U.S. patent number 3,800,792 [Application Number 05/244,439] was granted by the patent office on 1974-04-02 for laminated collagen film dressing.
This patent grant is currently assigned to Johnson & Johnson. Invention is credited to Jack Guldalian, Jr., James J. McKnight.
United States Patent |
3,800,792 |
McKnight , et al. |
April 2, 1974 |
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.
Inventors: |
McKnight; James J.
(Martinsville, NJ), Guldalian, Jr.; Jack (Laurence Twp.,
Mercer County, NJ) |
Assignee: |
Johnson & Johnson (New
Brunswick, NJ)
|
Family
ID: |
22922775 |
Appl.
No.: |
05/244,439 |
Filed: |
April 17, 1972 |
Current U.S.
Class: |
602/50; 530/356;
128/DIG.8; 602/58 |
Current CPC
Class: |
A61L
15/325 (20130101); A61L 15/325 (20130101); A61L
15/26 (20130101); A61L 15/26 (20130101); A61L
15/425 (20130101); A61L 15/26 (20130101); C08L
75/04 (20130101); A61L 15/18 (20130101); A61L
15/425 (20130101); C08L 75/04 (20130101); Y10S
128/08 (20130101) |
Current International
Class: |
A61L
15/16 (20060101); A61L 15/26 (20060101); A61L
15/42 (20060101); A61L 15/32 (20060101); A61l
015/00 () |
Field of
Search: |
;128/156,334,DIG.8
;260/114 ;264/28 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Gaudet; Richard A.
Assistant Examiner: Yasko; J.
Attorney, Agent or Firm: Sherman; Herbert I.
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.
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.
* * * * *