JP6944858B2 - Nerve adhesion prevention wrapping material - Google Patents

Description

The present invention relates to a nerve adhesion prevention wrapping material that can prevent nerves from adhering to other biological tissues by wrapping them around nerves.

After surgery, adhesions between living tissues often occur, which can cause pain and dysfunction, and in severe cases, surgery is required to remove the adhesions. This peeling of adhesions requires a high degree of skill. In addition, when such adhesions occur, it is necessary to proceed with the surgery while peeling off the adhesions at the time of reoperation of the primary disease, and the risk of surgery increases.
For example, the median nerve resides in the central carpal tunnel on the volar side of the wrist joint. The carpal tunnel is a space surrounded by bony walls and ligaments. The median nerve passes slowly through the carpal tunnel so that it is not compressed from the surroundings, but for some reason the internal pressure of the carpal tunnel increases, causing pain and numbness when the median nerve is compressed (hand). Carpal tunnel syndrome). Surgery to treat carpal tunnel syndrome involves ligament dissection and median nerve ablation to remove the tissue that causes nerve compression. However, although the surgery itself was successful, there were cases where nerves adhered to the walls and ligaments that make up the carpal tunnel after surgery, and surgery was required to remove the adhesions. In addition, surgery to remove the surrounding tissue that adheres to the nerve is very sophisticated, and the risk of nerve damage during the removal is very high.

As a method of preventing adhesions between living tissues, a method of isolating a site where adhesions may occur using a membrane called an adhesion prevention membrane has been proposed. The performance required for the adhesion-preventing membrane is that it has the flexibility to fit the affected area as a hydrogel, retains its morphology in the living body for a certain period of time, and is rapidly absorbed by the living body after that, and tissue reaction. Is minor. Anti-adhesion films satisfying such performance have been proposed in Patent Documents 1 to 6 and the like.
However, in the case of nerve adhesion prevention, there is a unique problem that the adhesion prevention film itself may crimp the nerve, so even if an adhesion prevention film for other biological tissues is used, it does not function sufficiently. .. Currently, collagen-based anti-adhesion membranes for nerves are commercially available, but they may narrow and press the nerve when flexed due to low strength, and they decompose in a short period of time. There was a problem that the adhesion of collagen may not be sufficiently prevented.

Japanese Unexamined Patent Publication No. 11-47258 Japanese Unexamined Patent Publication No. 11-279296 Japanese Unexamined Patent Publication No. 2000-212286 Japanese Unexamined Patent Publication No. 2003-62063 Japanese Unexamined Patent Publication No. 2004-209228 Japanese Patent No. 3517358

In view of the above situation, it is an object of the present invention to provide a nerve adhesion prevention wrapping material capable of preventing nerves from adhering to other biological tissues by wrapping them around nerves.

The present invention is a nerve adhesion prevention wrapping material that prevents nerves from adhering to other biological tissues by wrapping around the nerves, and is a foam made of a bioabsorbable material and a bioabsorbable material that reinforces the foam. A tubular body made of a reinforcing material made of a material, wherein the reinforcing material is a nerve adhesion prevention wrapping material located at the center or an outer surface of the foam and having an inner surface of the foam. ..
The present invention will be described in detail below.

The nerve adhesion prevention wrapping material of the present invention is a foam made of a bioabsorbable material (hereinafter, also simply referred to as “foam”) and a reinforcing material made of a bioabsorbable material that reinforces the foam (hereinafter, simply “foam”). It is also called "reinforcing material").
The foam is arranged on the nerve side when the nerve adhesion prevention wrapping material of the present invention is wrapped around a nerve, and prevents the nerve from adhering to other biological tissues, and the nerve adhesion prevention wrapping material is used. It acts as a cushioning material that prevents pressure on the nerves. On the other hand, the reinforcing material plays a role of preventing nerves from adhering to other biological tissues and imparting sufficient strength to the nerve adhesion preventing wrapping material of the present invention. Especially when the nerve adhesion prevention wrapping material is bent, if the inner diameter is narrowed, the nerve is compressed. By having the reinforcing material, it is possible to prevent nerve compression due to such stenosis.
Furthermore, by wrapping the nerve adhesion prevention wrapping material of the present invention around the nerve so that the foam is on the nerve side, the infiltration of inflammatory macrophages into the nerve can be reduced, and the nerve adheres to other biological tissues. You can even prevent it from happening.

Examples of the bioabsorbable material constituting the foam include polyglycolide, polylactide (D, L, DL form), polycaprolactone, glycolide-lactide (D, L, DL form) copolymer, and glycolide-ε-. Examples thereof include caprolactone copolymer, lactide (D, L, DL form) -ε-caprolactone copolymer and polydioxanone, glycolide-lactide (D, L, DL form) -ε-caprolactone copolymer. In addition, naturally bioabsorbable materials such as collagen, gelatin, hyaluronic acid, and alginic acid can also be used. These bioabsorbable materials may be used alone or in combination of two or more. Among them, polyglycolide, polylactide (D, L, DL form), glycolide-ε-caprolactone copolymer, and lactide (D, L, DL form) -ε-caprolactone copolymer weight because they can exhibit appropriate bioabsorption. Glycolide-ε-caprolactone copolymer and lactide (D, L, DL) -ε-caprolactone copolymer are more preferable because they are preferably combined and have excellent cushioning properties.

The pore size of the foam is not particularly limited, but a preferable lower limit is 1.0 μm and a preferable upper limit is 800 μm. When the pore diameter of the foam is within this range, sufficient cushioning property and physical strength that do not press the nerve can be exhibited. The more preferable lower limit of the pore size of the foam is 5.0 μm, and the more preferable upper limit is 600 μm.
The average pore size of the foam can be measured by a conventionally known method such as a mercury press-fitting method or an image analysis method.

The thickness of the foam is not particularly limited, but a preferable lower limit is 0.1 mm and a preferable upper limit is 30.0 mm. When the thickness of the foam is within this range, it is possible to exhibit sufficient cushioning property that does not press the nerve and excellent handleability when wrapping the nerve adhesion preventing wrapping material around the nerve. The more preferable lower limit of the thickness of the foam is 0.5 mm, and the more preferable upper limit is 20.0 mm.

The reinforcing material is not particularly limited as long as it has a higher strength than the foam, and examples thereof include a fibrous body, a non-woven fabric-like body, and a film-like body. Among them, fibrous bodies such as flat knitted fabrics, vertical knitted fabrics, braids, and woven fabrics in which fibers made of bioabsorbable materials are knitted are suitable because they can exhibit excellent strength, and the inner diameter is narrowed even when bent. Braids are more suitable because they are difficult to use.

Examples of the bioabsorbable material constituting the reinforcing material include polyglycolide, polylactide (D, L, DL form), polycaprolactone, glycolide-lactide (D, L, DL form) copolymer, and glycolide-ε-. Caprolactone copolymer, lactide (D, L, DL) -ε-caprolactone copolymer and polydioxanone, polydioxanone-ε-caprolactone copolymer, glycolide-lactide (D, L, DL) -ε-caprolactone copolymer Examples thereof include coalescence, glycolide-trimethylone carbonate copolymer and the like. In addition, naturally bioabsorbable materials such as collagen, gelatin, hyaluronic acid, and alginic acid can also be used. These bioabsorbable materials may be used alone or in combination of two or more. Among them, polylactide (D, L, DL form) is preferable because it can exhibit high strength and appropriate bioabsorbability, and has high hydrophobicity and excellent adhesion prevention property.

When the reinforcing material is made of a fibrous body such as a braid, the fibers constituting the reinforcing material may be a monofilament yarn or a multifilament yarn, but exhibit higher flexibility and strength. Multifilament yarns are suitable because they can be made.

When the reinforcing material is made of a fibrous body such as a braid, the thickness of the fibers constituting the reinforcing material is not particularly limited, but the preferable lower limit is 10 denier and the preferable upper limit is 500 denier. When the thickness of the fiber constituting the reinforcing material is within this range, sufficient strength and excellent handleability when wrapping the nerve adhesion preventing wrapping material around the nerve can be exhibited. A more preferable lower limit of the thickness of the reinforcing material is 30 denier, and a more preferable upper limit is 300 denier.

The reinforcing material is preferably heat-treated in advance. By using the reinforcing material that has been heat-treated in advance, when the nerve adhesion preventing wrapping material of the present invention is produced by the method described later, the reinforcing material is invaded by the solvent to reduce the strength and the bioabsorption rate becomes faster. It is possible to prevent it from being stowed.
The temperature of the heat treatment may be set to a condition higher than the glass transition temperature and lower than the melting temperature, depending on the type of the bioabsorbable material constituting the reinforcing material. For example, when the reinforcing material is made of polylactide (D, L, DL body), it is 10 ° C. or more higher than the glass transition temperature of the polylactide (D, L, DL body) and 10 ° C. or more lower than the melting temperature. It is preferable to perform the heat treatment at a temperature of about 0.5 to 24 hours.
The glass transition temperature and the melting temperature can be measured by a conventionally known method such as a method using a thermal differential scanning calorimeter (DSC).

Regarding the positional relationship between the foam and the reinforcing material, the reinforcing material is located at the center or the outer surface of the tubular body which is the nerve adhesion prevention wrapping material of the present invention, and the inner surface of the tubular body is the foam. .. Here, the reinforcing material may be inside the foam and integrally form a nerve adhesion prevention wrapping material, the foam may be an inner layer, and the reinforcing material may be an outer layer. In this case, the foam and the reinforcing material may be completely separated, or there may be a layer in which the foam and the reinforcing material coexist.

The inner diameter and length of the tubular body, which is the nerve adhesion prevention wrapping material of the present invention, may be selected according to the target nerve.
The preferable lower limit of the inner diameter of the tubular body of the nerve adhesion preventing wrapping material of the present invention is 0.1 mm, the preferable upper limit is 30.0 mm, the more preferable lower limit is 0.5 mm, and the more preferable upper limit is 20.0 mm.

The tubular body which is the nerve adhesion prevention wrapping material of the present invention may be vertically divided. Such a vertically divided tubular body can be easily wound around a nerve, and can be reliably fixed by suturing the vertically divided portion with a suture after winding.
FIG. 1 shows a schematic view showing an example of a vertically divided tubular body nerve adhesion prevention wrapping material. The nerve adhesion prevention wrapping material 1 of FIG. 1 has a layered structure in which a foam 11 and a reinforcing material 12 as an outer layer are laminated as an inner layer, and is vertically divided.
In addition, FIG. 2 shows a schematic diagram showing a method of preventing nerve adhesion using a vertically divided tubular body. In FIG. 2, after the vertically divided tubular body nerve adhesion prevention wrapping material 4 is wound around the nerve 3, the vertically divided portion of the vertically divided tubular body nerve adhesion prevention wrapping material 4 is sutured with a suture thread 5. It is fixed by.

The method for producing the nerve adhesion-preventing wrapping material of the present invention is not particularly limited, but for example, a bioabsorbable material in which the reinforcing material prepared in advance is installed in a mold and the foam is formed in the mold. After pouring the solution, freezing, and then freeze-drying (freeze-drying method), after adhering a mixed solution of the water-soluble substance and the bioabsorbable material forming the foam to the preliminarily prepared reinforcing material and drying. , A method (dissolution method) in which the water-soluble substance is washed away by washing with water and the like can be mentioned. In the freeze-drying method, foams having various pore sizes can be prepared depending on the freezing temperature, the concentration of the polymer, and the like. In the elution method, the pore size of the foam can be controlled by adjusting the particles of the water-soluble substance.

By wrapping the nerve adhesion prevention wrapping material of the present invention so that the foam is on the nerve side, the nerve is prevented from adhering to other biological tissues, and the foam wraps the nerve to form a cushioning material. The reinforcing material plays a role, and the reinforcing material reinforces the nerve adhesion preventing wrapping material, and even when bent, the inner diameter thereof is narrowed to prevent the nerve adhesion preventing wrapping material from pressing the nerve. Furthermore, by reducing the infiltration of inflammatory macrophages into nerves, it is possible to further prevent nerves from adhering to other biological tissues.

According to the present invention, it is possible to provide a nerve adhesion prevention wrapping material capable of preventing the nerve from adhering to other living tissues by wrapping the nerve around the nerve.

It is a schematic diagram which shows an example of the nerve adhesion prevention wrapping material of a vertically divided tubular body. It is a schematic diagram which shows the method of preventing the adhesion of nerve by using the vertically divided tubular body. It is a photograph of the nerve adhesion prevention wrapping material obtained in the Example. It is a photograph of the cross section of the nerve adhesion prevention wrapping material obtained in the Example. It is a photograph which shows the state of each group in the animal experiment of an Example. It is a Masson's trichrome stained image of the tissue section of each group 6 weeks after the operation in the animal experiment of an example. It is an immunostaining image using CD68 and CCR7 of the tissue section of each group 6 weeks after the operation in the evaluation of the intraneuronal infiltration of the inflammatory macrophage of 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)
Four 16-filament multi-yarns made of polylactide (L-form) were combined, twisted, and braided using a braiding machine to obtain a tubular reinforcing material. The obtained reinforcing material was heat-treated at 140 ° C. for 13 hours.
The heat-treated reinforcing material is fitted on a stainless steel rod, immersed in a dioxane solution (5% by weight) of lactide (L-form) / ε-caprolactone copolymer (molar ratio 50/50), and then frozen at -40 ° C. Then, it was freeze-dried at 30 ° C. for 24 hours. In this way, the inner layer has a foam made of a lactide (L-form) / ε-caprolactone copolymer, and the outer layer has a reinforcing material made of a lactide (L-form) braid, with an inner diameter of 2.0 mm and an outer diameter of 3.0 mm. , A tubular nerve adhesion-preventing wrapping material having a length of 15 mm was obtained.

The obtained nerve adhesion prevention wrapping material is shown in FIG. FIG. 3A is a photograph of the entire nerve adhesion preventing wrapping material, and FIG. 3B shows a state when the nerve adhesion preventing wrapping material is bent with a finger. From FIG. 3B, it can be seen that the inner diameter of the obtained nerve adhesion prevention wrapping material is not narrowed even when it is bent.
Moreover, the photograph of the cross section of the obtained nerve adhesion prevention wrapping material is shown in FIG. FIG. 4 (A) is a photograph of a cross section of the nerve adhesion prevention wrapping material taken at a magnification of 30 times, and FIG. 4 (B) is a photograph of a cross section of the nerve adhesion prevention wrapping material taken at a magnification of 150 times. be.

(Evaluation by animal experiments)
The sciatic nerve of a male Fisher 344 rat was temporarily dissected, and the following treatments were performed in each group.
(A) Sham group: Only nerve detachment was performed. FIG. 5 (A) shows a photograph of the state after nerve ablation (Sham surgery).
(B) Adhesion group: After the nerve was detached, the biceps femoris muscle, which forms the nerve bed, was cauterized with a bipolar electric knife to facilitate adhesion between the nerve and the muscle. FIG. 5B shows a photograph of the state after cauterizing the streaks.
(C) Wrapping group: After the nerve was peeled off, the biceps femoris muscle forming the nerve bed was cauterized with a bipolar electric knife, and then the nerve adhesion prevention wrapping material obtained in the vertically divided example was wrapped around the nerve. .. FIG. 5C shows a photograph of the state after the nerve adhesion prevention wrapping material is wrapped around the nerve.
(D) HA group: After the nerve was detached, the biceps femoris muscle forming the nerve bed was cauterized with a bipolar electric knife, and then the hyaluronic acid solution was directly sprayed on the detached nerve with a syringe to prevent nerve adhesion.

Six weeks after the operation, the sciatic nerve was removed and observed with the naked eye. In addition, sections of the nerve and its surrounding muscles were prepared, and Masson's trichrome staining was performed for observation. FIG. 6 shows each stained image, (A) Sham group, (B) adhesion group, (C) wrapping group, and (D) HA group.

Furthermore, by the following methods, (1) comprehensive evaluation of adhesion (Gross Assessment), (2) measurement of the detachment strength between the detached nerve and the surrounding muscle (Biomechanical Evaluation), (3) measurement of the induced myoelectric potential (3) Electrical Evolution) and (4) Measurement of gastrocnemius wet weight (Muscle Evaluation) were performed. The numerical values of each evaluation are (A) the average value of n = 8 in the Sham group, (B) the average value of n = 12 in the adhesion group, (C) the average value of n = 12 in the wrapping group, and (D). ) The HA group is an average value of n = 8.
The results are shown in Table 2.

(1) Comprehensive evaluation of adhesion (Gross Assessment)
Adhesiveness and detachability of the detached nerve site 6 weeks after the operation were evaluated as score values according to the definitions shown in Table 1 below.

(2) Measurement of exfoliation strength between the detached nerve and surrounding muscles (Biomechanical Examination)
Tensile tester (Digital Force Gauge FGP-0, manufactured by Nippon Densan Symposium Co., Ltd.) to cut one end of the proximal part of the detached nerve in each group and measure the strength of adhesion between the nerve and surrounding muscles. In .2), the tensile strength (N) was measured under the condition of a tensile speed of 2 cm / min, and this was used as the peel strength.

(3) Measurement of evoked myoelectric potential (Electrophysiological Evaluation)
Using an electromyogram, electrical stimulation was performed at the proximal and distal parts of the nerve that had been treated for nerve ablation in each group, and the motor nerve conduction velocity (NCV) was measured from the evoked electromyogram of the peroneal abdominal muscle. bottom.
The NCV is a value obtained by dividing the distance between the two stimulated points (15 mm) by the latency difference of the action potential obtained, and is calculated by the following formula.
NCV (m / s) = distance between two points (mm) / latency difference Δt (ms)

(4) Measurement of gastrocnemius wet weight (Muscle Assessment)
In each group, the gastrocnemius muscle, which is the innervating muscle of the sciatic nerve, was taken out and the gastrocnemius muscle wet weight (g) was measured.

(5) Evaluation of intraneuronal infiltration of inflammatory macrophages)
Sections of the sciatic nerve and its surrounding muscles excised 6 weeks after the operation were prepared and immunostained using CD68 and CCR7. FIG. 7 shows each stained image. An image of immunostaining the spleen tissue was also shown as a comparison target for staining.
From FIG. 7, a large number of brown-stained inflammatory macrophages were observed in the (B) adhesion group and the (D) HA group. On the other hand, in the (C) wrapping group, the number of brown-stained inflammatory macrophages was clearly small, and the stained image was close to that of the (A) Sham group.

According to the present invention, it is possible to provide a nerve adhesion prevention wrapping material capable of preventing the nerve from adhering to other living tissues by wrapping the nerve around the nerve.

1 Nerve adhesion prevention wrapping material 11 Foam 12 Reinforcing material 3 Nerve 4 Nerve adhesion prevention wrapping material for vertically divided tubular body 5 Suture

Claims (4)

It is a nerve adhesion prevention wrapping material that prevents nerves from adhering to other biological tissues by wrapping them around nerves.
A tubular body composed of a foam made of a bioabsorbable material and a reinforcing material made of a bioabsorbable material that reinforces the foam.
A nerve adhesion-preventing wrapping material, wherein the foam is an inner layer and the reinforcing material is an outer layer, or the reinforcing material is located inside the foam. The nerve adhesion according to claim 1, wherein the bioabsorbable material constituting the foam is a glycolide-ε-caprolactone copolymer or a lactide (D, L, DL form) -ε-caprolactone copolymer. Preventive wrapping material. The nerve adhesion prevention wrapping material according to claim 1 or 2, wherein the reinforcing material is a braid. The nerve adhesion prevention wrapping material according to claim 1, 2 or 3, wherein the bioabsorbable material constituting the reinforcing material is polylactide (D, L, DL body).

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