol solution was sprayed on the other surface of the nonwoven fabric made of polyglycolide using a spray to moisten the surface of the nonwoven fabric. 3.4 g of the prepared sol-like carboxymethylated cellulose solution was cast on the surface of the nonwoven fabric made of polyglycolide. Air bubbles generated after casting were pierced with a needle whose tip was wet with ethanol to remove as much as possible, and then dried at 60 ° C. for 2 hours.
As a result, a living tissue reinforcing material comprising a laminated structure in which a film composed of carboxymethylated cellulose was laminated on both sides of a nonwoven fabric composed of polyglycolide was obtained.
With respect to the obtained biological tissue reinforcing material, a pressure resistance test was performed in the same manner as in Example 1. The results are shown in Table 1.

(Comparative Example 1)
The pressure resistance when a fiber structure composed of a bioabsorbable polymer and fibrin glue were used in combination was evaluated by the following method.
A 150 μm-thick non-woven fabric made of polyglycolide (Neovail Type NV-M015G, manufactured by Gunze) was punched into a circular shape having a diameter of 11 mm.
At the center of the collagen film set in the filter holder of the pressure test apparatus prepared in Example 1, avoid the pores, and avoid fibrin glue (CSL Behring Co., Veriplast P: solution A obtained by mixing fibrinogen powder and aprotinin solution). 20 μL of the solution A (comprising a thrombin powder and a solution B in which a calcium chloride solution was mixed) was dropped and spread to about 11 mm in diameter. Next, a nonwoven fabric punched into a circle having a diameter of 11 mm was placed on the spread liquid A, and the liquid A was mixed. Next, 20 μL of the solution A was dropped on the nonwoven fabric, and was sufficiently blended. Next, 20 μL of the solution B was dropped on the nonwoven fabric.
Five minutes after the solution B was dropped, air was sent from the syringe, and the maximum pressure until the measurement sample was peeled was measured with a pressure gauge to evaluate the pressure resistance. The results are shown in Table 1.

(Comparative Example 2)
A 150 μm-thick non-woven fabric made of polyglycolide (Neovail Type NV-M015G, manufactured by Gunze) is cut into a size of 5.0 cm long and 5.0 cm wide to prepare a fiber structure made of a bioabsorbable polymer. did.
On the other hand, a 320 μm-thick fibrous structure made of oxidized cellulose (Surge Cell manufactured by Johnson & Johnson) was cut into a size of 5.0 cm in length and 5.0 cm in width to prepare.
A fibrous structure made of oxidized cellulose / a nonwoven fabric made of polyglycolide / a fibrous structure made of oxidized cellulose were laminated in this order, and were combined and integrated by a needle punch entanglement method to obtain a biological tissue reinforcing material.
With respect to the obtained biological tissue reinforcing material, a pressure resistance test was performed in the same manner as in Example 1. The results are shown in Table 1.

(Comparative Example 3)
A commercially available oxidized cellulose solution (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in distilled water to a solid content of 7.5% by weight to prepare a sol-like oxidized cellulose solution.
A 150 μm-thick non-woven fabric made of polyglycolide (Neovail Type NV-M015G, manufactured by Gunze) is cut into a size of 5.0 cm long and 5.0 cm wide to prepare a fiber structure made of a bioabsorbable polymer. did.
A small amount of a 70% ethanol solution was sprayed on one surface of the nonwoven fabric made of the polyglycolide using a spray to moisten the surface of the nonwoven fabric. 3.4 g of the prepared sol-state oxidized cellulose solution was cast on the surface of the non-woven fabric made of polyglycolide. Air bubbles generated after casting were pierced with a needle whose tip was wet with ethanol to remove as much as possible, and then dried at 60 ° C. for 2 hours.
Next, a small amount of a 70% ethanol solution was sprayed on the other surface of the nonwoven fabric made of polyglycolide using a spray to moisten the surface of the nonwoven fabric. 3.4 g of the prepared sol-state oxidized cellulose solution was cast on the surface of the non-woven fabric made of polyglycolide. Air bubbles generated after casting were pierced with a needle whose tip was wet with ethanol to remove as much as possible, and then dried at 60 ° C. for 2 hours.
As a result, a living tissue reinforcing material comprising a laminated structure obtained by laminating a film made of oxidized cellulose on both surfaces of a nonwoven fabric made of polyglycolide was obtained.
With respect to the obtained biological tissue reinforcing material, a pressure resistance test was performed in the same manner as in Example 1. The results are shown in Table 1.

ADVANTAGE OF THE INVENTION According to this invention, the living tissue reinforcement material which can prevent air leak and a bodily fluid leak and can reinforce weakened tissue more reliably without using fibrin glue which is a blood product can be provided.

DESCRIPTION OF SYMBOLS 1 Withstand pressure test device 2 Filter holder 3 Syringe 4 Three-way cock 5 Pressure gauge 6 Collagen film with perforated holes

Claims (8)

A biological tissue reinforcing material comprising a laminated structure of a fiber structure made of a bioabsorbable polymer and a film made of etherified cellulose in which a hydroxyl group of cellulose is etherified. The biological tissue reinforcing material according to claim 1, wherein the etherified cellulose obtained by etherifying a hydroxy group of cellulose is a hydroxyalkylated cellulose represented by the following general formula (1).

In the formula (1), n represents an integer, and R represents hydrogen or a -R'OH group. R ′ represents an alkylene group. The living tissue reinforcing material according to claim 1, wherein the etherified cellulose obtained by etherifying a hydroxy group of cellulose is hydroxyethylated cellulose. Etherified cellulose in which the hydroxy group of cellulose is etherified is characterized in that cellulose in which a part of the hydroxy group of unetherified cellulose is carboxylated, and the hydroxy group of cellulose is etherified and carboxylated. The biological tissue reinforcing material according to claim 1, wherein The cellulose in which the hydroxy group of the cellulose is etherified and carboxylated is a cellulose represented by the following general formula (2) in which the hydroxy group of the cellulose is hydroxyalkylated and carboxylated. Biological tissue reinforcement material.

In the formula (2), n represents an integer, and R represents hydrogen or a -R'OH group. R ′ represents an alkylene group. The biological tissue reinforcing material according to claim 1, 2, 3, 4, or 5, wherein the bioabsorbable polymer is an α-hydroxy acid polymer. The α-hydroxy acid polymer is a homopolymer or a copolymer obtained by polymerizing at least one monomer selected from the group consisting of glycolide, lactide, ε-caprolactone, dioxanone and trimethylene carbonate. The biological tissue reinforcing material according to claim 6. The living tissue according to claim 1, 2, 3, 4, 5, 6, or 7, wherein the form of the fibrous structure comprising a bioabsorbable polymer is a nonwoven fabric, a knitted fabric, a woven fabric, a gauze, or a thread. Reinforcement material.

Images