Laminated Collagen Film Dressing

Abstract

A surgical dressing that is particularly useful for the treatment of burn wounds is disclosed made from a thicker layer of a collagen compressed foam film to which has been laminated, without any adhesive, a thin continuous layer of an inert polymer material, such as polyurethane, having a moisture vapor transmission rate slightly higher than that of human skin and which preferably also contains finely divided silver metal impregnated in the collagen layer.

Description

BACKGROUND AND SUMMARY OF THE INVENTION

In the treatment of severe burn wounds, i.e. second and third degree burn wounds, the patient passes through a number of different treatment phases. The first phase is to clean and stabilize the wound area and control the bacterial flora at the wound site. This treatment is carried out by debridement of the wound site, maintaining an electrolyte balance and by the topical application of antibacterial medications such as silver nitrate, silver sulfadiazine and other similar medications. The wound then passes through development of a granulation bed. Once this phase of the treatment is under control, the status quo of the wound site must be maintained awaiting autografting to complete the treatment. Since in many cases a period of time will pass before autografting is possible, the maintenance of the status quo wound site, i.e. the granulation bed, is an absolute necessity. The present methods used to maintain the status quo are by the repeated applications of wet gauze dressings or by employing a temporary homograft or heterograft. The repeated application of wet dressings is not particularly satisfactory as these dressings require frequent changes within any 24-hour period and tend to add to the discomfort of the patient. Homografts and heterografts have been found to be effective, but they are not readily available.

An object of the present invention is therefore to develop a material which can be considered a substitute for a homograft or a heterograft and which will maintain the wound site, i.e. the granulation bed, in a status quo condition until an autograft becomes feasible.

The requirements for a substitute homograft or heterograft, which the dressing of the present invention meets, are the following:

1. It should be a readily available material.

2. It should be capable of being applied to the wound site so as to completely isolate the wound site from the environment.

3. It must have sufficient strength to be secured over the wound area by sutures, clips, gauze, or with adhesive bandages.

4. It must be capable of being sterilized and easily stored.

5. It must have no antigenic properties.

6. It must have a moisture vapor transmission rate which will allow the proper moisture balance in the repairing wound, i.e. to prevent both hydration and dessication of the repairing tissue.

Moisture vapor transmission rate is the weight of water lost by evaporation through a film membrane at 37.degree.C over a period of 24 hours. The weight loss is determined using a Twing Albert permeability cap in a Blue M Electric Company Model POM-203A forced air oven at 37.degree.C. The weight loss is observed periodically over a 24 to 48 hour period. This moisture vapor transmission rate figure will vary if measured by other possible procedures, and all rates described herein are those measured by the above method.

It was formerly thought that this rate should be similar to that of human skin, i.e. about 1-1.5 milligrams per hour per centimeter squared, but we have learned that the rate should be slightly higher, i.e. about 2-7 milligrams per hour per centimeter squared (2-7 mg/hr/cm.sup.2).

We have developed a simple dressing that meets these requirements. Our dressing is composed of a thicker layer (that which will be placed on the skin in actual use) of reconstituted collagen formed into a compressed tanned collagen foam film to which is laminated a thinner outer layer of an inert polymer plastic material, preferably polyurethane. A greatly preferred embodiment contains finely divided silver impregnated and distributed through the collagen layer.

Our new dressing can be 3-30 mils thick and is preferably about 18 mils thick. The dressing of our invention can have a moisture vapor transmission rate of from 2 to 7 mg/hr/cm.sup.2 and preferably has a rate of 3 mg/hr/cm.sup.2.

DISCUSSION OF PRIOR ART

Collagen in various forms has been used together with various other materials in the treatment of wounds and of burns. Braun, U.S. Pat. No. 3,491,760, discloses a "skin" used in heterotransplantation which is made from two different tanned collagen gel layers. The material is used to produce a heteroplastic skin by acting as a suitable nutrient medium. The layer next to the skin has a large-celled, foamy consistency (but is not a compressed foam), and it is covered by a collagen film which is very tough, elastic, and almost leathery to prevent the drying out of the first film. The patent teaches the optional cementing of an adhering plastic film, such as polyvinylchloride foil, over the leathery collagen film to prevent drying out of the collagen gel. The heteroplastic skin thus formed is fairly thick (the collagen foamy layer being well over 100 mils thick and much thicker than that which applicants use). The various layers are cemented together with adhesives. A collagen foil dressing product that appears to be made by this method has been sold in Germany. This prior art dressing appears to have a moisture vapor transmission rate different from that of the instant invention.

Battista U.S. Pat. No. 3,471,598 discloses freeze drying a dispersion of a microcrystalline collagen to form a mat, which can be used in various applications including surgical dressings.

British Pat. No. 1,195,062, entitled "Structures Comprising Microcrystalline Collagen and Methods of Forming Them," discloses the use of microcrystalline colloidal dispersions and gels to produce films, which may then be applied to coat various types of fibers including fibers of various organic polymers such as polyurethane.

Schulte, U.S. Pat. No. 2,202,566, discloses the use of collagen fibers in a bandage.

Robbins, U.S. Pat. No. 3,113,568, discloses the use of a polyurethane foam in a special type of bandage.

None of the art specifically discloses the concept of the present invention of dressing made from a particular type of collagen formed into a layer of compressed collagen foam having laminated thereto a polyurethane film which has a moisture vapor transmission slightly higher than that of skin.

Reference is now made to the drawings wherein are set forth by way of illustration and examples certain embodiments of the present invention.

Referring to the drawings:

FIG. 1 is a plan view of a microphotograph showing the top 10 (i.e. the part away from the skin in actual use) of the surgical dressing of the present invention taken at 3,000 times magnification, and it shows the outer surface of the thinner polyurethane layer 12, which contains a great many microscopic pores 14.

FIG. 2 is an inverted plan view of a microphotograph showing the bottom 20 (i.e. the part which goes next to the skin in actual use) of the surgical dressing of the present invention taken at 10,000 times magnification, and it shows the outer surface of the thicker compressed collagen foam 22, which contains a network of collagen fibers or fibrils 24 with pores or open spaces 26 between the collagen fibers or fibrils.

FIG. 3 is a diagrammatic cross-section view on line 3--3 from FIG. 1 showing a side view through the center of the surgical dressing of the present invention. It shows the polyurethane layer 10 laminated to the compressed collagen foam layer 20. Also visible in FIG. 3 are the pores 14 in the polyurethane, the collagen fibers 24 and the open spaces 26 between the collagen fibers, and the particles of silver metal 28 impregnated in the collagen foam 20.

THE STARTING COLLAGEN

The compressed collagen foam film used in the surgical dressing of the instant invention may be made from collagen obtained from various sources as long as it has the necessary properties hereinafter described. Bovine collagen is the most common source. In particular, we have found satisfactory results may be obtained from a commercial product which is marketed by FMC Corporation under the trademark "Avitene" or very small, fine, fluffy, collagen fiber particles which are relatively soft and not degraded, made as described in U.S. Pat. No. 3,471,598 and other patents assigned to FMC Corporation. Other usable collagen fibers are those used in the gels from which collagen sausage casings are extruded, which have been ground or milled to the smaller, fine, fluffy sizes used here. Bovine hide--dried, ground, or milled--can also be used to make the gel from which the compressed foam of the present invention is made.

PREPARATION OF COLLAGEN GEL

The starting collagen is separated into very fine, fluffy fibers (dry to feel and touch) on the order of 25, 35, and 50 mesh size. Avitene is sold as a dry fibrous blend of finely divided collagen fibers. These are screened through various sized sieves to separate the collagen into fibers of the same relative size on the order of 25-50 mesh. While specific size and mixtures of size is not critical and smaller or larger pieces of collagen could be used, we prefer to use equal parts of several different sizes, e.g. of 25, 35, and 50 mesh, blended together. The collagen fibers are then made into an aqueous dispersion with water, which dispersion contains about 3.5 percent by weight of said collagen fibers. The dispersion is homogenized and allowed to stand. The time of standing is not critical, but we have found 1 hour to be satisfactory. Then a fast evaporating organic solvent such as petroleum ether is added to the amount of about 15 percent by volume. The purpose of using the organic solvent is to prevent complete self-bonding of the fibers in the reconstituted product. When Avitene collagen is used, the petroleum ether is added to the initial aqueous dispersion. Where a dry collagen other than Avitene has been used, the resultant blend is then acid swollen in the well known fashion (we prefer to use 0.8 percent by weight of lactic acid, but other acids or amounts should work also) and allowed to stand. Where Avitene is used, this step is omitted since the material is already in the acid state. The fibers are swollen by the action of the lactic acid and take up the liquid present in the dispersion to form a gel. The gel is preferably permitted to stand long enough to attain equilibrium, e.g. for an hour, before being used in the next step of the process.

PREPARATION OF COLLAGEN FOAM FILM

The above gel, which contains acid swollen collagen, is spread into a thick wet film on the order of about 25 to 75 mils, preferably 50 mils thick. The thickness of this thick wet gel film can vary, of course, depending on the desired thickness of the collagen layer in the desired end product dressing. It is next desired to impart further porosity to the collagen film so it will be somewhat foamy and also to tan (i.e. to cross-link) the collagen. Various foaming agents and tanning agents could be used. We prefer to soak the wet film in a 5 percent sodium bicarbonate solution which also contains 400 parts per million or more glutaraldehyde for a period of 1 hour. The glutaraldehyde is the tanning agent. The sodium bicarbonate is used to control the porosity of the film since it introduces uniform size gas bubbles while the acid swollen film is being neutralized with bicarbonate ions.

The resultant porous collagen film which has now been neutralized with bicarbonate, has had its constituent collagen deswollen so it now has a lesser thickness about one-half its former swollen size. It is then dried, e.g. by air drying. The resultant dried porous collagen film is well rinsed with water. We prefer a rinsing time of 1 hour. The water-rinsed film is then plasticized slightly. A suitable method is by soaking in 20 percent glycerol for 15 minutes.

Because the glutaraldehyde present in the sodium bicarbonate serves as a tanning agent (cross-linking agent), the dried film contains an excess of glutaraldehyde. The wet plasticized porous collagen film is dried and is also slightly compressed, i.e. to about one-quarter of its original wet thickness (referring to the gel stage), for example, by being force dried on a heated cam under slight pressure. A typical thickness of the dried compressed collagen foam film at this point is about 12.5 mils.

The compressed collagen foam has been fairly well tanned so that it will not have antigenic activity. One method of determining the sufficiency of amount of tanning is by its resistance to collagenase attack. Here resistance to collagenase attack is assayed according to a procedure described by Mandl, I. in the J. Clinical Investigation, 32, 1323 (1953). We have found that our cross-linked collagen is essentially resistant to hydrolysis by the enzyme collagenase from Cl. histolyticum. We have reduced the ability of the enzyme to attack the collagen by greater than 90 percent.

ADDITION OF SILVER

Where the preferred embodiment is desired, i.e. the use of a fine dispersion of silver throughout the collagen film, one way of adding it is by the use of Tollen's reagent; e.g. the dried compressed foam collagen film can be soaked in Tollen's reagent for 5 minutes. Tollen's reagent, which has the formula Ag(NH.sub.3).sub.2 OH, is a reducing agent for aldehyde groups, and it serves to oxidize the excess glutaraldehyde and also to deposit silver metal on the accessible surfaces of the collagen fibers throughout the film. The specific amount of silver deposited or impregnated is that which is equivalent to the amount of excess aldehyde which has been oxidized to carboxyl. The silver acts as an antibacterial agent and is especially effective in amounts of from 1.5 mg silver per square inch to 0.5 mg silver per square inch when applied and impregnated in the manner herein suggested.

The collagen film, after being soaked in Tollen's reagent for 5 minutes, is then rinsed in water for about an hour and finally plasticized, e.g. by being soaked in 20 percent glycerol for 15 minutes, and it is then air dried.

While there can be a fair amount of variation, a typical compressed collagen foam film formed at this point might have a density of 1.8285 grams per cubic centimeter, a porosity of 76.4 percent, and a measured pore volume of 0.608 cubic centimeters per gram (as determined in the well-known manner on a Porosimeter, the particular machine being that manufactured by the American Instrument Company as their "Aminco Digital Readout Porosimeter, 15,000 PSI Motor Driven").

LAMINATION TO THIN PLASTIC FILM

The plasticized compressed collagen foam film is now ready to be coated with a plastic film. While it is physically possible to utilize various adhesives to attach the plastic film to the collagen film, animal tests have shown the resultant dressing to be unsatisfactory since they delaminated in actual use, wherefore the plastic film used in the present invention is laminated to the collagen film without any adhesive. While this can be accomplished various ways, we have found solvent casting to be quite satisfactory, i.e. dissolving the plastic in a solvent and then cast coating the collagen film with the dissolved plastic. The plastic we prefer is polyurethane, although other plastics ought work provided they give the desired moisture vapor transmission rates (slightly higher than that of skin) and do not release toxic or irritant chemiclas to the wound bed. The particular preferred polyurethane is a thermoplastic polyurethane sold by the B. F. Goodrich Chemical Company as "Tuftane" packaging film and which has high elongation and excellent stretch recovery properties as well as good strength and toughness. We have used their Tuftane No. 110 film in 1.0 mil thickness and dissolved it in an organic solvent, such as tetrahydrofuran. A dispersion of 20 percent polyurethane in tetrahydrofuran was found particularly suitable. This was used to coat the compressed collagen foam film using a number 60 Meyer Rod to apply five coatings. The number of coatings could vary since the real control is obtaining the desired moisture vapor transmission rate. This rate will decrease as the plastic film is made thicker.

Naturally the dressing should be sterilized before use. Cobalt irradiation is the method of choice, but other methods could be used also.

Typical examples of dressings of this invention such as illustrated in the drawings and their construction are as follows.

Example 1 Dressing With Silver

Starting with the collagen sold as Avitene by FMC Corporation, an equal parts blend of 25, 35, and 50 mesh collagen fibers are made into a 3.5 percent by weight aqueous dispersion containing 15 percent by volume petroleum ether, which immediately forms a gel. The fibers in the gel are subjected to attrition for 30 seconds at high speed in a Waring blender. The dispersion of fibers still in the gel state is allowed to stand for one hour. The resultant gel is spread into a 50 mil thick wet film. This wet film is soaked in a 5 percent sodium bicarbonate solution containing 400 ppm glutaraldehyde for 1 hour, which makes the wet film porous. The bicarbonate neutralized porous collagen film is then air dried. The dried film is rinsed with water for 1 hour and is then soaked in 20 percent glycerol for 15 minutes. The film is then force dried on a heated cam under slight pressure using a Bessler photographic dryer which used a coarse mesh nylon belt (in place of the usual cotton belt) to provide faster heat exchange. The dried film is soaked in Tollen's reagent, Ag(NH.sub.3).sub.2 OH, for 5 minutes, rinsed in water for 1 hour, and finally soaked in 20 percent glycerol for 15 minutes. It is then air dried. The resultant dried compressed tanned collagen foam film, which is about 12-15 mils thick, is then coated 5 times (with air drying after each coat) with a dispersion of 20 percent Tuftane 110 polyurethane in tetrahydrofuran using a No. 60 Meyer rod, which resulted in the addition to the collagen layer of a polyurethane film about 3-5 mils thick. This was then dried. The resultant laminated film of polyurethane on a compressed foam collagen film has a moisture vapor transmission rate of about 3 mg/hr/cm.sup.2. The dressing was sterilized by being subjected to 2.5 megarods of cobalt irradiation and was then suitable for use as a surgical dressing, particularly for burns.

The above dressing was tested on a Aminco Porosimeter and the collagen portion was found to have a porosity of 75.7 percent, of which 51 percent was from pores having pore diameters larger than 95.264 microns, and the other 24.7 percent was fairly well distributed among a very wide range of smaller pores, e.g. 6.3 percent was from pores ranging from 14.71 down to 10.13 microns, and there were 0.2 percent pores as small as 0.016-0.013 microns. This indicates a well-distributed porous collagen structure with varying size pores.

Example 2 Dressing Without Silver

Example 1 was repeated except that no silver metal was impregnated in the collagen layer, i.e. the step of soaking in Tollen's reagent was omitted. The resultant dressing was substantially identical to that of Example 1 except that it does not contain any silver.

The bacteriostatic activity advantage of the silver-impregnated dressing of Example 1 over the non-silver dressing of Example 2 is unexpectedly high and is demonstrated dramatically by a zone of inhibition microbiological test procedure wherein a culture is made from beef serum containing some 6,000 viable cells of Pseudomonas aeruginosa, which has been incubated and placed on an agar plate, and 1 inch discs of the dressing of Example 1 and of the dressing of Example 2 are placed, collagen side down, on the surface of the agar. The zone of inhibition for the Example 1 silver-containing dressing disc was 32.3 mm. while that for the Example 2 non-silver impregnated dressing disc was 0.

RELATED UNSUCCESSFUL PRODUCTS

Similar materials to those used in the dressing of our invention have been used by us in dressings made by different constructions, for example, through the use of adhesives, and these have failed because of delamination in animal tests. Collagen films have also been made by us as dense continuous sheets which were de-aired in the gel state before they were cast into a film and so lacked the porosity of the present collagen film. These nonporous collagen films failed in critical tests on certain species of experimental animals although they appeared satisfactory on other species of animals.

The dressings of the present invention have been successfully evaluated on a number of different experimental animals. The dressings were evaluated on full thickness skin injuries using rats and rabbits. Dressings were applied and the healing response was observed over a 4-7 day period. The results indicated a wound bed suitable for grafting.

The dressings of the present invention are elastic, pliable, flexible, soft, and have the ability when wet out to conform to the topography of the wound site.

Particular embodiments of the invention have been used to illustrate the same. The invention, however, is not limited to these specific embodiments. In view of the foregoing disclosure, variations or modifications thereof will be apparent, and it is intended to include within the invention all such variations and modifications except as do not come within the scope of the appended claims.

Claims

We claim:

1. A pliable, surgical dressing especially useful in the treatment of burns, comprising a thicker layer of a compressed, tanned collagen foam film and laminated to one surface of said compressed foam, a thinner layer of plastic film having a moisture vapor transmission rate from 2-7 mg/hr/cm.sup.2 .

2. The dressing of claim 1 wherein the plastic film is polyurethane.

3. The dressing of claim 1 wherein the compressed collagen foam layer is 3-30 mils thick.

4. A pliable, surgical dressing especially useful in the treatment of burns, comprising a thicker layer of compressed, tanned collagen foam film having silver metal impregnated therein and laminated to one surface of said compressed foam, an outer thinner layer of plastic film having a moisture vapor transmission rate from 2-7 mg/hr/cm.sup.2.

5. The dressing of claim 4 wherein the plastic film is polyurethane.

6. The dressing of claim 4 wherein the amount of silver metal is from 0.5-1.5 mg silver per square inch of collagen film.

7. The dressing of claim 4 wherein the compressed collagen foam layer is 3-30 mils thick.