KR20100013658A - Multi-layer tissue adhesion barrier membrane - Google Patents

Abstract

The present invention relates to a multi-layered tissue adhesion prevention film, and more particularly, to a tissue adhesive layer capable of stably protecting a wound surface without suture, and to a viscous material within a short time in a body, thereby wound surface from surrounding tissues and surrounding organs. The present invention relates to a tissue adhesion preventing film including a lubrication layer capable of separating the source at the same time.At the same time, it has excellent tissue adhesion preventing performance and ease of treatment compared to the prior art, and can be applied very easily without a suture process when applied in a human body. Has the ability to inhibit tissue adhesion.

Description

Multi-layer tissue adhesion barrier membrane

 The present invention relates to a multi-layered tissue adhesion prevention film for simultaneously imparting inhibitory performance and ease of treatment to tissue adhesion frequently occurring after surgery using a biocompatible polymer, and more particularly, suture process with high adhesion to tissues. Tissue adhesion layer that can stably protect the wound surface; and a lubrication layer that can be changed to a viscous material within the body within a short time to separate the wound surface from the surrounding tissues and organs; As it is, it is very easy to apply without a suture process, it has the characteristics of having excellent tissue adhesion inhibitory performance.

(W. L. Gore)와 분해성 고분자인 셀룰로우스 를 산화시켜 제조한 Interceed^TM(Johnson & Johnson Medical), 하이알룬산 (hyaluronic acid)과 카르복시메틸셀룰로우스(carboxymethyl cellulose)를 가교시켜 제조한 Seprafilm

(Genzyme), 고분자량의 폴리에틸렌옥사이드 (polyethylene oxide)와 카르복시메틸셀룰로우스를 가교시켜 제조한 Oxiplex

(FzioMed) 등이 사용되고 있다. 그러나 비분해성 고분자의 경우는 상처와 상처를 원천적으로 분리하므로 유착방지 성능은 양호하나 시술 후 이물질로 체 내에 계속 존재하므로 주변조직에 염증반응을 일으키거나 조직 재생에 장애요인이 되어, 경우에 따라서는 일정기간 후 제거를 위해 재수술이 필요하기도 하다. 생분해성 고분자의 경우는 체 내에서 일정기간 후 분해되어 소멸되므

로 이물질로 남지 않는다는 장점은 있으나 아직까지는 비분해성 고분자에 비해 유착방지 성능이 다소 낮은 편이다. 필름형태의 유착방지막을 이용할 경우 가장 큰 단점은 적용 부위에서 유착방지막의 이동을 막기 위해 봉합사를 이용해 주변조직과 봉합을 해 주어야 하는데 봉합부위에서 조직유착이 빈번하게 일어난다는 점이다. 이를 극복하기 위해 겔 형태의 카르복시메틸셀룰로우스, 덱스트란 70(dextran 70), 폴리에틸렌옥사이드-폴리프로필렌옥사이드 공중합체(polyethylene oxide-polypropylene oxide 공중합체; Pluronic F127)로 제조한 Flowgel

(Mediventures), 폴리락틱산을 기본으로 한 Adcon-L

Gliatech), 하이알룬산을 기본으로 한 Intergel

(Lifecore Biomedical), 천연고분자를 원료로 한 AdbA

(Amitie)와 스프레이 형태의 폴리에틸렌옥사이드를 기본으로 한 Spraygel

(Confluent Surgical) 등이 연구되거나 일부 시판되고 있지 만, 겔 형태의 유착방지제의 경우에 상처가 치유되기 전에 체 내(수용액상)에서 쉽게 분해·흡수되어 유착방지제로서의 효능이 낮은 문제점을 가지고 있다. 이러한 문제점으로 인해 기존의 유착방지제를 사용시 유착방지 효능이 50 ~ 70% 정도에 불과한 것으로 알려져 있다(J. M. Becker, et al., presented at Clinical Congress of Am. College of Surgeon, New Orleans, October 22 (1995)). 참고로 일반적으로 수술 부위의 상처 치유는 7일 정도 걸리는 것으로 되어 있다. 고분자를 이용한 유착방지제 사용 이외에도 약리적인 방법에 의해 조직유착을 방지하고자 하는 시도가 되어져 왔는데, 조직유착의 한 원인으로 알려진 염증반응을 억제하게 위해 수술부위에 소염제를 주입해주는 방법이 그 한 예이다. 그러나 이 방법은 적용 부위에 소염제가 장시간 머물지 못해 유착방지 성능이 그다지 높지 않은 것으로 나타나고 있다. In surgery today, laparotomy is one of the routine operations. Adhesion of organs and tissues that occurs frequently after surgery is one of the natural phenomena that occurs when cells of damaged tissues proliferate and regenerate, but they cause continuous discomfort or dysfunction and require reoperation for adhesion detachment. It can also be a life threatening factor. In women, especially, pelvic surgery may cause infertility due to uterine adhesions (DB John, et al., "Reduction of adhesion formation by postoperative administeration of ionically cross-linked hyaluronic acid", Fertil. Steril. , 68, 37-42 (1997). This complication is closely related to the body's biological defense mechanisms, and the process is complicated, and there are many difficulties in preventing it in the clinic. Therefore, despite many research efforts since abdominal surgery, it remains one of the most important surgical problems that have not yet been completely solved. The incidence of adhesion after open surgery has been reported to be quite high (55-93%) (D. Menzies, "Postoperative adhesions: their treatment and relevance in clinical practice", Ann. Royal Coll. Surg. Engl. , 75, 147-153 (1993)). It is not an exaggeration to say that such adhesion occurs in almost all parts of the human body such as muscles, sclera, conjunctiva, tenon cyst, and mesentery, but the biggest clinical problem is repetitive peritoneal or intestinal adhesion after abdominal surgery. It is known to be caused by surgery, coarse surgery, excessive bleeding, tissue response of sutures, foreign bodies during surgery, and postoperative inflammation (L. Holmdahl, et al., "Experimental models for quantitative studies on adhesion formation in rats and rabbits). ", Eur. Surg. Res. , 26, 248-256 (1994)). In addition, since adhesion occurs as a part of the wound healing process by the surgery itself, complete prevention is difficult and the extent of minimization can be minimized by accurate tissue detachment, bleeding prevention, aseptic surgery, shortening of operation time and appropriate selection of suture during surgery. Therefore, in order to solve the problem of tissue adhesion after surgery, there have been attempts to suppress the adhesion between tissues after surgery using various types of anti-adhesion agents. Such materials include preforms made of Teflon, a non-degradable polymer, in the form of a film.

Seprafilm prepared by cross-linking WL Gore with degradable polymer cellulose, Interceed ^TM (Johnson & Johnson Medical), hyaluronic acid and carboxymethyl cellulose.

(Genzyme), Oxiplex prepared by crosslinking high molecular weight polyethylene oxide and carboxymethyl cellulose

(FzioMed) and the like are used. However, in the case of non-degradable polymers, the adhesion between the wound and the wound is good, but the anti-adhesion performance is good, but since it remains in the body as a foreign substance after the procedure, it causes an inflammatory reaction to surrounding tissues or becomes a barrier to tissue regeneration. Reoperation may be necessary to remove after a period of time. Biodegradable polymers are decomposed and destroyed after a certain period in the body.

Although it has the advantage of not remaining as a foreign substance, the anti-adhesion performance is still somewhat lower than that of a non-degradable polymer. The biggest disadvantage of using the film-type anti-adhesion film is that the suture is used to suture the surrounding tissues to prevent the movement of the anti-adhesion film at the application site, and tissue adhesion occurs frequently at the suture site. Flowgel made of carboxymethylcellulose, dextran 70, polyethylene oxide-polypropylene oxide copolymer (Pluronic F127) in gel form to overcome this problem

(Mediventures), Adcon-L based on polylactic acid

Gliatech), Intergel based on hyaluronic acid

(Lifecore Biomedical), AdbA from Natural Polymers

Spraygel based on Amitie and sprayed polyethylene oxide

(Confluent Surgical), etc. have been studied or some commercially available, but gel-type anti-adhesions have a problem of low efficacy as anti-adhesion agents because they are easily decomposed and absorbed in the body (aqueous solution) before the wound is healed. Due to these problems, it is known that the anti-adhesion efficacy of existing anti-adhesion agents is only about 50 to 70% (JM Becker, et al., Presented at Clinical Congress of Am. College of Surgeon, New Orleans, October 22 (1995). )). For reference, wound healing at the surgical site usually takes about 7 days. In addition to the use of anti-adhesion agents using polymers, attempts have been made to prevent tissue adhesion by pharmacological methods. For example, an anti-inflammatory agent is injected into the surgical site to suppress an inflammatory reaction known as a cause of tissue adhesion. However, this method shows that anti-adhesion performance is not so high because anti-inflammatory agents do not stay in the application area for a long time.

As described above, many researches on preventing tissue adhesion occurring after surgery have been conducted, but the conventional materials that do not improve the above problems have not been shown to pay an expensive treatment fee and have no corresponding effect.

Accordingly, the present inventors have made a research effort to solve the problem of movement from the application site, the suture to prevent it, the low adhesion prevention effect caused by low body stability, etc., which is a problem of the conventional film-type tissue adhesion inhibitors. The application of the present invention was completed by eliminating the process of suture of the wound surface and producing a film-type tissue adhesion prevention film in which a lubrication layer was originally laminated to separate the wound surface from the surrounding tissue and the wound organ.

The present invention for solving the above problems relates to a multi-layered tissue adhesion prevention film, a tissue adhesive layer containing one or more tissue adhesive polymers selected from collagen, gelatin, elastin, chitin and chitosan; And a lubricating layer containing one or two or more polysaccharide-based polymers selected from alginic acid, pectin, carrageenan, gellan gum, carboxymethylcellulose, hyaluronic acid, and dextran; It features.

Since the present invention has a high adhesion to the tissue, when the present invention is applied to the human body, it is possible to operate on the wound surface very easily without a suture process, and the tissue adhesion of the new concept is very excellent because of the prevention of tissue adhesion. It can be very usefully used as an inhibitor.

When explaining the present invention in more detail as follows.

Multi-layered tissue adhesion prevention film of the present invention

A tissue adhesive layer containing one or more tissue adhesive polymers selected from collagen, gelatin, elastin, chitin and chitosan; And

Lubrication layer containing single or two or more polysaccharide-based polymers selected from alginic acid, pectin, carrageenan, gellan gum, carboxymethylcellulose, hyaluronic acid, and dextran; alternately stacked It is done.

In addition, the tissue adhesive layer of the multi-layered tissue adhesion prevention film may use the tissue adhesive polymer without crosslinking or crosslinking.

In the multilayered structure adhesion preventing film of the present invention, the multilayered structure may be manufactured in a form in which the tissue bleeding layer and the lubricating layer are laminated in a plurality of layers depending on the application of the wound. Although the present invention is not limited thereto, for example,

A two-layer structure in which a tissue adhesive layer and a lubricating layer are laminated; or

It can be prepared in a three-layer structure laminated in the order of the tissue adhesive layer, the lubricating layer and the tissue adhesive layer. In detail, the tissue adhesive layer and the lubricating layer may be used in which one or more layers are alternately stacked. When explaining the tissue adhesion prevention film in which the tissue adhesive layer and the lubricating layer are laminated one by one, respectively, It looks like this:

When the tissue adhesion prevention film of the present invention is introduced to the wound tissue surface in the direction of the tissue adhesion layer, the tissue adhesion layer is coated on the wound tissue surface to cover the wound tissue surface. Thereafter, the polysaccharide-based polymer of the lubricating layer on the coated tissue adhesive layer is changed into a viscous material by body fluid, and the tissue adhesive layer is coated with a tissue surface on which the biocompatible polymer of the lubricating layer turned into a viscous material is wound. Covering again to increase the coverage of the tissue adhesive layer, as well as to provide a slippery surface that is not easily adhered to the surrounding tissue to separate the wound surface from the surrounding tissue and organs at the source. . In addition, according to the application environment, the tissue adhesion prevention film of the present invention may be composed of three layers in which a tissue adhesion layer-lubrication layer-tissue adhesion layer are alternately stacked as shown in FIG. 1, and the tissue adhesion layer and the lubrication layer are from above. As described, it works on the wounded tissue. Thus, the tissue adhesion prevention film of the present invention having a structure in which the tissue adhesion layer and the lubrication layer are laminated may be formed in the form of a plurality of layers depending on the application environment.

The tissue adhesive layer in the present invention, having a good adhesion properties with tissues and cells, serves to adhere quickly and stably to the wound surface, due to this role wound tissue adhesion preventing film of the present invention without a separate closure process Applicable to the site. The tissue adhesive layer having such characteristics contains a tissue adhesive polymer, wherein the biodegradable polymer has an average molecular weight of 1,000 to 1,500,000 g / mol, preferably 3,000 to 800,000 g / mol, and more preferably 5,000 to 500,000 g / mol. Characterized by using a biodegradable polymer, wherein, when the average molecular weight of the tissue-adhesive polymer is less than 1,000 g / mol can quickly dissolve in the body may cause a problem that does not exhibit tissue adhesion, more than 1,500,000 g / mol It is preferable to use within the above range because high handling viscosity may cause a problem that the handling process for preparing the film form is not easy.

The tissue adhesive layer has a thickness of 0.1 to 1,000 μm, preferably 1 to 500 μm. Here, when the thickness of the tissue adhesive layer is less than 0.1 μm, there is a problem in that the adhesive strength with the tissue is low and the physical properties are weak, and when the thickness of the tissue adhesive layer is 1,000 μm or more, there is a problem in that the film is inflexible or unnecessary waste of the polymer. .

In addition, the tissue adhesive layer can be crosslinked using a crosslinking agent, thereby slowing down the decomposition rate of the adhesive layer by enzymes present in the body, thereby stably increasing the effect of protecting the wound. do. The crosslinking agent is glutaraldehyde, formalin, N- (3-dimethylamidopropyl) -N'-ethylcarbodiimide {N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide), and One or a mixture of two selected from N-hydroxysulfo-succinimide sodium salt (EDAC / NHS) can be used.

In the present invention, the lubricating layer changes to a viscous material within a short time in the sieve and serves to naturally separate the wound surface from surrounding tissues and organs. The lubricating layer may contain one or two or more polysaccharide-based polymers selected from alginic acid, pectin, carrageenan, gellan gum, carboxymethylcellulose, hyaluronic acid and dextran, wherein the polysaccharide-based polymer A molecular weight of 1,000 to 1,500,000 g / mol, more preferably 1,000 to 800,000 g / mol can be used. In particular, the alginic acid and hyaluronic acid is preferably used that has an average molecular weight of 5,000 ~ 500,000 g / mol, if the average molecular weight of the alginic acid and hyaluronic acid is less than 5,000 g / mol does not play a role as a lubricating layer low viscosity May occur, and when the amount exceeds 500,000 g / mol, the viscosity may be too high to make handling difficult.

The lubricating layer has a thickness of 1 to 1,000 μm, preferably 10 to 500 μm. Here, if the thickness of the lubrication layer is less than 1 μm, there is a problem that the effective lubrication action is not possible, and if the thickness of the lubrication layer is 1,000 μm or more, there is a problem that the film is not flexible or unnecessary waste of the polymer.

The tissue adhesion prevention film of the present invention preferably has a total thickness of 1.1 ~ 3,000 ㎛, where the total thickness of the tissue adhesion prevention film is less than 1.1 ㎛, the physical properties are too weak to use, or the problem of low adhesion prevention may occur It is preferable to have a thickness within the above range, since the film may be inflexible or waste of the polymer unnecessarily when exceeding 3,000 μm.

The tissue adhesion prevention film of the present invention described above may be prepared using a film casting method and an electrospinning technique, which are generally used in the art, and may include a lubricating layer and a lubricating layer based on a tissue adhesive layer. The multilayered structure alternately laminated in order of the adhesive layer can be used as an anti-adhesion agent, and when applying the anti-adhesion film of the present invention to the wound surface, it is characterized in that no separate tissue suture surgery is required.

Although this invention is demonstrated in detail based on an Example, this invention is not limited to an Example.

Example 1

Alginate aqueous solution of natural polymer and dissolving alginic acid (Medium viscosity, Sigma, USA) with excellent biocompatibility in 2% by weight of ultrapure water was prepared, and the size (5 cm x 5 cm x 2 cm, width x height x height) Cast on and dried completely in a 37 ° C. dryer to produce an uncrosslinked alginic acid film. The produced film can serve as a lubrication layer that can turn into a material that exhibits viscosity within a short time in the body and can naturally separate the wound surface from surrounding tissues and organs. Collagen (Type) in 20 ml of 1,1,1,3,3,3-hexafluoroisoprophenol (1,1,1,3,3,3-hexafluoroisopropanol, HFIP) I, Kenko, Japan) was prepared by dissolving about 1.74 g of 8% (w / v) collagen solution, which was prepared above under conditions of voltage 15 kV, spinning distance 8 cm, solution rate 0.02 ml / min. Electrospinning was performed on one side of to prepare a tissue adhesion preventing film of the collagen electrospinning sheet / alginic acid film (tissue adhesion layer / lubrication layer). The total thickness of the prepared tissue adhesion preventing film was about 100 μm, the thickness of the electrospun sheet was about 50 μm, and the thickness of the alginic acid film was about 50 μm.

Example 2

Collagen was electrospun on both sides of the alginic acid film prepared under the same conditions as in Example 1 to prepare three layers of collagen electrospinning sheet / alginic acid film / collagen electrospinning sheet (tissue adhesion layer / lubrication layer / tissue adhesion layer). . The total thickness of the prepared tissue adhesion preventing film was about 150 μm, the thickness of the electrospun sheet was about 50 μm, and the thickness of the alginic acid film was about 50 μm.

Example 3 and Example 4

The same procedure as in Examples 1 and 2, except that 0.5% concentration of glutaraldehyde solution was placed in a desiccator and vaporized at room temperature, and then the tissue adhesion prevention film prepared on the desiccator was placed thereon. By crosslinking the electrospinning sheet of the tissue adhesion prevention film [see Lee et al., Development of a composite vascular scaffolding system that withstands physiological vascular conditions, Biomaterials, 29, 2891 (2008)], Examples 3 and 4 were carried out. It was.

Tissue adhesion inhibition effect through the experimental examples of Examples 3 and 4 showed the same tendency as Examples 1 and 2.

Comparative Example 1

Prepare a single layer of collagen electrospinning sheet under the same conditions as in Example 1, and experimented with the same animal model as in Example 1, the collagen electrospinning sheet prepared on the wound (2cm x 2cm x 100μm, horizontal x vertical x height ) Was introduced into the wound surface.

Comparative Example 2

Interceed ^TM (Johnson & Johnson Medical) prepared by oxidizing degradable polymer cellulose among commercialized anti-adhesion agents used in the clinic was tested in the same animal model as Example 1, but Interceed ^TM (2cm x 2cm, width x length) ) Was introduced into the wound surface.

Experimental Example

Animal rats (SD rats) were used to evaluate the tissue adhesion prevention performance of the tissue adhesion prevention membranes of Examples and Comparative Examples. First, tiltamine / zolazepam (10 mg / kg) and 2% nitrazine hydrochloride (2 mg / kg) were mixed, followed by anesthesia by injection into the lower abdomen of rats. An incision is made in the anesthetized rat's abdomen, a 1 x 1 cm ² wound is formed on the epidermis of the peritoneum using a surgical knife, and the wound is slightly peeled off from the cecum in contact with the wound. Was formed using sandpaper. Tissue adhesion was confirmed by dividing the control group and the collagen electrospinning sheet / alginic acid film (2 cm x 2 cm x 150 μm, width x length x height), which were sealed without inserting any material between the wound and the wound. Since wounds in the body are known to heal within 7 days, the extent of tissue adhesion was checked 7 days after surgery. According to the degree of tissue adhesion, the grades were summed and averaged using a grading system of 4 levels (0, 1, 2, 3, the larger the number, the more severe the adhesion) (AA Luciano, et al., "Evaluation of commonly used adjuvants in the prevention of postoperative adhesions", Am. J. Obstet. Gynecol ., 146, 88-92, 1983), and the results are shown in FIG.

In Examples 1 and 2, as shown in FIG. 2, tissue adhesion was significantly reduced compared to the control group (the group which did not undergo any treatment after wounding the abdominal wall and the cecum) and Comparative Examples 1 and 2. .

Figure 1 is a schematic diagram of the mechanism of action of the tissue adhesion prevention film prepared in a three-layer structure in Example 2.

Figure 2 is a graph showing the degree of tissue adhesion obtained through the animal experiments of Examples 1, 2 and Comparative Example 1 of the present invention, n is the number of mice used in the experiment.

Claims (6)

A tissue adhesive layer containing one or more tissue adhesive polymers selected from collagen, gelatin, elastin, chitin and chitosan; And Lubrication layer containing single or two or more polysaccharide-based polymers selected from alginic acid, pectin, carrageenan, gellan gum, carboxymethylcellulose, hyaluronic acid and dextran; multilayer structure characterized in that the alternately stacked Tissue adhesion prevention film. The method of claim 1, wherein the tissue adhesive layer is glutaraldehyde, formalin, N- (3-dimethylamidopropyl) -N'-ethylcarbodiimide, and N-hydroxysulfone A multi-layered tissue adhesion preventing film, characterized in that it is crosslinked with one or two or more crosslinking agents selected from succinimide sodium salt. The multi-layered tissue adhesion preventing film of claim 1, wherein the tissue adhesive polymer and the polysaccharide-based polymer have an average molecular weight of 1,000 to 1,500,000 g / mol. According to claim 1, wherein the tissue adhesive layer is a multi-layered tissue adhesion prevention film, characterized in that the thickness of 0.1 ~ 1,000 ㎛. According to claim 1, wherein the lubricating layer is a multi-layered tissue adhesion prevention film, characterized in that the thickness of 1 ~ 1,000 ㎛. The method according to any one of claims 1 to 5, wherein the multilayer structure A two-layer structure in which a tissue adhesive layer and a lubricating layer are laminated; Or a three-layer structure laminated in order of a tissue adhesive layer, a lubricating layer, and a tissue adhesive layer.

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