GB2118068A - Artificial skin - Google Patents

Abstract

An artificial skin is provided usable more especially for the treatment of burns or wounds, characterized in that it is obtained by pouring simultaneously on a support (1) two polymer solutions (8, 9) one on the other which, after coagulation in a bath and separation from the support (1) form two flexible and distinct layers (10, 11) joined together. Preferably, the first layer (11) applied to the wound is bioresorbable and is formed from an amino polyacid based polymer. The second layer (10) is advantageously formed from acrylonitrile homopolymers or acrylonitrile copolymers comprising at least 40% by weight of units coming from the acrylonitrile. <IMAGE>

Description

SPECIFICATION Artificial skin The present invention relates to an artificial skin, usable more especially in the treatment, for men or animals, of burns, skin sores or wounds, zones where skin has been removed for grafting purposes, or else for covering the grafts themselves. More particularly, the present invention relates to an artificial skin comprising two superimposed layers.

Such skins are already known from the prior art. French Patents No. 2077361 to PARKE DAVIS, No. 2377205 to BATTELLE MEMORIAL INSTITUTE and No. 2332863 to the MASSACHUSETTS INSTITUTE OF TECHNOLOGY may be cited. All those Patents relate to skins comprising two layers, one of them, so called external layer, forming a protection of the sore with respect to external microorganisms while being permeable to gases and vapors, particularly water, whereas the other layer, placed in contact with the sore, is spongy and alveolar. This latter layer is bioresorbable in the skin according to French Patent No. 2377205 where it is not so in the other two afore-mentioned Patents, the layer according to French Patent No. 2077361 serving essentially as receptacle for the waste from the exudates of the sore.

However, during the preparation of artificial skins according to the above-mentioned Patents, an intermediate adhesive layer or an adhesive ribbon is generally used to join together the two layers previously prepared independently of each other. If need be, the previously independently prepared layers may be joined together by thermoplastic fusion. All the skins thus prepared have in particular the disadvantage of requiring numerous handling operations to obtain them. Furthermore, it has proved that some artificial skins could not be prepared industrially in a satisfactory way according to the above mentioned processes, for the adhesion between the two layers was not sufficient or because one of the two layers was too fragile, taken individually, to be handled.

One aim of the present invention is then to provide an artificial skin not having the drawbacks of the skins of the prior art and being able to be produced industrially according to a simple process.

An aim of the present invention is more precisely to provide an artificial skin, the two layers of which may be obtained simultaneously.

Another aim of the present invention is to provide ansrtificial skin having improved mechanical properties, and therefore able to be handled easily.

Another aim of the present invention is to provide an artificial skin which is well tolerated by man.

A further aim of the present invention is an artificial skin permitting rapid healing of the sore.

Yet another aim of the present invention is to provide an artificial skin which may be left on the sore for several days, thus requiring no daily renewal by the medical staff.

Thus, the skin of the present invention may be left in contact with the sore during the whole healing period.

More precisely, in its preferred embodiment, the aim of the present invention is to provide an artificial skin easily obtained and in which the layer applied in contact with the sore is resorbable.

There has now been discovered, and this is what forms the subject matter of the present invention, an artificial skin characterized in that it is obtained by simultaneous pouring on a support, of two polymer solutions, one on the other, which after coagulation and release from the support form two flexible and separate layers joined together.

The invention will be better understood from the accompanying drawing which shows schematically and without a definite scale a preferred method of industrially preparing an artificial skin in accordance with the present invention.

To obtain an artificial skin in accordance with the present invention, the following describes how to set about it with reference to Figure 1. An endless strip (1), generally made from polished metal and advantageously from stainless steel, is set in motion for example by means of the drive roller (2), whereas the other rollers (3) serve as change of direction rollers and allow the strip (1) to have the circuit shown in Figure 1. Of course, this circuit may have any other configuration. Strip (1) penetrates into a bath (4) contained in a container (5), this so called coagulation bath being more generally formed from water or water to which a surface active wetting agent and/or possibly a product such as acetic acid have been added, in an amount less than 15% by weight.When strip (1) is moving, there is poured on this latter by means of pouring devices (6 and 7) respectively the polymer solutions (8 and 9) intended to form respectively the two layers (10 and 11) of the artificial skin which is being prepared, the devices (6, 7) being arranged so that the layers (10, 11) obtained are disposed one on the other.

More precisely, one of the pouring devices (6 or 7) will be disposed upstream of the other (7 or 6). l his is shown schematically on a larger scale in Figure 2, which is a longitudinal section of the part of the complete circuit defined by the dash-dot lines (12, 13), the thickness of the strip (1) not being shown in this sectional view. Pouring devices (6, 7) are of any known type and comprise an elongate slit in their part the ciosest to the strip (1), this slit being disposed perpendicularly to the direction of advance of the strip (1) shown by the arrow. The spacing of the slit of each device (6, 7) may determine the thickness of the layers (10, 11) of the polymer solutions (8, 9) deposited on the strip.If need be the thickness of the layers (1 0,11) of the polymer solutions may be obtained by the spacing between the lower end of the devices (6, 7) and the strip (1). The pouring devices may comprise a scraper for adjusting the thickness of the layers. Advantageously, the polymer solution (8) intended to form the thinnest layer (10) of the skin is deposited first on the moving strip (1), the polymer solution (9) being deposited on layer (10). In this case, device (6) containing the polymer solution (8) is disposed upstream of the device (7) containing the polymer solution (9). The two polymer solutions (8, 9) are deposited on the strip (1) before this latter penetrates into the coagulation bath (4). When the two layers (10, 11) of polymer solution penetrate into the bath (4), coagulation occurs.At the position where roller (3 bis) is located, the assembly (14) formed by the two coagulated layers (10, 11) is separated from the strip (1) and is wound about the roller (1 5) as shown by the arrow. Thus, the artificial skin is obtained and generally the thicknesses of the two layers (1 0, 11) forming the assembly (14) are less than those of the layers (10, 11) of the polymer solutions deposited on the strip (1). However, in the description, for the sake of simplicity, the same numbering will be kept to designate either the layers (10, 11) of the polymer solutions deposited on the strip 1, or the layers (10, 11) of the skin, that is to say of the assembly (14) obtained after coagulation in the bath (4).

It should be pointed out that assembly (14) passes advantageously into washing troughs (not shown) disposed after container (5) before being wound on a take-up roller. Moreover, the polymer solution (9) comprises advantageously a pore forming agent in suspension and, in this case, there should be provided at the outlet of container (5) troughs for lixivating this pore forming agent which may for example be sodium chloride. This pore forming agent may be preferably formed by calcium carbonate having a well defined grain size and in this case the assemly (14) is advantageously fed into troughs containing dilute acetic acid (in a concentration generally between 0.1 and 15% by weight), which increases the porosity and promotes communication between the pores of this layer (11) when the calcium carbonate suspension reacts with the acetic acid.Advantageously, the grain size of the calcium carbonate used is between 4 and 20 microns and it is added to the polymer solution (9) in an amount such that it corresponds from 2 to 20 times to the weight of the polymer in solution (9). If need be, the assembly (14) may be wound directly on roller (15) at the same time as a plastic grid disposed between the turns of the wound assembly (14) and lixivation may be carried out by causing the wound assembly to soak in the acetic solutions, then by washing with water. The skin obtained according to the above described process comprises two flexible and separate layers joined together over the whole of their surface.

The thickness of layers (10, 11) deposited on strip (1) is chosen so.that the artificial skin obtained has a first layer (11), which is applied in contact with the skin, whose thickness is between 100 and 2,500 microns, preferably between 20Q and 1,500 microns, and a second'layer(l0), forming an external protection, whose thickness is between 10 and 200 microns, preferably between 20 and 100 microns.

Generally, the polymer solutions (8. 9) are deposited on strip (1) at a temperature between 1 and 500C and preferably between 5 and 400 C. The temperature of the bath (4) is generally between 1 and 500C and preferably between 5 and 400C. Devices, not shown in the figure, may possibly be provided for continuously renewing the bath while agitating it to homogenize it. Similarly, when strip (1) leaves the bath, rubber scrapers, not shown, advantageously rub against these two faces so as to hold back the liquid of the bath (4) as much as possible and to cause it to drop back into the container (5). In the neighbourhood of the drive roller (2), strip (1) is advantageously dried by any appropriate device (not shown).

The polymer solutions (8, 9) are chosen so that the artificial skin obtained comprises a first layer (11), applied in contact with the sore, whose structure is alveolar and porous, the diameter of the pores is generally between 10 and 100 microns, the porosity being between 70 and 95%. The porosity is defined as being the ratio (multiplied by 100) between the volume of the pores and the volume of the pores + the volume of the polymer in this first skin layer (11) of the artificial skin. Preferably, the polymer solution (9) is chosen so that it allows an artificial skin to be obtained in which the layer (11) is bioresorbable during healing of this sore.The polymer solution (8) is advantageously chosen so that the artificial skin obtained has a second layer (10), which offers a selective permeability promoting: ~discharge from the sore of the serosities with retention of the proteins, ~protection of the sore against external micro-organisms, such as microbes, viruses or fungi, ~maintenance at the level of the sore of sufficient humidity for allowing renewal of the tissues.

A section of this layer (10) has a dense appearance under the microscope (magnification of 200).

The polymer in solution (9) is advantageously chosen from the amino polyacid based polymers.

Thus, these polymers are generally polymers or copolymers of alpha amino acids or alpha amino acids comprising another carboxylic group, possibly esterified.

The preparation of such macromolecular substances is well known, particularly from "Synthetic Polypeptides" by Bamford, Elliot and Hauby, Academic Press, New York (1956) and from "Advances in Protein Chemistry" 13, 243 and following (1958).

As amino diacid esters, alkyl esters, for example lower alkyl (methyl, ethyl) esters may more especially be used. The alpha amino diacids are for example glutamic acid and aspartic acid.

The polymer in solution (9) is preferably a L-Leucine and aspartic ester copolymer. The molar percentage of L-Leucine is generally between 30 and 70%, the rest of the copolymer comprising the esterified diacid. Such copolymers have advantageously a reduced specific viscosity, measured at 250C in dichloroacetic acid at 2 g/liter, between 20 and 100 ml/g and preferably between 30 and 70 ml/g.

For preparing this copolymer, the N-carboxyanhydrides (NCA) of leucine and of the ester of the alpha amino diacid (the alpha COOH function not being esterified) are prepared first of all by action of phosgene on the free amino acid function of these substances. Then copolymerization of the NCAs is carried out in the presence of a polymerization catalyst, for example sodium hydride and/or of triethylamine. In the case where benzyl aspartate is used, a transesterification of the copolymer obtained is then advantageously carried out to replace the benzyl group by a methyl group. All or part of the ester functions of the copolymer may also be hydrolized so that it contains units of aspartic acid in its macromolecular chain.Advantageously, the copolymer contains in molar amount less than 15% of aspartic acid units and less than 5% of benzylic ester which has not been transesterified.

The solvents used for preparing the polymer solution (9) are advantageously organic solvents, or mixtures of solvents chosen more especially from dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMAC) and tetrahydrofuranne (THF). The concentration of the polymer solution (9) is advantageously between 1 and 20% by weight, and preferably between 2 and 15% of polymer.

The polymer of solution (8) is not bioresorbable and it is chosen for example from the homopolymers of acrylonitrile or from the polymers or mixture of polymers comprising in their macromolecular chain recurrent units coming from the polymerization of acrylonitrile and monomers comprising sulfonic groups and/or from the polymerization of acrylonitrile and monomers comprising tertiary nitrogens which are quaternized.

Among the acrylonitrile and sulfonic monomer based polymers may be mentioned by way of illustration those obtained by copolymerization of acrylonitrile with vinylsulfonic, 1-propen 1-sulfonic, allylsulfonic, methallylsulfonic or allyloxyethylsulfonic acid; 2-buten or 3-buten sulfonic acid; hexenesulfonic, more especially hexene-1-sulfonic acid; methylbutenesulfonic, methallyloxyethylsulfonic, 3 allyloxy 2-propanol 1"sulfonic, allylthioethylsulfonic or 3-allylthio 2-propanol 1 -suEfonic acid; vinylbenzene sulfonic, more especially 3-vinyl benzene 1-sulfonic acid; vinyloxybenzenesulfonic, more especially 2-vinyloxy or 4-vinyloxy benzene 1 -sulfonic acid; isopropenylbenzenesulfonic, more especially 2-isopropenyl or 4-isopropenyl 1 -sulfonic acid; bromovinylbenzenesulfonic, more especially 2-bromo or 4-bromo 3-vinyl benzene 1-sulfonic acid; alpha-methylstyrenesulfonic, alpha-ethylstyrenesulfonic or isopropenylcumenesulfonic acid; mono, di- or trihydroxyvinyl-benzene-sulfonic acid; 2,5dichloro vinylbenzene 1 -sulfonic, isopropenylnaphtalene-sulfonic or vinyldichlornnaphtalene-sulfonic acid; or o- or p-allylbenzenesulfonic acid; o- or p-methallylbenzenesulfonic acid; 4-(o- or pisopropenylphenyl) n-butene 1-sulfonic acid; vinylchlorophenylethanesulfonic acid; o- or pallyloxybenzene-sulfonic acid; o- or p-methallyloxybenzene-sulfonic acid; vinylhydroxyphenylmethanesulfonic acid; vinyltrihydroxyphenylethanesulfonic acid; or 2-isopropyl 2-ethylene 1 -sulfonic acids, these acids being possibly salified.

In these polymers, the proportion of units coming from the acrylonitrile is generally between 40 and 99% and preferably between 60 and 96% (by weight with respect to the total weight of the copolymer). As particular examples of such copolymers, the copolymers of acrylonitrile with methallylsulfonic acid or the salts thereof may more especially be mentioned, the method of obtaining of which is described in French Patent No. 2076854.

Among the acrylonitrile and tertiary nitrogen monomer based polymers there may be mentioned by way of illustration those obtained by copolymerization of acrylonitrile with vinyldimethylamine, allyldimethylamine, 1-dimethylamino 1 -propene, 2-dimethylamino 1 -propene, 1-dimethylamino 2butene, 4-dimethylamino 1-butene, 3-dimethylamino 1-butene, 3-dimethylamino 2-methyl 1-propene, methylethylallylamine, vinyldiethylamine, 5-dimethylamino 1 -pentene, 4-dimethylamino 3-methyl 1butene, methylpropylallylamine, allyldiethylamine, 6-dimethylamino 1 -hexene, ethylvinylbutylamine, allyldiisopropylamine, 3-dimethylamino 2-propyl 1 -pentene, allyldibutyiamine, dialkylaminostyrenes, in particular dimethylaminostyrene and diethylamino styrene, vinylpyridines in particular N-vinyl-pyridine, 2-vinyl pyridine, 3-vinyl pyridine, 4-vinyl pyridine, or the substitution derivatives thereof such as 5methyl 2-vinyl pyridine, 5-ethyl 2-vinyl pyridine, 6-methyl 2-vinyl pyridine, 4,6-dimethyl 2-vinyl pyridine, N-vinylcarbazol,4-vinyl pyrimidine, 2-vinyl benzimidazol.

In these polymers, the proportion of units coming from the acrylonitrile is generally between 40 and 99% and preferably between 60 and 96% (by weight with respect to the total weight of the copolymer).

The agents for quaternizing tertiary amino groups as well as the processing conditions have been described in written works. Generally, mineral acid esters such as alkyl, cycloalkyl or aralkyl halide are used. Preferably, the alkyl, cycloalkyl and aralkyl radicals contain at most 14 carbon atoms. As such quaternization agents there may be mentioned ethyl, methyl, propyl, cyclohexyl or benzyl chlorides, bromides and iodides and dimethyl or diethyl sulfates.

The copolymers having sulfonic groups or quaternary ammonium groups described above are insoluble in water (solubility generally less than 1% by weight) at room temperature, whereas they are soluble in organic solvents or solvent mixtures. Thus, the solvents used for preparing the polymer solution (8) are organic solvents or solvent mixtures, preferably polar and aprotic, chosen more especially from DMF, NMP and DMAC.

The concentration of the polymer solution (8) is generally between 1 and 50% of copolymer, preferably between 5 and 40%.

The polymer solution (8) may further comprise a mixture of a polymer comprising in its macromolecular chain units resulting from the copolymerization of acrylonitrile and of a monomer having sulfonic group and a polymer comprising in its macromolecular chain units resulting from the copolymerization of acrylonitrile and of a monomer having tertiary nitrogen which is quaternized, such as those described above. Such biionic polymers are included in the French Patent published under the No.2144922.

The artificial skin of the present invention is advantageously cut up into convenient formats for clinical use and is generally kept in a humid condition after being treated with an hydrophile additive such, for example, as glycerine or preferably polyethylene glycol in a molecular weight between 300 and 1000 for example. This impregnation treatment with an hydrophile additive may take place in troughs, just before the skin (14) is rolled about the take-up roller (15).

EXAMPLE An artificial skin is prepared continuously by using the apparatus, previously described and shown in the figures.

The polymer solution (8) introduced into the pouring device (6) is a 19.6% solution in DMF of acrylonitrile-sodium methallylsulfonate copolymer, comprising 0.6 Eq/kg of group SO, and whose reduced specific viscosity at 5 g/l in DMF (containing 4.25 g/l of sodium nitrate) at 250C is 200 ml/g.

This copolymer comprises by weight 90.5% of units coming from the acrylonitrile.

The polymer solution (9) introduced into the pouring device (7) comprises: - 8 g of leucine-methyl aspartate polycondensate (molar ratio 62/38, whose reduced specific viscosity measured at 250C in dichloroacetic acid at 2 g/l is: 50 ml/g); - 108 g of N-methylpyrrolidone; ~132 g of tetrahydrofuran; - 80 g of calcium carbonate (grain size 12 microns).

The device (6) allows a layer (10) of a thickness of 100 microns to be deposited on strip (1), made from stainless steel of a thickness of 0.5 mm, whereas device (7) allows a layer (11) of a thickness of 400 microns to be deposited on layer (10).

The positioning of device (7) is such that the two layers (10, 11) are in contact for 12 seconds before being immersed in the coagulation bath (4).

The width of the strip is 20 cm and the width of the layers (1 0, 11) is 1 6 cm, which corresponds to the length of the slit of the devices (6, 7).

The coagulation bath (4) is a 1% (volume/volume) acetic acid and 0.2% (volume/volume) "DECON 90" solution maintained at 200C. "DECON 90", commercialized by the firm PROLABO (No.

23280 in the 1975 catalogue) is an aqueous solution of KOH, triethanolamine, sodium citrate, sodium laurylethoxysulfate, polyoxyethylenated alkylphenol and alkylbenzenesulfonic acid.

The polymer solutions (8, 9) are at 200C in pouring devices (6, 7).

With a length of 1 meter of strip (1) immersed in bath (4), the speed of advance of the strip is adjusted to 0.25 m/min so that the coagulation time is sufficient.

Assembly (14) is collected on roller (15) on leaving the coagulation bath, after it (14) has been separated from the supporting strip at (3 bis).

Assembly (14) is then unwound from roller (15) and soaked for 3 hours in a solution Identical to the above described coagulation bath (4).

Assembly (14) is then rinsed with distilled water for 2 hours.

Assembly (14) is then cut into elements of 20 cm in length and 14 cm in width and is impregnated with a 80/20 (by volume) mixtures of polyethylene glycol having a molecular weight of 300 and of PBS solution/No. 83501 in the BIOMERIEUX catalogue. The PBS is an aqueous solution comprising the following elements: NaCI 8 g/l KCI 0.2 g/i CaCI2, 2H20 0.132 g/l MgCI2, 6H2O 0,100 g/l Na2HPO4, 2H20 1.441 g/i KH2PO4 0.2 g/l The final product is advantageously presented in a heat sealed impermeable bag sterilized by radiation (2.5 megarads).

The artificial skin thus obtained comprises an external layer (10), made from acrylonitrile copolymer, whose thickness is 65 microns and whose appearance is dense under the microscope (magnification of 200) and a bioresorbable layer (11) whose thickness is 280 microns and in which the pore diameter varies from 20 to 60 microns.

The artificial skin thus formed has a permeability to water vapor of 1.35 1/jm2 (at 220C, EH 60%) and a water flow under a 2 bars differential pressure of 1,1 50 1/jm2.

Samples of this sterilized artificial skin were applied, on 49 patients, in zones where skin had been taken for self-grafting. These technical tests showed that tolerance was very good and that in particular no allergic reaction was noted. The artificial skin was left on each patient for the whole period of healing of the place from which the graft had been taken. At the end of the healing period, it was noted that the bioresorbable layer (11) had completely disappeared. The experimenters emphasize the fact that the zones where skin had been taken for grafting ceased to be painful within a few hours after the operation, contrary to what usually happens. In the two series of patients studied, a reduction of three to four days on average of the usual healing time was noted in most of the patients. Healing left a scar zone of good quality and very satisfactory appearance.

Although the above-described artificial skin was obtained by pouring the polymer solution (8) directly on support (1), that is to say on the moving metal strip, it is of course within the scope of the invention if the polymer solution (8) is poured on a fabric or porous non woven ribbon having the same speed of advance and substantially the same width as that of strip (1). This ribbon of a very fine thickness (of the order of 20 to 60 microns) may be made from polypropylene, polyester or polyamide more particularly. It is supported by strip (1) at the time when polymer solutions (8 and 9) are deposited and forms an integral part of the artificial skin obtained after this latter has been separated from strip (1) at the point shown at (3 bis). Advantageously, this ribbon is situated only in the second layer (10) of the skin obtained whose mechanical resistance it reinforces.

Furthermore, the polymer solution (8) may possibly be poured on a film resting on strip (1) and advancing therewith (at the same speed), said film being subsequently separated from the artificial skin (14) obtained.

An advantageous variant of the process consists in not winding the skin (14) about a take-up roller (15) and in carrying but continuously, in successive troughs, the coagulation, soaking, rinsing, impregnation treatment operations, then (outside the troughs) in cutting up and packing said skin.

Claims (11)

1. An artificial skin, usuable more especially for treating burns and wounds or sores, which is obtained by pouring simultaneously on a support two polymer solutions one on the other which, after coagulation in a bath and separation from the support, form two flexible and distinct layers joined together.

2. An artificial skin according to Claim 1, wherein the polymer solutions are chosen so that said skin comprises: - a first layer applied in contact with the wound, resorbable by the organism, of a biodegradable, alveolar, hygroscopic material having communicating cells and being spongy and permeable to liquids, and - a second layer forming an external protection, permeable to gases but maintaining sufficient humidity and stopping the external pathogenic micro-organisms.

3. An artificial skin according to Claim 2 wherein the polymer solution skin according to Claim 2 wherein the polymer solution for obtaining the first layer comprises essentially an alpha amino acid polymer or copolymer, and the polymer solution for obtaining the second layer comprises essentially a polymer chosen from the homopolymers of acrylonitrile or from the polymers or polymer mixtures comprising in their macromolecular chain recurrent units coming from the polymerization of acrylonitrile and of monomers comprising sulfonic groups and/or from the polymerization of acrylonitrile and monomers comprising tertiary nitrogens which are quaternized.

4. An artificial skin according to Claim 3, wherein the polymer solution for obtaining the first layer comprises e polycondensate of leucine and aspartic acid whose carboxylic group the furthest from the amino group is, at least in part, esterified by a methyl group, and in that the polymer solution for obtaining the second layer comprises a polymer obtained by copolymerization of acrylonitrile and sodium methallylsulfonate.

5. An artificial skin according to any one of Claims 2 to 4, wherein the polymer solution for obtaining the layer comprises a polymer in which the proportion of units coming from acrylonitrile is greater than 40% by weight, with respect to the total weight of the polymer.

6. An artificial skin according to any one of Claims 2 to 5, wherein the polymer solution for obtaining the first layer comprises a pore forming agent in an amount such that it corresponds from 2 to 20 times to the weight of the polymer of this solution.

7. An artificial skin according to any one of the preceding claims, wherein the polymer solution comprises as pore forming agent calcium carbonate and in that the coagulation bath is an aqueous solution comprising between 0.1 and 15% of acetic acid (by weight).

8. An artificial skin according to any one of Claims 2 to 7, wherein the polymer solution comprises from 1 to 50% by weight of polymer, in that the polymer solution comprises between 1 and 20% by weight of polymer, in that solution for forming the external layer of the skin is poured on the support and in that the solution is poured on layer which has just been deposited on the support.

9. An artificial skin according to any one of the preceding claims, wherein the polymer solutions are poured on an endless moving strip.

10. An artificial skin according to any one of the preceding claims, wherein the polymer solutions are poured on a reinforcing ribbon disposed on the support, said ribbon forming an integral part of the skin obtained after separation thereof from the support.

11. An artificial skin substantially as herein described and exemplified with reference to the accompanying drawings.