WO2008056090A1

WO2008056090A1 - Device for regenerating human skin and method for manufacturing said device

Info

Publication number: WO2008056090A1
Application number: PCT/FR2007/052323
Authority: WO
Inventors: Bernard Ragaru; Benjamin Herbage
Original assignee: Symatese
Priority date: 2006-11-10
Filing date: 2007-11-12
Publication date: 2008-05-15
Also published as: FR2908290A1; FR2908290B3; EP2083751A1

Abstract

The invention relates to a device for regenerating human skin in the form of a multi-layered complex that comprises a resorptive polymer inner matrix (1) capable of inducing skin regeneration by contact with the muscle or the subcutaneous tissues (3), a non-resorptive net-like textile ply, and a transparent outer carrier, characterised in that the net-like textile ply is entirely contained in the mass of the transparent carrier (4.1, 4.2).

Description

DEVICE FOR REGENERATING HUMAN DERMA AND

METHOD OF MANUFACTURING THE SAID DEVICE

The invention relates to a device for the regeneration of the human dermis. It also relates to a method for the manufacture of such a device.

The regeneration of the human dermis by means of collagen matrix or equivalent followed by an epidermal graft is one of the most used techniques to reform the skin. Third degree burns are one of the major indications of this technique. Regeneration of the dermis is also required in reconstructive surgery for the treatment of keloids, retractile bridles, scarred wardrobes, hypertrophic scars, cutaneous necrosis following failure of a skin graft, nevi. Dermal regeneration is also required after cutaneous tumor excision, for the treatment of chronic or acute wounds when the dermis needs to be regenerated as well as in reconstructive trauma surgery.

The document US Pat. No. 4,060,081 describes a device for the regeneration of the derm of the type of that of the invention in the form of a multilayer complex successively associating: a resorbable polymeric matrix, intended to be in contact, depending on the indication, with the muscle or the subcutaneous tissue,

a textile web of unspecified characteristics applied on the face of the matrix, not in contact with the muscle or the subcutaneous tissue, a permeable film acting as a temporary pseudo epidermis, applied to the blade, directly on the textile web.

The complex is thus in the form of three distinct layers, respectively: a resorbable polymeric matrix, a textile web, - a transparent permeable layer, in practice in the form of a silicone film.

When these multilayer complexes are used for the regeneration of the dermis, particularly in burn victims, the surgeon proceeds as follows. First and if necessary, the nonviable burnt dermis parts are excised, so as to obtain a viable underlying tissue.

Directly on the muscle, or depending on the case, on the subcutaneous tissue: the multilayer complex is positioned so that the resorbable polymeric matrix is in contact with the muscle or the subcutaneous tissue, the device is then fixed on the muscle or cutaneous tissue, by means of staples or by suture, so as to prevent it from moving during the regeneration phase of the dermis and to seal the wound. - When the dermis is regenerated, which can take about three weeks, remove the double layer transparent film / textile web, then, in a final step, we proceed to an epidermis graft on the dermis thus regenerated.

One of the major drawbacks of the device described in document US Pat. No. 4,060,081 is that it presents a direct contact between the dermis during formation and the textile web. Indeed, at the time of tearing of the double layer permeable film / textile web, two situations can occur.

In some cases, tearing of the film / textile web assembly causes at least partial tearing of the dermis formed due to the colonization of the textile by the host cells. It follows possible bleeding and irregularity of the dermis. The epidermis graft is then performed on a non-homogeneous dermis with the risk of persistence of skin defects after reconstruction.

In other cases, the film can separate from the sheet, so that it remains fixed in the dermis during training. In this hypothesis, the epidermis graft will be performed on a dermis containing a non-resorbable and useless material, with risks of loss of functionality of the skin in terms of flexibility, elasticity and aesthetics due to the persistence of the textile structure.

Another disadvantage of the device of the prior art is to cause tear formation within the transparent sheet and the collagen matrix, at the time of fixing by stapling and during the regeneration of the dermis. The tearing of the matrix of collagen then leaves a hole that will be filled by the formation of a designated tissue

"granulation tissue", a sign of poor dermal reconstruction.

A third disadvantage is that the permeable sheet, in view of its small thickness, manages to tear near the attachment points, under the effect of the movements of the patient. In this hypothesis, the subcutaneous tissue or the muscle is no longer isolated from the ambient air, open to a significant risk of contamination.

A fourth disadvantage is that the textile web provides a certain rigidity to the device. The latter may then not adapt to the wound to be treated in certain regions of the body with a pronounced relief such as the fingers, the face. However, the contact between the polymeric material and the wound bed is essential for good dermal reconstruction.

Finally, the transparency of the permeable film can be affected by the presence of the textile web. However, transparency is essential for the follow-up of wounds and in particular the verification of the absence of infection or hematomas which can lead to the failure of the dermal regeneration. Transparency also makes it possible to check the progress of regeneration of the dermis for the planning of the epidermal graft.

To solve all these problems, the Applicant has developed a new device in which the textile web is integrated in the mass of the transparent layer.

The transparent layer thus reinforced allows the certain removal, not only of the transparent sheet, but also that of the textile material when the dermis is formed definitively, just before the grafting of the epidermis. Furthermore, the Applicant has conducted experiments showing that the layer reinforced in this way, was not subject to widening of the holes formed by the staples, thus preventing any risk of contamination or unsatisfactory reconstruction.

Furthermore, the Applicant has found that the transparency of the layer reinforced with the textile web was better than the transparency of the superimposed layer and textile web. EP 0 943 298 discloses a surgical plate also composed of a multilayer complex comprising two layers, respectively a macroporous textile knitted or nonwoven coated on one side by a non-adherent film.

The problem posed in this document concerns the difficulty of manufacturing such a device by producing a very thin continuous and smooth non-stick silicone film applied to a macroporous fabric (paragraph 23). To do this, the process used, corresponding to that of Figure 2 of the document, consists of dipping a composite glass + tefion sheet in a silicone solution. The silicone-coated composite sheet is then applied to a porous textile, the assembly then being fired at a temperature of about 150 ^° C. in order to allow the silicone to be polymerized. As mentioned in the document, the glass + tefion composite sheet is then removed to leave the silicone film on the porous textile. In other words, the surgical plate described in EP 943 298 as used on the patient consists only of a biocompatible textile layer covered on one of its faces with a thin silicone film.

EP 305 052 discloses a method of manufacturing artificial skin, the problem being based essentially on the combination of the biodegradable regeneration material with the release film. In the final product, and particularly in support of Figure 1, the silicone film partially covers the synthetic biodegradable polymer. There is no question in this document to incorporate in the complex a reinforcing element in the form of a textile web. The fibrous material in question is not related to the reinforcing textile of the nonabsorbable invention, but is instead intended to be colonized by the host cells.

The subject of the invention is therefore a device intended for the regeneration of the human dermis in the form of a multilayer complex associating a resizable colonizable polymeric internal matrix able to induce, by contact with the muscle or the subcutaneous tissue, the regeneration of the dermis, a non-resorbable openwork textile sheet, a transparent external support.

This device is characterized in that the openwork textile web is contained entirely in the mass of the transparent support thus constituting a reinforced transparent support. By the expression "openwork textile web" is meant a woven, a knit, a nonwoven, the textile being openwork.

To promote the joining of the reinforced transparent support, by the textile material, with the resorbable polymeric matrix, the device comprises, between said support and the matrix, an adhesive layer, advantageously a silicone adhesive.

In practice, the resorbable polymeric material may consist of collagen, polysaccharides (cellulose, alginate, agarose, chitosan), glycosaminoglycans (hyaluronic acid, chondroitin sulfate, heparin), glycoproteins (fibronectin, laminin, chondronectin), proteins of structure (for example elastin, gelatin) or resorbable synthetic polymers (polylactic gly colic ...), alone or in combination. Other compounds may be added to the absorbable polymeric material such as for example growth factor, antiseptics, antibiotics. In known manner, the polymeric material may be crosslinked before being applied to the transparent support depending on its nature. In practice, for collagen, the crosslinking agent is glutaraldehyde, formaldehyde, N-hydroxysuccinimide, ethyl 3-dimethylaminopropylcarbodiimide, a polysaccharide functionalized to react with collagen. The crosslinking can also be carried out by physical treatment such as vacuum heat treatment, irradiation.

In the case where the material consists of collagen, it may be native collagen, fibrous, atelocollagen or partially or completely denatured collagen.

In an advantageous embodiment, the resorbable polymeric material consists exclusively of collagen, which is crosslinked before association with the reinforced transparent support.

With regard to the perforated textile web, it must be sufficiently dense to allow effective reinforcement of the support, and therefore avoid the risk of tearing, at the point of contact with the staples, while not affecting the transparency of the support, essential to the visualization of the formation of the dermis by the surgeon, and its conformability essential for its adaptation to the site to be treated. In practice, the density of the textile ply is between 0.6 and 60 g / m ² , advantageously between 15 and 20 g / m ² .

According to another characteristic, the constituent yarn of the web has a dtex value of between 10 and 30, advantageously between 20 and 25 dtex.

Moreover and according to another characteristic, the web contains between 3 and 100, advantageously between 10 and 60 threads and as many picks per centimeter.

In practice, the material constituting the textile web consists of synthetic fibers (polyester, polypropylene) or natural fibers (silk, cellulose), or cotton, in the form of single or multi-strand wire.

As regards the transparent support, it advantageously has a permeability to water vapor, identical to that of the epidermis. In practice, it is preferably in the form of a film of silicone, polyurethane (PU), or polyolefin (polyethylene (PE), polyethylene terephthalate copolysester (PETG), polyvinyl chloride (PVC)) transparent and non-absorbable on time of dermal reconstruction.

To have a transparent support in which the textile web is arranged in a regular manner, that is to say that the distance between said web and one or the other of the surfaces of the support is constant, the transparent support is present in the form of a sandwich comprising two silicone films applied on either side of the textile web.

In practice, the thickness of the reinforced transparent support is between 20 and 1000 microns, advantageously between 200 and 300 microns.

It has also been shown that the regeneration of the dermis could be accelerated by putting the wound to be treated under negative pressure conditions. More specifically, the application of a negative pressure makes it possible to extract the exudates from the wound and consequently, to reduce the edema, to improve the local blood circulation, to promote the neovascularization and to limit the risks of infection. . Epidermal grafting can therefore be considered at a shorter time. This advantage is particularly interesting when treating mobile areas such as hands that require rehabilitation in the shortest possible time.

To allow the exudates to be extracted and the entire treated site to be put under negative pressure, the transparent support assembly - perforated textile sheet of the device of the invention is provided with orifices distributed over all or part of the surface. In practice the orifices are calibrated and distributed so as to allow a satisfactory extraction of exudates and a homogeneous distribution of pressures on the treated area. Preferably, the orifices are through, that is to say that the orifices present in the transparent support communicate with the orifices provided in the textile. With regard to the textile part, the orifices may correspond to the previously mentioned openings or to orifices created in the thickness of the textile.

The invention also relates to the method of manufacturing the device described above.

According to this method: an adhesive layer is sprayed on the surface of a transparent support having in its mass, a perforated textile web, - the polymeric resorbable matrix, possibly crosslinked, is applied to the bonded surface of the transparent support.

In practice, the transparent support is formed by application on both sides of the textile web of two silicone films. In a manner known to those skilled in the art, the films may be bonded together by thermofusion or hot or cold pressing, optionally followed by heat treatment. The presence of the textile web in the support also allows to have a perfectly flat surface, not deformed, adapted to receive the adhesive layer by spraying.

The polymeric resorbable matrix is obtained from collagen or other materials alone or as a mixture, as previously described.

In a particular embodiment, the resorbable matrix consists entirely of collagen. In practice, the collagen is crosslinked and forms a porous dry structure applied directly to the surface of the reinforced transparent layer in the form of a sheet.

The device thus produced is optionally cut and then conditioned before being sterilized.

In the embodiment in which the device of the invention has holes, the orifices are formed in the support assembly - textile web before its association with the resorbable matrix. In this way, the matrix has the advantage of keeping all its integrity, without any defects on the surface in contact with the support or at the level of holes. The perforations can be performed by any technique known to those skilled in the art, in particular laser or mechanically

The invention also relates to a dermal regeneration method consisting of: - beforehand and if necessary, to excise the non-viable or scarred dermis parts,

applying to the subcutaneous tissue or the muscle, the device of the invention, so that the resorbable polymeric matrix is in contact with the said muscle or subcutaneous tissue, to fix the said device on the muscle or tissue cutaneous by fastening means such as stapling or suturing,

when the dermis is regenerated, to remove the fixing means, then the reinforced transparent support,

grafting the epidermis by means of an autograft, a sheet of cultured keratinocytes, a keratinocyte spray or another epidermal regeneration technique.

In practice, before application of the device, it is hydrated.

The invention and the advantages which result therefrom will emerge from the attached exemplary embodiment, with reference to the appended figures.

Figure 1 is an exploded schematic representation of the device of the invention. FIG. 2 is a photograph of the dermal reconstruction carried out by means of the device of the invention compared with that of a device of the trade.

As shown in FIG. 1, the device of the invention comprises a first layer in the form of a resorbable polymeric matrix (1) made in practice of 100% collagen.

The starting collagen is native collagen of bovine dermis, in particular veal, milled and then transformed into gel before being lyophilized, and then cross-linked using glutaraldehyde. The product formed is in the form of a dry sheet, which can be glued directly onto the reinforced transparent support. Preferably, the excess crosslinking agent is removed by washing or chemical reduction.

As shown in FIG. 1, the reinforced transparent support (2) comprises a textile ply (3) consisting of single-strand polyester threads, whose texture corresponds to 36 threads and 36 picks per centimeter, while the density is 17 g / cm.sup.2. m ² .

This textile web (3) is sandwiched between two silicone films (4.1, 4.2), each of thickness about 100 microns.

In practice, the two silicone films are previously applied to each of the surfaces of the textile web to form the reinforced transparent support. The joining of the assembly is obtained by cold pressing followed by a heat treatment. On one of the surfaces of this layer is then applied, by spraying or other coating technique, a silicone adhesive, and then comes to apply the collagen matrix previously prepared.

In a not shown embodiment, the textile web support assembly is perforated with several orifices before being associated with the resorbable matrix. This improved device will be used more particularly for the regeneration of dermis carried out under negative pressure, thus allowing the extraction of exudates satisfactorily and an activation of the dermal regeneration. FIG. 2 is a photograph of the dermal reconstruction (just before the epidermal grafting) carried out by means of the device of the invention (right part (5)) applied on the back of a patient initially burned in the 3 ^rd degree and presenting a scar patch that has been excised. The product was applied directly to the muscle and compared to the INTEGRA® DRT product (left side of the image (6)).

In practice, the surgeon, after excising the rest of the dermis, applies the device so that the face provided with collagen is in contact with the muscle. The size of the device is chosen according to the size of the burn. Once the device is applied, it is then stapled on the adjacent cutaneous tissue or on another device of the same nature. After formation of the dermis, the device is removed as already said by tearing of the only reinforced support. A thin epidermal dermo graft is then performed on the regenerated dermis.

Figure 2 shows the reconstructed dermis in the device after three weeks. As shown in this photograph, the reconstructed dermis in the INTEGRA® DRT device shows granulation tissue budding at stitches (8), indicating poor dermal regeneration. These buds are the result of the holes formed by the staples in the INTEGRA DRT product, holes that expanded during the neoderm formation period.

Conversely, the device of the invention (5) has not torn at the holes formed by the staples and this, thanks to the presence of the textile web in the thickness of the transparent layer. As a result, the reconstructed dermis in the device according to the invention does not show any granulation of granulation tissue at the point of stapling (7).

The presence of the textile web inside the transparent layer has also completely avoided the colonization of the textile by the neoderm, the surface of the neoderm after removal of the transparent layer is smooth and free of bleeding. Removal of the transparent layer could be achieved without any partial excision of the newly formed dermis.

The invention and the advantages derived therefrom are apparent from the foregoing description. It is noted that the good behavior of the device of the invention during the formation of the dermis by virtue of the presence of the perforated sheet in the thickness of the transparent film has allowed: "The absence of contamination

"To avoid the formation of a granulation tissue at the attachment points

"The absence of excision of the neo-formed dermis to the removal of the transparent layer and the textile web" Obtaining a better transparency

Claims

1 / Device for the regeneration of the dermis in the form of a multilayer complex associating a resorbable polymeric matrix capable of inducing, by contact with the muscle or the subcutaneous tissue, the regeneration of the dermis, a nonwoven textile web resorbable, a transparent outer support characterized in that the openwork textile web is contained entirely in the mass of the transparent support.

2 / Apparatus according to claim 1, characterized in that the resorbable polymeric material is exclusively constituted by crosslinked collagen.

3 / Apparatus according to claim 1, characterized in that the density of the textile web is between 0.6 and 60 g / m ² , preferably between 15 and 20 g / m ² .

4 / Apparatus according to claim 1, characterized in that the constituent wire of the textile web has a dtex value between 10 and 30, preferably between 20 and 25.

5 / Apparatus according to claim 1, characterized in that the textile web contains between 3 and 100, preferably between 10 and 60 son and as many picks per centimeter.

6 / Apparatus according to claim 1, characterized in that the constituent material of the textile web is polyester, polypropylene, or cotton, in the form of single or multi-strand wire.

11 Apparatus according to claim 1, characterized in that the transparent support is in the form of a sandwich comprising two silicone films applied on either side of the textile web.

8 / Apparatus according to claim 7, characterized in that the thickness of the transparent support is between 20 and 1000 microns, preferably between 200 and 300 microns.

9 / Apparatus according to claim 1, characterized in that the device comprises, between the transparent support and the polymeric matrix, an adhesive layer. 10 / Apparatus according to claim 1, characterized in that the transparent support assembly - perforated textile web is provided with through holes distributed over all or part of the surface.

11 / A method of manufacturing the device according to one of claims 1 to 10, characterized in that:

- An adhesive layer is applied to the surface of a reinforced transparent support having in its mass, a perforated textile web is applied to the adhesive surface, the polymeric resorbable matrix.

12 / A method according to claim 11, characterized in that the reinforced transparent support is formed by application on both sides of the textile web of two silicone films.

13 / A method according to claim 11, characterized in that the transparent support assembly - perforated textile web is perforated on all or part of its surface, prior to application to the polymeric matrix.