JPH03295561A - Adhesion preventive film - Google Patents

Abstract

PURPOSE:To easily prevent tissue adhesion at the time of an operation by forming the adhesion preventive film for preventing biotissue adhesion of a film essentially consisting of collagen and allowing fibrous collagen having a network structure to exist in this film. CONSTITUTION:The adhesion preventive film is applied to a section where the adhesion is anticipated to arise. This film acts as a physical barrier and since the material constituting the film is the collagen which is the essential component to constitute the biotissue, the film has the tissue adaptability without causing foreign matter reaction; in addition, the fibrous collagen of the network structure existing in the film has the function to improve the dynamical strength of the film itself and has the effect excellent as the adhesion preventive film. The collagen referred to in this case is not limited to the collagen alone and also includes the derivatives of the collagen; for example, alkaline-soluble collagen, aterocollagen, succinylated collagen, crosslinked collagen, etc., which are properly selected according to the sections to be applied and symptoms.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to an anti-adhesion membrane, and more particularly to an anti-adhesion membrane useful for preventing adhesion of living tissues that occurs after surgical operations.

(Prior Art) Tissue adhesions associated with surgical operations are a clinically extremely important problem as one of the postoperative complications. That is, inflammation occurs when tissue continuity is disrupted due to injury or the like. Adhesion can be said to be an excessive reaction of inflammation when tissue repair is performed by the wound healing mechanism of the body. As a result of this excessive reaction, insoluble fibrin that is not absorbed into tissues is precipitated together with soluble fibrin, forming a fibrin network.

If the fibrin network is not resorbed, surrounding tissues and organs fuse together, and the aggregated fibrin network undergoes vascularization, which eventually leads to infiltration of fibroblasts. At the same time, infiltration of inflammatory cells occurs, which leads to infiltration of fibroblasts. Fibroblasts layer the intercellular material necessary for tissue repair. Organization and tissue adhesion are completed by proliferation of fibroblasts.

Conventionally, various adhesion prevention methods have been attempted to prevent the above-mentioned adhesions. For example, direct administration of coagulants and antithrombotic agents (e.g., heparin, dextran, antihistamines, chondroitin sulfate, etc.) that prevent the deposition of precipitated fibrin networks, and administration of drugs that dissolve fibrin networks such as urokinase, pepsin, papain, etc. A method of administering fibroblast proliferation inhibitors such as steroids, 5-FU, etc. has been investigated.

However, although some of these methods have been reported to be effective experimentally or in individual cases, they are difficult to administer for boat fishing, and although they prevent adhesions, tissue repair is difficult. There are many things that hinder this, and there is still nothing to be satisfied with.

Therefore, it is strongly desired to develop an anti-adhesion agent or material that has reliable adhesion-preventing ability against all types of adhesions and is easy to use.

The present inventor has conducted various studies to prevent tissue adhesions associated with surgical operations, eliminate re-surgery (adhesion dissection) due to adhesions, which is a postoperative complication, and facilitate the patient's functional recovery and social reintegration. We believe that by placing a film-like membrane at the site where adhesions are expected to occur, this film-like membrane can act as a physical barrier to prevent adhesions.As a result of examining various material structures suitable for this purpose, we have developed the present invention. It is completed,
An object of the present invention is to provide an anti-adhesion membrane useful for preventing tissue adhesion that can be easily applied during surgery.

(Means for Solving the Problems) The gist of the present invention is a membrane mainly composed of collagen, which is characterized by the presence of fibrous collagen with a network structure in the membrane. It is.

That is, the adhesion prevention membrane of the present invention is applied to a site where adhesions are expected to occur, and acts as a physical barrier, and the material constituting the membrane is collagen, which is the main component of the main tissue. Therefore, it has tissue compatibility without causing a foreign body reaction when it comes into contact with living tissue, and the network-structured fibrous collagen present in the membrane has the function of improving the mechanical strength of the membrane itself and preventing adhesion. It has an excellent effect as a preventive film.

Collagen in the present invention refers to collagen derivatives such as alkali-solubilized collagen, atelocollagen, succinylated collagen, crosslinked collagen, etc., and refers to the site where it is applied,
It should be selected appropriately according to the symptoms.

The anti-adhesion film according to the present invention is a film whose main component is collagen, and in addition to collagen, for example, when flexibility and elongation are particularly required, gelatin may be mixed therein, or gelatin may be mixed therein. When tensile strength is required, various materials are mixed depending on the required properties, such as mixing fibrous collagen.

The adhesion prevention membrane according to the present invention can be used, for example, as a substitute membrane for preventing adhesion between organs and the abdominal wall in the abdominal surgery field, or as a pleura substitute in the thoracic surgery field, and also for m-adhesion, fallopian tube occlusion due to fallopian tube adhesion, Used for intestinal obstruction due to intestinal adhesions, ileus, etc. Therefore, the shape thereof is a film shape, a tube shape, or the like, which suits the area to which it is applied.

Collagen, which is the main component of the anti-adhesion membrane according to the present invention, is decomposed by the collagenase of the living body, so it can be said to be a material that is decomposed and absorbed in the body, and is a preferable material for the anti-adhesion membrane. may cause an inflammatory response. In particular, if it is degraded and absorbed within the period required for tissue repair, it not only fails to function as a physical barrier, but also induces an inflammatory response that follows the degradation, increasing the risk of adhesions. In such cases, the collagen film as an anti-adhesion membrane is preferably cross-linked in order to control the decomposition time in vivo.

For crosslinking, crosslinking can be done using crosslinking agents such as aldehyde compounds such as glutaraldehyde and formaldehyde, isocyanate compounds such as hexamethylene diisocyanate, epoxy compounds such as ethylene glycol and glycidyl ether glycerol borocidyl ether, ultraviolet rays, gamma rays, etc. Crosslinking by irradiation is used, and collagen crosslinked with an epoxy compound is particularly preferred because it can impart flexibility without reducing the hydrophilicity of the collagen.

Furthermore, collagen films containing heparin are also effective in cases where fibrin network formation easily occurs due to large amounts of bleeding during partial resection of the liver.

Applying large amounts of heparin can inhibit not only adhesion formation but also tissue repair;
usp/cn! The following are desirable.

Succinylated collagen, which is a collagen derivative, is also effective in reducing inflammatory reactions. Succinylated collagen is collagen in which negative charges are introduced into collagen by reacting collagen with succinic anhydride. It is known that negative charges on the surface of materials suppress the infiltration of inflammatory cells. Therefore, succinylated collagen is also effective.

Further, in the anti-adhesion membrane according to the present invention, fibrous collagen having a network structure is present in the membrane. The fibrous collagen includes water-insoluble tendon collagen, or
Preferably, fibrous collagen is made by spinning soluble collagen and making it insolubilized. For example, tendon kolaken is a water-insoluble fibrous collagen made by crushing and purifying collagen derived from cow wrinkles. Due to the presence of the fibrous collagen having this network structure, the anti-adhesion membrane has high strength, and in particular, the anti-adhesion membrane according to the present invention can be applied to and sutured on a post-operative wound.

The method for producing the anti-adhesion membrane according to the present invention may be any method and is not particularly limited.

All of these anti-adhesion films were colorless and transparent, and had a stiff and somewhat inflexible feel, but when moistened, after a while, they turned into white, highly flexible films. This membrane did not tend to swell or dissolve even after being soaked in distilled water for - months.

Next, the present invention will be explained with reference to examples.

[Example-1 After swelling purified fibrous collagen with sterile distilled water, p
H2.8 was adjusted to a concentration of 0.4%, freeze-dried, and then compressed to obtain fibrous collagen with a network structure. next,
Succinylated atelocollagen solution with a concentration of 0.4% (pH
3) A 0.4% atelocollagen solution (pH 3) was prepared. These succinylated collagen solutions were impregnated into the network-structured fibrous collagen described above, and then air-dried to obtain a succinylated atelocollagen film (SC, F) with a fibrous collagen skeleton.

In addition, atelocollagen was used in place of succinylated atelocollagen, and a fibrous collagen skeleton atelocollagen film (ACF) was prepared in the same manner.

Furthermore, atelocollagen was mixed with an appropriate amount of heparin solution, stirred and dispersed, and then air-dried.

After air drying, the film was insolubilized by irradiation with ultraviolet rays to obtain a heparin-containing fibrous collagen skeleton atelocollagen film (heparin 18.5 u/ad HCF).

Thereafter, the films were irradiated with ultraviolet rays to insolubilize them, and these films were sterilized with ethylene oxide gas and used in experiments. That is, the samples used are as follows.

Fibrillar collagen skeleton Succinylated collagen film (S CF) Heparin-containing fibrillar collagen skeleton Atelocollaken film (Heparin 18.5u/cnl HCF) Fibrillar collagen skeleton Atelocollagen film (ACF) These samples were then used to test animals. We compared and examined their effectiveness. Sixteen 5-week-old, 5D-rat, male, group were used.

〔Method〕

Anesthetize by intraperitoneal administration of 0.1 mfi Nembutal,
Afterwards, continuous anesthesia was performed with ether. After pricking the abdomen, it was disinfected with isodine. A U-shaped incision measuring 4 to 5 cm on each side was made in the abdomen, and a burn wound was created with a soldering iron (surface temperature 250° C.) while pulling the abdominal wall with a hook. The burn wound is
It was about 1 x 2 cm, and was pressed for 3 seconds to the extent that the wound surface was burnt brown. Incidentally, blood from the skin incision was collected in advance and applied to the burn wound. A membrane moistened with physiological saline was placed on the wound surface, and an anti-adhesion membrane (2 x 3 cm) and the peritoneum were placed on the wound surface.
The skin was sutured using nine needles with a -0 nylon thread, and the skin was sutured with a square needle with a 5-0 nylon thread. One week later, the animals were sacrificed, the abdomen was opened, and the presence or absence of adhesions was visually examined.

The results are shown in Table 1.

[Results] (±) Although some of the ocular tissue adhered, it could be easily peeled off.

(10) Strong adhesions were observed in the cataract, liver, intestinal tract, etc.

[Example-2] [Method] Three types of membranes prepared in Example-1, SCF, HCF,
ACF was used.

Ten mixed-breed adult dogs weighing 10 kg were used in each group. The serosa of the descending colon was dissected at two locations over a 5×5 cm area.

In reality, it was difficult to remove only the serosa, so the underlying muscular layer was also removed. Since the intestinal tract contracts after peeling, it should not be stretched, so a 5 x 5 cm membrane was fixed.
Nine locations were fixed using -0 nylon thread, and holes for drainage were created using an 18G injection needle.

One month later, the animals were sacrificed, opened and visually evaluated.

〔result〕

The results are shown in Table 2.

Table 2 (-) No adhesions.

(±) Although some of the ocular tissue adheres, it can be easily peeled off.

(+) Strong adhesions of the cataract, intestinal tract, etc. were observed.

The findings were as follows.

5CF-At the time of laparotomy, there seemed to be more ochuran tissue in the peritoneal cavity than at the time of implantation.

Macroscopically, no membrane was observed, and the implant site was confirmed by the presence of sutures. The serosa was removed over a 5 x 5 cm area, but the suture spacing had expanded to 8-1 Oc+n. No intestinal stenosis or obstruction was observed. The surface of the descending colon at the implant site was macroscopically smooth, but in some individuals, oculata were attached to some areas.

HCF - Findings at laparotomy were similar to SCF, but the attachment of the halos was less than SCF.

Some individuals showed a severe decrease in ACF body weight. Laparotomy findings revealed that the intestinal tract was narrower than in other specimens, and many individuals had a large number of attachments.

[Example 3] Chicken foot key cutting suture The HCF and ACF prepared in Example 1 were used.

〔Method〕

Evaluation was performed using 40 female broiler chickens weighing 2.0 to 2.5 kg. This chicken 3rd jump 2nd chin flexor muscle key (E
After cutting the key on the left gong (leaf), key suturing was performed using a 7-0 loop needle using the undercut method. Furthermore, a membrane (HCF) was inserted so as to wrap around the key, and fixed using 7-0 nylon thread. For the right hand, only one limb was cut and sutured.

After being immobilized in a cast for 4 weeks, it was left free for 1 week, and then the layer was removed.
The state of slippage and adhesion of the key, as well as histological evaluation of the area around the key, were performed.

In addition, the membrane was implanted, dissected 5 weeks later, and FDP
The evaluation was made by applying a tensile force of 500 g to.

〔result〕

The above results are shown in Table 3.

Table 3 Evaluation of adhesion prevention by keyway chemotaxis (effect) As described above, the adhesion prevention membrane according to the present invention is composed of a material whose main component is collagen, and collagen constitutes biological tissue. Because it is the main component of the anti-spread adhesion membrane, it is difficult to cause foreign body reactions in vivo and has excellent tissue compatibility.The presence of fibrous collagen with a network structure in the membrane provides the mechanical strength of the anti-spreading membrane. In particular, the anti-adhesion membrane can be sutured to living tissue using a surgical needle.

Claims (5)

[Claims] (1) A membrane for preventing adhesion, which is a membrane containing collagen as a main component, and is characterized in that fibrous collagen with a network structure is present in the membrane. (2) The adhesion prevention membrane according to claim 1, wherein the collagen is atelocollagen. (3) The adhesion prevention membrane according to claim 1, wherein the collagen is a collagen derivative. (4) Claim 1 characterized in that it contains heparin.
The adhesion prevention film described in each of Items 1 to 3. (5) The adhesion prevention membrane according to any one of claims 1 to 4, wherein the collagen is crosslinked.