JPH0234171A - Wound coating material - Google Patents

Abstract

PURPOSE:To prevent bacteria infection and the outflow of the bodily fluid by successively laminating a wound contact layer consisting of a cell infiltrative material, a base layer consisting of fibroin, and a moisture permeation control layer. CONSTITUTION:This wound coating material is formed by successively laminating the wound contact layer consisting of the cell infiltrative material, the base layer consisting of the fibroin and the moisture permeation control layer. The matrix of fibered collagen having a crosslinking structure and modified collagen of 0-80% helix content, mucopolysaccharides or alginic acid are used for the cell infiltrative material and silicone having 5-200mum film thickness, etc., are used for the moisture permeation control layer.

Description

[Detailed description of the invention] [Industrial application fields] The present invention relates to a novel wound dressing.

The wound dressing of the present invention is applied to the injured surface of the skin when the skin is damaged due to a wound, burn, etc., and protects the wound and allows cells with tissue repair functions to enter therein, thereby repairing the wound. It promotes healing.

[Prior art and its problems] Diseases or wounds such as burns, suction wounds, traumatic skin defects, bedsores, etc. As a wound dressing material,
Conventionally, gauze, absorbent cotton, etc. have been used, but these have low bacterial infection prevention properties and absorb exudate quickly, drying the wound surface and causing pain and bleeding when removed. Met. In addition, ointments and the like have also been used, but in this case, the exudate is not sufficiently absorbed and the wound surface becomes excessively moist.

In addition, as an alternative to these, especially when the wound surface is extensive, artificial fibers such as silicone gauze, silicone rubber, and synthetic fibrous sheets such as nylon and Teflon with a velor-like surface structure can be used. Coating films made of materials and bio-derived materials such as freeze-dried pig skin, chitin nonwoven fabric, collagen membranes, polyamino acid sponges, and mucopolysaccharide complex collagen membranes are also known. However, among these, artificial coating membranes still have various problems in terms of adhesion to the affected area, water vapor permeability, cracking, etc., while coating membranes made of bio-derived materials have characteristics such as biocompatibility. However, many of them are antigenic and have disadvantages such as bacterial infection and deterioration due to exudate, and there are also problems such as the raw materials are difficult to handle. More recently, a composite membrane consisting of a collagen-treated nylon mesh and a silicone membrane has been developed and put into practical use, and although it adheres well to the wound surface and has moderate moisture permeability, it also adheres to the wound surface and causes granulation tissue. There was a drawback that it penetrated into the coating film.

[Problems to be Solved by the Invention] As mentioned above, conventional wound dressings each have their own drawbacks, so autologous transplantation is currently the only treatment for the affected area when skin tissue is lost due to burns, etc. considered to be the best method. However, this is extremely difficult in cases where the skin defect is extensive, and even if it is applicable, it is necessary to repeat the transplantation many times over a long period of time.

Therefore, instead of autologous transplantation, it is necessary to develop a wound dressing that temporarily or permanently covers the affected area to prevent bacterial infection and the outflow of body fluids, and also promotes tissue repair by proliferating tissue cells. desired.

[Means for Solving the Problems] The above object is achieved by the wound dressing of the present invention having the following configuration.

1) A wound dressing in which a wound contact layer made of a cell-penetrating material, a support layer made of fibroin, and a water permeation regulating layer are sequentially laminated.

2) The wound dressing according to item 1, wherein the cell-invasive material is a matrix of fibrotic collagen having a crosslinked structure and denatured collagen, mucopolysaccharide or alginic acid having a hesox content of 0 to 80%.

3) The wound dressing material according to item 1, wherein the moisture permeation regulating layer is silicone.

4) The moisture permeation regulating layer has a film thickness of 5 to 200 mm.
Section 3 or Section 3 wound dressings.

As described above, the wound dressing of the present invention consists of three layers: the wound contact layer (lower layer), the support layer (middle layer), and the moisture permeation regulating layer (upper layer).

The wound contact layer directly covers the wound surface to keep it soft and supple, suppress pain, provide adequate moisture, and prevent bacterial contamination. Furthermore, since the wound contact layer is made of a cell-penetrating material, when applied to the wound surface, macrophages, neutrophils, and other inflammatory cells infiltrate, and fibroblasts invade early, resulting in the formation of dermal-like connective tissue. structure and promote wound healing. The wound contact layer eventually absorbs into the wound surface and disappears. The cell-penetrating material constituting the wound contact layer and 1- are fibrotic collagen with a crosslinked structure and a helix content of 0 to 80.
%, a matrix of the fibrotic collagen and mucopolysaccharide, or a matrix of the fibrotic collagen and alginic acid is suitable.

Since collagen is derived from a living body, it has a high affinity for cell tissues, but is easily degraded and absorbed by collagenase in the living body. When used in this situation, it is necessary to introduce crosslinking by some means to strengthen the physical properties.

However, when crosslinking is introduced, the affinity of collagen for cells and tissues that it had before introduction is significantly lowered, and cell invasion tends to be inhibited.

In other words, it is difficult to simultaneously strengthen physical properties and improve biological performance such as affinity for cells and tissues.

As a result of extensive research, the present inventors have found that by combining fibrotic collagen with a crosslinked structure with denatured collagen with a helical content of 0 to 80%, mucopolysaccharide, or alginic acid, the physical properties of the collagen can be strengthened. It has been found that this method is compatible with improved biological performance.

Cross-linking of collagen is carried out by heat-treating collagen or treating it with a cross-linking agent according to a conventional method.

In the case of heat treatment, the collagen is heated to 110°C under vacuum.
It is preferable to dehydrate for 2 hours.

When processing with a crosslinking agent, there are no particular restrictions on the crosslinking agent;
An aldehyde crosslinking agent such as glutaraldehyde, an isocyanate crosslinking agent such as hexamethylene diisocyanate, a carboside crosslinking agent such as 1-ethyl-3-(3-dimethylmininopropyl)carbodiimide hydrochloride, etc. are used.

If the degree of crosslinking is too low, it will not be possible to obtain sufficient physical strength as a medical material, and if it is too high, the structure and properties of collagen will be impaired, so it should be avoided.

0.01-5% (ν/v), preferably 1-3% (ν/v)
v) Collagen with an appropriate degree of crosslinking can be obtained by crosslinking at a crosslinking agent concentration.

If the collagen to be cross-linked is a dispersed water-soluble type with socks in the double strands, the physical properties will not improve much even if cross-linked, so the dispersed collagen should be prepared at 37°C using a phosphate buffer. It is preferable to perform a neutralization treatment to form reconstituted fibrotic collagen having a periodic line f structure similar to that found in vivo. This dramatically improves the physical properties due to the synergistic effect with the crosslinking treatment.

On the other hand, denatured collagen with a helical content of 0 to 80% is produced by treating collagen derived from bovine dermis with an acid or alkali, and applying a collagen aqueous solution containing wax to the resulting double strands at 37 to 90°C in the presence of water. Obtained by heating. When treated at 60° C. for 30 minutes, a helix content of 40% can be obtained.

The raw material collagen for fibrosis and denaturation is preferably acid- or alkali-treated collagen, which is further digested with protase or pepsin to remove the telopeptide at the molecular end, thereby eliminating antigenicity.

The degree of collagen denaturation is indicated by the content of hesox structures. Containing helices means the content of socks in the double chains peculiar to collagen, and since the hesocks in denatured collagen are randomly coiled, the hesocks content corresponds to the degree of denaturation. This helix content is circularly polarized light 2
Chromatic fraction; can be measured with t-(CD) or infrared spectrophotometer (IR) (P, L, Gordon eL)
al, ; Macromoleaules, l (
6) 954 (1974)) The hesox content of the denatured collagen of the present invention is 0 to 80%, more preferably 0 to 50%.

When using the matrix of fibrotic collagen and mucopolysaccharide, examples of the mucopolysaccharide include chondroitin sulfate,
Acidic mucopolysaccharides such as heparan sulfate, dermatan sulfate, hyaluronic acid, and heparin are preferred, and chondroitin sulfate is particularly preferred.

The alginic acid used is obtained by boiling seaweed in dilute sodium carbonate.

The wound contact layer is obtained by mixing the fibrotic collagen aqueous solution with the denatured collagen, mucopolysaccharide or alginic acid aqueous solution, and freeze-drying the mixture.

Further, the matrix of the fibrotic collagen and the modified collagen can also be obtained by heating an aqueous solution of crosslinked fibrotic collagen to about 70 to 90°C.

In the wound dressing of the present invention, the support layer reinforces the mechanical strength of the wound contact layer and also smoothes cell invasion.

As mentioned above, the wound contact layer has resistance to collagenase, but it does not have sufficient mechanical strength as a ffl structure and will eventually be assimilated into the living body (7), so it cannot be stimulated by external stimulation. Therefore, the material of the support layer must have a certain level of mechanical strength, but at the same time it must not inhibit cell invasion into the wound contact layer. Fibroin is an example of a substance that satisfies these conditions.

Fibroin is a material derived from living organisms and is a protein that constitutes silk thread, which is a protein with excellent in-vivo stability, as can be seen from the fact that silk thread is used as a surgical mta binding thread. After dissolving fibroin in a concentrated neutral aqueous solution of salts such as lithium bromide or calcium chloride,
When salts are removed by a method such as dialysis, an aqueous fibroin solution is obtained. This aqueous fibroin solution is frozen at -18°C to 0°C and then thawed to form β-type crystals, resulting in a water-insoluble non-woven porous material (Jun Umakoshi, Polymer Chemistry, 3058
2 (1973)). Fibroin is more stable in vivo than cross-linked collagen, and can be suitably used as a support layer for long-term use in wound dressings.

The moisture permeation regulating layer is a layer for regulating moisture in the wound when the dressing is applied to the wound surface.

It is conventionally known to provide a moisture permeation regulating layer in a wound dressing, and a known layer can be used in the present invention. that is, about 0.1 to about 1 m of non-toxic material.
A layer with a moisture flux of g/e+#/h is used. The appropriate thickness is 5 to 200 μs.

As non-toxic materials, silicone resins, polyacrylate esters, polymethacrylate esters, and polyurethanes are used, with silicone being particularly preferred.

The wound dressing of the present invention is prepared by slowly placing a fibroin matrix on a wound contact layer in a solution state, quickly freezing it at -30°C, freezing it sufficiently, and freeze-drying it, and applying a known method on top of the fibroin matrix. It is manufactured by placing a separately prepared moisture permeation regulating layer membrane and heating it to about 50 to 120°C.

Next, the present invention will be explained in more detail with reference to Examples.

[Example] 1) Preparation of wound contact layer a) Preparation of fibrotic collagen-denatured collagen matrix Atelocollagen 1. Og was dissolved in dilute hydrochloric acid at pH 3.0 to 0.3 w/v%. This solution was placed in a constant temperature bath at 4°C, and while stirring, phosphate buffer was added until the final concentration was 0.
lv/v% atelocollagen, 30mM phosphate-2-
A collagen solution was prepared that was sodium, room N4 Na CΩ. Then, it was immersed in a constant temperature bath at 37° C. for one day to obtain a fibrotic collagen (FC) solution. Centrifuge this solution! (5000 r, p, m, 10 min) and concentrated to 0.3 v/v% fibrotic atelocollagen (F
C) A solution was prepared. On the other hand, a 1.0% atelocollagen (pf (3,0 hydrochloric acid) solution) was treated in a constant temperature bath at 60°C for 30 minutes, and then left at room temperature for 2 hours to obtain a solution of denatured atelocollagen (HAC). The solutions prepared above were mixed at 37°C and stirred for 1 hour.
After rapid freezing at ℃, a sponge was prepared by freeze-drying.

(1) Preparation of RIMized collagen-chondroitin-6-sulfate matrix 1.0% sodium chondroitin-6-sulfate was dissolved in distilled water to prepare a 1 v/v% chondroitin-6-sulfate aqueous solution.

While vigorously stirring the 0.3 w/v % fibrotic atelocollagen solution obtained above, 1 v/v 96 chondroitin-6-sulfuric acid aqueous solution was slowly added dropwise, and the mixture was further stirred for 1 hour. This solution was quickly frozen at -30°C and then freeze-dried to produce a sponge.

A fibrotic collagen-alginate matrix was obtained by the same method as above using sodium alginate instead of sodium chondroitin-6-sulfate.

2) Preparation of fibroin matrix Dissolve refined silk thread in 8M lithium bromide aqueous solution,
This was placed in a cellophane tube and dialyzed against water. After confirming that lithium bromide was completely removed, the obtained fibroin aqueous solution was poured into a polystyrene container and frozen at 10° C. for 24 hours. Thereafter, it was thawed at room temperature, confirmed to be in the form of a nonwoven fabric, and freeze-dried.

3) Preparation of wound dressing a) Inject the collagen-denatured collagen mixed solution into a stainless steel vat in 1) above, and then inject the mixed solution of collagen and denatured collagen in 2) above.
The fibroin matrix sponge prepared in step 1 was slowly placed on top, rapidly frozen at -30°C in this state, sufficiently frozen, and then freeze-dried to obtain a two-layered sponge. Next, a hexane solution of 50% 5ilastic silicone adhesive type A (Dow Corning) was applied onto the Teflon using a precision coating tool (applicator) to form a film. Immediately after application, place the above sponge so that the fibroin matrix is on the silicone side,
After standing at room temperature for about 10 minutes, it was cured in an oven at 60° C. for at least 1 hour. The vacuum was further applied under vacuum for 1 hour, the temperature was further increased to 110° C. and kept under vacuum for 2 hours, after which the temperature was lowered to room temperature and the sample was removed to obtain a wound dressing.

(1) A wound dressing material is prepared by the above method using collagen-chondroitin-6-sulfuric acid or collagen-alginic acid solution LFK obtained in (1)) above in place of the collagen-denatured collagen solution in (3) (B) above. I got it.

No. 9 In 3)-1') above, add 25 mg of silver sulfadiazine powder to 50 cc of the collagen-denatured collagen mixed solution, stir thoroughly, pour into a stainless steel vat, and then slowly add fibroin matrix. In this state, the mixture was rapidly frozen to -30°C, sufficiently frozen, and then freeze-dried to obtain a sponge with a two-layer structure containing an antibacterial agent. A silicone film was laminated onto this sponge in the same manner as above to obtain a wound dressing containing an antibacterial agent.

[Effects of the Invention] According to the present invention, a wound dressing is provided in which a wound contact layer made of a cell-penetrating material, a support layer made of fibroin, and a water permeation regulating layer are sequentially laminated.

The wound dressing of the present invention is applied to the injured surface when the skin is damaged due to a wound, burn, bedsore, etc., to soften and protect the wound surface, relieve pain, and prevent bacterial infection.

Furthermore, in the wound dressing of the present invention, since the wound contact surface is made of a cell-penetrating material, when applied to the wound surface, fibroblasts quickly invade the wound contact layer and build a dermis-like connective tissue. This accelerates wound healing. When the wound dressing of the present invention is applied, the wound surface heals cleanly without leaving any scars.

(2 others)

Claims (1)

[Scope of Claims] 1) A wound dressing comprising a wound contact layer made of a cell-penetrating material, a support layer made of fibroin, and a water permeation regulating layer laminated in this order. 2) The wound dressing according to claim 1, wherein the cell-invasive material is a matrix of fibrotic collagen having a crosslinked structure and denatured collagen, mucopolysaccharide, or alginic acid having a helical content of 0 to 80%. 3) The wound dressing according to claim 1, wherein the moisture permeation regulating layer is silicone. 4) The wound dressing according to claim 1 or 3, wherein the water permeation regulating layer has a thickness of 5 to 200 μm.