Biomaterials Comprising At Least One Elastomeric Matrix and Non-Sulfated Polysaccharides and Uses Thereof - Patent application

Abstract

The present invention relates to a biomaterial comprising at least one elastomeric matrix and a polysaccharide, and its use in reinforcing, reconstructing and / or filling tissue defects, preferably in reinforcing, reconstructing and / or filling soft tissue and / or epithelial tissue, preferably in repairing skin and / or mucosa.

Description

[Technical Field]

[0001] The present invention relates to biomaterials and their use in reinforcing, reconstructing and / or filling tissue, preferably reinforcing, reconstructing and / or filling defects of soft tissue and / or epithelial tissue, preferably repairing skin, gums and / or mucosa. [Background technology]

[0002] Periodontal "mucogingival reconstruction" addresses the problems associated with gingival-mucosal soft tissue defects, which have functional, aesthetic, and biological consequences around dental implants as well as around natural teeth. For example, gingival recession can result in an unaesthetic appearance when smiling, can be the cause of spontaneous and / or induced hypersensitivity, promote the progression of deep caries, and induce functional disorders associated with the presence of periodontal inflammation, which can threaten the tooth-supporting tissues (periodontal tissues) that allow the teeth to be anchored within the bone base of the maxilla and mandible.

[0003] This periodontal disease manifests itself as a shift of the marginal gingiva and epithelial-connective tissue attachment junction apically relative to the enamel-cementum junction. Its etiology is multifactorial and involves multiple predisposing factors (e.g., thin biotype, bone dehiscence, low keratinized tissue height and thickness, tooth malposition), mechanical factors such as traumatic tooth brushing, bacteriological factors (presence of plaque and inflammation), or other factors such as occlusal trauma, smoking, and others. Soft tissue defects, especially those of the oral cavity and teeth, can often result in trauma or surgical resection, resulting in the loss of the underlying anatomical structures. Furthermore, alterations at the soft tissue level negatively impact aesthetic appearance and thus patient satisfaction. Depending on the size of the defect, tissue deformities can be aesthetically corrected by soft tissue augmentation, soft tissue reconstruction, or surgical techniques.

[0004] Tissue management may also incorporate other indications such as peri-implant tissue and maxillary crest adjustment. To resolve this tissue deficiency, surgical techniques of tissue transfer must be undertaken.

[0005] Numerous surgical approaches documented in the literature have been proposed to obtain coverage of the tooth root (or exposed implant surface) for the treatment of gingival recession, for tissue thickening and augmentation of the keratinized gingival zone, and for the long-term sustainability of the periodontal and peri-implant environment. Most of these techniques require a second surgical site in the palate (autograft harvested from the mouth), which prolongs the surgical time and contributes to poor postoperative outcomes, resulting in a number of adverse outcomes (pain, excessive bleeding during or after surgery, morbidity, delayed healing, osteonecrosis, paresthesia, or permanent palate numbness). These adverse outcomes are sometimes linked to anatomical constraints, such as the palate being too thin to provide sufficient tissue volume, or to refusal of treatment due to the patient's objection to tissue harvesting from other "donor" sites, which can lead to painful complications.

[0006] The first proposed solution for repairing soft tissue defects is the transplantation of a portion of connective tissue harvested from elsewhere in the patient's body. This is then called autologous connective tissue transplantation. Autologous transplantation does not generate an immune response because the tissue is derived from the patient. However, autologous transplantation results in significant cell death in the transplanted tissue. This loss can be compensated for if the transplant has the ability to produce new cells, which depends in particular on the vascularization of the transplant. This vascularization is in fact essential for the tissue being reconstructed; that is, blood vessels provide the nutrients and energy necessary for cell growth. Furthermore, autologous transplantation requires two surgeries (harvesting and subsequent transplantation) that can induce complications (pain, abscesses, neuralgia). The size of the graft required for replacement represents another important limitation.

[0007] Another alternative is to use allogeneic substitutes.

[0008] A commonly used allogeneic dermal substitute for soft tissue reconstruction and / or filling defects in general practice is the product AlloDerm®, available from Biohorizons. AlloDerm® is a human-derived acellular dermal matrix obtained from cadaveric skin of human donors that has undergone physical and chemical treatment involving tissue de-epidermalization, which induces the detachment of hemidesmosome anchoring fibers from basal keratinocytes while removing all cellular content (epithelial cells, connective tissue cells, viral cells, and bacterial cells). This implies the elimination of the epidermal layer along with all cellular components without damaging the components of the connective tissue matrix under conditions that do not modify collagen bundles or damage the basement membrane complex. This process leaves behind extracellular collagen, which provides the basis for cell growth and subsequent tissue remodeling.

[0009] Another allogeneic substitute conventionally used by general practitioners to reconstruct soft tissue and / or fill in soft tissue defects is the product Mucoderm®, available from Botiss, Inc. Mucoderm® is a type I / III native collagen-based matrix derived from porcine dermis and elastin.

[0010] However, these products have many disadvantages. In fact, they are relatively expensive, require very long postoperative follow-up, and early exposure of the matrix can limit vascularization of the implant and subsequently reduce the potential for recessive coverage. Furthermore, Mucoderm® undergoes a necrotic process. The healing and replacement of AlloDerm® or Mucoderm® by neoplastic tissue is extremely slow, taking approximately 10 weeks. In fact, due to their devitalized structure, the healing and replacement of AlloDerm® or Mucoderm® depends on the cells and blood vessels present in the neighboring tissue, leading to a slowdown in incorporation that can manifest itself in the form of structural and functional irregularities. Furthermore, their macromolecular structure differs from that of physiological gingiva, despite the supposed similarity of their macromolecular composition. In fact, the very dense collagen network of allogeneic substitutes appears to limit cell colonization in vitro and tissue remodeling in vitro and in vivo. In fact, the gingival extracellular matrix is ​​constantly remodeling to withstand mechanical stress. However, the observed fibrotic process is due to non-physiological remodeling of the gingiva at the implant site. Furthermore, the continuous presence of multinucleated giant cells bearing foreign bodies may induce poor adhesion of allogeneic substitutes and persistent clinical redness. Furthermore, Mucoderm®, once implanted, has been shown to contract during healing, and a remodeling process occurs during this healing process that may lead to wound contraction. Furthermore, Mucoderm® has been shown to pose a problem of disintegration when the implant is subjected to significant mechanical stress, causing a strong inflammatory response. Finally, the animal-derived nature of some allogeneic substitutes can sometimes lead to rejection due to religious or philosophical beliefs.

[0011] Other surgical fields are also seeking biocompatible materials to compensate for tissue defects or losses related to trauma (burns, abrasions, lacerations), aging, or disease; or to reinforce tissue after trauma, aging, or disease. For example, many companies specialize in designing implants to be used as reinforcements in gynecological, urological, or visceral (or parietal) surgery. These materials can be designed for the treatment of vascular wounds, digestive wounds, evisceration, and the like. These biomaterials are thus applicable to the design of reinforcement implants for the treatment of pelvic organ prolapse, more specifically, for the treatment of pelvic organ prolapse in women (anterior (urinary, cystocele, stress incontinence), middle (genital, colpocele), and / or posterior (digestive, rectocele)) or Peyronie's disease in men. Here, the biomaterials can be used in the form of expandable reinforcement sheets, membrane wicks of any shape, or implant wicks. The biomaterials that have been used with more or less success are currently of xenogeneic origin (for example Pelvicol® available from Bard France SAS) or synthetic origin (for example polypropylene such as Parietex® available from SOFRADIM). However, Pelvicol® poses the problem of disintegration when the implant is subjected to high mechanical stress and is the cause of a strong inflammatory reaction.

[0012] US Patent Application Publication No. 2012 / 239161 describes an elastomeric matrix based on caprolactone and agar or gelatin. China Patent No. 108034225 describes a method for preparing a composite material containing an elastomeric matrix and chitosan. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US Patent Application Publication No. 2012 / 239161 [Patent Document 2] Chinese Patent No. 108034225 Summary of the Invention [Problem to be solved by the invention]

[0014] For these reasons, there is a need to provide novel biomaterials that are easy for general practitioners to use, have suitable mechanical properties in terms of elasticity and volume preservation for implantation in soft tissues, and have the ability to reinforce, reconstruct, and / or fill tissue defects. This also means providing biomaterials with excellent biocompatibility and degradation suitable for tissue regeneration. This also means providing biomaterials that are not derived from animals. [Means for solving the problem]

[0015] Therefore, the present invention provides at least one elastomer matrix, - non-sulfated saccharide polymers, The present invention relates to a biomaterial for tissue repair, comprising:

[0016] The present invention is also directed to the use of said biomaterial in tissue repair, preferably in soft tissue and / or epithelial tissue repair, preferably in skin and / or mucosal repair.

[0017] The present invention is also directed to a method for preparing a biomaterial.

[0018] Therefore, the present invention provides at least one elastomer matrix, - non-sulfated saccharide polymers, The present invention relates to a biomaterial for tissue repair, comprising:

[0019] The present invention has the advantage of proposing a porous, bioabsorbable / biodegradable elastomeric biomaterial that favors cell migration and angiogenesis. The biomaterial according to the invention also provides better tissue biointegration without any risk of microbial contamination.

[0020] In the context of the present invention, a "biomaterial" is a material used and adapted for medical applications. Advantageously, the biomaterial according to the present invention is a physical support on or within which fibroblasts can adhere, migrate and proliferate, which is resorbable and biodegradable, thus allowing its replacement by newly formed connective tissue.

[0021] Advantageously, the biomaterial according to the invention comprises at least one elastomeric matrix or non-sulfated polysaccharide, the individual properties of which combine with one another to provide a significantly improved overall performance, properties which cannot be observed with at least one elastomeric matrix or non-sulfated polysaccharide when used individually.

[0022] The inventors have surprisingly found that a biomaterial according to the invention comprising at least one elastomeric matrix and a non-sulfated polysaccharide: - sufficient mechanical properties to withstand the stresses of the forces exerted by the cells as well as the regeneration processes in the zone to be repaired and to provide a support for the soft tissues in this zone; - a porosity and interconnectivity that allows the internal vascularization of the biomaterial of the invention, while allowing the circulation of fibroblasts, nutrients and other molecules that intervene in the regulation of these processes; - roughness that allows cell adhesion and the adsorption of molecules that intervene in the regulation of these processes; It was shown that

[0023] Advantageously, the inventors have shown that the biomaterial, when implanted in a patient, has the ability to activate collagen synthesis and angiogenesis, allowing for rapid reconstruction of damaged tissue.

[0024] In one particular embodiment of the present invention, the non-sulfated polysaccharides may be covalently attached to the elastomeric matrix, hi another particular embodiment of the present invention, the non-sulfated polysaccharides may be dispersed within and on the surface of the elastomeric matrix.

[0025] In the context of the present invention, an "elastomeric matrix" is a structure composed of a single elastomer or a combination of two or more elastomeric systems, said structure being capable of incorporating non-sulfated polysaccharides. Advantageously, the isocyanate index of the elastomeric 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.

[0026] Advantageously, the at least one elastomeric matrix according to the invention has good biodegradability, good biocompatibility and good mechanical properties.

[0027] In the context of the present invention, "elastomer" means one or more polymers having "rubber-elastic" properties obtained after crosslinking. In a particular embodiment of the present invention, the elastomer must be biocompatible and biodegradable. Advantageously, the compressive Young's modulus of the biomaterial of the present invention is between 1 kPa and 1000 kPa, advantageously between 50 kPa and 900 kPa, advantageously between 50 kPa and 800 kPa, advantageously between 50 kPa and 700 kPa, advantageously between 50 kPa and 600 kPa, advantageously between 50 kPa and 500 kPa, advantageously between 100 kPa and 400 kPa.

[0028] In the sense of the present invention, a "biocompatible" elastomeric matrix is ​​one that is both suitable for implantation into a patient's body and suitable for incorporating non-sulfated polysaccharides therein, and that is adapted for soft tissue reconstruction once the biomaterial is implanted in a human or animal patient.

[0029] In the context of the present invention, "suitable for implantation into a patient's body" means an elastomeric matrix that, when implanted, has a beneficial benefit / risk ratio that is favorable from a therapeutic point of view, e.g. within the meaning of Directive 2001 / 83 / CE.

[0030] In the context of the present invention, "compatible with the incorporation of a non-sulfated polysaccharide" refers to an elastomeric matrix that allows the incorporation of a non-sulfated polysaccharide without any or minimal degradation of the activity of said non-sulfated polysaccharide within the elastomeric matrix. Advantageously, the non-sulfated polysaccharide is incorporated into the elastomeric matrix. In other words, the non-sulfated polysaccharide is directly incorporated into the elastomeric matrix during the manufacture of the biomaterial according to the present invention.

[0031] Within the meaning of the present invention, a "biodegradable" elastomeric matrix is ​​one that is bioresorbable and / or biodegradable and / or bioabsorbable, with the common goal of gradual elimination through one or more different or complementary mechanisms of degradation, solubilization, or absorption of the elastomeric matrix within the body of a human or animal patient into which the material is implanted.

[0032] In one particular embodiment of the invention, at least one elastomeric matrix according to the invention comprises a poly(ester-urea-urethane) based elastomer.

[0033] In one highly advantageous embodiment of the invention, at least one elastomeric matrix of the biomaterial according to the invention comprises a poly(ester-urea-urethane) based elastomer, the esters being chosen from among caprolactone oligomers (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyric acid oligomers (PHB), hydroxyvaleric acid oligomers (PVB), dioxanone oligomers (PDO), poly(ethylene adipate) oligomers (PEA), poly(butylene adipate) oligomers (PBA) or combinations thereof.

[0034] In one specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(hydroxyvaleric acid-urea-urethane)-based elastomer.

[0035] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxybutyrate-urea-urethane).

[0036] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(dioxanone-urea-urethane) based elastomer.

[0037] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(ethylene adipic acid-urea-urethane) based elastomer.

[0038] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(butylene adipic acid-urea-urethane) based elastomer.

[0039] In one specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(lactic acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(glycolic acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(hydroxyvaleric acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(hydroxybutyric acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(dioxanone-urea-urethane)-based elastomer. In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(ethylene adipic acid-urea-urethane) based elastomer. In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane) and poly(butylene adipic acid-urea-urethane) based elastomer.

[0040] In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane) and poly(glycolic acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane) and poly(hydroxyvaleric acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane) and poly(hydroxybutyric acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane) and poly(dioxanone-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane) and poly(ethylene adipic acid-urea-urethane)-based elastomer. In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(lactic acid-urea-urethane) and poly(butylene adipate-urea-urethane) based elastomer.

[0041] In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane) and poly(hydroxyvaleric acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane) and poly(hydroxybutyric acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane) and poly(dioxanone-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane) and poly(ethylene adipic acid-urea-urethane)-based elastomer. In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(glycolic acid-urea-urethane) and poly(butylene adipic acid-urea-urethane)-based elastomer.

[0042] In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxyvaleric acid-urea-urethane) and poly(hydroxybutyric acid-urea-urethane). In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxyvaleric acid-urea-urethane) and poly(dioxanone-urea-urethane). In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxyvaleric acid-urea-urethane) and poly(ethylene adipic acid-urea-urethane). In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxyvaleric acid-urea-urethane) and poly(butylene adipic acid-urea-urethane).

[0043] In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxybutyrate-urea-urethane) and poly(dioxanone-urea-urethane). In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxybutyrate-urea-urethane) and poly(ethylene adipic acid-urea-urethane). In another specific embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(hydroxybutyrate-urea-urethane) and poly(butylene adipic acid-urea-urethane).

[0044] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(dioxanone-urea-urethane) and poly(ethylene adipic acid-urea-urethane). In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(dioxanone-urea-urethane) and poly(butylene adipic acid-urea-urethane).

[0045] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(ethylene adipic acid-urea-urethane) and poly(butylene adipic acid-urea-urethane).

[0046] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane) and poly(glycolic acid-urea-urethane) based elastomers.

[0047] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), and poly(hydroxyvaleric acid-urea-urethane) based elastomers.

[0048] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), and poly(hydroxybutyric acid-urea-urethane) based elastomers.

[0049] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane), poly(lactic-urea-urethane), poly(glycolic-urea-urethane), poly(hydroxyvaleric-urea-urethane), and poly(hydroxybutyric-urea-urethane) based elastomer. In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising a poly(caprolactone-urea-urethane), poly(lactic-urea-urethane), poly(glycolic-urea-urethane), poly(hydroxyvaleric-urea-urethane), poly(hydroxybutyric-urea-urethane), and poly(dioxanone-urea-urethane) based elastomer.

[0050] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), poly(hydroxyvaleric acid-urea-urethane), poly(hydroxybutyric acid-urea-urethane), poly(dioxanone-urea-urethane), and poly(ethylene adipic acid-urea-urethane) based elastomers.

[0051] In another particular embodiment, at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane), poly(glycolic acid-urea-urethane), poly(hydroxyvaleric acid-urea-urethane), poly(hydroxybutyric acid-urea-urethane), poly(dioxanone-urea-urethane), poly(ethylene adipic acid-urea-urethane), and poly(butylene adipic acid-urea-urethane).

[0052] These elastomers indeed allow the implementation of the present invention and, furthermore, have the advantages of being cytocompatible, allowing the restoration of physiological stresses in the defective tissue, avoiding the need for reoperation after the restoration, and allowing the proper reconstruction of the defective tissue. Highly advantageously, at least one elastomer matrix of the porous biomaterial is a matrix containing a poly(caprolactone-urea-urethane)-based elastomer. This matrix containing a poly(caprolactone-urea-urethane)-based elastomer also has the advantage of having elastomeric properties that give it flexibility and an interconnected porous structure adapted to tissue reconstruction.

[0053] In one particular embodiment of the present invention, the non-sulfated polysaccharide may be selected from the group comprising carrageenan, alginate, xanthan, chitosan, chitin, hyaluronic acid, glycogen, cellulose and its derivatives, pectin, starch and its derivatives, dextran and xylan, or mixtures thereof. Advantageously, the non-sulfated polysaccharide may therefore consist of a single polysaccharide or a mixture of non-sulfated polysaccharides.

[0054] In one highly advantageous embodiment of the invention, the non-sulfated polysaccharide according to the invention is hyaluronic acid.

[0055] In the context of the present invention, "hyaluronic acid" means hyaluronic acid, crosslinked or not, alone or in mixtures; optionally chemically modified by substitution, alone or in mixtures; and / or optionally in the form of one of its salts, alone or in mixtures.

[0056] Advantageously, hyaluronic acid is high molecular weight hyaluronic acid.In the meaning of the present invention, "high molecular weight hyaluronic acid" refers to the hyaluronic acid with molecular weight of 1,000 kDa or more.On the other hand, "low molecular weight hyaluronic acid" refers to the hyaluronic acid with molecular weight of less than 1,000 kDa.

[0057] In a particular embodiment of the present invention, hyaluronic acid has a molecular weight of 1,000 kDa or more, advantageously 10,000 kDa or more, advantageously 100,000 kDa or more, advantageously 1,000,000 kDa or more, advantageously 1,500,000 kDa or more, advantageously 2,000,000 kDa or more.Advantageously, the hyaluronic acid of the present invention has a molecular weight of 1,500,000 kDa.Advantageously, the use of high molecular weight hyaluronic acid, in addition to its non-immunogenic and anti-angiogenic properties, allows for the structuring of matrix macromolecules, especially collagen, in the early stage of healing, which is not possible with low molecular weight hyaluronic acid.

[0058] In one advantageous embodiment of the invention, the biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(ester-urea-urethane)-based elastomer, wherein the ester is selected from among caprolactone oligomers (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyric acid oligomers (PHB), hydroxyvaleric acid oligomers (PVB), dioxanone oligomers (PDO), poly(ethylene adipic acid) oligomers (PEA), poly(butylene adipic acid) oligomers (PBA), or combinations thereof; and -Non-sulfated polysaccharide.

[0059] In a first particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0060] In a second particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(lactic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0061] In a third particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(glycolic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0062] In a fourth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) and poly(lactic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0063] In a fifth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) and a poly(glycolic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0064] In a sixth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(lactic acid-urea-urethane) and a poly(glycolic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0065] In a seventh particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising poly(caprolactone-urea-urethane), poly(lactic acid-urea-urethane) and poly(glycolic acid-urea-urethane) based elastomers, and - Non-sulfated polysaccharide.

[0066] In an eighth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(hydroxybutyrate-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0067] In a ninth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(hydroxyvaleric acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0068] In a tenth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(dioxanone-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0069] In an eleventh particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(ethylene adipic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0070] In a twelfth particular embodiment of the invention, the porous biomaterial according to the invention comprises: - at least one elastomer matrix comprising a poly(butylene adipic acid-urea-urethane) based elastomer, and - Non-sulfated polysaccharide.

[0071] Advantageously, according to one of the above-mentioned embodiments (embodiments 1 to 12), the non-sulfated polysaccharide may be hyaluronic acid. Advantageously, the hyaluronic acid is a high molecular weight hyaluronic acid.

[0072] In one particularly advantageous embodiment of the invention, the porous biomaterial according to the invention comprises: - an elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer; and - Hyaluronic acid.

[0073] Advantageously, the porous biomaterial comprises: - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) based elastomer, and - High molecular weight hyaluronic acid.

[0074] Advantageously, the porous biomaterial consists solely of: - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) based elastomer, and - High molecular weight hyaluronic acid.

[0075] In one advantageous embodiment of the invention, the biomaterial according to the invention contains: - at least one elastomer matrix comprising a poly(ester-urea-urethane)-based elastomer, wherein the ester is selected from among caprolactone oligomers (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyric acid oligomers (PHB), hydroxyvaleric acid oligomers (PVB), dioxanone oligomers (PDO), poly(ethylene adipic acid) oligomers (PEA), poly(butylene adipic acid) oligomers (PBA), or combinations thereof; and - Non-sulfated polysaccharide.

[0076] Advantageously, the porous biomaterial contains: - at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) based elastomer, and - High molecular weight hyaluronic acid.

[0077] Advantageously, the inventors have shown that a specific combination of hyaluronic acid, particularly high molecular weight hyaluronic acid, with at least one elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer not only allows for increased cell migration, but also better vascularization and tissue remodeling within and around the porous biomaterial, compared to the use of a porous elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer alone. Indeed, the addition of hyaluronic acid leads to increased collagen synthesis, thus making it possible to obtain a more structured tissue.

[0078] In a specific embodiment of the present invention, the biomaterial has multiscale pore sizes ranging from 50 μm to 2000 μm. In the context of the present invention, the terms "pore size" and "pore diameter" can be used interchangeably. "Multiscale pore size" refers to a variable distribution of pore sizes, i.e., a distribution of pore sizes that includes a variable proportion of pores of several microns as well as smaller pores. By way of example, a biomaterial having multiscale pore sizes ranging from 50 μm to 2000 μm means that the biomaterial contains pores with variable sizes ranging from 50 μm to 2000 μm, simultaneously and within the same biomaterial. By way of non-limiting example, a biomaterial having multiscale pore sizes ranging from 50 μm to 2000 μm means that the biomaterial contains pores with sizes of, for example, 50 μm, 100 μm, 500 μm, 1500 μm, and 2000 μm, simultaneously and within the same biomaterial. Advantageously, the biomaterial has a multiscale pore size between 50 μm and 1200 μm. Advantageously, the average pore size is between 500 μm and 700 μm.

[0079] Advantageously, said biomaterial has multi-scale pore sizes between 500 μm and 2000 μm.

[0080] In one advantageous embodiment of the invention, the pores of the biomaterial have a rough surface.

[0081] In one advantageous embodiment of the invention, the biomaterial has a total porosity of 60% or more. In the context of the present invention, "total porosity" refers to the ratio of the volume of material-free space to the overall volume of the biomaterial.

[0082] Advantageously, the total porosity of the porous 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%, is 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 one particularly advantageous embodiment, the biomaterial has a total porosity of 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 one highly advantageous embodiment, the porous biomaterial has a total porosity of between 70% and 95%.

[0083] In one particular embodiment of the invention, the biomaterial has an inter-pore interconnectivity of between 60% and 100%. Advantageously, the inter-pore 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 one highly advantageous embodiment of the invention, the pore-pore 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 one highly advantageous embodiment of the invention, the biomaterial has an pore-pore interconnectivity of 100%.

[0084] In one highly advantageous embodiment, the biomaterial according to the invention has a pore size of 50 μm to 2000 μm, a total porosity of 60% or more and an interconnectivity between the pores of 60% to 100%.

[0085] Advantageously, the biomaterial according to the invention has an average pore size of between 50 μm and 1200 μm, a total porosity of between 60% and 95% and an interconnectivity between the pores of between 60% and 100%.

[0086] Advantageously, the biomaterial according to the invention has an average pore size of 500 μm to 700 μm, a total porosity of 70% to 95% and an interconnectivity between the pores of 100%.

[0087] In one highly advantageous embodiment, the porous biomaterial comprising at least one elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid has a pore size of 500 μm to 2000 μm, a total porosity of 60% to 95% and an inter-pore interconnectivity of 60% to 100%.

[0088] Advantageously, the biomaterial, comprising at least one elastomeric matrix comprising a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid, has an average pore size of 500 μm to 700 μm, a total porosity of 70% to 95%, and an interconnectivity between the pores of 100%. The porosity, pore size, and their interconnectivity of the material have a significant impact on the biomaterial's ability to be vascularized and gradually resorbed.

[0089] Thus, due to its 60% to 95% total porosity, its 500 μm to 2000 μm pore size, and its 100% inter-pore interconnectivity, biomaterials comprising at least one elastomeric matrix containing a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid are highly suitable for cell adhesion and migration of connective tissue and blood vessels. Indeed, the interconnected porous network allows for cell attachment and growth, and thus the growth of newly formed connective tissue. Furthermore, the presence of hyaluronic acid stimulates angiogenesis, thus improving revascularization and biomaterial integration. At the same time, fibroblasts adhere and proliferate within and around the biomaterial. Resorption of the biomaterial and the simultaneous production of collagen by the fibroblasts present within and around the biomaterial lead to its complete replacement by newly formed connective tissue after several months. Thus, biomaterials comprising at least one elastomeric matrix containing a poly(caprolactone-urea-urethane)-based elastomer and hyaluronic acid favor revascularization, fast soft tissue integration, and provide a reliable substitute for autologous graft connective tissue.

[0090] The size of the biomaterial of the present invention depends on the size and thickness of the tissue defect. In one particular embodiment of the present invention, the biomaterial has a size of 5 mm to 20 cm and a thickness of 100 μm to 4 cm.

[0091] 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.

[0092] Advantageously, the thickness of the biomaterial is between 100 μm and 4 cm, advantageously between 200 μm and 4 cm, advantageously between 500 μm 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.

[0093] In one advantageous particular embodiment, the thickness of the biomaterial is between 1 and 3 mm when the biomaterial according to the invention is used in reinforcing, reconstructing and / or filling tissue defects of the mucosa, in particular the gingiva.

[0094] In one advantageous particular embodiment, the surface of the biomaterial is at least 25 mm 2 Advantageously, 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 2 , advantageously at least 450 mm 2 , advantageously at least 500 mm2 , 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 biomaterial has a surface of 25 mm 2 ~400cm2 It has a volume of

[0095] In one particular embodiment of the invention, the biomaterial is at least 1 mm 3 Advantageously, the biomaterial has a volume of 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 cm 3 , 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 one advantageous embodiment, the biomaterial has a volume of 1 mm 3 ~10cm 3 It has a volume of

[0096] In one advantageous embodiment of the invention, the biomaterial according to the invention may be in the form of a sponge, a film, a membrane, granules, a monolith or a wound dressing.

[0097] In a specific embodiment of the present invention, the biomaterial of the present invention is used alone. In another embodiment of the present invention, the biomaterial can be further used in combination with an active agent. Advantageously, the active agent is disposed inside the pores of the biomaterial of the present invention, partially or completely covering the pores of the biomaterial. Advantageously, the active agent can be added by one of the following methods: coating the biomaterial with the active agent, immersing the biomaterial in the active agent, spraying the active agent onto the biomaterial, vaporizing the active agent onto the biomaterial, or any other technique known to those skilled in the art that allows filling and / or replenishing the pores of the biomaterial. Advantageously, the active agent can be any therapeutic or pharmaceutically active ingredient (including, but not limited to, nucleic acids, proteins, lipids, and carbohydrates) that has the physiological properties desired for application to the implantation site. Therapeutic agents include, but are not limited to, anti-infective agents such as antibiotics and antivirals; chemotherapeutic agents (e.g., anti-cancer agents); anti-rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones such as steroids; growth factors (including, but not limited to, cytokines, chemokines, and interleukins), clotting factors (Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor V), albumin, fibrinogen, von Willebrand factor, thrombin inhibitors, antithrombotic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antibacterial agents, antibiotics, surface glycoprotein receptor inhibitors, antiplatelet agents, antimitotic agents, microtubule inhibitors. This list includes, but is not limited to, agents, antisecretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, antimetabolites, antiproliferative agents, anti-cancer chemotherapeutic agents, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory drugs, immunosuppressants, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, angiotensin converting enzyme inhibitors (ACE), free radical scavengers, chelating agents, antioxidants, antipolymerase agents, antivirals, photodynamic therapy agents and gene therapy agents, and other naturally occurring or genetically modified proteins, polysaccharides, glycoproteins and lipoproteins, or combinations thereof.In one highly advantageous embodiment of the invention, the active agent is a combination of therapeutic agents, and in particular a combination of an antibiotic and a growth factor.

[0098] Another aspect of the present invention relates to a biomaterial according to the present invention for its use in reinforcing, reconstructing and / or filling a tissue defect. In the context of the present invention, "reinforcing a tissue defect" means increasing tissue density by inducing collagen synthesis and / or collagen deposition due to the biocompatibility of the biomaterial, and in particular due to the presence of hyaluronic acid.

[0099] In the context of the present invention, "reconstruction of a tissue defect" means repair of a tissue defect by inducing collagen synthesis and / or collagen deposition due to the biocompatibility of the biomaterial, and in particular due to the presence of hyaluronic acid.

[0100] In the context of the present invention, "filling of a tissue defect" means filling of the tissue defect by inducing collagen synthesis and / or collagen deposition due to the biocompatibility of the biomaterial, and in particular due to the presence of hyaluronic acid.

[0101] In one particular embodiment of the invention, the tissue reinforcement, reconstruction and / or filling is 5% or more by volume of the volume of the tissue defect to be reinforced, reconstructed and / or filled. Advantageously, the tissue reinforcement, reconstruction and / or filling is 6% or more by volume of the volume of the tissue to be reconstructed and / or filled, advantageously 7% or more, advantageously 8% or more, advantageously 9% or more, advantageously 10% or more, advantageously 11% or more, advantageously 12% or more, advantageously 13% or more, advantageously 14% or more, advantageously 15% or more, advantageously 16% or more, advantageously 17% or more, advantageously 18% or more, advantageously 19% or more, advantageously 20% or more, advantageously 21% or more, advantageously 22% or more, advantageously 23% or more, advantageously 24% or more, advantageously 25% or more. Advantageously, it is 26% or more, advantageously 27% or more, advantageously 28% or more, advantageously 29% or more, advantageously 30% or more, advantageously 31% or more, advantageously 32% or more, advantageously 33% or more, advantageously 34% or more, advantageously 35% or more, advantageously 36% or more, advantageously 37% or more, advantageously 38% or more, advantageously 39% or more, advantageously 40% or more, advantageously 41% or more, advantageously 42% or more, advantageously 43% or more, advantageously 44% or more, advantageously 45% or more, advantageously 46% or more, advantageously 47% or more, advantageously 48% or more, advantageously 49%. Advantageously, the tissue reinforcement, reconstruction and / or filling represents 50% or less by volume of the volume of the tissue defect to be reinforced, reconstructed and / or filled.

[0102] In one highly advantageous embodiment of the invention, the porous biomaterial according to the invention can be used for tissue reinforcement, reconstruction and / or replacement in humans or animals. By way of example, the animals may be horses, ponies, dogs, cats, rats, mice, boars, sows, cows, steers, bulls, calves, goats, ewes, rams, female lambs, rams, donkeys, camels, dromedaries, but this list is not limiting.

[0103] Advantageously, the porous biomaterial according to the invention can be used to reinforce, reconstruct and / or fill soft tissue and / or epithelial tissue defects.

[0104] In the context of the present invention, "soft tissue" means non-bony, non-epithelial tissue that surrounds, supports and connects organs and other tissues. Advantageously, soft tissue surrounds, supports and connects organs and other parts of the body; gives the body shape and structure; protects organs; circulates fluids such as blood from one part of the body to another; and stores energy.

[0105] In one particular embodiment of the invention, the biomaterial according to the invention can be used to reinforce, reconstruct and / or supplement any type of soft tissue of human or animal origin, advantageously selected from the group comprising fibrous tissue, muscle, in particular smooth muscle, skeletal muscle and cardiac muscle, synovial tissue, blood vessels, lymphatic vessels, visceral organs and nerves, although this list is not limiting.

[0106] In a particular embodiment, the biomaterial according to the invention can be used to reinforce, reconstruct and / or fill any type of epithelial tissue of human or animal origin. Advantageously, the biomaterial according to the invention can be used to reinforce, reconstruct and / or fill defects of the skin and / or mucosa. Advantageously, the mucosa can be the oral mucosa.

[0107] In a particular embodiment, the biomaterial according to the invention can be used to reinforce, reconstruct and / or replace any type of epithelial tissue, advantageously in the reinforcement, reconstruction and / or replacement of the gums, in particular to obtain root coverage, to treat gingival recession, to thicken tissue for thick biotypes, to increase the keratinized gingival zone, to restore tooth support and anchorage or to rebuild tissue following periodontitis.

[0108] In a particular embodiment, the biomaterial according to the invention can be used to reinforce soft tissue and / or epithelial tissue defects, in particular within the framework of gynecological, urological or visceral (or parietal) surgery, for example to reinforce vascular wounds, gastrointestinal injuries or evisceration. In another embodiment, the biomaterial according to the invention can be used for the design of reinforcing implants for the treatment of pelvic organ prolapse, more particularly in the treatment of female pelvic organ prolapse, i.e. anterior (urinary, cystocele, stress urinary incontinence), middle (genital, colpocele) and / or posterior (digestive, rectocele) stages.

[0109] Another aspect of the present invention relates to the biomaterial according to the present invention for its use in the treatment of burns. Advantageously, the biomaterial according to the present invention is highly useful for the treatment of burns. Advantageously, the biomaterial according to the present invention is highly useful for the treatment of thermal burns, freeze burns, electrical burns, chemical burns and radiation burns.

[0110] An aspect of the present invention relates to a biomaterial according to the present invention for its use in the treatment of burns, preferably thermal, cryoburns, electrical, chemical, radiation and photochemical burns.

[0111] Within the meaning of the present invention, "burn" means an external burn caused by external contact or contact with flames, hot steam or boiling liquids (the severity of which depends on the temperature of the object and the duration of contact), while internal burns concern the respiratory or digestive tract and result from the absorption or inhalation of hot products (food, gases, especially those produced by combustion) or caustic substances (chemical products).

[0112] In the context of the present invention, "freeze burn" refers to frostbite, which can be caused by anything cold and by friction.

[0113] In the sense of the present invention, "electrical burn" means a partial or total destruction that may involve the skin, mucous membranes (in some cases internal mucous membranes), soft parts of tissues, caused by an electric arc (burn from a fire) or by direct contact with a conductor (always deep).

[0114] In the sense of the present invention, "chemical burn" means a partial or total destruction that may involve the skin, mucous membranes (in some cases internal mucous membranes), soft parts of tissues, caused by the caustic action of strong acids (hydrochloric acid, sulfuric acid, nitric acid) or strong bases (sodium hydroxide, potassium hydroxide).

[0115] In the sense of the present invention, "radiation burns" means burns or radiation dermatitis caused by electromagnetic radiation, particulate matter.

[0116] In one highly advantageous embodiment of the invention, the biomaterial according to the invention can be used for the treatment of burns in humans or animals, by way of example only, the animals may be horses, ponies, dogs, cats, rats, mice, boars, sows, cows, bulls, steers, calves, goats, ewes, rams, female lambs, rams, donkeys, camels, dromedaries, but this list is not limiting.

[0117] Another aspect of the present invention relates to a method for preparing the biomaterial according to the present invention. In one particular embodiment of the present invention, the biomaterial according to the present invention is obtained by the poly-HIPE method (formation of a high internal phase emulsion and polymerization / crosslinking). A high internal phase emulsion or HIPE consists of an immiscible liquid / liquid dispersion system in which the volume of the internal phase, also called the dispersed phase, occupies more than about 74%-75% of the total volume of the emulsion, i.e., a volume larger than what is geometrically possible for compact packaging of monodisperse spheres.

[0118] In one particular embodiment, the method for preparing the biomaterial comprises the following steps: a) preparing an organic phase containing compounds necessary for the synthesis of poly(ester-urea-urethane); b) solubilizing a non-sulfated polysaccharide in an aqueous liquid phase to form an emulsion, and then adding the solubilized non-sulfated polysaccharide to the organic phase of step a); c) polymerizing / crosslinking the emulsion obtained in step b) to obtain said biomaterial; d) washing the biomaterial obtained in step c); e) drying the biomaterial obtained in step d).

[0119] In one embodiment of the present invention, step a) consists of preparing an organic phase containing the compounds necessary for the synthesis of poly(ester-urea-urethane). Advantageously, the organic phase further comprises an oligoester, an organic solvent, a crosslinker, a catalyst, and a surfactant. Advantageously, the organic phase comprises an organic solvent, a polycaprolactone triol oligomer, a surfactant Span 80, a crosslinker hexamethylene diisocyanate (HMDI), and a catalyst dibutyltin dilaurate (DBTDL). Advantageously, the organic solvent is toluene.

[0120] In one particular embodiment, step a) comprises a first step a1) consisting of solubilizing the polycaprolactone triol oligomer and the surfactant Span 80 in an organic solvent, followed by a second step a2) consisting of adding the crosslinker HMDI and the catalyst DBTDL to the solution of step a1) to form an organic layer. In one advantageous embodiment of the present invention, 2.4 ml of organic solvent is used, along with 1.3 g of polycaprolactone triol oligomer, 1.3 g of surfactant Span 80, 1.04 ml of crosslinker HMDI, and 12 drops of catalyst DBTDL. Advantageously, a person skilled in the art can adapt the amounts of toluene, polycaprolactone triol oligomer, surfactant Span 80, crosslinker HMDI, and catalyst DBTDL depending on the desired pore size of the porous biomaterial according to the present invention. Advantageously, the organic solvent is toluene.

[0121] In a particular embodiment, step b) of the method comprises solubilizing a non-sulfated polysaccharide in an aqueous liquid phase to form an emulsion, followed by adding the solubilized non-sulfated polysaccharide to the organic phase of step a). In a particular embodiment of the present invention, the non-sulfated polysaccharide must be solubilized in the aqueous liquid phase. In a particular embodiment of the present invention, the aqueous liquid phase is sterile purified water. Advantageously, a person skilled in the art can adapt the amount of water depending on the pore size desired for the biomaterial. In an advantageous embodiment of the present invention, the amount of purified water used is 50 mL.

[0122] In one particular embodiment of the invention, the aqueous liquid phase is gradually poured into the organic phase under stirring until an emulsion is obtained. Advantageously, the non-sulfated polysaccharide is present 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 least 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 least The non-sulfated polysaccharide is preferably introduced at a concentration of 0.5 mg / mL to 20 mg / mL.

[0123] In a particular embodiment, the polysaccharide is hyaluronic acid, advantageously high molecular weight hyaluronic acid. Advantageously, the hyaluronic acid is at a concentration of at least 0.5 mg / mL, advantageously at least 1.0 mg / mL, advantageously at least 1.5 mg / mL, advantageously at least 2.0 mg / mL, advantageously at least 2.5 mg / mL, advantageously at least 3.0 mg / mL, advantageously at least 3.5 mg / mL, advantageously at least 4.0 mg / mL, advantageously at least 4.5 mg / mL, advantageously 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 least 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 least and preferably at least 15.5 mg / mL, advantageously at least 16.0 mg / mL, advantageously at least 16.5 mg / mL, advantageously at least 17.0 mg / mL, advantageously at least 17.5 mg / mL, advantageously at least 18.0 mg / mL, advantageously at least 18.5 mg / mL, advantageously at least 19.0 mg / mL, advantageously at least 19.5 mg / mL, advantageously at least 20.0 mg / mL.

[0124] In one particular embodiment of the invention, the amount of non-sulfated polysaccharides represents 0.05% to 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the non-sulfated polysaccharides represent at least 0.05% by weight 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% by weight relative to the weight of the aqueous liquid phase present in the emulsion. %, 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). Advantageously, the amount of non-sulfated polysaccharides corresponds to between 0.05% and 2.0% by weight (w / w) relative to the mass of the aqueous phase present in the emulsion.Advantageously, the non-sulfated polysaccharides represent, relative to the mass of the aqueous phase present in the emulsion, between 0.06% and 2.0% by weight, advantageously between 0.07% and 2.0% by weight, advantageously between 0.08% and 2.0% by weight, advantageously between 0.09% and 2.0% by weight, advantageously between 0.10% and 2.0% by weight, advantageously between 0.20% and 2.0% by weight, advantageously between 0.30% and 2.0% by weight, advantageously between 0.40% and 2.0% by weight, advantageously between 0.50% and 2.0% by weight, advantageously between 0.60% and 2.0% by weight, advantageously between 0.70% and 2.0% by weight. % by weight, advantageously between 0.80% and 2.0% by weight, advantageously between 0.90% and 2.0% by weight, advantageously between 1.0% and 2.0% by weight, advantageously between 1.10% and 2.0% by weight, advantageously between 1.20% and 2.0% by weight, advantageously between 1.30% and 2.0% by weight, advantageously between 1.40% and 2.0% by weight, advantageously between 1.50% and 2.0% by weight, advantageously between 1.60% and 2.0% by weight, advantageously between 1.70% and 2.0% by weight, advantageously between 1.80% and 2.0% by weight, advantageously between 1.90% and 2.0% by weight (w / w). In one highly advantageous embodiment of the invention, the non-sulfated polysaccharides represent 0.10% by weight (w / w) relative to the mass of the aqueous liquid phase present in the emulsion.

[0125] In one particular embodiment of the present invention, the amount of hyaluronic acid corresponds to 0.05% to 2.0% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion. Advantageously, the hyaluronic acid is at least 0.05% by weight relative to the weight of the aqueous liquid phase present in the emulsion, advantageously at least 0.06% by weight relative to the weight of the aqueous phase present in the emulsion, advantageously at least 0.07% by weight, advantageously at least 0.08% by weight, advantageously at least 0.09% by weight, advantageously at least 0.10% by weight, advantageously at least 0.20% by weight, advantageously at least 0.30% by weight, advantageously at least 0.40% by weight, advantageously at least 0.50% by weight, advantageously at least 0.60% by weight. %, advantageously at least 0.70% by weight, advantageously at least 0.80% by weight, advantageously at least 0.90% by weight, advantageously at least 1.0% by weight, advantageously at least 1.10% by weight, advantageously at least 1.20% by weight, advantageously at least 1.30% by weight, advantageously at least 1.40% by weight, advantageously at least 1.50% by weight, advantageously at least 1.60% by weight, advantageously at least 1.70% by weight, advantageously at least 1.80% by weight, advantageously at least 1.90% by weight, advantageously at least 2.0% by weight (w / w). Advantageously, the amount of hyaluronic acid corresponds to 0.05% to 2.0% by weight (w / w) relative to the weight of the aqueous phase present in the emulsion.Advantageously, the hyaluronic acid represents from 0.06% to 2.0% by weight, advantageously from 0.07% to 2.0% by weight, advantageously from 0.08% to 2.0% by weight, advantageously from 0.09% to 2.0% by weight, advantageously from 0.10% to 2.0% by weight, advantageously from 0.20% to 2.0% by weight, advantageously from 0.30% to 2.0% by weight, advantageously from 0.40% to 2.0% by weight, advantageously from 0.50% to 2.0% by weight, advantageously from 0.60% to 2.0% by weight, advantageously from 0.70% to 2.0% by weight. %, preferably 0.80% to 2.0% by weight, advantageously 0.90% to 2.0% by weight, advantageously 1.0% to 2.0% by weight, advantageously 1.10% to 2.0% by weight, advantageously 1.20% to 2.0% by weight, advantageously 1.30% to 2.0% by weight, advantageously 1.40% to 2.0% by weight, advantageously 1.50% to 2.0% by weight, advantageously 1.60% to 2.0% by weight, advantageously 1.70% to 2.0% by weight, advantageously 1.80% to 2.0% by weight, advantageously 1.90% to 2.0% by weight (w / w). In one highly advantageous embodiment of the invention, hyaluronic acid represents 0.10% by weight (w / w) relative to the weight of the aqueous liquid phase present in the emulsion.

[0126] In one particular embodiment, step c) of the method consists in polymerizing / crosslinking the emulsion obtained in step b) to obtain the biomaterial according to the invention. Advantageously, crosslinking is carried out in a mold in order to give the biomaterial the desired shape. Advantageously, the emulsion obtained in step b) is kept at a temperature between 30°C and 80°C for a period of 10 to 30 hours. Advantageously, the emulsion obtained in step b) is kept 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 a period of 10 to 30 hours, advantageously between 11 and 29 hours, advantageously between 12 and 29 hours, advantageously between 13 and 28 hours, advantageously between 14 and 27 hours, advantageously between 15 and 27 hours, advantageously between 16 and 27 hours, advantageously between 17 and 27 hours, advantageously between 18 and 26 hours, advantageously between 19 and 25 hours, advantageously between 20 and 24 hours, advantageously between 22 hours. Advantageously, the skilled person will be able to adapt the temperature depending on the pore size desired in the biomaterial.

[0127] In one particular embodiment of the invention, the biomaterial according to the invention obtained in step c) is annealed prior to step d). Advantageously, the biomaterial according to the invention obtained in step c) is annealed at a temperature of at least 50°C for at least 1 hour. Advantageously, the porous biomaterial according to the invention obtained in step c) is annealed at a temperature of 100°C for 2 hours.

[0128] In one particular embodiment, the washing step of step d) makes it possible to remove the reagents necessary for the synthesis of the poly(ester-urea-urethane) that have not reacted during crosslinking, as well as any surfactants and catalysts still present. Advantageously, the washing of step d) is carried out using dichloromethane, dichloromethane / hexane, hexane, water, a mixture of one of these products, or using successive applications of these products. Advantageously, the washing of step d) is carried out by contacting the dried porous biomaterial according to the invention with dichloromethane for at least 24 hours, followed by a washing step with dichloromethane / hexane (50% by volume / 50% by volume) for at least 24 hours, followed by a washing step with hexane for at least 24 hours, and a final washing step with purified water for at least 24 hours.

[0129] In one particular embodiment, the method according to the invention may further comprise a drying step between steps c) and d). Advantageously, this drying step may be carried out by air drying or in an oven. A person skilled in the art will be able to adapt the oven temperature depending on the material to be dried. Advantageously, drying is carried out by air drying for at least 7 days.

[0130] In a particular embodiment, the drying of step e) can be carried out by air drying or in an oven. A person skilled in the art will be able to adapt the temperature of the oven depending on the material to be dried. Advantageously, drying is carried out by air drying for at least 15 days.

[0131] In one particular embodiment, the method according to the invention can further comprise a sterilization step f) after the drying step e) of the biomaterial. In one particular embodiment, the sterilization step f) can be carried out directly on the dried biomaterial or after vacuum washing of the biomaterial in an aqueous medium. Advantageously, the sterilization is carried out after vacuum washing in an aqueous medium.

[0132] In one embodiment, the sterilization step f) may be carried out as follows: f1) contacting the biomaterial according to the invention in sterile water under vacuum for 1 hour; f2) replacing the sterile water and contacting the biomaterial of the present invention with the replaced sterile water under vacuum for 4 hours; f3) contacting the biomaterial according to the invention from step e2) in 70% ethanol under vacuum for 1 hour; f4) replacing the 70% ethanol with sterile water and contacting the biomaterial according to the invention from step e3) in sterile water overnight under ambient pressure; f5) Sterilizing the biomaterial according to the invention from step f4) by autoclaving in water.

[0133] In another embodiment, the sterilization step f) may be carried out by gamma radiation. In another embodiment, the sterilization step f) may be carried out by beta radiation. Advantageously, the dose of beta and / or gamma radiation may be between 15 and 45 kGy. Advantageously, the dose of beta and / or gamma radiation is 25 kGy. Advantageously, the dose of beta and / or gamma radiation is 15 kGy.

[0134] In another embodiment, the sterilization step f) may be carried out by contacting the biomaterial with ethylene oxide.

[0135] In another embodiment, the sterilization step f) may be carried out by contacting the biological material with a plasma phase derived from a gas.

[0136] In another embodiment, the sterilization step f) can be performed by irradiating the biomaterial with an electron beam (E-beam). The irradiation treatment with an electron beam has the following advantages: shorter processing time, improved efficiency of the supply line, less risk of embrittlement of the elastomeric matrix, less oxidative damage in the biomaterial, and no discoloration of the elastomeric matrix, making the biomaterial clean and safe. Moreover, the irradiation treatment with an electron beam is an ecological treatment.

[0137] In one particular embodiment, the method according to the invention may further comprise, after the sterilization step f), a step g) of storing said biomaterial, which is advantageously carried out by placing said biomaterial in contact with 70% ethanol until use.

[0138] In one particular embodiment of the present invention, the method for preparing a biomaterial comprises the following steps: a) preparing an organic phase containing the compounds necessary for the synthesis of poly(ester-urea-urethane); b) solubilizing a non-sulfated polysaccharide in an aqueous liquid phase to form an emulsion, and then adding the solubilized non-sulfated polysaccharide to the organic phase of step a); c) polymerizing / crosslinking the emulsion obtained in step b) to obtain said porous biomaterial; d) washing the porous biomaterial obtained in step c); e) drying the biomaterial obtained in step d); f) sterilizing the biomaterial from step d); and g) Optionally, storing the biomaterial.

[0139] In one highly advantageous embodiment of the invention, the method for preparing a biomaterial according to the invention comprises the following steps: a) preparing an organic phase containing compounds necessary for the synthesis of poly(ester-urea-urethane), comprising a first step a1) consisting of solubilizing polycaprolactone triol oligomer and surfactant Span 80 in an organic solvent, followed by a second step a2) consisting of adding a crosslinker HMDI and a catalyst DBTDL to the solution of step a1) to form an organic layer; b) solubilizing the non-sulfated polysaccharide in a sterile purified water-based aqueous liquid phase to form an emulsion, and then adding the non-sulfated polysaccharide solubilized in the organic phase to the liquid of step a); c) polymerizing / crosslinking the emulsion obtained in step b) to obtain said porous biomaterial; and d) washing the biomaterial obtained in step c); e) drying the biomaterial obtained in step d) for at least 15 days; f) sterilizing the porous biomaterial resulting from step e); and g) Optionally, storing the biomaterial.

[0140] In one highly advantageous embodiment of the invention, the method for preparing a biomaterial according to the invention comprises the following steps: a) preparing an organic phase containing compounds necessary for the synthesis of poly(ester-urea-urethane), comprising a first step a1) consisting of solubilizing polycaprolactone triol oligomer and surfactant Span 80 in toluene, followed by a second step a2) consisting of adding a crosslinker HMDI and a catalyst DBTDL to the solution of step a1) to form an organic layer; b) solubilizing hyaluronic acid, advantageously high molecular weight hyaluronic acid, in a sterile purified water-based aqueous liquid phase to form an emulsion, followed by adding to the liquid of step a) the non-sulfated polysaccharide solubilized in an organic phase, c) polymerizing / crosslinking the emulsion obtained in step b) to obtain said porous biomaterial; d) washing the biomaterial obtained in step c); e) drying the biomaterial obtained in step d) for at least 15 days; f) sterilizing the porous biomaterial resulting from step e); and g) Optionally, storing the biomaterial. [Brief explanation of the drawings]

[0141] [Figure 1] 1 shows a porous biomaterial according to the present invention. The image was obtained by 3D microscopy (VHX Keyence). [Figure 2] 1 shows Fourier transform infrared (FTIR) analysis of hyaluronic acid (a), poly(caprolactone-urea-urethane) elastomer matrix alone (b), a porous biomaterial according to the invention containing hyaluronic acid (c), and spectra c and subtraction of b (d). [Figure 3] Figure 1 shows the mass loss and mass resorption rates during in vitro degradation at 37°C and accelerated temperatures of 55°C and 75°C for poly(caprolactone-urea-urethane)-based elastomeric matrices alone (a, c) and porous biomaterials according to the present invention containing hyaluronic acid (b and d). [Figure 4] Figure 1 shows the migration of cells (gingival fibroblasts) from days 10 to 40 within a poly(caprolactone-urea-urethane)-based elastomer matrix alone (elastomer) and within a porous biomaterial of the present invention containing hyaluronic acid (elastomer-HA). [Figure 5] Figure 1 shows colonization by cells (gingival fibroblasts) after 20 days of migration inside a poly(caprolactone-urea-urethane)-based elastomer matrix alone (Elastomer) and inside a porous biomaterial according to the invention containing hyaluronic acid (Elastomer-HA) (digital 3D microscopy - hematoxylin staining). [Figure 6]Figure 1 shows the appearance of cells (gingival fibroblasts) on the periphery and well bottom of a poly(caprolactone-urea-urethane)-based elastomer matrix alone (elastomer) and a porous biomaterial according to the present invention containing hyaluronic acid (elastomer-HA) after 10 days of culture (light microscopy, 40x magnification). [Figure 7] Figure 1 shows the cellularization of a poly(caprolactone-urea-urethane)-based elastomeric matrix alone (Elastomer) and a porous biomaterial according to the present invention containing hyaluronic acid (Elastomer-HA) 36 days after subcutaneous implantation in rats (material marked with a white box; neovascularization; multinucleated giant cells) (Digital 3D microscopy - Hematoxylin / Eosin staining). [Figure 8] Figure 1 shows the collagen structure inside a poly(caprolactone-urea-urethane)-based elastomer matrix alone (Elastomer) and inside a porous biomaterial according to the invention containing hyaluronic acid (Elastomer-HA) after 36 days of subcutaneous implantation in rats (materials marked with white boxes) (digital 3D microscopy - Picrosirius Red staining - 4x and 40x magnification). [Figure 9] 1 shows the marking of T lymphocytes present within a poly(caprolactone-urea-urethane)-based elastomeric matrix alone (Elastomer) and within a porous biomaterial according to the invention containing hyaluronic acid (Elastomer-HA) 36 days after subcutaneous implantation in rats (materials marked with a black box) (digital 3D microscopy - marking CD3 - magnifications 4x and 40x). [Figure 10] 1 shows the marking of macrophages present within a poly(caprolactone-urea-urethane)-based elastomeric matrix alone (Elastomer) and within a porous biomaterial according to the invention containing hyaluronic acid (Elastomer-HA) 36 days after subcutaneous implantation in a rat (material marked with a black box) (digital 3D microscopy - marking CD163 - magnifications 4x and 40x). [Figure 11]1 shows the mean optical density values ​​obtained after staining of hyaluronic acid with Alcian blue for a poly(caprolactone-urea-urethane)-based elastomeric matrix alone (Elastomer) and for a porous biomaterial according to the invention containing hyaluronic acid (Elastomer-HA). [Figure 12] 1 shows a poly(caprolactone-urea-urethane)-based elastomeric matrix alone (Elastomer) and a porous biomaterial according to the present invention containing hyaluronic acid (Elastomer-HA) before and after 15 kGy of beta radiation. Images were obtained by 3D microscopy (VHX Keyence). DETAILED DESCRIPTION OF THE INVENTION

[0142] Example 1: Preparation and synthesis of porous biomaterials according to the present invention In the first step, high-molecular-weight hyaluronic acid was solubilized in sterile purified water at 37°C for 24 hours. The solution was then filtered through a 0.2 μm filter. In the second step, this aqueous solution was poured into an organic phase containing the compounds necessary for the synthesis of a poly(caprolactone-urea-urethane)-based elastomeric matrix to obtain an emulsion with a high internal phase. The emulsion was then polymerized / crosslinked to obtain the porous biomaterial of the present invention. Several hyaluronic acid concentrations were tested. Several aqueous / organic phase volume ratios were tested. Different synthesis temperatures were also investigated. These different parameters affect the pore size of the material. The scaffolds selected for applications such as gingival substitutes have pores with diameters ranging from 50 μm to 1400 μm, with an average size of 600 ± 170 μm. These materials are characterized in the following examples.

[0143] The formulation and synthesis chosen to obtain the porous biomaterial according to the invention are as follows: - Hyaluronic acid concentration in aqueous phase: 1mg / mL - Aqueous phase / organic phase volume ratio: 92.5 / 7.5% - Synthesis temperature: 37°C for 18 hours; 55°C for 4 hours; 100°C for 2 hours.

[0144] Example 2: Physicochemical and mechanical properties of the porous biomaterial according to the invention The physicochemical properties of the obtained porous biomaterial according to the invention were tested by the following methods: - Fourier transform infrared spectroscopy (FTIR) for the analysis of chemical functional groups present in synthesized biomaterials; - 3D microscopy for morphological observation of biomaterials (VHX Keyence); - Volumetric absorption rate (rv) measurements to determine the degree of interconnectivity of the porous structure; - Young's modulus (E1 * Measurement of the average molecular mass (Mc) between cross-link nodes by swelling allows evaluation of the molecular mass (Mc).

[0145] 1. Interconnectivity / porosity, Images obtained by 3D microscopy (Figure 1) show that the biomaterial according to the present invention has a highly interconnected (rv=100%) porous morphology (porosity=90+ / -2%) with multiscale pore sizes ranging from 50 μm to 1400 μm in diameter with an average size of 600+ / -170 μm.

[0146] 2. Chemical composition and hydrophilicity, FTIR analysis (Figure 2) confirms the presence of hyaluronic acid within the poly(caprolactone-urea-urethane) elastomer matrix. The spectrum of the poly(caprolactone-urea-urethane) elastomer matrix alone shows a peak at 3333 cm -1 , 1537cm -1 and 1248 cm -1 -NH group of urethane at 1730cm -1 of urethane at 1620cm -1 -C=O group of urea at 1575cm -1 -CNH group of urea at 1164cm -1The subtraction between the spectra corresponding to the poly(caprolactone-urea-urethane)-based elastomeric matrix alone and the porous biomaterial of the present invention reveals the presence of hyaluronic acid in the porous biomaterial of the present invention, particularly at 1612 cm, which is typical of the -CCH, -OCH, and -COH groups of the polysaccharide ring. -1 The belt and 1554cm -1 and 1381 cm -1 This is revealed through the presence of bands in the

[0147] The incorporation of hyaluronic acid increases the hydrophilicity of the material, as evidenced by a measured water contact angle of θ=112±16° for the poly(caprolactone-urea-urethane)-based elastomeric matrix alone versus θ=69±12° for the porous biomaterial containing hyaluronic acid. Thus, the porous biomaterial of the present invention possesses a surface hydrophilicity more suitable for the adhesion of fibroblasts, which have greater adhesion on surfaces with water contact angles between 60° and 80°.

[0148] Furthermore, after immersion of the material in purified water for 15 days, the water absorption rate shifts from approximately 400% for the poly(caprolactone-urea-urethane)-based elastomeric matrix alone to approximately 700% for the porous biomaterial containing hyaluronic acid, indicating that the porous biomaterial of the present invention is more suitable for fluid penetration and therefore cell infiltration.

[0149] 3. Mechanical properties The average molar mass (Mc) between crosslinked nodes was determined by dilatometric measurements in toluene. The poly(caprolactone-urea-urethane)-based elastomeric matrix alone had an Mc value of 4860 + / - 240 g / mol, which indicates that the Young's modulus E1 of the porous material is 4860 + / - 240 g / mol. *The value of 220 + / - 25 kPa attests to the elastomeric nature of the material. The porous biomaterial of the present invention containing hyaluronic acid (with a pore size equivalent to the porosity of the poly(caprolactone-urea-urethane)-based elastomeric matrix alone) has an Mc value of 5380 + / - 1460 g / mol, which results in an E1 of 123 + / - 11 kPa. * Thus, hyaluronic acid contributes to a slight decrease in the modulus of the porous biomaterial according to the invention while preserving the elastomeric properties of the polymer matrix, thus enabling the biomaterial according to the invention to withstand the contractile forces exerted by fibroblasts during cell migration inside the material.

[0150] 4. Decomposition Reaction Rate An important criterion for the fabrication of porous biomaterials for tissue engineering is their resorbability, as they must be replaced by neoplastic tissue over time. In vitro degradation studies were performed according to the ISO 10993-13 standard. Degradation kinetics was evaluated, specifically, by measuring water adsorption and mass loss at 37°C, 55°C, and 75°C (Figure 3). No differences were observed between the poly(caprolactone-urea-urethane)-based elastomeric matrix alone and the biomaterial of the present invention containing hyaluronic acid at 37°C and 55°C up to six months. Accelerated degradation studies at 75°C showed that the biomaterial of the present invention containing hyaluronic acid degraded significantly more rapidly than the poly(caprolactone-urea-urethane)-based elastomeric matrix alone. This is attributed to the increased hydrophilicity of the material. The biomaterial of the present invention was stable for more than six months at 37°C. The lifespan of biomaterials is significantly shortened in vivo due to more extreme conditions. Nevertheless, the biomaterials of the present invention are sufficiently stable to be used in tissue engineering applications.

[0151] Example 3: Interaction between the porous biomaterial according to the invention and cells (gingival fibroblasts) - an in vitro study To test the "attractive" ability of the porous biomaterial of the present invention containing hyaluronic acid and the poly(caprolactone-urea-urethane)-based elastomeric matrix alone, a colony formation test using gingival fibroblasts was performed. The material was applied to a gingival fibroblast mat at 80% confluence. Cell migration was determined 10, 30, and 40 days after contact with the material. The count of cells present on and within the material was performed after cell detachment by enzymatic treatment. The results demonstrated the ability of cells to migrate within the material (Figure 4). Gingival fibroblasts were able to migrate, proliferate, and spread on the surface of the pores of the material (Figure 5).

[0152] Interestingly, cells at the bottom of the wells were oriented perpendicular to the material when placed near the porous biomaterial of the present invention containing hyaluronic acid (Figure 6). It has been shown that dermal fibroblasts tend to spread and align near cross-linked hyaluronic acid-based dermal prosthetic products, resulting in overall improved fibroblast function (Quan et al., Journal of Investigative Dermatology, 2013, vol. 133, pp. 658-667). While this result was attributed to the structural reinforcement of the dermal extracellular matrix by the prosthetic product, our results clearly demonstrate that the porous biomaterial of the present invention containing hyaluronic acid exerts an effect on the cells surrounding it.

[0153] Example 4: In vivo study of the potential of porous biomaterials according to the present invention for soft tissue regeneration within a subcutaneous pocket model in rats In vivo testing was performed by implanting scaffolds subcutaneously along the dorsal midline of rats (Sprague-Dawley, 8-week-old male rats). This study allows the evaluation of the biocompatibility, biointegration, and efficacy of the porous biomaterial of the present invention upon implantation.

[0154] To evaluate the efficacy of the porous biomaterial of the present invention containing hyaluronic acid compared to poly(caprolactone-urea-urethane)-based elastomeric matrix alone, several animal lots were followed up to 36 days after subcutaneous implantation of the matrix. The efficacy of the material of the present invention was evaluated by histological study of material harvested after animal sacrifice.

[0155] For each time point of the study, 7 and 36 days, lots of 5 rats (20 rats) were composed of the following groups: - Animal group with poly(caprolactone-urea-urethane) elastomer matrix alone - Animal group of poly(caprolactone-urea-urethane)-based elastomeric matrices containing non-sulfated polysaccharides.

[0156] The subcutaneous pocket model consists of making a midline incision on the back of a rat and creating a subcutaneous pocket into which the material to be evaluated will be inserted.

[0157] 1. Surgical Procedure The animals were anesthetized with 1.2 mL / kg intramuscular injection of ketamine / xylazine (50 / 15 mg / kg). The animals' backs were twisted and then disinfected with Betadine®. A midline incision was made on the rat's back, and skin flaps were elevated on both sides. Polymer matrices (1 cm diameter x 2-3 mm thick) were inserted on both sides of the midline for stabilization. The skin plane was then sutured with 5.0 absorbable sutures.

[0158] The animals were monitored daily to observe their general condition and behavior. Throughout the experiment, the animals showed no loss of mobility or signs of aggression. The weight curves were regular. There were no signs of inflammation or necrosis at the wounds.

[0159] 2. Preparation of implants The poly(caprolactone-urea-urethane)-based elastomeric matrices are removed from their storage medium (70% ethanol) and rinsed with physiological serum for 5 minutes under agitation, after which they are placed in subcutaneous pockets.

[0160] 3. Histology Animals were sacrificed after 7–36 days. Elastomeric matrices were removed, fixed in 10% paraformaldehyde, dehydrated in increasing alcohol baths, and then embedded in paraffin. 5 μM sections were then made with a manual microtome.

[0161] After deparaffinization and rehydration, sections are stained with hematoxylin-eosin (0.2% hematein / 2% aqueous eosin in a 5% aqueous solution of hematoxylin:potassium alum) or picrosirius red (0.1% picrosirius red in a saturated picric acid solution) to reveal collagen.

[0162] 4. Results The pores of the biomaterial implanted subcutaneously in the dorsal region of laboratory rats are infiltrated with fibrillar connective tissue, as shown by histological sections after staining with hematoxylin-eosin (Figure 7) and picrosirius red (Figure 8).

[0163] Seven days after implantation, one-third of the pores of the biomaterial closest to the surface were infiltrated with fibrous connective tissue and contained numerous fibroblast-type cells. Thirty-six days after implantation, slightly fewer than 50% of the pores in the poly(caprolactone-urea-urethane)-based elastomeric matrix alone were colonized, while approximately 100% of the pores in the porous biomaterial of the present invention containing hyaluronic acid were colonized (Figure 7). At higher magnification, the pores in the poly(caprolactone-urea-urethane)-based elastomeric matrix alone were infiltrated with a connective matrix that did not appear to be completely adhered to the pore surface. The surface appeared to be colonized by numerous round-nucleated cells, likely inflammatory cells as well as red blood cells. In contrast, the pores in the porous biomaterial of the present invention containing hyaluronic acid were infiltrated with fibrous connective tissue that remained in contact with the pore surface. The number of round-nucleated cells appeared significantly reduced compared to the elastomeric matrix alone, indicating a reduction in the inflammatory component. Fully organized vessels are present within the connective tissue, and red blood cells are well confined therein without signs of extravasation. Multinucleated giant cells are also present on the surface of the pores and on the material itself. The connective tissue inside the pores remains in contact with the biomaterial. 36 days after implantation, a decrease in the number of lymphocytes and macrophages is observed, and more significantly in the porous biomaterial of the present invention containing hyaluronic acid (Figures 9 and 10). The porous biomaterial of the present invention containing hyaluronic acid appears to be more compatible.

[0164] Example 5: Quantitative assay for hyaluronic acid Quantitative assay of hyaluronic acid was performed using a colorimetric assay technique using Alcian blue. Briefly, poly(caprolactone-urea-urethane)-based elastomer matrix alone (Elastomer) and the porous biomaterial of the present invention containing hyaluronic acid (Elastomer-HA) were cut, weighed, and then incubated in Alcian blue solution for 2 hours. Excess dye was replaced with sodium acetate buffer solution (50 mM / 50 mM MgCl, pH 5.8). The materials were then incubated in 60% ethanol solution, followed by 80% acetic acid solution. The optical density was measured at 675 nm.

[0165] Hyaluronic acid quantitative assays were performed at different stages of the manufacturing process, which allowed determining an average concentration of 425 μg HA per gram of porous biomaterial according to the invention (see FIG. 11).

[0166] Example 6: Sterilization by beta and gamma radiation Sterilization by beta treatment was performed by an ionization method consisting of passing the biological material continuously at a controlled speed through beta rays emitted by an electron accelerator. Doses of 15, 25, and 45 Gy were tested. For example, a dose of 25 kGy + / - 10% was performed under the following treatment conditions: frequency 640 Hz / scan setting 2.6 / rotation speed: 1 / speed: 0.898 m / min.

[0167] Sterilization by gamma treatment was performed by an ionizing method consisting of exposing the biological material to gamma rays emitted by a cobalt-60 source for a limited duration. The dose administered was 25 kGy + / - 10%.

[0168] Images obtained by 3D microscopy (Figure 12) show that sterilization with beta radiation at 15 kGy did not result in structural modifications of the poly(caprolactone-urea-urethane)-based elastomeric matrix alone (Elastomer) and the porous biomaterial of the present invention containing hyaluronic acid (Elastomer-HA). The same results were obtained for beta and gamma radiation doses between 15 and 45 kGy, regardless of whether the biomaterial of the present invention was dry or in an aqueous medium.

Claims

1. at least one elastomer matrix comprising a poly(caprolactone-urea-urethane) based elastomer, - non-sulfated polysaccharides, 1. A biomaterial for tissue repair comprising: a non-sulfated polysaccharide; and a hyaluronic acid having a molecular weight of 1,000 kDa or more.

2. 2. The biomaterial according to claim 1, wherein the elastomeric matrix has an isocyanate index of 0.1 to 6.

0.

3. The biomaterial according to claim 1 or 2, characterized in that the biomaterial has a multiscale pore size of 500 μm to 2000 μm.

4. The biomaterial of claim 1 , characterized in that the biomaterial has a total porosity of 60% or more.

5. The biomaterial according to claim 1, characterized in that it is in the form of a sponge, a film, a bandage, granules, a monolith or a membrane.

6. 6. A biomaterial according to any one of claims 1 to 5 for use in reinforcing, reconstructing and / or filling tissue defects, preferably in reinforcing, reconstructing and / or filling soft tissue and / or epithelial tissue defects, preferably in reinforcing, reconstructing and / or filling skin and / or mucosal defects.

7. The biomaterial according to claim 6, wherein the tissue reinforcement, reconstruction and / or filling is 5% by volume or more of the volume of the tissue defect to be reinforced, reconstructed and / or filled.

8. 8. A biomaterial according to any one of claims 1 to 7 for use in the reconstruction and / or reinforcement of gingival tissue.

9. 8. A biomaterial according to any one of claims 1 to 7 for use in the reconstruction and / or reinforcement of visceral and / or pelvic and / or parietal tissues, advantageously in the treatment of pelvic organ prolapse, in the repair of pelvic tissues, in the reconstruction and / or reinforcement of walls, in the reconstruction and / or reinforcement of digestive wounds.

10. 8. A biomaterial according to any one of claims 1 to 7 for use in the treatment of burns, preferably thermal, cryoburns, electrical, chemical, radiation and photochemical burns.

11. 1. A method for preparing a biomaterial, comprising: a) preparing an organic phase containing the compounds necessary for the synthesis of poly(caprolactone-urea-urethane); b) solubilizing hyaluronic acid having a molecular weight of 1,000 kDa or greater in an aqueous liquid phase to form an emulsion, and then adding the solubilized hyaluronic acid to the organic phase of step a); c) polymerizing / crosslinking the emulsion obtained in step b) to obtain said biomaterial; d) washing the biomaterial obtained in step c); e) drying the biomaterial obtained in step d); A method comprising:

12. A method for preparing a biomaterial as described in claim 11, wherein the amount of hyaluronic acid is 0.05% to 2.0% (w / w) in relation to the mass of the aqueous liquid phase present in the emulsion.

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