Biological material comprising at least one elastomer matrix and a non-sulfated polysaccharide and uses thereof

Abstract

The present invention relates to a biomaterial comprising at least one elastomer matrix and a polysaccharide, and to its use in the reinforcement, reconstruction and / or filling of tissues, preferably in the reinforcement, reconstruction and / or filling of soft and / or epithelial tissue defects, preferably in the repair of skin and / or mucosa.

Description

TECHNICAL FIELD

[0001] The present invention relates to a biomaterial and its use in the augmentation, reconstruction and / or filling of a tissue, preferably in the augmentation, reconstruction and / or filling of a soft tissue defect and / or epithelial tissue, preferably in the repair of the skin, gingiva and / or mucosa. BACKGROUND

[0002] The "flapless" periodontal surgery solves the problems associated with the functional, aesthetic and biological morbidity caused by the gingival-mucosal soft tissue defects around natural teeth and implants. For example, the gingival recession leads to an unaesthetic smile, it can also be a source of spontaneous and / or induced hypersensitivity, it promotes the development of deep caries and it causes functional discomfort associated with periodontal inflammation, which can compromise the tooth supporting tissues (periodontium), which allow the teeth to be fixed to the maxillary and mandibular base.

[0003] This periodontal disease causes the marginal gingiva and the epithelial-connective junction to move apically with respect to the cement-enamel junction. Their etiology is multifactorial, associated with some predisposing factors (thin biotype, bone fracture, low height and thickness of keratinized tissue, malpositioned teeth, etc.), mechanical factors such as traumatic brushing, bacterial factors (presence of plaque and inflammation) or other factors such as occlusal trauma, smoking, etc.). The soft tissue defects, especially in the oral and dental soft tissues, can be due to trauma or surgical extraction, which often leads to the loss of the original anatomy of the soft tissues. In addition, the changes in the soft tissues have a negative impact on the aesthetic appearance of the patient, thus affecting their satisfaction. Depending on the size of the defect, the tissue deformation can be corrected aesthetically by soft tissue augmentation or by soft tissue reconstruction or by surgical techniques.

[0004] This tissue management can also be combined with other indications such as the improvement of the peri-implant tissues and the maxillary ridge. To solve this tissue loss, it is necessary to consider the use of surgical tissue grafting techniques.

[0005] There are several surgical methods documented in the literature to achieve root coverage (or coverage of exposed implant surfaces) for the treatment of gingival recession, tissue thickening to obtain a robust biotype, and to enhance the keratinized gingival band, which is necessary for the long-term durability of the periodontal and peri-implant environment. Most of these techniques require a second palatal surgical site, (autografts taken from the oral cavity, which lengthens the intervention time and can be a source of postoperative adverse outcomes, with many disadvantages (pain, intraoperative or postoperative massive bleeding, morbidity, delayed healing, osteonecrosis, foreign body sensation or permanent sensory loss of the palate have been reported). These disadvantages are sometimes related to anatomical limitations, since the palate is too thin to provide a sufficient amount of tissue, or when the patient opposes the extraction of the tissue sample from another "donor" site, the patient refuses to receive medical care, since it is very painful and can cause complications.

[0006] A first solution to repair soft tissue defects is to transplant parts of connective tissue from other parts of the patient's body. This is thus called connective tissue autograft. Autograft does not generate a defensive immune reaction, since the tissue comes from the patient. However, it causes a considerable cell death in the transplanted tissue. The ability of the transplanted tissue to generate new cells is able to compensate for this loss, but this depends in particular on the vascularization of the transplanted tissue. Indeed, the latter is essential for tissue reconstruction: blood vessels provide the necessary energy and nutrients for cell proliferation. In addition, autograft requires two surgical sites (excision then transplantation), which can cause complications (pain, abscess, neuralgia). The size of the graft required to fill represents another important limitation.

[0007] Another alternative is to use allogeneic substitutes.

[0008] An allogeneic dermal substitute conventionally used by medical practitioners to reconstruct soft tissues and / or to fill soft tissue defects is the AlloDerm® product sold by the company Biohorizon. AlloDerm® is a cell-free dermal matrix of human origin, from human donor cadaver skin, which has been physically and chemically treated, including histodermic, which consists in separating the fixed fibrous half-bridges from the basal keratinocytes by eliminating all cellular content (epithelial cells, connective tissue, viruses and bacteria), which means that all cellular components of the epidermis layer are removed without altering the collagen fiber bundles or compromising the basement membrane complex, without compromising the components of the connective tissue matrix. This process leaves the extracellular collagen proteins, which provide a basis for cell growth and tissue reconstruction.

[0009] Another allogeneic substitute conventionally used by medical practitioners to reconstruct soft tissues and / or to fill soft tissue defects is the Mucoderm® product sold by the company Botiss. Mucoderm® is a matrix based on natural collagen type I / III and elastin from porcine dermis.

[0010] However, these products have many drawbacks. Indeed, these products are relatively costly, require long post-operative monitoring and early exposure of the matrix limits the vascularization of the graft, leading to a decreased potential of coverage retraction. Moreover, Mucoderm®undergoes a necrotic process. The healing and replacement process by newly formed tissue of AlloDerm®or Mucoderm®is particularly slow, about 10 weeks. Indeed, due to its non-living structure, the healing and replacement of AlloDerm®or Mucoderm®depend on cells and blood vessels present in the surrounding tissue, which leads to a merger slowdown that can result in structural and functional abnormalities. Moreover, their macromolecular structure is different from the physiological gingiva, although their macromolecular composition should be similar. Indeed, the highly dense collagen network of the allogeneic substitute seems to limit cell colonization in vitro and tissue reconstruction in vitro and in vivo. Indeed, the gingival extracellular matrix is constantly restructured to resist mechanical stress. However, the observed fibrotic process is due to a non-physiological restructuring of the gingiva at the implant site. Moreover, the persistence of foreign multinucleated giant cells can induce poor integration of the allogeneic substitute and persistent clinical redness. Furthermore, it has been demonstrated that Mucoderm®shrinks during the healing process of the restructuring process once implanted, leading to a contraction of the wound. Moreover, it has been demonstrated that Mucoderm®presents a problem of disintegration when the implant is subjected to high mechanical stress, inducing a high inflammatory reaction. Finally, the animal origin of certain allogeneic substitutes can sometimes lead to rejection due to religious or philosophical beliefs.

[0011] Other surgical fields are also looking for biocompatible materials allowing to fill tissue defects or losses due to trauma (burns, (dehiscence, laceration), aging or pathologies; or to reinforce tissues after trauma, aging or pathologies. For example, many companies are specialized in the design of implants for the reinforcement of gynecological, urinary or visceral (or parietal) surgery. These materials can be designed for the treatment of vascular wounds, digestive wounds, abdominal hernias, etc. Thus, these biomaterials can be used to design reinforcing implants for the treatment of pelvic organ prolapse, more particularly for the treatment of female pelvic organ prolapse (anterior (urological, cystocele, stress urinary incontinence), middle (genital, vaginal prolapse) and / or posterior (digestive rectocele)) or male Peyronie's disease. This biomaterial can then be made into a stretchable reinforcement sheet, a membrane or an implant core of any shape. The biomaterials currently used with varying degrees of success are of xenogeneic origin (such as Pelvicol®, sold by Bard France SAS) or synthetic (polypropylene such as Parietex®, sold by SOFRADIM). However, Pelvicol®presents a problem of disintegration when the implant is subjected to high mechanical stress, inducing a high inflammatory reaction.

[0012] Document US2012 / 239161 describes an elastomer matrix based on caprolactone and agarose or gelatin. Document CN108034225 describes a method for preparing a composite material comprising an elastomer matrix and chitosan.

[0013] There is therefore a need to provide a new biomaterial, capable of enhancing, reconstructing and / or filling tissue defects, facilitating the use by the practitioner and having mechanical properties suitable for implantation in soft tissues in terms of elasticity and volume retention. There is also a need for a biomaterial having good biocompatibility and a degradation suitable for tissue regeneration. There is also a need to provide a biomaterial of non-animal origin. SUMMARY

[0014] The subject of the application is therefore a biomaterial for tissue repair, comprising:

[0015] - at least one elastomer matrix, and

[0016] - a non-sulfated sugar polymer.

[0017] Another subject of the application is the use of this biomaterial in tissue repair, preferably in soft and / or epithelial tissue repair, preferably in skin and / or mucosa repair.

[0018] Another subject of the application is a method for preparing a biomaterial. DETAILED DESCRIPTION

[0019] The subject of the application is therefore a biomaterial for tissue repair, comprising:

[0020] - at least one elastomer matrix, and

[0021] - a non-sulfated sugar polymer.

[0022] The advantage of the application is to provide a porous bioabsorbable / biodegradable elastic biomaterial that promotes cell migration and vascularization. The biomaterial according to the application also provides better tissue bio-integration without any risk of microbial contamination.

[0023] In the meaning of the application, the term "biomaterial" means a material for and suitable for medical applications. Advantageously, the biomaterial according to the application is a physical support on the surface and inside of which fibroblasts can adhere, migrate and proliferate, which is absorbable or biodegradable, thus allowing it to be replaced by newly formed connective tissue.

[0024] Advantageously, the biomaterial according to the present application comprises at least one elastomer matrix and non-sulphated polysaccharides, the individual properties of which combine together, with greatly improved overall performance, which properties are not observed with the at least one elastomer matrix or non-sulphated polysaccharide alone.

[0025] The inventors have surprisingly shown that the biomaterial according to the present application, comprising at least one elastomer matrix and non-sulphated polysaccharides, has:

[0026] - mechanical properties sufficient to withstand the stresses exerted by the cells, but also to withstand the regeneration process of the area to be repaired, and to become a support for the soft tissues of this area,

[0027] - porosity and interconnectivity allowing circulation of fibroblasts, nutrients and other molecules involved in the regulation of these processes, while allowing internal vascularization of the biomaterial of the application,

[0028] - roughness allowing cell adhesion and adsorption of molecules involved in the regulation of these processes.

[0029] Advantageously, the inventors have shown that this biomaterial, after implantation in a patient, is able to activate collagen synthesis and vascularization, allowing rapid reconstruction of damaged tissues.

[0030] In a particular embodiment of the application, the non-sulphated polysaccharides can be linked to the elastomer matrix by covalent bonds. In another particular embodiment of the application, the non-sulphated polysaccharides can be dispersed in the elastomer matrix and on its surface.

[0031] Within the meaning of the present application, the term "elastomer matrix" means a structure consisting of a single elastomer or a combination of two or more elastomers, which can comprise non-sulphated polysaccharides. Advantageously, the isocyanate index of the elastomer matrix is between 0.1 and 6.0. Advantageously, the isocyanate index is between 0.1 and 5.0, advantageously between 0.2 and 4.9, advantageously between 0.3 and 4.8, advantageously between 0.4 and 4.7, advantageously between 0.5 and 4.7, advantageously between 0.6 and 4.6, advantageously between 0.7 and 4.5, advantageously between 0.8 and 4.5, advantageously between 0.9 and 4.5, advantageously between 1 and 4.5, advantageously between 1.05 and 4.5, advantageously between 1.1 and 4.5, advantageously between 1.2 and 4.5, advantageously between 1.3 and 4.5, advantageously between 1.4 and 4.5, advantageously between 1.5 and 4.5, advantageously between 2.0 and 4.5, advantageously between 2.5 and 4.5, advantageously between 2.6 and 4.4, advantageously between 2.7 and 4.3, advantageously between 2.8 and 4.2, advantageously between 2.9 and 4.1, advantageously between 3.0 and 4.0.

[0032] Advantageously, the at least one elastomer matrix according to the present application has good biodegradability, good biocompatibility and good mechanical properties.

[0033] Within the meaning of the present application, the term "elastomer" means one or more polymers which, after cross-linking, have "rubber-elastic" properties. In a particular embodiment of the present application, the elastomer must be biocompatible and biodegradable. Advantageously, the compression Young's modulus of the biomaterial of the present application is between 1 kPa and 1000 kPa, preferably between 50 kPa and 900 kPa, preferably between 50 kPa and 800 kPa, preferably between 50 kPa and 700 kPa, preferably between 50 kPa and 600 kPa, preferably between 50 kPa and 500 kPa, preferably between 100 kPa and 400 kPa.

[0034] Within the meaning of the present application, the term "biocompatible" elastomer matrix means an elastomer matrix which is advantageously both compatible with the implantation in the patient's body and with the non-sulphated polysaccharides contained therein, and suitable for soft tissue reconstruction once the biomaterial has been implanted in a human or animal patient.

[0035] Within the meaning of the present application, the term "compatible with the implantation in the patient's body" means that the elastomer matrix has, after implantation, an advantageous benefit / risk ratio from a therapeutic point of view, for example in the meaning of Directive 2001 / 83 / EC.

[0036] In the meaning of the present application, "compatible with non-sulfated polysaccharides" means that the elastomer matrix allows the incorporation of non-sulfated polysaccharides without or with a slight decrease of the activity of the non-sulfated polysaccharides in the elastomer matrix. Advantageously, the non-sulfated polysaccharides are incorporated into the elastomer matrix. In other words, during the process of manufacturing the biomaterial according to the present application, the non-sulfated polysaccharides are directly incorporated into the elastomer matrix.

[0037] In the meaning of the present application, the term "biodegradable" elastomer matrix means a bioresorbable and / or biodegradable and / or bioabsorbable elastomer matrix, the common goal of which is to gradually disappear, with one or more different or complementary degradation, dissolution or absorption mechanisms of the elastomer matrix in the human or animal patient into which the material has been implanted.

[0038] In a particular embodiment of the present application, the at least one elastomer matrix of the biomaterial according to the present application comprises a poly(ester-urea-urethane)-based elastomer.

[0039] In a particularly advantageous embodiment of the present application, the at least one elastomer matrix of the biomaterial according to the present application comprises a poly(ester-urea-urethane)-based elastomer, the ester being selected from polycaprolactone oligomers (PCL), polylactic acid oligomers (PLA), polyglycolic acid oligomers (PGA), polyhydroxybutyrate oligomers (PHB), polyhydroxyvalerate oligomers (PVB), para-dioxanone oligomers (PDO), poly(ethylene adipate) oligomers (PEA), poly(butylene adipate) oligomers (PBA) or a combination thereof.

[0040] In a particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane)-based elastomer. In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane)-based elastomer. In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane)-based elastomer. In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(hydroxyvalerate-urea-urethane)-based elastomer.

[0041] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(hydroxybutyrate-urea-urethane)-based elastomer.

[0042] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(hydroxybutyrate-urea-urethane)-based elastomer.

[0043] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(ethylene adipate-urea-urethane)-based elastomer.

[0044] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(butylene adipate-urea-urethane)-based elastomer.

[0045] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(butylene adipate-urea-urethane)-based elastomer.

[0046] In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(lactic acid-urea-urethane) and poly(glycolic acid-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(lactic acid-urea-urethane) and poly(hydroxyvalerate-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(lactic acid-urea-urethane) and poly(p-dioxanone-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(lactic acid-urea-urethane) and poly(ethylene adipate-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(lactic acid-urea-urethane) and poly(butylene adipate-urea-urethane).

[0047] In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(glycolic acid-urea-urethane) and poly(hydroxyvalerate-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(glycolic acid-urea-urethane) and poly(hydroxybutyrate-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(glycolic acid-urea-urethane) and poly(p-dioxanone-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(glycolic acid-urea-urethane) and poly(ethylene adipate-urea-urethane). In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(glycolic acid-urea-urethane) and poly(butylene adipate-urea-urethane).

[0048] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane- urea) and poly(hydroxybutyrate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(p-dioxanone- urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate- urethane-urea) and poly(ethylene adipate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(butylene adipate- urethane-urea).

[0049] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(hydroxybutyrate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(p-dioxanone- urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate- urethane-urea) and poly(ethylene adipate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(butylene adipate- urethane-urea).

[0050] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(hydroxybutyrate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(p-dioxanone- urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate- urethane-urea) and poly(ethylene adipate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(butylene adipate- urethane-urea).

[0051] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(hydroxybutyrate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(p-dioxanone- urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate- urethane-urea) and poly(ethylene adipate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(butylene adipate- urethane-urea).

[0052] In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(hydroxybutyrate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(p-dioxanone- urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate- urethane-urea) and poly(ethylene adipate-urethane-urea). In another particular embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(hydroxyvalerate-urethane-urea) and poly(butylene adipate- urethane-urea).

[0053] In another specific embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), and poly(hydroxyvalerate-urea-urethane).

[0054] In another specific embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), and poly(hydroxybutyrate-urea-urethane).

[0055] In another specific embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), and poly(hydroxyvalerate-urea-urethane).

[0056] In another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), poly(hydroxyvalerate-urea-urethane), and poly(hydroxybutyrate-urea-urethane). In yet another specific embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), poly(hydroxyvalerate-urea-urethane), poly(hydroxybutyrate-urea-urethane), and poly(p-dioxanone-urea-urethane).

[0057] In another specific embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), poly(hydroxyvalerate-urea-urethane), poly(hydroxybutyrate-urea-urethane), poly(p-dioxanone-urea-urethane), and poly(ethylene adipate-urea-urethane).

[0058] In another specific embodiment, the at least one elastomer matrix of the porous biomaterial is a matrix comprising elastomers based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), poly(hydroxyvalerate-urea-urethane), poly(hydroxybutyrate-urea-urethane), poly(p-dioxanone-urea-urethane), poly(ethylene adipate-urea-urethane), and poly(butylene adipate-urea-urethane).

[0059] These elastomers do indeed allow the invention to be implemented, and have the advantages of cell compatibility, allowing the physiological stresses of the damaged tissue to be restored, avoiding re-operations after restoration, and allowing the damaged tissue to be properly reconstructed. In particular, advantageously, this at least one elastomer matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane)-based elastomer. This matrix comprising a poly(caprolactone-urea-urethane)-based elastomer also has the advantage of having elastomer properties, providing flexibility to the matrix, and a porous structure that is interconnected and suitable for tissue reconstruction.

[0060] In a particular embodiment of the application, the non-sulfated polysaccharide can be chosen from carrageenans, alginate, xanthan gum, chitosan, chitin, hyaluronic acid, glycogen, cellulose and its derivatives, pectin, starch and its derivatives, dextrin and xylan, or mixtures thereof. Advantageously, the non-sulfated polysaccharide can thus consist of a single polysaccharide or a mixture of non-sulfated polysaccharides.

[0061] In a particularly advantageous embodiment of the application, the non-sulfated polysaccharide according to the application is hyaluronic acid.

[0062] In the present application, the term "hyaluronic acid" means hyaluronic acid, crosslinked or not, alone or as a mixture; optionally, hyaluronic acid chemically modified by substitution, alone or as a mixture; and / or optionally, hyaluronic acid in the form of its salts, alone or as a mixture.

[0063] Advantageously, the hyaluronic acid is a high molecular weight hyaluronic acid.

[0064] In the present application, the term "high molecular weight hyaluronic acid" means hyaluronic acid having a molecular weight greater than or equal to 1000 kDa. Conversely, the term "low molecular weight hyaluronic acid" means hyaluronic acid having a molecular weight less than 1000 kDa.

[0065] In a particular embodiment of the application, the hyaluronic acid has a molecular weight greater than or equal to 1000 kDa, advantageously greater than or equal to 10,000 kDa, advantageously greater than or equal to 100,000 kDa, advantageously greater than or equal to 1,000,000 kDa, advantageously greater than or equal to 1,500,000 kDa, advantageously greater than or equal to 2,000,000 kDa. Advantageously, the hyaluronic acid according to the application has a molecular weight of 1,500,000 kDa. Advantageously, the use of high molecular weight hyaluronic acid, in addition to these non-immunogenic and anti-angiogenic properties, also makes it possible to structure the matrix macromolecules, in particular the collagen, in the early stages of healing, which is not possible with low molecular weight hyaluronic acid.

[0066] In an advantageous embodiment of the application, the biomaterial according to the application comprises:

[0067] - at least one elastomer matrix comprising a poly(ester-urea-urethane)-based elastomer, the ester being selected from caprolactone oligomers (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), para-dioxanone oligomers (PDO), poly(ethylene adipate) oligomers (PEA), poly(butylene adipate) oligomers (PBA), or combinations thereof.

[0068] - a non-sulfated polysaccharide.

[0069] In a first particular embodiment of the application, the porous biomaterial according to the application comprises:

[0070] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)-based elastomer, and

[0071] - a non-sulfated polysaccharide.

[0072] In a second particular embodiment of the application, the porous biomaterial according to the application comprises:

[0073] - at least one elastomer matrix comprising a poly(lactic acid-urea-urethane)-based elastomer, and

[0074] - a non-sulfated polysaccharide.

[0075] In a third particular embodiment of the application, the porous biomaterial according to the application comprises:

[0076] - at least one elastomer matrix comprising a poly(glycolic acid-urea-urethane)-based elastomer, and

[0077] - a non-sulfated polysaccharide.

[0078] In a fourth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0079] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)- and poly(lactic acid-urea-urethane)-based elastomer, and

[0080] - a non-sulfated polysaccharide.

[0081] In a fifth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0082] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)- and poly(glycolic acid-urea-urethane)-based elastomer, and

[0083] - a non-sulfated polysaccharide.

[0084] In a sixth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0085] - at least one elastomer matrix comprising elastomers based on poly(lactic-urethane-amide) and poly(glycolic-urethane-amide), and

[0086] - a non-sulfated polysaccharide.

[0087] In a seventh particular embodiment of the application, the porous biomaterial according to the application comprises:

[0088] - at least one elastomer matrix comprising elastomers based on poly(caprolactone-urethane-amide), poly(lactic-urethane-amide) and poly(glycolic-urethane-amide), and

[0089] - a non-sulfated polysaccharide.

[0090] In an eighth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0091] - at least one elastomer matrix comprising elastomers based on poly(hydroxybutyrate-urethane-amide), and

[0092] - a non-sulfated polysaccharide.

[0093] In a ninth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0094] - at least one elastomer matrix comprising elastomers based on poly(hydroxyvalerate-urethane-amide), and

[0095] - a non-sulfated polysaccharide.

[0096] In a tenth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0097] - at least one elastomer matrix comprising elastomers based on poly(p-dioxanone-urethane-amide), and

[0098] - a non-sulfated polysaccharide.

[0099] In an eleventh particular embodiment of the application, the porous biomaterial according to the application comprises:

[0100] - at least one elastomer matrix comprising elastomers based on poly(ethylene adipate-urethane-amide), and

[0101] - a non-sulfated polysaccharide.

[0102] In a twelfth particular embodiment of the application, the porous biomaterial according to the application comprises:

[0103] - at least one elastomer matrix comprising a poly(butylene adipate-urea- urethane)-based elastomer, and

[0104] - a non-sulfated polysaccharide.

[0105] Advantageously, according to one of the preceding embodiments (embodiments 1 to 12), the non-sulfated polysaccharide can be hyaluronic acid. Advantageously, the hyaluronic acid is a high molecular weight hyaluronic acid.

[0106] In a particularly advantageous embodiment of the application, the porous biomaterial according to the application comprises:

[0107] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)- based elastomer, and

[0108] - hyaluronic acid.

[0109] Advantageously, the porous biomaterial comprises:

[0110] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)- based elastomer, and

[0111] - high molecular weight hyaluronic acid.

[0112] Advantageously, the porous biomaterial consists only of:

[0113] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)- based elastomer, and

[0114] - high molecular weight hyaluronic acid.

[0115] In an advantageous embodiment of the application, the biomaterial according to the application comprises:

[0116] - at least one elastomer matrix comprising a poly(ester-urea-urethane)-based elastomer, the ester being chosen from caprolactone oligomers (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), para-dioxanone oligomers (PDO), poly(ethylene adipate) oligomers (PEA), poly(butylene adipate) oligomers (PBA) or a combination thereof.

[0117] - a non-sulfated polysaccharide.

[0118] Advantageously, the porous biomaterial comprises:

[0119] - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)- based elastomer, and

[0120] - high molecular weight hyaluronic acid.

[0121] Advantageously, the inventors have demonstrated that the particular combination of hyaluronic acid, in particular of high molecular weight, and at least one elastic matrix comprising a poly(caprolactone-urea-urethane)-based elastomer, allows to increase cell migration and, compared to the use of a porous elastomer matrix comprising a poly(caprolactone-urea-urethane)-based elastomer alone, a better vascularization and tissue reconstruction inside and outside the porous biomaterial. In fact, the addition of the acidic hyaluronic acid leads to an increase in collagen synthesis, so that a more structured tissue can be obtained.

[0122] In a particular embodiment of the application, the biomaterial has a multiscale porosity between 50 pm and 2000 pm. In the present application, the terms "pore size" and "pore diameter" can be used interchangeably. By "multiscale porosity" it is meant a variable distribution of the pore size, that is to say, the inclusion of pores of several microns and of smaller size, in variable proportions. By way of example, a biomaterial having a multiscale porosity between 50 pm and 2000 pm is a biomaterial that includes, in the same biomaterial, pores having a variable pore size between 50 pm and 2000 pm. By way of non-limiting example, a biomaterial having a multiscale porosity between 50 pm and 2000 pm is a biomaterial that includes, in the same biomaterial, for example, pores having a pore size of 50 pm, pores having a pore size of 100 pm, pores having a pore size of 500 pm, pores having a pore size of 1500 pm, pores having a pore size of 2000 pm. Advantageously, the biomaterial has a multiscale porosity between 50 pm and 1200 pm. Advantageously, the average pore size is between 500 pm and 700 pm.

[0123] Advantageously, the biomaterial has a multiscale porosity between 500 pm and 2000 pm.

[0124] In an advantageous embodiment of the application, the pores of the biomaterial have a rough surface.

[0125] In a particular embodiment of the application, the biomaterial has a total porosity greater than or equal to 60%. In the meaning of the present application, the term "total porosity" means the ratio between the volume of voids of the material and the total volume of the biomaterial.

[0126] Advantageously, the total porosity of the biomaterial is greater than 60%, advantageously greater than 61%, advantageously greater than 62%, advantageously greater than 63%, advantageously greater than 64%, advantageously greater than 65%, advantageously greater than 66%, advantageously greater than 67%, advantageously greater than 68%, advantageously greater than 69%, advantageously greater than 70%, advantageously greater than 71%, advantageously greater than 72%, advantageously greater than 73%, advantageously greater than 74%, advantageously greater than 75%, advantageously greater than 76%, advantageously greater than 77%, advantageously greater than 78%, advantageously greater than 79%, advantageously greater than 80%, advantageously greater than 81%, advantageously greater than 82%, advantageously greater than 83%, advantageously greater than 84%, advantageously greater than 85%, advantageously greater than 86%, advantageously greater than 87%, advantageously greater than 88%, advantageously greater than 89%, advantageously greater than 90%, advantageously greater than 91%, advantageously greater than 92%, advantageously greater than 93%, advantageously greater than 94%, advantageously greater than 95%, advantageously greater than 96%, advantageously greater than 97%, advantageously greater than 98%, advantageously greater than 99%. In an advantageous embodiment of the application, the total porosity of the biomaterial is greater than 80%. Advantageously, the total porosity of the biomaterial is between 60% and 95%, advantageously between 61% and 89%, advantageously between 62% and 88%, advantageously between 63% and 87%, advantageously between 64% and 86%, advantageously between 65% and 85%, advantageously between 66% and 84%, advantageously between 67% and 83%, advantageously between 68% and 82%, advantageously between 69% and 81%, advantageously between 70% and 80%. In an advantageous embodiment of the application, the total porosity of the porous biomaterial is between 70% and 95%.

[0127] In an advantageous embodiment of the application, the interporous interconnectivity of the biomaterial is between 60% and 100%. Advantageously, the interporous interconnectivity is between 65% and 100%, advantageously between 70% and 100%, advantageously between 75% and 100%, advantageously between 80% and 100%, advantageously between 85% and 100%, advantageously between 90% and 100%, advantageously between 91% and 100%, advantageously between 92% and 100%, advantageously between 93% and 100%, advantageously between 94% and 100%, advantageously between 95% and 100%, advantageously between 96% and 100%, advantageously between 97% and 100%, advantageously between 98% and 100%, advantageously between 99% and 100%. In a particularly advantageous embodiment of the application, the interporous interconnectivity is greater than 65%, advantageously greater than 70%, advantageously greater than 75%, advantageously greater than 80%, advantageously greater than 85%, advantageously greater than 90%, advantageously greater than 91%, advantageously greater than 92%, advantageously greater than 93%, advantageously greater than 94%, advantageously greater than 95%, advantageously greater than 96%, advantageously greater than 97%, advantageously greater than 98%, advantageously greater than 99%. In an advantageous embodiment of the application, the interporous interconnectivity of the biomaterial is 100%.

[0128] In an advantageous embodiment, the biomaterial according to the application has a pore size between 50 μιη and 2000 μιη, a total porosity greater than or equal to 60%, and an interporous interconnectivity between 60% and 100%.

[0129] Advantageously, the biomaterial according to the application has a mean pore size between 50 μιη and 1200 μιη, a total porosity between 60% and 95%, and an interporous interconnectivity between 60% and 100%.

[0130] Advantageously, the biomaterial according to the application has a mean pore size between 500 μιη and 700 μιη, a total porosity between 70% and 95%, and an interporous interconnectivity of 100%.

[0131] In a particularly advantageous embodiment, the porous biomaterial comprising at least one elastomer matrix comprising a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid has a pore size between 500 μιη and 2000 μιη, a total porosity between 60% and 95%, and an interporous interconnectivity between 60% and 100%.

[0132] Advantageously, the biomaterial comprising at least one elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid, has a pore size between 500 μιη and 700 μιη, a total porosity between 70% and 95%, and a pore interconnectivity of 100%. The porosity, the pore size and their interconnectivity of the material have a great influence on the ability of the biomaterial to vascularize and gradually absorb.

[0133] Thus, the biomaterial comprising at least one elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid, having a total porosity between 60% and 95%, a pore size between 50 μιη and 2000 μιη, and a pore interconnectivity of 100%, is particularly suitable for cell adhesion and migration of connective tissue and blood vessels. Indeed, the interconnected porous network allows it to guide the attachment and growth of cells, thus guiding the growth of newly formed tissue. Moreover, the presence of hyaluronic acid stimulates angiogenesis, thus making it possible to improve the revascularization and integration of the biomaterial. At the same time, fibroblasts adhere and proliferate inside and around the biomaterial. The absorption of the biomaterial and the presence of fibroblasts, which are present inside and around the biomaterial, produce collagen, resulting in its complete replacement by newly formed connective tissue after a few months. Thus, the biomaterial comprising at least one elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid, promotes vascular regeneration, rapid integration of soft tissues, and provides a safe alternative to autologous connective tissue.

[0134] The size of the biomaterial according to the application depends on the size and thickness of the tissue defect. In a particular embodiment of the application, the size of the biomaterial is between 5 mm and 20 cm and the thickness is between 100 μιη and 4 cm.

[0135] Advantageously, the size of the biomaterial is between 5 mm and 20 cm, advantageously between 10 mm and 20 cm, advantageously between 50 mm and 20 cm, advantageously between 100 mm and 20 cm, advantageously between 500 mm and 20 cm, advantageously between 1 cm and 20 cm, advantageously between 2 cm and 20 cm, advantageously between 3 cm and 20 cm, advantageously between 4 cm and 20 cm, advantageously between 5 cm and 20 cm, advantageously between 6 cm and 20 cm, advantageously between 7 cm and 20 cm, advantageously between 8 cm and 20 cm, advantageously between 9 cm and 20 cm, advantageously between 10 cm and 20 cm, advantageously between 11 cm and 20 cm, advantageously between 12 cm and 20 cm, advantageously between 13 cm and 20 cm, advantageously between 14 cm and 20 cm, advantageously between 15 cm and 20 cm.

[0136] Advantageously, the thickness of the biomaterial is between 100 pm and 4 cm, advantageously between 200 pm and 4 cm, advantageously between 500 pm and 4 cm, advantageously between 1 mm and 4 cm, advantageously between 2 mm and 4 cm, advantageously between 3 mm and 4 cm, advantageously between 4 mm and 4 cm, advantageously between 5 mm and 4 cm, advantageously between 6 mm and 4 cm, advantageously between 7 mm and 4 cm, advantageously between 8 mm and 4 cm, advantageously between 9 mm and 4 cm, advantageously between 1 cm and 4 cm, advantageously between 1 cm and 3 cm.

[0137] In a particularly advantageous embodiment, when the biomaterial according to the application is used to reinforce, reconstruct and / or fill a tissue defect of a mucosa, in particular of a gingiva, the thickness of the biomaterial is between 1 and 3 mm.

[0138] In a particularly advantageous embodiment, the surface area of the biomaterial is at least 25 mm 2 . Advantageously, the surface area of the biomaterial is at least 50 mm 2 , advantageously at least 100 mm 2 , advantageously at least 150 mm 2 , advantageously at least 200 mm 2 , advantageously at least 250 mm 2 , advantageously at least 300 mm 2 , advantageously at least 350 mm 2 , advantageously at least 400 mm 2advantageously at least 450 mm 2 advantageously at least 500 mm 2 advantageously at least 550 mm 2 advantageously at least 600 mm 2 advantageously at least 650 mm 2 advantageously at least 700 mm 2 advantageously at least 750 mm 2 advantageously at least 800 mm 2 advantageously at least 850 mm 2 advantageously at least 900 mm 2 advantageously at least 950 mm 2 advantageously at least 1000 mm 2 advantageously at least 15 cm 2 advantageously at least 20 cm 2 advantageously at least 25 cm 2 advantageously at least 30 cm 2 advantageously at least 35 cm 2 advantageously at least 40 cm 2 advantageously at least 45 cm 2 advantageously at least 50 cm 2 advantageously at least 55 cm 2 advantageously at least 60 cm 2 advantageously at least 65 cm 2 advantageously at least 70 cm 2 advantageously at least 75 cm 2 advantageously at least 80 cm 2 advantageously at least 85 cm 2 advantageously at least 90 cm 2 advantageously at least 95 cm 2 advantageously at least 100 cm 2 advantageously at least 150 cm 2 advantageously at least 200 cm 2 advantageously at least 250 cm 2 advantageously at least 300 cm 2 advantageously at least 350 cm 2 advantageously at least 400 cm 2 In one advantageous embodiment, the volume of the biological material is between 25 mm 2 and 400 cm 2 .

[0139] In one particular embodiment of the application, the volume of the biological material is at least 1 mm3 . Advantageously, the volume of the biomaterial is at least 2 mm 3 , advantageously at least 3 mm 3 , advantageously at least 4 mm 3 , advantageously at least 5 mm 3 , advantageously at least 6 mm 3 , advantageously at least 7 mm 3 , advantageously at least 8 mm 3 , advantageously at least 9 mm 3 , advantageously at least 10 mm 3 , advantageously at least 20 mm 3 , advantageously at least 30 mm 3 , advantageously at least 40 mm 3 , advantageously at least 50 cm 3 , advantageously at least 60 mm 3 , advantageously at least 70 mm 3 , advantageously at least 80 mm 3 , advantageously at least 90 mm 3 , advantageously at least 100 mm 3 , advantageously at least 150 mm 3 , advantageously at least 200 mm 3 , advantageously at least 250 mm 3 , advantageously at least 300 mm 3 , advantageously at least 350 mm 3 , advantageously at least 400 mm 3 , advantageously at least 450 mm 3 , advantageously at least 500 mm 3 , advantageously at least 550 mm 3 , advantageously at least 600 mm 3 , advantageously at least 650 mm 3 , advantageously at least 700 mm 3 , advantageously at least 750 mm 3 , advantageously at least 800 mm 3 , advantageously at least 850 mm 3 , advantageously at least 900 mm 3 , advantageously at least 950 mm 3 , advantageously at least 1 cm 3 , advantageously at least 1.5 cm 3 , advantageously at least 2 cm 3 , advantageously at least 2.5 cm 3 , advantageously at least 3 cm 3 , advantageously at least 3.5 cm3 advantageously at least 4 cm 3 advantageously at least 4.5 cm 3 advantageously at least 5 cm 3 advantageously at least 5.5 cm 3 advantageously at least 6 cm 3 advantageously at least 6.5 cm 3 advantageously at least 7 cm 3 advantageously at least 7.5 cm 3 advantageously at least 8 cm 3 advantageously at least 8.5 cm 3 advantageously at least 9 cm 3 advantageously at least 9.5 cm 3 advantageously at least 10 cm 3 In an advantageous embodiment, the volume of the biomaterial is between 1 mm 3 and 10 cm 3 .

[0140] In an advantageous embodiment of the application, the biomaterial according to the application can be in the form of a sponge, a film, a membrane, a granule, a monolith or a wound dressing.

[0141] In an advantageous embodiment of the present application, the biomaterial according to the present application is used alone. In another embodiment of the present application, the biomaterial can further be used in combination with an active agent. Advantageously, the active agent is disposed within the pores of the biomaterial according to the present application, partially or completely covering the pores of the biomaterial. Advantageously, the active agent can be added by one of the following methods: covering the biomaterial with the active agent, soaking the biomaterial in the active agent, spraying the active agent onto the biomaterial, steaming the active agent onto the biomaterial, or any other technique known to the skilled person that allows the pores of the biomaterial to be filled and / or packed. Advantageously, the active agent can be any therapeutic or pharmaceutically active agent (including but not limited to nucleic acids, proteins, lipids and carbohydrates) having desirable physiological properties for application to the implantation site. Therapeutic agents include but are not limited to anti-infective agents such as antibiotics and antiviral agents; chemotherapeutic agents (such as anticancer agents); anti-rejection agents; analgesics and analgesic agents; anti-inflammatory agents; hormones such as steroids; growth factors (including but not limited to cytokines, chemokines and interleukins), coagulation factors (factors VII, VIII, IX, X, XI, XII, V), albumin, fibrinogen, Von Willebrand factor, thrombin inhibitors, anti-thrombotic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel inhibitors, vasodilators, anti-hypertensive agents, antibacterial agents, antibiotics, antibodies, surface glycoprotein receptor inhibitors, anti-platelet agents, anti-mitotic agents, microtubule inhibitors, anti-platelet agents, anti-mitotic agents, microtubule inhibitors, actin inhibitors, anti-secretory agents, reconstitution inhibitors, antisense nucleotides, antimetabolites, anti-proliferative agents, anti-cancer chemotherapeutic agents, anti-inflammatory steroids, non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, angiotensin-converting enzyme (ACE) inhibitors, free radical scavengers, chelators, antioxidants, antipolymerases, antiviral agents, photodynamic therapy agents and gene therapy agents and other naturally occurring or genetically engineered proteins, polysaccharides, glycoproteins and lipoproteins, or combinations thereof, this list being non-limiting. In a particularly advantageous embodiment of the present application, the active agent is a combination of therapeutic agents, in particular a combination of an antibiotic and a growth factor.

[0142] Another aspect of the present application relates to the use of the biomaterial according to the present application for the augmentation, reconstruction and / or filling of tissue defects. In the meaning of the present application, the term "augmentation of tissue defects" means an increase in tissue density by inducing collagen synthesis and / or collagen deposition due to the biocompatibility of the biomaterial, in particular due to the presence of hyaluronic acid.

[0143] In the meaning of the present application, the term "reconstruction of the tissue defect" means that, thanks to the biocompatibility of the biomaterial, in particular thanks to the presence of hyaluronic acid, the tissue defect is repaired by inducing the synthesis of collagen and / or the deposition of collagen.

[0144] In the meaning of the present application, the term "filling of the tissue defect" means that, thanks to the biocompatibility of the biomaterial, in particular thanks to the presence of hyaluronic acid, the tissue defect is filled by inducing the synthesis of collagen and / or the deposition of collagen.

[0145] In a particular embodiment of the present application, the tissue augmentation, reconstruction and / or filling is greater than or equal to 5% by volume of the volume of the tissue defect to be augmented, reconstructed and / or filled. Advantageously, the tissue augmentation, reconstruction and / or filling is greater than or equal to 6% by volume of the volume of the tissue. Advantageously, the tissue augmentation, reconstruction and / or filling is greater than or equal to 7% by volume of the volume of the tissue defect to be augmented, reconstructed and / or filled, advantageously greater than or equal to 8%, advantageously greater than or equal to 9%, advantageously greater than or equal to 10%, advantageously greater than or equal to 11%, advantageously greater than or equal to 12%, advantageously greater than or equal to 13%, advantageously greater than or equal to 14%, advantageously greater than or equal to 15%, advantageously greater than or equal to 16%, advantageously greater than or equal to 17%, advantageously greater than or equal to 18%, advantageously greater than or equal to 19%, advantageously greater than or equal to 20%, advantageously greater than or equal to 21%, advantageously greater than or equal to 22%, advantageously greater than or equal to 23%, advantageously greater than or equal to 24%, advantageously greater than or equal to 25%, advantageously greater than or equal to 26%, advantageously greater than or equal to 27%, advantageously greater than or equal to 28%, advantageously greater than or equal to 29%, advantageously greater than or equal to 30%, advantageously greater than or equal to 31%, advantageously greater than or equal to 32%, advantageously greater than or equal to 33%, advantageously greater than or equal to 34%, advantageously greater than or equal to 35%, advantageously greater than or equal to 36%, advantageously greater than or equal to 37%, advantageously greater than or equal to 38%, advantageously greater than or equal to 39%, advantageously greater than or equal to 40%, advantageously greater than or equal to 41%, advantageously greater than or equal to 42%, advantageously greater than or equal to 43%, advantageously greater than or equal to 44%, advantageously greater than or equal to 45%, advantageously greater than or equal to 46%, advantageously greater than or equal to 47%, advantageously greater than or equal to 48%, advantageously greater than or equal to 49% by volume of the volume of the tissue defect to be augmented, reconstructed and / or filled. Advantageously, the tissue augmentation, reconstruction and / or filling is less than or equal to 50% by volume of the volume of the tissue defect to be augmented, reconstructed and / or filled.

[0146] In a particular embodiment of the application, the porous biomaterial according to the application can be used for the augmentation, reconstruction and / or filling of a tissue of human or animal origin. By way of example, the animal can be a horse, pony, dog, cat, rat, mouse, pig, sow, cow, beef cattle, bull, calf, goat, sheep, ram, ewe lamb, lamb, donkey, camel, dromedary, this list not being limiting.

[0147] Advantageously, the porous biomaterial according to the application can be used for the augmentation, reconstruction and / or filling of a defect of soft tissue and / or epithelial tissue.

[0148] In the meaning of the application, the term "soft tissue" means a tissue that is not osseous and does not consist of epithelial cells, which surrounds, supports and connects organs and other tissues. Advantageously, soft tissue surrounds, supports and connects organs and other body parts; gives the body shape and structure; protects organs; circulates liquids, such as blood, from one body part to another; stores energy.

[0149] In a particular embodiment of the application, the biomaterial according to the application can be used for the augmentation, reconstruction and / or filling of soft tissue of human or animal origin. Advantageously, the soft tissue can be chosen from the group consisting of fibrous tissue, muscle, in particular smooth muscle, skeletal muscle and cardiac muscle, synovial tissue, blood vessels, lymphatic vessels, internal organs and nerves, this list not being limiting.

[0150] In a particular embodiment, the biomaterial according to the application can be used for the augmentation, reconstruction and / or filling of any type of epithelial tissue of human or animal origin. Advantageously, the biomaterial according to the application can be used for the augmentation, reconstruction and / or filling of a defect in the skin and / or mucosa. Advantageously, the mucosa can be an oral mucosa.

[0151] In a particular embodiment, the biomaterial according to the application can be used for the augmentation, reconstruction and / or filling of any type of epithelial tissue, advantageously for the augmentation, reconstruction and / or filling of the gingiva, in particular to obtain a root coverage, for the treatment of gingival recession, to thicken the tissue to obtain a robust biological type, to increase the keratinized gingival band, to restore the support and anchoring of the teeth, or to reconstruct the tissue after periodontitis.

[0152] In a particular embodiment, the biomaterial according to the application can be used for the augmentation of a defect of soft tissue and / or epithelial tissue, in particular in the case of gynecological, urological or internal organ (or parietal) surgery, for example, to augment a vascular wound, a digestive tract wound or an abdominal organ herniation. In another embodiment, the biomaterial according to the application can be used for the design of an augmentation implant intended for the treatment of pelvic organ prolapse, more particularly for the treatment of female pelvic organ prolapse: early stage (urological, cystocele, stress urinary incontinence), mid-stage (genital, vaginal prolapse) and / or late stage (digestive tract prolapse).

[0153] Another aspect of the application relates to the use of the biomaterial according to the application in the treatment of burns. Advantageously, the biomaterial according to the application is particularly useful for the treatment of burns. Advantageously, the biomaterial according to the application is particularly useful for the treatment of thermal burns, cold burns, electrical burns, chemical burns and radiological burns and photochemical burns.

[0154] An aspect of the application relates to the use of the biomaterial according to the application in the treatment of burns, advantageously in the treatment of thermal burns, cold burns, electrical burns, chemical burns, radiological burns and photochemical burns.

[0155] In the meaning of the application, "thermal burns" means external thermal burns caused by contact with a flame, hot steam or boiling liquid, or by contact with an external heat source (the severity of which depends on the temperature of the object and the duration of contact), as well as internal thermal burns involving the respiratory or digestive tract and caused by the absorption or inhalation of hot products (food, gases, in particular combustion gases) or corrosive substances (chemical products).

[0156] In the application, "cold burns" means frostbite. Frostbite can be caused by cold things and friction.

[0157] In the application, the term "electrical burns" means partial or total destruction of the skin, mucous membranes (optionally internal), soft parts of the tissues, associated with the skin, mucous membranes (optionally internal), tissues, caused by an electric arc (thermal burn caused by deflagration) or direct contact with a conductor (always very deep).

[0158] In the application, the term "chemical burns" means partial or total destruction of the skin, mucous membranes (optionally internal), soft parts of the tissues, associated with the skin, mucous membranes (optionally internal), tissues, caused by the corrosive action of strong acids (hydrochloric acid, sulfuric acid, nitric acid) or strong bases (sodium hydroxide, potassium hydroxide).

[0159] In the application, the term "radiological burns" means burns or radiodermatitis caused by electromagnetic radiation, caused by the crown cell body.

[0160] In a particular embodiment of the application, the biomaterial according to the application can be used for the treatment of burns in humans or animals. By way of example, the animals can be horses, ponies, dogs, cats, rats, mice, pigs, sows, cows, bulls, beef cattle, calves, goats, sheep, rams, ewe lambs, lambs, donkeys, camels, dromedaries, this list not being limiting.

[0161] Another aspect of the application relates to a method for preparing a biomaterial according to the application. In a particular embodiment of the application, the biomaterial according to the application is obtained by the poly-HIPE method (formation and polymerization / crosslinking of emulsions with high internal phase). A high internal phase emulsion or HIPE consists of a liquid / liquid immiscible dispersion system in which the internal phase, also called dispersed phase, represents more than 74 - 75% of the total volume of the emulsion, that is to say, more than the compact packing of monodisperse spheres in the volume possible in geometry.

[0162] In a particular embodiment, the method for preparing a biomaterial comprises the following steps:

[0163] a) preparing an organic phase comprising the compounds necessary for the synthesis of poly(ester-urethane-amide),

[0164] b) dissolving a non-sulfated polysaccharide in an aqueous liquid phase, then adding the dissolved non-sulfated polysaccharide to the organic phase of step a), forming an emulsion,

[0165] c) polymerizing / crosslinking the emulsion obtained in step b) to obtain the biomaterial,

[0166] d) washing the biomaterial obtained in step c), and

[0167] e) drying the biomaterial obtained in step d).

[0168] In an embodiment of the application, step a) consists in preparing an organic phase comprising the compounds necessary for the synthesis of poly(ester-urethane). Advantageously, the organic phase also comprises an oligomer, an organic solvent, a crosslinking agent, a catalyst and a surfactant. Advantageously, the organic phase comprises an organic solvent, a polycaprolactone triol oligomer, a Span 80 surfactant, a hexamethylene diisocyanate crosslinking agent (HMDI) and a dibutyltin dilaurate catalyst (DBTDL). Advantageously, the organic solvent is toluene.

[0169] In a particular embodiment, step a) comprises a first step al) of dissolving a polycaprolactone triol oligomer and a Span 80 surfactant in an organic solvent, followed by a second step a2) of adding a crosslinking agent HMDI and a catalyst DBTDL to the solution of step al) to form the organic phase. In an advantageous embodiment of the application, 2.4 mL of organic solvent, 1.3 g of polycaprolactone triol oligomer, 1.3 g of Span 80 surfactant, 1.04 mL of HMDI crosslinking agent and 12 drops of DBTDL catalyst are used. Advantageously, the person skilled in the art will know how to adjust the amounts of toluene, polycaprolactone triol oligomer, Span 80 surfactant, HMDI crosslinking agent and DBTDL catalyst according to the desired pore size of the porous biomaterial. Advantageously, the organic solvent is toluene.

[0170] In a particular embodiment, the process of step b) consists in dissolving the non-sulfated polysaccharide in an aqueous liquid phase, then adding the dissolved non-sulfated polysaccharide to the organic phase of step a), forming an emulsion. In a particular embodiment of the application, the non-sulfated polysaccharide must have been dissolved in an aqueous liquid phase. In a particular embodiment of the application, the aqueous liquid phase is sterile distilled water. Advantageously, the person skilled in the art will know how to adjust the amount of water according to the pore size required for the biomaterial. In an advantageous embodiment of the application, the amount of distilled water is 50 mL.

[0171] In a particular embodiment of the application, the aqueous phase is gradually poured into the organic phase while stirring until an emulsion is obtained. Advantageously, the non-sulphated polysaccharide is introduced at a concentration of at least 0.5 mg / mL, advantageously at a concentration of at least 1.0 mg / mL, advantageously at a concentration of at least 1.5 mg / mL, advantageously at a concentration of at least 2.0 mg / mL, advantageously at a concentration of at least 2.5 mg / mL, advantageously at a concentration of at least 3.0 mg / mL, advantageously at a concentration of at least 3.5 mg / mL, advantageously at a concentration of at least 4.0 mg / mL, advantageously at a concentration of at least 4.5 mg / mL, advantageously at a concentration of at least 5.0 mg / mL, advantageously at a concentration of at least 5.5 mg / mL, advantageously at a concentration of at least 6.0 mg / mL, advantageously at a concentration of at least 6.5 mg / mL, advantageously at a concentration of at least 7.0 mg / mL, advantageously at a concentration of at least 7.5 mg / mL, advantageously at a concentration of at least 8.0 mg / mL, advantageously at a concentration of at least 8.5 mg / mL, advantageously at a concentration of at least 9.0 mg / mL, advantageously at a concentration of at least 9.5 mg / mL, advantageously at a concentration of at least 10.0 mg / mL, advantageously at a concentration of at least 10.5 mg / mL, advantageously at a concentration of at least 11.0 mg / mL, advantageously at a concentration of at least 11.5 mg / mL, advantageously at a concentration of at least 12.0 mg / mL, advantageously at a concentration of at least 12.5 mg / mL, advantageously at a concentration of at least 13.0 mg / mL, advantageously at a concentration of at least 13.5 mg / mL, advantageously at a concentration of at least 14.0 mg / mL, advantageously at a concentration of at least 14.5 mg / mL, advantageously at a concentration of at least 15.0 mg / mL, advantageously at a concentration of at least 15.5 mg / mL, advantageously at a concentration of at least 16.0 mg / mL, advantageously at a concentration of at least 16.5 mg / mL, advantageously at a concentration of at least 17.0 mg / mL, advantageously at a concentration of at least 17.5 mg / mL, advantageously at a concentration of at least 18.0 mg / mL, advantageously at a concentration of at least 18.5 mg / mL, advantageously at a concentration of at least 19.0 mg / mL, advantageously at a concentration of at least 19.5 mg / mL, advantageously at a concentration of at least 20.0 mg / mL. Advantageously, the non-sulphated polysaccharide is introduced at a concentration of between 0.5 mg / mL and 20 mg / mL.

[0172] In a particular embodiment, the polysaccharide is hyaluronic acid, advantageously high molecular weight hyaluronic acid. Advantageously, the hyaluronic acid is introduced at a concentration of at least 0.5 mg / mL, advantageously at a concentration of at least 1.0 mg / mL, advantageously at a concentration of at least 1.5 mg / mL, advantageously at a concentration of at least 2.0 mg / mL, advantageously at a concentration of at least 2.5 mg / mL, advantageously at a concentration of at least 3.0 mg / mL, advantageously at a concentration of at least 3.5 mg / mL, advantageously at a concentration of at least 4.0 mg / mL, advantageously at a concentration of at least 4.5 mg / mL, advantageously at a concentration of at least 5.0 mg / mL, advantageously at a concentration of at least 5.5 mg / mL, advantageously at a concentration of at least 6.0 mg / mL, advantageously at a concentration of at least 6.5 mg / mL, advantageously at a concentration of at least 7.0 mg / mL, advantageously at a concentration of at least 7.5 mg / mL, advantageously at a concentration of at least 8.0 mg / mL, advantageously at a concentration of at least 8.5 mg / mL, advantageously at a concentration of at least 9.0 mg / mL, advantageously at a concentration of at least 9.5 mg / mL, advantageously at a concentration of at least 10.0 mg / mL, advantageously at a concentration of at least 10.5 mg / mL, advantageously at a concentration of at least 11.0 mg / mL, advantageously at a concentration of at least 11.5 mg / mL, advantageously at a concentration of at least 12.0 mg / mL, advantageously at a concentration of at least 12.5 mg / mL, advantageously at a concentration of at least 13.0 mg / mL, advantageously at a concentration of at least 13.5 mg / mL, advantageously at a concentration of at least 14.0 mg / mL, advantageously at a concentration of at least 14.5 mg / mL, advantageously at a concentration of at least 15.0 mg / mL, advantageously at a concentration of at least 15.5 mg / mL, advantageously at a concentration of at least 16.0 mg / mL, advantageously at a concentration of at least 16.5 mg / mL, advantageously at a concentration of at least 17.0 mg / mL, advantageously at a concentration of at least 17.5 mg / mL, advantageously at a concentration of at least 18.0 mg / mL, advantageously at a concentration of at least 18.5 mg / mL, advantageously at a concentration of at least 19.0 mg / mL, advantageously at a concentration of at least 19.5 mg / mL, advantageously at a concentration of at least 20.0 mg / mL.

[0173] In a particular embodiment of the application, the amount of non-sulphated polysaccharide is between 0.05% and 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the amount of non-sulphated polysaccharide is at least 0.05%, advantageously at least 0.06%, advantageously at least 0.07%, advantageously at least 0.08%, advantageously at least 0.09%, advantageously at least 0.10%, advantageously at least 0.20%, advantageously at least 0.30%, advantageously at least 0.40%, advantageously at least 0.50%, advantageously at least 0.60%, advantageously at least 0.70%, advantageously at least 0.80%, advantageously at least 0.90%, advantageously at least 1.0%, advantageously at least 1.10%, advantageously at least 1.20%, advantageously at least 1.30%, advantageously at least 1.40%, advantageously at least 1.50%, advantageously at least 1.60%, advantageously at least 1.70%, advantageously at least 1.80%, advantageously at least 1.90%, advantageously at least 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the amount of non-sulphated polysaccharide is between 0.05% and 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the amount of non-sulphated polysaccharide is between 0.06% and 2.0%, advantageously between 0.07% and 2.0%, advantageously between 0.08% and 2.0%, advantageously between 0.09% and 2.0%, advantageously between 0.10% and 2%, advantageously between 0.20% and 2.0%, advantageously between 0.30% and 2.0%, advantageously between 0.40% and 2.0%, advantageously between 0.50% and 2.0%, advantageously between 0.60% and 2.0%, advantageously between 0.70% and 2.0%, advantageously between 0.80% and 2.0%, advantageously between 0.90% and 2.0%, advantageously between 1.0% and 2.0%, advantageously between 1.10% and 2.0%, advantageously between 1.20% and 2.0%, advantageously between 1.30% and 2.0%, advantageously between 1.40% and 2.0%, advantageously between 1.50% and 2.0%, advantageously between 1.60% and 2.0%, advantageously between 1.70% and 2.0%, advantageously between 1.80% and 2.0%, advantageously between 1.90% and 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. In a particular embodiment of the application, the amount of non-sulphated polysaccharide is 0.10% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion.

[0174] In a particular embodiment of the application, the amount of hyaluronic acid is between 0.05% and 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the amount of hyaluronic acid is at least 0.05% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion, advantageously at least 0.06%, advantageously at least 0.07%, advantageously at least 0.08%, advantageously at least 0.09%, advantageously at least 0.10%, advantageously at least 0.20%, advantageously at least 0.30%, advantageously at least 0.40%, advantageously at least 0.50%, advantageously at least 0.60%, advantageously at least 0.70%, advantageously at least 0.80%, advantageously at least 0.90%, advantageously at least 1.0%, advantageously at least 1.10%, advantageously at least 1.20%, advantageously at least 1.30%, advantageously at least 1.40%, advantageously at least 1.50%, advantageously at least 1.60%, advantageously at least 1.70%, advantageously at least 1.80%, advantageously at least 1.90%, advantageously at least 2.0%. Advantageously, the amount of hyaluronic acid is between 0.05% and 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the amount of non-sulfated polysaccharide is between 0.06% and 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion, advantageously between 0.07% and 2.0%, advantageously between 0.08% and 2.0%, advantageously between 0.09% and 2.0%, advantageously between 0.10% and 2%, advantageously between 0.20% and 2.0%, advantageously between 0.30% and 2.0%, advantageously between 0.40% and 2.0%, advantageously between 0.50% and 2.0%, advantageously between 0.60% and 2.0%, advantageously between 0.70% and 2.0%, advantageously between 0.80% and 2.0%, advantageously between 0.90% and 2.0%, advantageously between 1.0% and 2.0%, advantageously between 1.10% and 2.0%, advantageously between 1.20% and 2.0%, advantageously between 1.30% and 2.0%, advantageously between 1.40% and 2.0%, advantageously between 1.50% and 2.0%, advantageously between 1.60% and 2.0%, advantageously between 1.70% and 2.0%, advantageously between 1.80% and 2.0%, advantageously between 1.90% and 2.0%. In a particular embodiment of the application, the amount of hyaluronic acid is 0.10% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion.

[0175] In a particular embodiment, step c) of the method comprises polymerizing / crosslinking the emulsion obtained in step b) to obtain the biomaterial according to the application. Advantageously, the crosslinking is performed in a mold in order to give the biomaterial the desired shape. Advantageously, the emulsion obtained in step b) is left at a temperature between 30 °C and 80 °C for 10 to 30 hours. Advantageously, the emulsion obtained in step b) is left at a temperature between 35 °C and 65 °C, advantageously at a temperature between 40 °C and 60 °C, advantageously at a temperature between 45 °C and 65 °C, advantageously at a temperature between 50 °C and 60 °C, advantageously at a temperature of 55 °C. Advantageously, the emulsion obtained in step b) is left at a temperature between 30 °C and 70 °C for 10 to 30 hours, advantageously for 11 to 29 hours, advantageously for 12 to 29 hours, advantageously for 13 to 28 hours, advantageously for 14 to 27 hours, advantageously for 15 to 27 hours, advantageously for 16 to 27 hours, advantageously for 17 to 27 hours, advantageously for 18 to 26 hours, advantageously for 19 to 25 hours, advantageously for 20 to 24 hours, advantageously for 22 hours. Advantageously, the person skilled in the art will know how to adapt the temperature according to the desired pore size of the biomaterial.

[0176] In a particular embodiment of the application, the biomaterial according to the application obtained in step c) is annealed before step d). Advantageously, the biomaterial according to the application obtained in step c) is annealed at a temperature of at least 50 °C for at least 1 hour. Advantageously, the biomaterial according to the application obtained in step c) is annealed at a temperature of 100 °C for 2 hours.

[0177] In a particular embodiment, the washing step of step d) can remove the reagents that did not react during the synthesis of the poly(ester-urea-urethane) required for the crosslinking process, as well as the surfactants and catalysts that remain present. Advantageously, the washing of step d) is performed using one of the following products: dichloromethane, dichloromethane / n-hexane, n-hexane, water, a mixture of these products or a succession of applications of these products. Advantageously, the washing of step d) is performed by contacting the dry porous biomaterial according to the application with dichloromethane for at least 24 hours, then with dichloromethane / n-hexane (50% by volume / 50% by volume) for at least 24 hours, then with n-hexane for at least 24 hours, then with distilled water for a final washing of at least 24 hours.

[0178] In a particular embodiment, the method according to the application can also comprise a drying step between step c) and step d). Advantageously, this drying step can be performed by drying in the open air or in an oven. Advantageously, the person skilled in the art will know how to adjust the oven temperature depending on the material to be dried. Advantageously, the drying is performed by open-air airing for at least 7 days.

[0179] Advantageously, the drying of step e) can be performed by drying in the open air or in an oven. Advantageously, the person skilled in the art will know how to adjust the oven temperature depending on the material to be dried. Advantageously, the drying is performed by open-air airing for at least 15 days.

[0180] In a particular embodiment, the method according to the application can also comprise a sterilization step f) after the step e) of drying the biological material. In a particular embodiment, the sterilization step f) can be performed directly on the dried biological material or after vacuum washing of the biological material in an aqueous medium. Advantageously, the sterilization is performed after vacuum washing in an aqueous medium.

[0181] In one embodiment, the sterilization step f) can be performed as follows:

[0182] f1) placing the biological material according to the application in sterile water under vacuum for 1 hour,

[0183] f2) replacing the sterile water and placing the biological material according to the application in the replaced sterile water under vacuum for 4 hours,

[0184] f3) placing the biological material according to the application from step e2) in 70% ethanol under vacuum for 1 hour,

[0185] f4) replacing the 70% ethanol with sterile water and placing the biological material according to the application from step e3) in the sterile water under ambient pressure overnight,

[0186] f5) sterilizing the biological material according to the application resulting from step f4) in an autoclave with water.

[0187] In another embodiment, the sterilization step f) can be performed by gamma (γ) irradiation. In another embodiment, the sterilization step f) can be performed by beta (β) irradiation. Advantageously, the dose of β and / or γ irradiation can be between 15 and 45 kGy. Advantageously, the dose of β and / or γ irradiation is 25 kGy. Advantageously, the dose of β and / or γ irradiation is 15 kGy.

[0188] In another embodiment, the sterilization step f) can be performed by contacting the biological material with ethylene oxide.

[0189] In another embodiment, the sterilization step f) can be performed by contacting the biomaterial with a plasma from a gas.

[0190] In another embodiment, the sterilization step f) can be performed by irradiating the biomaterial with an electron beam (E-beam, Faisceau E). The electron beam irradiation treatment has the following advantages: reduction of the treatment time, increase of the efficiency of the supply line, reduction of the risk of weakening of the elastomer matrix, reduction of the oxidative damage of the biomaterial, no color change of the elastomer matrix, making it clean and safe. Moreover, the electron beam irradiation treatment is an ecological treatment.

[0191] In a particular embodiment, the method according to the application can also comprise a step g) of preserving the biomaterial after the sterilization step f). Advantageously, the step g) of preserving the material is performed by contacting the biomaterial with 70% ethanol until use.

[0192] In a particular embodiment of the application, the method of preparation of the biomaterial comprises the following steps:

[0193] a) preparing an organic phase comprising the compounds necessary for the synthesis of poly(ester-urea-urethane),

[0194] b) dissolving the non-sulfated polysaccharide in an aqueous liquid phase, then adding the dissolved non-sulfated polysaccharide to the organic phase of step a) to form an emulsion,

[0195] c) polymerizing / crosslinking the emulsion obtained in step b) to obtain the porous biomaterial, and

[0196] d) washing the porous biomaterial obtained in step c),

[0197] e) drying the biomaterial obtained in step d),

[0198] f) sterilizing the biomaterial obtained in step d), and

[0199] g) optionally, storing the biomaterial.

[0200] In a particularly advantageous embodiment of the application, the process for the preparation of the biomaterial according to the application comprises the following steps:

[0201] a) preparing an organic phase comprising the compounds necessary for the synthesis of poly(ester-urea-urethane), this step a) comprising a first step al) of dissolving a polycaprolactone triol oligomer and a Span 80 surfactant in an organic solvent, then a second step a2) of adding a crosslinking agent HMDI and a catalyst DBTDL to the solution of step al) to form the organic phase,

[0202] b) dissolving the non-sulfated polysaccharide in an aqueous liquid phase based on sterile distilled water, then adding the non-sulfated polysaccharide dissolved in an organic solvent to the liquid of step a), forming an emulsion,

[0203] c) subjecting the emulsion obtained in step b) to polymerization / crosslinking to obtain the porous biomaterial, and

[0204] d) washing the biomaterial obtained in step c), and

[0205] e) drying the biomaterial obtained in step d) for at least 15 days,

[0206] f) sterilizing the porous biomaterial resulting from step e), and

[0207] g) optionally, storing the biomaterial.

[0208] In a particularly advantageous embodiment of the application, the process for the preparation of a biomaterial according to the application comprises the following steps:

[0209] a) preparing an organic phase comprising the compounds necessary for the synthesis of poly(ester-urea-urethane), this step a) comprising a first step al) of dissolving polycaprolactone triol oligomers and Span 80 surfactant in toluene, then a second step a2) of adding the crosslinking agent HMDI and the catalyst DBTDL to the solution of step al) to form the organic phase,

[0210] b) dissolving the hyaluronic acid, advantageously of high molecular weight, in an aqueous liquid phase based on sterile distilled water, then adding the non-sulfated polysaccharide dissolved in an organic solvent to the liquid of step a), forming an emulsion,

[0211] c) subjecting the emulsion obtained in step b) to polymerization / crosslinking to obtain the porous biomaterial, and

[0212] d) washing the biomaterial obtained in step c),

[0213] e) drying the biomaterial obtained in step d) for at least 15 days,

[0214] f) sterilizing the porous biomaterial resulting from step e), and

[0215] g) optionally, storing the biomaterial.

[0216] Figures

[0217] Figure 1 : Figure 1 A porous biomaterial according to the application is shown. The image was obtained by 3D microscope (VHX Keyence);

[0218] Figure 2 : Figure 2 Fourier transform infrared spectroscopy (FTIR) analysis of hyaluronic acid (a), poly(caprolactone-urea-urethane) elastomer matrix alone (b), porous biomaterial comprising hyaluronic acid according to the present application (c) and subtraction of the spectra of c and b (d) is shown;

[0219] Figure 3 : Figure 3 Mass loss and mass uptake of poly(caprolactone-urea-urethane) based elastomer matrix alone (a, c) and porous biomaterial comprising hyaluronic acid according to the present application (b and d) at 37 °C in vitro degradation and accelerated degradation at 55 °C and 75 °C are shown;

[0220] Figure 4 : Figure 4 Migration of cells (gingival fibroblasts) from day 10 to day 40 within poly(caprolactone-urea-urethane) based elastomer matrix alone (elastomer matrix) and porous biomaterial comprising hyaluronic acid according to the present application (elastomer matrix-AH) is shown;

[0221] Figure 5 : Figure 5 Colonization of cells (gingival fibroblasts) after 20 days of migration within poly(caprolactone-urea-urethane) based elastomer matrix alone (elastomer matrix) and porous biomaterial comprising hyaluronic acid according to the present application (elastomer matrix-AH) is shown. (3D digital microscope - hemalun staining);

[0222] Figure 6 : Figure 6 Appearance of cells (gingival fibroblasts) at the bottom and periphery of poly(caprolactone-urea-urethane) based elastomer matrix alone (elastomer matrix) and porous biomaterial comprising hyaluronic acid according to the present application (elastomer matrix-AH) after 10 days of culture is shown. (Optical microscope - x 40 magnification);

[0223] Figure 7 : Figure 7 Cellularization of poly(caprolactone-urea-urethane) based elastomer matrix alone (elastomer matrix) and porous biomaterial comprising hyaluronic acid according to the present application (elastomer matrix-AH) after 36 days of subcutaneous implantation in rats is shown. (Material is marked by white box;†neovessels;* multinucleated giant cells) (3D digital microscope - hematoxylin / eosin staining);

[0224] Figure 8 : Figure 8Representation of the structure of the collagen present in the poly (caprolactone-urea-urethane) -based elastomer matrix alone (Elastomer matrix) and in the porous biomaterial comprising hyaluronic acid according to the application (Elastomer matrix-AH) after 36 days of subcutaneous implantation in rats. (The material is marked by the white box) (3D digital microscope - Picrosirius staining - x4 and x40 magnification);

[0225] Figure 9 : Figure 9 Representation of the labeling of the T lymphocytes present in the poly (caprolactone-urea-urethane) -based elastomer matrix alone (Elastomer matrix) and in the porous biomaterial comprising hyaluronic acid according to the application (Elastomer matrix-AH) after 36 days of subcutaneous implantation in rats. (The material is marked by the black box) (3D digital microscope - CD3 labeling - x4 and x40 magnification);

[0226] Figure 10 : Figure 10 Representation of the labeling of the macrophages present in the poly (caprolactone-urea-urethane) -based elastomer matrix alone (Elastomer matrix) and in the porous biomaterial comprising hyaluronic acid according to the application (Elastomer matrix-AH) after 36 days of subcutaneous implantation in rats. (The material is marked by the black box) (3D digital microscope - CD163 labeling - x4 and x40 magnification);

[0227] Figure 11 : Figure 11 Representation of the average values of the optical density obtained for the poly (caprolactone-urea-urethane) -based elastomer matrix alone (Elastomer matrix) and for the porous biomaterial comprising hyaluronic acid according to the application (Elastomer matrix-AH) after staining with Alcian blue of the hyaluronic acid;

[0228] Figure 12 : Figure 12 Representation of the poly (caprolactone-urea-urethane) -based elastomer matrix alone (Elastomer matrix) and of the porous biomaterial comprising hyaluronic acid according to the application (Elastomer matrix-AH) before and after beta radiation of 15 kGy. The images were obtained by 3D microscope (VHX Keyence).

[0229] Example

[0230] Example 1 : Formulation and synthesis of the porous biomaterial according to the application

[0231] First, the high molecular weight hyaluronic acid is dissolved in sterile distilled water at 37 °C for 24 hours. Then the solution is filtered through a 0.2 pm filter. In a second step, this aqueous solution is poured into the organic phase comprising the compound based on the poly(caprolactone-urea-urethane)-based elastomer matrix synthesis required to obtain a high internal phase emulsion. Subsequently, the polymerization / crosslinking of this emulsion leads to the production of the porous biomaterial according to the application. Several concentrations of hyaluronic acid were tested. Several volume ratios of the aqueous phase / organic phase were tested. Different synthesis temperatures were also investigated. These different parameters affect the pore size of the material. In the case of use as a gingival substitute, the scaffolds retained are those with pores with a diameter from 50 pm to 1400 pm, with an average size of 600 + / - 170 pm. These materials are characterized in the examples below.

[0232] The formulation and synthesis method chosen to obtain the porous biomaterial according to the application are:

[0233] - hyaluronic acid concentration in the aqueous phase: 1 mg / mL;

[0234] - aqueous phase / organic phase volume ratio: 92.5 / 7.5%,

[0235] - synthesis temperature: 18 h at 37 °C; 4 h at 55 °C; 2 h at 100 °C.

[0236] Example 2: physicochemical and mechanical properties of the porous biomaterial according to the application

[0237] The physicochemical properties of the biomaterial obtained according to the application were tested by:

[0238] - Fourier transform infrared spectroscopy (FTIR) for the analysis of the chemical functions present in the synthesized biomaterial;

[0239] - 3D microscope (VHX Keyence) for morphological observation of the biomaterial;

[0240] - measurement of the volume absorbance (rv) to determine the interconnectivity of the porous structure;

[0241] - the average molar mass (Mc) between crosslinking nodes was measured by swelling, which makes it possible to evaluate the Young's modulus (E1 * ).

[0242] 1. Interconnectivity / porosity

[0243] The images obtained by 3D microscope ( Figure 1) shows that the biomaterial according to the present application has a highly interconnected porous morphology (porosity = 90+ / -2%) (rv = 100%) with a multi-scale pore diameter ranging from 50 pm to 1400 pm, with an average size of 600+ / -170 pm.

[0244] 2. Chemical composition and hydrophilicity

[0245] FTIR analysis ( Figure 2 ) confirmed the presence of hyaluronic acid in the poly(caprolactone-urea-urethane)-based elastomer matrix. The spectrum of the poly(caprolactone-urea-urethane)-based elastomer matrix alone shows the important bands of these materials, such as the -NH groups of the urethanes at 3333 cm -1 , 1537 cm -1 and 1248 cm -1 , the -C=0 groups of the esters at 1730 cm -1 and the -C=0 groups of the ureas at 1620 cm -1 , the -CNH groups of the ureas at 1575 cm -1 and the -COO ester groups at 1164 cm -1 . The subtraction between the corresponding spectra of the poly(caprolactone-urea-urethane)-based elastomer matrix alone and the porous biomaterial according to the present application highlights the presence of hyaluronic acid in the latter, in particular the typical bands of the -CCH, -OCH and -COH groups of the polysaccharide ring at 1612 cm -1 , 1554 cm -1 and 1381 cm -1 .

[0246] The incorporation of hyaluronic acid increases the hydrophilicity of the material, as demonstrated in the measurement of the water contact angle: 0 = 112+ / -16° for the poly(caprolactone-urea-urethane)-based elastomer matrix alone and 0 = 69+ / -12° for the porous biomaterial including hyaluronic acid. Therefore, the porous biomaterial according to the present application has a surface hydrophilicity more suitable for the adhesion of fibroblasts, which have greater adhesion on surfaces with a water contact angle of 60° to 80°.

[0247] In addition, the water absorption rate obtained by soaking the material in distilled water for 15 days goes from about 400% for the poly(caprolactone-urea-urethane)-based elastomer matrix alone to about 700% for the porous biomaterial including hyaluronic acid. This indicates that the porous biomaterial according to the present application will be more suitable for liquid penetration and therefore also for cell infiltration.

[0248] 3. Mechanical properties

[0249] The average molar mass (Mc) between cross-linking nodes was determined by toluene swelling measurements. The Mc value of the poly (caprolactone-urea-urethane) -based elastomer matrix alone was 4860 + / - 240 g / mol, which made it possible to estimate the Young's modulus E1 * of the porous material. The value of 220 + / - 25 kPa demonstrated the elastic properties of the material. The Mc value of the porous biomaterial according to the application comprising hyaluronic acid (comparable to the porosity and pore size of the poly (caprolactone-urea-urethane) -based elastomer matrix alone) was 5380 + / - 1460 g / mol, which made it possible to estimate the E1 * value of 123 + / - 11 kPa. Thus, the hyaluronic acid participates in a slight decrease in the modulus of the porous biomaterial according to the application, while preserving the elastic properties of the polymeric matrix, which will enable the biomaterial according to the application to resist the contractile forces exerted by fibroblasts when cells migrate within the material.

[0250] 4. Degradation kinetics

[0251] In the process of generating a porous biomaterial for tissue engineering, an important criterion is its resorbability, since it must be replaced over time by newly formed tissue. The in vitro degradation study was performed according to the standard ISO 10993-13. Therein, the degradation kinetics was evaluated by measuring the mass loss and water adsorption rate at 37 °C, 55 °C and 75 °C (ISO 10993-12:2012). Figure 3 At 37 °C and 55 °C, no differences were observed between the poly (caprolactone-urea-urethane) -based elastomer matrix alone and the biomaterial according to the application comprising hyaluronic acid within 6 months. The accelerated degradation test at 75 °C showed that the biomaterial according to the application comprising hyaluronic acid degrades slightly faster than the poly (caprolactone-urea-urethane) -based elastomer matrix alone. This is due to the increase in the hydrophilicity of the material. The biomaterial according to the application is stable at 37 °C for more than 6 months. Due to the more stringent conditions, the lifetime of the biomaterial is greatly reduced in vivo; however, the biomaterial according to the application has sufficient stability for tissue engineering applications.

[0252] Example 3: Interaction between the porous biomaterial according to the application and cells (gingival fibroblasts) - in vitro study

[0253] Settling test with gingival fibroblasts to test the "attractive" power of the porous biomaterial comprising hyaluronic acid according to the application and of the poly(caprolactone-urea-urethane)-based elastomer matrix alone. These materials were deposited on a bed of gingival fibroblasts at 80% of confluence. The migration of the cells was determined 10 days, 30 days and 40 days after contact with the materials. After separation of the cells by enzymatic treatment, the cells present on and in the materials were counted. The results obtained show that the cells are able to migrate into the material Figure 4 . The gingival fibroblasts are able to migrate, proliferate and spread on the surface of the pores of the material Figure 5 .

[0254] Interestingly, when the cells are at the periphery of the porous biomaterial comprising hyaluronic acid according to the application, the cells present at the bottom of the pores are directly perpendicular to the material Figure 6 . Skin fibroblasts have been shown to spread and tend to align in the vicinity of dermal fillers based on crosslinked hyaluronic acid, generally leading to an improvement of the fibroblast function (Quan et al., Journal of Investigative Dermatology , 2013, vol 133, pages 658-667). Although this result is more attributed to the structural reinforcement of the dermal extracellular matrix by the filling product, it is clear from our results that the porous biomaterial comprising hyaluronic acid according to the application has an impact on the cells in its vicinity.

[0255] Example 4: In vivo study of the soft tissue regeneration potential of the porous biomaterial according to the application in a rat subcutaneous pocket model

[0256] The in vivo test was performed by implanting the scaffolds subcutaneously along the midline of the back of rats (Sprague-Dawley, 8-week-old males). This study can evaluate the biocompatibility, bio-integration and effectiveness of the porous biomaterial according to the application during the implantation process.

[0257] To evaluate the effectiveness of the porous biomaterial comprising hyaluronic acid according to the application relative to the poly(caprolactone-urea-urethane)-based elastomer matrix alone, several batches of animals were monitored until 36 days after subcutaneous implantation of the matrix. The effectiveness of the material according to the application was evaluated by histological studies of the material collected after sacrifice of the animals. For each study time, 7 days and 36 days, 5 rats per batch (20 rats): poly(caprolactone-urea-urethane)-based elastomer matrix alone animal group - poly(caprolactone-urea-urethane)-based elastomer matrix including non-sulfated polysaccharide animal group.

[0258] The subcutaneous pocket model consists in making a median incision on the back of the rat and creating a subcutaneous pocket into which the material to be evaluated is inserted.

[0259] 1. Surgical procedure

[0260] The animals were anesthetized with ketamine / xylazine (50 / 15 mg / kg) by intramuscular injection at 1.2 mL / kg. The back of the animals was shaved and then disinfected with Betadine®. A median incision was made on the back of the rats and the flaps were raised on both sides. The polymeric matrices (1 cm in diameter, 2 to 3 mm thick) were inserted on both sides of the median line and stabilized. The skin plane was then sutured with absorbable 5.0 sutures.

[0261] The animals were monitored daily for their general condition and behavior. During the entire experiment, the animals showed no decrease in their ability to move and no signs of aggressiveness. The body weight curve evolved regularly. At the wound site, there was no evidence of inflammation or necrosis.

[0262] 2. Preparation of the implant

[0263] The poly (caprolactone-urea-urethane) based elastomeric matrices were taken out of their storage medium (70% ethanol) and rinsed under agitation with physiological saline for 5 minutes. They were then placed in subcutaneous pockets.

[0264] 3. Histology

[0265] After 7 and 36 days, the animals were sacrificed. The elastomeric matrices were taken out, fixed with 10% paraformaldehyde, dried in increasing baths of alcohol and then embedded in paraffin. Sections of 5 µM were then made with a manual microtome.

[0266] After deparaffination and rehydration, the sections were tested for collagen with hematoxylin-eosin (hematoxylin: 0.2% of a water solution of hematoxylin / eosin 2% in 5% of a water solution of potassium alum) or with picric acid-sirius red (0.1% of picric acid-sirius red in a saturated solution of picric acid).

[0267] 4. Results

[0268] The pores of the biomaterial implanted in the subcutaneous dorsal region of the experimental rats were invaded by fibrous connective tissue, as shown in the histological sections after staining with hematoxylin-eosin ( Figure 7 ) and picric acid-sirius red ( Figure 8 ).

[0269] Seven days after implantation, one third of the pores of the biomaterial closest to the surface were invaded by fibrous connective tissue, in which there were many cells of the fibroblastic type. Thirty-six days after implantation, less than 50% of the pores were colonized in the poly(caprolactone-urea-urethane)-based elastomer matrix alone, while about 100% of the pores were colonized in the porous biomaterial comprising hyaluronic acid according to the application. Figure 7 At high magnification, the pores of the poly(caprolactone-urea-urethane)-based elastomer matrix alone were invaded by conjunctival stroma that did not appear to adhere completely to the surface of the pores. This surface appeared to be colonized by many round cells, which can be inflammatory cells as well as red blood cells. In contrast, the pores of the porous biomaterial comprising hyaluronic acid according to the application were invaded by fibrous connective tissue that remained in contact with the surface of the pores. The number of round cells appeared to be greatly reduced compared to the elastomer matrix alone, indicating a reduction in the inflammatory component. Fully constituted blood vessels were present in the connective tissue, in which red blood cells were well confined, with no signs of extravasation. Multinucleated giant cells were also present on the surface of the pores and on the material itself. The connective tissue inside the pores remained in contact with the biomaterial. Thirty-six days after implantation, a decrease in the number of lymphocytes and macrophages was noted, more pronounced in the porous biomaterial comprising hyaluronic acid according to the application. Figure 9 and Figure 10 The porous biomaterial comprising hyaluronic acid according to the application appeared to be more compatible.

[0270] Example 5: Quantitative detection of hyaluronic acid

[0271] The quantitative detection of hyaluronic acid was carried out by colorimetry using Alcian Blue. Briefly, the poly(caprolactone-urea-urethane)-based elastomer matrix alone (elastomer matrix) and the porous biomaterial comprising hyaluronic acid according to the application (elastomer matrix-AH) were cut, weighed, then incubated in an Alcian Blue solution for 2 hours. The excess dye was removed and then replaced with a sodium acetate buffer solution (50 mM / MgCl 250 mM, pH 5.8). These materials were then incubated in a 60% ethanol solution and then in an 80% acetic acid solution. The optical density was measured at 675 nm. The quantitative detection of hyaluronic acid was carried out at various steps of the manufacturing process, and it could be determined that the average concentration of the porous biomaterial according to the application was 425 μg of HA / g (see Example 5). Figure 11

[0272] Example 6: Beta and gamma radiation sterilization

[0273] ​The sterilization by beta treatment is carried out by ionizing method, in that the biological material is continuously conveyed at a controlled speed into the beta rays emitted by an electronic accelerator. The doses tested are 15, 25 and 45 Gy. For example, a dose of 25 kGy + / - 10% is obtained under the following treatment conditions: frequency 640 Hz / scan setting 2.6 / number of turns: 1 / speed: 0.898 m / min.

[0274] The sterilization by gamma treatment is carried out by ionizing method, in that the biological material is exposed to gamma radiation emitted by a cobalt 60 source for a limited time. The dose performed is 25 kGy + / - 10%.

[0275] The pictures obtained by 3D microscope ( Figure 12 ) show that for a sterilization by beta radiation at 15 kGy, the poly(caprolactone-urea-urethane)-based elastomer matrix alone (elastomer matrix) and the porous biological material according to the application comprising hyaluronic acid (elastomer matrix-AH) do not show any structural alteration. The same results are obtained for beta and gamma radiation doses from 15 to 45 kGy, whether the biological material according to the application is dry or in water medium.

Claims

1. A biomaterial for tissue repair, comprising: - at least one elastomer matrix, and -Non-sulfated polysaccharides; Wherein, the biomaterial is a biomaterial used for the reconstruction and / or enhancement of gingival tissue; The at least one elastomer matrix includes an elastomer based on poly(caprolactone-urea-urethane); The isocyanate index of the elastomer matrix is ​​between 1.2 and 4.5; The non-sulfated polysaccharide is hyaluronic acid with a molecular weight greater than or equal to 1000 kDa.

2. The biomaterial of claim 1, wherein, The biomaterial has a multi-scale pore size between 500 μm and 2000 μm.

3. The biomaterial according to any one of claims 1 and 2, characterized in that, The total porosity of the biomaterial is greater than or equal to 60%.

4. The biomaterial according to any one of claims 1 and 2, characterized in that, The biomaterial is in the form of a sponge, film, dressing, granules, monolith, or membrane.

5. The biomaterial of claim 1, wherein, The volume of the reconstructed and / or enhanced tissue is greater than or equal to 5% of the volume of the tissue defect to be reconstructed and / or enhanced.

6. A method for preparing biomaterials as described in any one of claims 1 to 5, comprising the following steps: a) Prepare an organic phase comprising the compounds required for the synthesis of poly(caprolactone-urea-urethane), b) Dissolve hyaluronic acid in an aqueous phase, then add the dissolved hyaluronic acid to the organic phase from step a) to form an emulsion. c) The emulsion obtained in step b) is polymerized / crosslinked to obtain the biomaterial. d) Clean the biomaterial obtained in step c), and e) Dry the biomaterial obtained in step d).

7. The method for preparing biomaterials according to claim 6, wherein the amount of hyaluronic acid is between 0.05% and 2.0% by weight (w / w) relative to the weight of the aqueous phase present in the emulsion.

Images