Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/26—Mixtures of macromolecular compounds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
  • C08G18/72—Polyisocyanates or polyisothiocyanates
  • C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/728—Hyaluronic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/56—Porous materials, e.g. foams or sponges
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/08—Processes
  • C08G18/16—Catalysts
  • C08G18/22—Catalysts containing metal compounds
  • C08G18/24—Catalysts containing metal compounds of tin
  • C08G18/244—Catalysts containing metal compounds of tin tin salts of carboxylic acids
  • C08G18/246—Catalysts containing metal compounds of tin tin salts of carboxylic acids containing also tin-carbon bonds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
  • C08G18/40—High-molecular-weight compounds
  • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
  • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
  • C08G18/4269—Lactones
  • C08G18/4277—Caprolactone and/or substituted caprolactone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/23—Carbohydrates
  • A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

• Biomaterial comprising at least one elastomeric matrix and a non-sulfated polysaccharide and its uses.
• the present invention relates to a biomaterial and its uses in tissue strengthening, reconstruction and / or filling, preferably strengthening reconstruction and / or filling defects of soft tissue and / or epithelial tissue, preferably repair of soft tissue and / or epithelial tissue. the skin, gums and / or mucous membranes.
• gingival periodontal surgery responds to problems linked to deficits in gingivomucosal soft tissues inducing a functional, aesthetic and biological impact both around natural teeth and dental implants.
• gingival recession results in an unsightly smile, can also be the source of spontaneous and / or provoked hypersensitivity, promote the development of deep caries and cause functional discomfort linked to the presence of periodontal inflammation that can put at risk the supporting tissues of the tooth (periodontal) allowing the anchoring of these in the maxillary and mandibular bone bases.
• This periodontal disease results in a displacement of the marginal gingiva and the epithelial-conjunctive attachment junction apically to the enamel-cemental junction.
• Their etiology is multifactorial and linked to several predisposing factors (fine biotype, bone dehiscences, low height and thickness of keratinized tissue, dental malposition, etc.), mechanical factors such as traumatic brushing, bacteriological factors (presence plaque and inflammation) or other factors such as bite trauma, smoking and others).
• Soft tissue defects including oral and dental soft tissue, can result from trauma or surgical removal, frequently causing loss of the original soft tissue structure. In addition, changes in soft tissue negatively affect the aesthetic appearance and therefore patient satisfaction. Depending on the size of the defect, tissue deformities can be corrected aesthetically by soft tissue augmentation or by soft tissue reconstruction or by surgical techniques.
• This tissue management can also integrate other indications such as peri-implant tissue and maxillary ridge arrangements.
• a surgical tissue grafting technique should be considered.
• Multiple surgical approaches documented in the literature have been proposed to achieve root coverage (or exposed implant surfaces) for the treatment of gingival recessions, tissue thickening for a thick biotype, and band augmentation. of keratinized gingiva, necessary for the long-term sustainability of the periodontal and peri-implant environment.
• the first solution considered for repairing soft tissue defects is to graft a fraction of connective tissue taken from elsewhere in the patient's body. This is called an autologous connective tissue transplant.
• the autologous transplant does not produce a defensive immune response, since the tissue comes from the patient. However, it results in significant cell death in the transplanted tissue.
• the capacity of the graft to produce new cells can compensate for this loss, but it depends in particular on the vascularity of the graft. The latter is indeed essential for the tissue undergoing reconstruction: the vessels provide the energy and nutrients necessary for cell proliferation.
• autologous transplantation involves two operations (removal then transplant) that can cause complications (pain, abscess, neuralgia). Another important limitation is the size of the graft necessary for filling.
• Another alternative is to use an allogeneic substitute.
• AlloDerm ® is an acellular dermal matrix of human origin, obtained from the skin of cadavers of human donors, having undergone a physical and chemical treatment involving a de-epidermization of the tissue, which induces the separation of the anchoring fibrils from the hemidesmosomes , basal keratinocytes by removing all cellular content (epithelial, connective, viral and bacterial cells), which involves the removal of the epidermal layer with all cellular components without damaging the components of the connective tissue matrix, under conditions that do not alter the collagen bundles or damage the membrane complex basal. This process leaves behind extracellular collagen which provides the basis for cell growth followed by tissue remodeling.
• Mucoderm® is a matrix based on natural type l / l II collagen derived from porcine dermis and elastin.
• Mucoderm® presents crumbling problems when the implant is subjected to high mechanical stresses and is the cause of strong inflammatory reactions.
• animal origin of certain allogeneic substitutes can sometimes generate a refusal for religious or philosophical convictions.
• biocompatible materials which aim to fill tissue defects or losses, linked to trauma (burn, (tearing, tear), aging or pathologies; or which aim to strengthen tissue following trauma, aging or pathology.
• many companies specialize in the design of implants used as reinforcement in gynecological, urinary or visceral (or parietal) surgery. These materials can be designed for the treatment of vascular wounds, digestive wounds, eventrations etc.
• biomaterials can thus be applied for the design of reinforcement implants for the treatment of pelvic organ prolapse and more particularly in the treatment of pelvic organ prolapse in women (anterior stage (urinary, cystocele, incontinence of stress), middle (genital, colpocele) and / or posterior (digestive rectocele)), or Peyronie's disease in humans.
• the biomaterial can then be available in the form of an extensible reinforcing sheet, a membrane wick or an implant of any shape.
• the biomaterials used with varying degrees of success are currently of xenogenic origin (such as Pelvicol®, marketed by Bard France SAS) or synthetic (polypropylene such as Parietex®, marketed by SOFRADIM).
• Pelvicol® presents crumbling problems when the implant is subjected to high mechanical stresses and be the cause of strong inflammatory reactions.
• Document US2012 / 239161 describes an elastomeric matrix based on caprolactone and agar or gelatin.
• Document CN 108034225 describes a process for preparing a composite material comprising an elastomeric matrix and chitosan.
• the present invention therefore relates to a biomaterial for tissue repair comprising
• the present invention also relates to the use of said biomaterial in tissue repair, preferably repair of soft tissue and / or epithelial tissue, preferably repair of skin and / or mucous membranes.
• a subject of the present invention is also a process for preparing a biomaterial. detailed description
• the subject of the present invention is therefore a biomaterial for tissue repair comprising:
• the invention has the advantage of providing a porous bioresorbable / biodegradable elastomeric biomaterial which promotes cell migration and vascularization.
• the biomaterial according to the invention also offers better tissue biointegration without any risk of microbial contamination.
• the term “biomaterial” is understood to mean a material used and suitable for a medical application.
• the biomaterial according to the invention is a physical support on which fibroblasts can adhere, migrate and proliferate on the surface and inside said physical support, said physical support being capable of being absorbed or of being biodegradable, thus allowing its substitution by the newly formed connective tissue.
• the biomaterial according to the invention comprises at least one elastomeric matrix and one non-sulphated polysaccharide, the individual properties of which combine and having greatly improved overall performance, properties which cannot be observed with the at least one elastomeric matrix or the unsulfated polysaccharide, used individually.
• the biomaterial comprising at least one elastomeric matrix and a non-sulphated polysaccharide according to the invention has:
• the biomaterial when it is implanted in the patient is capable of activating the synthesis of collagen and the vascularization, allowing rapid reconstruction of the damaged tissue.
• the unsulphated polysaccharide can be attached by a covalent bond to the elastomeric matrix.
• the unsulphated polysaccharide can be dispersed in and on the surface of the elastomeric matrix.
• the term “elastomeric matrix” is understood to mean a structure consisting of a single elastomer or of a combination of two or more elastomer systems, said structure being capable of including the unsulphated polysaccharide.
• the isocyanate number of the elastomeric matrix is between 0.1 and 6.0.
• the isocyanate number 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.
• At least one elastomeric matrix according to the present invention has good biodegradability, good biocompatibility and good mechanical properties.
• the term “elastomer” is understood to mean one or more polymers exhibiting “rubbery elasticity” properties, obtained after crosslinking.
• the elastomer must be biocompatible and biodegradable.
• the Young's modulus in compression of the biomaterial of the invention is between 1kPa to 1000kPa, advantageously between 50kPa and 900 kPa, advantageously between 50kPa and 800 kPa, advantageously between 50kPa and 700 kPa, advantageously between 50kPa and 600 kPa , advantageously between 50kPa and 500 kPa, advantageously between 100kPa and 400kPa.
• biocompatible elastomeric matrix is understood to mean an elastomeric matrix which is both compatible for implantation in a patient, and compatible to include the unsulfated polysaccharide therein, and which is suitable for the reconstruction of soft tissue once the biomaterial is implanted in a patient, human or animal.
• compatible for implantation in a patient an elastomeric matrix which presents a favorable benefit / risk ratio from a therapeutic point of view when it is implanted, for example within the meaning of Directive 2001 / 83 / EC.
• an elastomeric matrix which allows the incorporation of the non-sulfated polysaccharide, without degradation or little of the activity of said non-sulfated polysaccharide in the elastomer matrix.
• the unsulphated polysaccharide is incorporated into the elastomeric matrix.
• the unsulphated polysaccharide is directly integrated into the elastomeric matrix during the manufacture of the biomaterial according to the invention.
• biodegradable elastomer matrix is understood to mean an elastomeric matrix which is bioresorbable and / or biodegradable and / or bioabsorbable, with a common goal of gradual disappearance, with one or more different or complementary degradation mechanisms, solubilization or absorption of the elastomeric matrix in the patient, human or animal, in which the material has been implanted.
• At least one elastomeric matrix according to the invention comprises an elastomer based on poly (ester-urea-urethane).
• the at least one elastomeric matrix of the biomaterial according to the invention comprises an elastomer based on poly (ester-urea-urethane), the ester being chosen from oligomers of caprolactone (PCL), lactic acid oligomers (PLA), glycolic acid oligomers (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), dioxanone oligomers (PDO), poly (ethylene adipate) (PEA) oligomers, poly (butylene adipate) (PBA) oligomers or combinations thereof.
• PCL caprolactone
• PLA lactic acid oligomers
• PGA glycolic acid oligomers
• PHB hydroxybutyrate oligomers
• PVB hydroxyvalerate oligomers
• PDO dioxanone oligomers
• PEA poly (ethylene adipate)
• PBA poly (butylene adipate) oli
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane). In another particular embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane). In another particular embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane). In another particular embodiment, the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxybutyrate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (dioxanone-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (ethylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (butylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (lactic acid-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (glycolic acid-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (hydroxyvalerate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (dioxanone-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (ethylene adipate-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (butylene adipate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (acid lactic-urea-urethane) and poly (glycolic acid-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and on poly (hydroxyvalerate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and on poly (hydroxybutyrate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and on poly (dioxanone-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and on poly (ethylene adipate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and on poly (butylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (hydroxyvalerate-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (dioxanone-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (ethylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (glycolic acid-urea-urethane) and poly (butylene adipate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and on poly (hydroxybutyrate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and on poly (dioxanone-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and poly (ethylene adipate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane) and on poly (butylene adipate-urea-urethane).
• 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).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxybutyrate-urea-urethane) and poly (ethylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (hydroxybutyrate-urea-urethane) and poly (butylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (dioxanone-urea-urethane) and poly (ethylene adipate-urea-urethane).
• at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (dioxanone-urea-urethane) and poly (butylene adipate-urea-urethane).
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (ethylene adipate-urea-urethane) and poly (butylene adipate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane) and on poly ( glycolic acid-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane) and poly (hydroxyvalerate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane) and poly (hydroxybutyrate-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane) and poly (dioxanone-urea-urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane), poly (dioxanone-urea-urethane) and poly (ethylene adipate-urea urethane).
• poly (caprolactone-urea-urethane) on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane), poly (dioxanone-urea-urethane) and poly (ethylene adipate-urea urethane).
• the at least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane), poly (dioxanone-urea-urethane), poly (ethylene adipate-urea-urethane) and poly (butylene adipate-urea-urethane).
• poly (caprolactone-urea-urethane) on poly (lactic acid-urea-urethane), on poly ( glycolic acid-urea-urethane), poly (hydroxyvalerate-urea-urethane), poly (hydroxybutyrate-urea-urethane), poly (dioxanone-urea-urethane), poly (ethylene adipate-urea-urethane) and poly (
• At least one elastomeric matrix of the porous biomaterial is a matrix comprising an elastomer based on poly (caprolactone-urea-urethane).
• This matrix comprising an elastomer based on poly (caprolactone-urea-urethane) has the advantage of having an elastomeric character, giving it flexibility and an interconnected porous structure suitable for tissue reconstruction.
• the non-sulfated polysaccharide can be chosen from the group comprising carrageenans, alginates, xanthan, chitosan, chitin, hyaluronic acid, glycogen, cellulose and its compounds. derivatives, pectins, starch and its derivatives, dextrans and xylans, or a mixture thereof.
• the nonsulfated polysaccharide can therefore consist of a single polysaccharide or of a mixture of nonsulfated polysaccharides.
• the non-sulfated polysaccharide according to the invention is hyaluronic acid.
• hyaluronic acid is understood to mean hyaluronic acid, crosslinked or uncrosslinked, alone or as a mixture; optionally chemically modified by substitution, alone or as a mixture; and / or optionally in the form of one of its salts, alone or as a mixture.
• hyaluronic acid is a high molecular weight hyaluronic acid.
• high molecular weight hyaluronic acid is understood to mean a hyaluronic acid having a molecular weight greater than or equal to 1000 kDa.
• low molecular weight hyaluronic acid is understood to mean a hyaluronic acid having a molecular weight of less than 1000 kDa.
• the hyaluronic acid has a molecular weight greater than or equal to 1000 kDa, advantageously greater than or equal to 10,000 kDa, advantageously greater than or equal to 100,000 kDa, advantageously greater than or equal to 1000 000 kDa, advantageously greater than or equal to 1,500,000 kDa, advantageously greater than or equal to 2,000,000 kDa.
• the hyaluronic acid according to the invention has a molecular weight of 1,500,000 kDa.
• the use of a high molecular weight hyaluronic acid in addition to these non-immunogenic and anti-angiogenic properties, allows the structuring of the matrix macromolecules and particularly of the collagens during the early phases of healing, which cannot be obtained with a low molecular weight hyaluronic acid.
• the biomaterial according to the invention comprises:
• elastomeric matrix comprising an elastomer based on poly (ester-urea-urethane), the ester being chosen from oligomers of caprolactone (PCL), oligomers of lactic acid (PLA), oligomers of acid glycolic (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), dioxanone oligomers (PDO), poly (ethylene adipate) oligomers (PEA), poly (butylene adipate) oligomers (PBA) or combinations thereof, and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (lactic acid-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (glycolic acid-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (lactic acid-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and poly (glycolic acid-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (lactic acid-urea-urethane) and poly (glycolic acid-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), on poly (lactic acid-urea-urethane) and on poly (glycolic acid-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (hydroxybutyrate-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (hydroxyvalerate-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (dioxanone - urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (ethylene adipate-urea-urethane), and
• the porous biomaterial according to the invention comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (butylene adipate-urea-urethane), and
• the unsulfated polysaccharide can be hyaluronic acid.
• hyaluronic acid is a high molecular weight hyaluronic acid.
• the porous biomaterial according to the invention comprises: - at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
• the porous biomaterial comprises:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
• the porous biomaterial consists only of:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
• the biomaterial according to the invention contains:
• elastomeric matrix comprising an elastomer based on poly (ester-urea-urethane), the ester being chosen from oligomers of caprolactone (PCL), oligomers of lactic acid (PLA), oligomers of acid glycolic (PGA), hydroxybutyrate oligomers (PHB), hydroxyvalerate oligomers (PVB), dioxanone oligomers (PDO), poly (ethylene adipate) oligomers (PEA), poly (butylene adipate) oligomers (PBA) or combinations thereof, and
• the porous biomaterial contains:
• At least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane), and
• the inventors have demonstrated that the specific combination of hyaluronic acid, in particular of high molecular weight hyaluronic acid, and of at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) , allows an increase in cell migration, but also better vascularization and better tissue reconstruction inside and at the periphery of the porous biomaterial compared to the use of the porous elastomer matrix comprising an elastomer based on poly (caprolactone-urea -urethane) alone.
• the addition of acid hyaluronic causes an increase in the synthesis of collagen, thus making it possible to obtain a more structured tissue.
• the biomaterial has a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m.
• pore size and “pore diameter” can be used interchangeably.
• multiscale pore size is meant a variable distribution of pore sizes, that is to say comprising both pores of several microns and pores of smaller sizes, in varying proportions.
• a biomaterial having a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m means that the biomaterial comprises both and in the same biomaterial, pores having variable sizes, between 50 ⁇ m and 2000 ⁇ m. pm.
• a biomaterial having a multiscale pore size of between 50 ⁇ m and 2000 ⁇ m means that the biomaterial comprises both and in the same biomaterial, pores having for example a size of 50 ⁇ m, pores having a size of 100 ⁇ m, pores having a size of 500 ⁇ m, pores having a size of 1500 ⁇ m, pores having a size 2000 ⁇ m.
• the biomaterial has a multiscale pore size of between 50 ⁇ m and 1200 ⁇ m.
• the average pore size is between 500 ⁇ m and 700 ⁇ m.
• said biomaterial has a multiscale pore size of between 500 ⁇ m and 2000 ⁇ m.
• the pores of the biomaterial have a rough surface.
• the biomaterial has a total porosity greater than or equal to 60%.
• total porosity is understood to mean the ratio of the volume of empty spaces of material to the overall volume of the biomaterial.
• 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 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%, advantageous
• the biomaterial has a total porosity greater than 80%.
• 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%.
• the porous biomaterial has a total porosity of between 70% and 95%.
• the biomaterial has an interconnectivity between the pores of between 60% and 100%.
• the interconnectivity between the pores 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%.
• the interconnectivity between the pores is greater than 65%, advantageously greater than 70%, advantageously greater than 75%, advantageously greater than 80%, advantageously greater than 85%, advantageously greater 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%.
• the biomaterial exhibits interconnectivity between the pores of 100%.
• the biomaterial according to the invention has a pore size of between 50 ⁇ m and 2000 ⁇ m, a total porosity of greater than or equal to 60% and an interconnectivity between the pores of between 60% and 100%.
• the biomaterial according to the invention has an average pore size of between 50 ⁇ m and 1200 ⁇ m, a total porosity of between 60% and 95% and an interconnectivity between the pores of between 60% and 100%.
• the biomaterial according to the invention has an average pore size of between 500 ⁇ m and 700 ⁇ m, a total porosity of between 70% and 95% and an interconnectivity between the pores of 100%.
• the porous biomaterial comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and on hyaluronic acid, has a pore size of between 500 ⁇ m and 2000 ⁇ m. , a total porosity of between 60% and 95% and an interconnectivity between the pores of between 60% and 100%.
• the biomaterial comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and on hyaluronic acid, has an average pore size of between 500 ⁇ m and 700 ⁇ m, a total porosity of between 70% and 95% and 100% interconnectivity between pores.
• the porosity of the material, the size of the pores and their interconnection have a major influence on the capacity of the biomaterial to vascularize and gradually reabsorb.
• the biomaterial comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and hyaluronic acid is particularly suitable for adhesion and migration of connective tissue cells and blood vessels.
• the interconnected porous network helps guide the attachment and growth of cells, and therefore the growth of newly formed connective tissue.
• the presence of hyaluronic acid stimulates angiogenesis, thus improving the revascularization and integration of the biomaterial.
• the fibroblasts adhere and proliferate inside and around the biomaterial.
• the biomaterial comprising at least one elastomeric matrix comprising an elastomer based on poly (caprolactone-urea-urethane) and hyaluronic acid promotes revascularization, rapid integration of soft tissues and offers a safe alternative to autologous connective tissue. .
• the size of the biomaterial according to the invention is dependent on the size and thickness of the tissue defect.
• the biomaterial has a size of between 5 mm and 20 cm and a thickness of between 100 ⁇ m and 4 cm.
• 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 20cm, 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 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.
• the thickness of the biomaterial is between 100 ⁇ m and 4 cm, advantageously between 200 ⁇ m and 4 cm, advantageously between 500 ⁇ m 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.
• the thickness of the biomaterial is between 1 and 3 mm, when the biomaterial according to the invention is used in the reinforcement, reconstruction and / or filling of tissue defects of the mucous membranes, and in particular of the gum.
• the surface of the biomaterial is at least 25 mm 2 .
• the biomaterial has a surface area of at least 50 mm 2 , advantageously at least 100 mm 2 advantageously at least 150 mm 2 advantageously at least 200 mm advantageously at least 250 mm 2 advantageously at least 300 mm advantageously at least 350 mm 2 advantageously at least 400 mm 2 advantageously at least 450 mm 2 advantageously at least 500 mm 2 advantageously at least 550 mm 2 advantageously at least 600 mm 2 advantageously at least 650 mm 2 advantageously at least 700 mm 2 advantageously at least 750 mm 2 advantageously at least 800 mm 2 advantageously at least 850 mm 2 advantageously at least 900 mm advantageously at least 950 mm 2, advantageously at least 1000 mm 2 , advantageously at least 15 cm, advantageously at least 20 cm, advantageously at least 25 cm, advantageously at least 30 cm, advantageously at least 35 cm, advantageously at least 40 cm, advantageously at least 45 cm, advantageously at least 50 cm
• the biomaterial has a volume of at least 1 mm 3 .
• 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 less 250 mm 3 , advantageously at least 300 mm 3 , advantageously
• the biomaterial according to the invention can be in the form of a sponge, a film, a membrane, granules, monoliths or a dressing.
• the biomaterial according to the invention is used alone.
• the biomaterial can further be used in combination with an active agent.
• the active agent is placed inside the pores of the biomaterial according to the invention, partially or completely covering the pores of the biomaterial.
• the active agent can be added by one of the following methods: covering the biomaterial with the active agent, immersion of the biomaterial in the active agent, spraying of the active agent on the biomaterial, vaporization of the agent active on the biomaterial, or any other technique well known to those skilled in the art making it possible to fill and / or fill the pores of said biomaterial.
• the active agent can be any therapeutic or pharmaceutically active agent (including, but not limited to nucleic acids, proteins, lipids and carbohydrates) which possesses desirable physiological characteristics for application to the site. implantation.
• Therapeutic agents include, without limitation, anti-infectives such as antibiotics and antiviral agents; chemotherapeutic agents (eg, anticancer 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), coagulation factors (factors VII, VIII, IX, X, XI, XII, V,), albumin, fibrinogen, von Willebrand factor, thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, surface glycoprotein receptor inhibitors, antiplatelet agents
• Another aspect of the invention relates to the biomaterial according to the invention for its use in strengthening, reconstructing and / or filling tissue defects.
• the term “reinforcement of tissue defects” means the increase in tissue density by induction of collagen synthesis and / or collagen deposition, due to the biocompatibility of the biomaterial, and in particular thanks to the presence of hyaluronic acid.
• the term “reconstruction of tissue defects” is understood to mean the repair of tissue defects by induction of collagen synthesis and / or collagen deposition, due to the biocompatibility of the biomaterial, and in particular thanks to the presence of collagen. hyaluronic acid.
• the term “filling of tissue defects” means the filling of tissue defects by induction of collagen synthesis and / or collagen deposition, due to the biocompatibility of the biomaterial, and in particular thanks to the presence of collagen. hyaluronic acid.
• the reinforcement, reconstruction and / or tissue filling is greater than or equal to 5% by volume of the volume of the tissue defect to be reinforced, reconstructed and / or filled.
• the reinforcement, reconstruction and / or tissue filling is greater than or equal to 6% by volume of the volume of tissue to be reconstructed and / or filled, advantageously greater than or equal to 7%, advantageously greater than or equal to 8%, advantageously greater than or equal to 9%, advantageously greater than or equal to 10%, advantageously greater than or equal to 11%, advantageously greater than or equal to 12%, advantageously greater than or equal to 13%, advantageously greater than or equal to 14%, advantageously greater than or equal to 15%, advantageously greater than or equal to 16%, advantageously greater than or equal to 17%, advantageously greater or equal to 18%, advantageously greater than or equal to 19%, advantageously greater than or equal to 20%, advantageously greater than or equal to 21%, advantageously greater than or equal to 22%, advantageously greater than or equal to 23%
• the reinforcement, reconstruction and / or tissue filling is less than or equal to 50% by volume of the volume of the tissue defect to be reinforced, reconstructed and / or filled.
• the porous biomaterial according to the invention can be used for strengthening, reconstruction and / or tissue filling in humans or animals.
• the animal can be a horse, a pony, a dog, a cat, a rat, a mouse, a pig, a sow, a cow, an ox, a bull, a calf, a goat, a sheep, a ram, a lamb, a lamb, a donkey, a camel, a dromedary, the list not being exhaustive.
• the porous biomaterial according to the invention can be used for the reinforcement, the reconstruction and / or the filling of the defects of the soft tissues and / or the epithelial tissues.
• the term “soft tissues” is understood to mean tissues, not osseous and not composed of epithelium, which surround, support and connect the organs and other tissues.
• the soft tissues surround, support and connect the organs and other parts of the body; give shape and structure to the body; protect organs; move fluids, such as blood, from one part of the body to another; store energy.
• the biomaterial according to the invention can be used to strengthen, reconstruct and / or fill any type of soft tissue, of human or animal origin.
• the soft tissue can be chosen from the group comprising: fibrous tissue, muscles, in particular smooth muscles, skeletal muscles and cardiac muscle, synovial tissue, blood vessels, lymphatic vessels, viscera and nerves, the list not being exhaustive.
• the biomaterial according to the invention can be used to strengthen, reconstruct and / or fill any type of epithelial tissue, of human or animal origin.
• the biomaterial according to the invention can be used for the strengthening, reconstruction and / or filling of defects of the skin and / or mucous membranes.
• the mucosa can be an oral mucosa.
• the biomaterial according to the invention can be used to reinforce, reconstruct and / or fill any type of epithelial tissue, advantageously in the reinforcement, reconstruction and / or gingival filling, in particular to obtain a covering of the gingival tissues. roots, for the treatment of gum recessions, thickening of tissue for a thick biotype, increasing the keratinized gum band, restoring support and anchoring of teeth, or rebuilding tissue following periodontitis.
• the biomaterial according to the invention can be used to reinforce the defects of the soft tissues and / or the epithelial tissues, in particular in the context of gynecological, urinary or visceral (or parietal) surgery, as by example to strengthen a vascular wound, a digestive wound, or an eventration.
• the biomaterial according to the invention could be used for the design of reinforcing implants for the treatment of pelvic organ prolapse, more particularly in the treatment of pelvic organ prolapse in women: anterior stage (urinary , cystocele, stress incontinence), medium (genital, colpocele) and / or posterior (digestive rectocele).
• biomaterial according to the invention for its use in the treatment of burns.
• the biomaterial according to the invention is particularly useful for the treatment of burns.
• the biomaterial according to the invention is particularly useful for the treatment of thermal burns, cold burns, electrical burns, chemical burns and radiological burns.
• One aspect of the invention relates to the biomaterial according to the invention for its use in the treatment of burns, preferably thermal burns, cold burns, electrical burns, chemical burns, radiological burns and photochemical burns.
• thermal burns is understood to mean external thermal burns caused by external contact with a flame, hot vapors or boiling liquids, or by contact (the severity then depends on the temperature of the object. and contact time) and internal thermal burns concern the respiratory or digestive tracts and result from the absorption or inhalation of a hot product (food, a gas among other gases produced by combustion) or of a caustic substance (chemical).
• frostbite can be caused by something cold and rubbing.
• the term “electrical burns” is understood to mean the partial or total destruction which may concern the skin, mucous membranes (possibly internal), the soft parts of tissues due to an electric arc (thermal burn by ignition) or by direct contact with the driver (always deep).
• the term “chemical burns” is understood to mean the partial or total destruction which may concern the skin, the mucous membranes (possibly internal), the soft parts of the tissues due to the caustic action of a strong acid (acidic acid). hydrochloric acid, sulfuric acid, nitric acid) or a strong base (soda, potash).
• radio burns is understood to mean the burns or radiodermatitis caused by electromagnetic radiation, by corpuscular bodies.
• the biomaterial according to the invention can be used for the treatment of burns in humans or animals.
• the animal can be a horse, a pony, a dog, a cat, a rat, a mouse, a pig, a sow, a cow, a bull, an ox, a calf, a goat, a sheep, a ram, a lamb, a lamb, a donkey, a camel, a dromedary, the list not being exhaustive.
• Another aspect of the invention relates to a process for preparing a biomaterial according to the invention.
• the biomaterial according to the invention is obtained by the poly-HIPE method (formation and polymerization / crosslinking of high internal phase emulsions).
• High Internal Phase Emulsions or HIPEs consist of liquid / liquid immiscible dispersed systems, in which the volume of the internal phase, also called the dispersed phase, occupies a volume greater than about 74% - 75% of the total volume of the emulsion. , that is to say a volume greater than what is geometrically possible for the compact packaging of monodisperse spheres.
• the process for preparing the biomaterial comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of the poly (ester-urea-urethane), b) dissolving the non-sulfated polysaccharide in a aqueous liquid phase then add the unsulfated polysaccharide solubilized in the organic phase of step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain said biomaterial, and d) wash said biomaterial obtained in step c). e) drying said biomaterial obtained in step d).
• step a) consists in preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane).
• the organic phase further comprises an oligoester, an organic solvent, a crosslinking agent, a catalyst and a surfactant.
• the organic phase comprises an organic solvent, the polycaprolactone triol oligomer, the Span80 surfactant, the crosslinking agent hexamethylene diisocyanate (HMDI) and the dibutyl tin dilaurate (DBTDL) catalyst.
• the organic solvent is toluene.
• step a) comprises a first step a1) consisting in dissolving in the organic solvent, the oligomer of polycaprolactone triol and the surfactant Span80, then a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase.
• a first step a1) consisting in dissolving in the organic solvent, the oligomer of polycaprolactone triol and the surfactant Span80
• a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase.
• 2.4 ml of organic solvent is used, 1.3 g of polycaprolactone triol oligomer, 1.3 g of Span80 surfactant, 1.04 ml of HMDI crosslinking agent and 12 drops.
• DBTDL catalyst are used.
• the organic solvent is toluene.
• step b) of the process consists in dissolving the unsulfated polysaccharide in an aqueous liquid phase and then adding the unsulfated polysaccharide solubilized in the organic phase of step a) to form an emulsion.
• the unsulphated polysaccharide must have been solubilized in an aqueous liquid phase.
• the aqueous liquid phase is sterilized distilled water.
• the amount of distilled water used is 50ml_.
• the aqueous liquid phase is gradually poured into the organic phase with stirring, until an emulsion is obtained.
• the unsulfated polysaccharide is introduced at a concentration of at least 0.5 mg / ml, advantageously at a concentration of at least 1.0 mg / ml, advantageously at a concentration of at least 1.5 mg / ml , advantageously at a concentration of at least 2.0 mg / mL, advantageously at a concentration of at least 2.5 mg / mL, advantageously at a concentration of at least 3.0 mg / mL, advantageously at a concentration 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
• the unsulfated polysaccharide is introduced at a concentration of between 0.5 mg / ml_ to 20 mg / ml_.
• the polysaccharide is hyaluronic acid, preferably high molecular weight hyaluronic acid.
• the hyaluronic acid is introduced at a concentration of at least 0.5 mg / ml_, advantageously at a concentration of at least 1.0 mg / ml_, advantageously at a concentration of at least 1.5 mg / ml_ , advantageously at a concentration of at least 2.0 mg / ml_, advantageously at a concentration of at least 2.5 mg / ml_, advantageously at a concentration of at least 3.0 mg / ml_, advantageously at a concentration at least
• the amount of unsulphated polysaccharide represents between 0.05% and 2.0% by weight (m / m) relative to the mass of the aqueous liquid phase present in the emulsion .
• the non-sulfated polysaccharide represents at least 0.05% by weight relative to the mass of aqueous liquid phase present in the emulsion, advantageously at least 0.06%, advantageously at least 0.07%, advantageously at least 0 , 08%, advantageously at least 0.09%, advantageously at least 0.10%, advantageously at least 0.20%, advantageously at least 0.30%, advantageously at least 0.40%, advantageously at least 0.50 %, advantageously at least 0.60%, advantageously at least 0.70%, advantageously at least 0.80%, advantageously at least 0.90%, advantageously at least 1.0%, advantageously at least 1.10%, advantageously at least 1.20%, advantageously at least 1.30%, advantageously at least 1.40%, advantageously at least 1.50%, advantageously
• the amount of unsulfated polysaccharide represents between 0.05% and 2.0% by weight (m / m) relative to the mass of aqueous phase present in the emulsion.
• the unsulphated polysaccharide represents between 0.06% and 2.0%, advantageously between 0.07% and 2.0%, advantageously between 0.08% and 2.0%, advantageously between 0.09% and 2 , 0%, advantageously between 0.10% and 2.0%, advantageously between 0.20% and 2.0%, advantageously between 0.30% and 2.0%, advantageously between 0.40% and 2.0 %, advantageously between 0.50% and 2.0%, advantageously between 0.60% and 2.0%, advantageously between 0.70% and 2.0%, advantageously between 0.80% and 2.0%, advantageously between 0.90% and 2.0%, advantageously between 1.0% and 2.0%, advantageously between 1.10% and 2.0%, advantageously between 1.20% and 2.0%, advantageously between 1.30% and 2.0%, advantageously between 1.40% and 2.0%, advantageously between 1.50% and 2.0%, advantageously between
• the amount of hyaluronic acid represents between 0.05% and 2.0% by weight (m / m) relative to the mass of the aqueous liquid phase present in the emulsion .
• the hyaluronic acid represents at least 0.05% by weight relative to the mass of aqueous liquid phase present in the emulsion, advantageously at least 0.06%, advantageously at least 0.07%, advantageously at least 0 , 08%, advantageously at least 0.09%, advantageously at least 0.10%, advantageously at least 0.20%, advantageously at least 0.30%, advantageously at least 0.40%, advantageously at least 0.50 %, advantageously at least 0.60%, advantageously at least 0.70%, advantageously at least 0.80%, advantageously at least 0.90%, advantageously at least 1.0%, advantageously at least 1.10%, advantageously at least 1.20%, advantageously at least 1.30%, advantageously at least 1.40%, advantageously at least 1.50%, advantageously at least 1.60%
• the amount of hyaluronic acid represents between 0.05% and 2.0% by weight (m / m) relative to the mass of aqueous phase present in the emulsion.
• the hyaluronic acid represents between 0.06% and 2.0%, advantageously between 0.07% and 2.0%, advantageously between 0.08% and 2.0%, advantageously between 0.09% and 2 , 0%, advantageously between 0.10% and 2.0%, advantageously between 0.20% and 2.0%, advantageously between 0.30% and 2.0%, advantageously between 0.40% and 2.0 %, advantageously between 0.50% and 2.0%, advantageously between 0.60% and 2.0%, advantageously between 0.70% and 2.0%, advantageously between 0.80% and 2.0%, advantageously between 0.90% and 2.0%, advantageously between 1.0% and 2.0%, advantageously between 1.10% and 2.0%, advantageously between 1.20% and 2.0%, advantageously between 1.30% and 2.0%, advantageously between 1.40% and 2.0%, advantageously between 1.50% and 2.0%, advantageously between 1.60%
• the hyaluronic acid represents 0.10% by weight (m / m) relative to the mass of aqueous liquid phase present in the emulsion.
• step c) of the process consists in polymerizing / crosslinking the emulsion obtained in step b) to obtain said biomaterial according to the invention.
• the crosslinking is carried out in a mold to give the biomaterial the desired shape.
• the emulsion obtained in step b) is placed at a temperature of between 30 ° C and 80 ° C for 10 to 30 hours.
• the emulsion obtained in step b) is placed 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.
• the emulsion obtained in step b) is placed at a temperature of between 30 ° C and 70 ° C for 10 to 30 hours, advantageously for 11 to 29 hours, advantageously for 12 to 29 hours, advantageously for 13 to 28 hours, advantageously for 14 to 27 hours, advantageously for 15 to 27 hours, advantageously for 16 to 27 hours, advantageously for 17 to 27 hours, advantageously for 18 to 26 hours, advantageously for 19 to 25 hours, advantageously for 20 to 24 hours, preferably for 22 hours.
• those skilled in the art will know how to adapt the temperature as a function of the size of the pores desired for the biomaterial.
• the biomaterial according to the invention obtained in step c) is annealed prior to step d).
• the biomaterial according to the invention obtained in step c) is annealed for at least 1 hour at a temperature of at least 50 ° C.
• the porous biomaterial according to the invention obtained in step c) is annealed for 2 hours at a temperature of 100 ° C.
• the washing step of step d) makes it possible to remove the reagents necessary for the synthesis of the poly (ester-urea-urethane) which have not reacted during the crosslinking as well as the surfactant and catalyst still present.
• the washing of step d) is carried out using one of the following products: dichloromethane, dichloromethane / hexane, hexane, water, a mixture of these products or the successive application of these products.
• the washing of step d) is carried out by contacting the porous biomaterial according to the invention, dried with dichloromethane for at least 24 hours, followed by a washing step with dichloromethane / hexane (50% vol / 50% vol) for at least 24 hours, followed by a washing step with hexane for at least 24 hours, then a final wash with distilled water for at least 24 hours.
• the method according to the invention can further comprise a drying step between step c) and step d).
• this drying step can be carried out by drying in the open air or in an oven. Those skilled in the art will know how to adapt the temperature of the oven according to the material to be dried.
• the drying is carried out by drying in the open air for at least 7 days.
• the drying of step e) can be carried out by drying in the open air or in an oven.
• a person skilled in the art will know how to adapt the temperature of the oven according to the material to be dried.
• the drying is carried out by drying in the open air for at least 15 days.
• the method according to the invention may further comprise a step f) of sterilization after step e) of drying said biomaterial.
• step f) of sterilization can be carried out directly on the dry biomaterial or after washing the biomaterial under vacuum in an aqueous medium.
• the sterilization is carried out after washing under vacuum in an aqueous medium.
• step f) of sterilization can be carried out as follows: f1) bringing the biomaterial according to the invention into contact in sterile water for one hour under vacuum, f2) replacing the sterile water and contacting the biomaterial according to the invention in sterile water replaced for 4 hours under vacuum, f3) contacting the biomaterial according to the invention from step e2) in 70% ethanol for 1 hour under vacuum, f4) replacing the 70% ethanol with sterile water and bringing the biomaterial according to the invention from step e3) into contact in sterile water, overnight at ambient pressure, f5) sterilization by autoclave of the biomaterial according to the invention resulting from step f4) in water.
• step f) of sterilization can be performed by gamma radiation.
• step f) of sterilization can be performed by beta radiation.
• the dose of beta and / or gamma radiation can be between 15 and 45 kGy.
• the dose of beta and / or gamma radiation is 25 kGy.
• the dose of beta and / or gamma radiation is 15 kGy.
• step f) sterilization can be performed by contacting the biomaterial with ethylene oxide.
• step f) of sterilization can be carried out by bringing the biomaterial into contact with a plasma phase derived from a gas.
• step f) of sterilization can be carried out by irradiating the biomaterial with an electron beam (E-beam, E-beam).
• the electron beam irradiation treatment has the following advantages: shorter processing time, improved supply chain efficiency, less risk of embrittlement of the elastomeric matrix, less oxidative damage in the biomaterial , no color change of the elastomeric matrix, making it clean and safe.
• the electron beam irradiation treatment is an environmentally friendly treatment.
• the method according to the invention may further comprise a step g) of conservation of said biomaterial after step f) of sterilization.
• step g) of conservation of said biomaterial is carried out by contacting the biomaterial in 70% ethanol until it is used.
• the process for preparing a biomaterial comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane), b) dissolving the unsulfated polysaccharide in an aqueous liquid phase then add the unsulfated polysaccharide solubilized in the organic phase of step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain said biomaterial porous, and d) washing said porous biomaterial obtained in step c), e) drying said biomaterial obtained in step d) f) sterilization of the biomaterial obtained from step d), and g) optionally, conservation of the biomaterial.
• the process for preparing a biomaterial comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane ), said step a) comprising a first step a1) consisting in dissolving in the organic solvent, the oligomer of polycaprolactone triol and the surfactant Span80, then a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase, b) solubilize the unsulfated polysaccharide in an aqueous liquid phase based on sterilized distilled water and then add the unsulfated polysaccharide solubilized in the organic phase to the liquid of the step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain said porous biomaterial, and d) wash said bio
• the process for preparing a biomaterial comprising the following steps: a) preparing an organic phase comprising the compounds necessary for the synthesis of poly (ester-urea-urethane ), said step a) comprising a first step a1) consisting in dissolving in toluene, the oligomer of polycaprolactone triol and the surfactant Span80, then a second step a2) consisting in adding the crosslinking agent HMDI and the DBTDL catalyst in the solution of step a1) to form the organic phase, b) solubilize hyaluronic acid, advantageously high molecular weight hyaluronic acid in an aqueous liquid phase based on sterilized distilled water and then add the solubilized unsulfated polysaccharide in the organic phase to the liquid of step a) to form an emulsion, c) polymerize / crosslink the emulsion obtained in step b) to obtain
• Figure 1 shows the porous biomaterial according to the invention. The images were obtained by 3D microscopy (VHX Keyence).
• Figure 2 shows the analysis by Fourier transform infrared spectroscopy (I RTF) of hyaluronic acid (a), of the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (b), porous biomaterial according to the invention comprising hyaluronic acid (c), and the subtraction (d) of spectra c and b.
• I RTF Fourier transform infrared spectroscopy
• Figure 3 represents the loss of mass and the rate of mass absorption of the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (a, c) and porous biomaterial according to the invention comprising hyaluronic acid (b and d) during degradation in vitro at 37 ° C and accelerated at 55 ° C and 75 ° C.
• Figure 4 shows the migration of cells (gingival fibroblasts) from day 10 to day 40 within the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and the porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH).
• Figure 5 shows colonization by cells (gingival fibroblasts) after 20 days of migration within the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH). (3D digital microscopy - hemalun stain).
• Figure 6 shows the appearance, after 10 days of culture, of the cells (gingival fibroblasts) on the bottom of the well and on the periphery of the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH). (Optical microscopy - x40 magnification).
• Figure 7 shows the cellularization, after 36 days of subcutaneous implantation in rats, of the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and of the porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH).
• Elastomer-AH hyaluronic acid
• Figure 8 shows the structure of the collagens, after 36 days of subcutaneous implantation in rats, within the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and the biomaterial porous according to the invention comprising hyaluronic acid (Elastomer-AH). (Material identified by the white frame) (3D digital microscopy - picrosirius red staining - x4 and x40 magnification).
• Figure 9 shows the labeling of the T lymphocytes present, after 36 days of subcutaneous implantation in the rat, within the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH). (Material identified by the black frame) (3D digital microscopy - CD3 marking - x4 and x40 magnification).
• Figure 10 shows the labeling of the macrophages present, after 36 days of subcutaneous implantation in rats, within the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH). (Material identified by the black frame) (3D digital microscopy - CD163 marking - x4 and x40 magnification).
• Figure 11 shows the average optical density values obtained after staining of hyaluronic acid with Alcian Blue for the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and the porous biomaterial according to l invention comprising hyaluronic acid (Elastomer-AH).
• Figure 12 shows the elastomer matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH) before and after beta radiation at 15 kGy.
• the images were obtained by 3D microscopy (VHX Keyence).
• Example 1 Formulation and synthesis of the porous biomaterial according to the invention
• hyaluronic acid was dissolved for 24 hours at 37 ° C in sterilized distilled water. The solution was then filtered through a 0.2 ⁇ m filter. Secondly, this aqueous solution was poured into the organic phase comprising the compounds necessary for the synthesis of the elastomeric matrix based on poly (caprolactone-urea-urethane) in order to obtain an emulsion with a high internal phase. Subsequently, the polymerization / crosslinking of this emulsion leads to the production of the porous biomaterial according to the invention. Several concentrations of hyaluronic acid were tested. Several volume ratios aqueous phase / organic phase were tested. Different synthesis temperatures were also studied.
• the scaffolds used are those having pores having diameters ranging from 50 ⁇ m to 1400 ⁇ m with an average size of 600 +/- 170 ⁇ m. These materials are characterized in the examples below.
• the formulation and synthesis used to obtain the porous biomaterial according to the invention are:
• IRTF Fourier transform infrared spectroscopy
• the IRTF analyzes confirm the presence of hyaluronic acid in the elastomeric matrix based on poly (caprolactone-urea-urethane).
• the spectrum of the elastomeric matrix based on poly (caprolactone-urea-urethane) alone shows the significant bands of these materials, such as the -NH groups of the urethane at 3333 cm -1 , 1537 cm -1 and 1248 cm - 1 , the -C 0 groups of the urethane and the ester at 1730 cm -1 and of the urea at 1620 cm -1 , the -CNH group of the urea at 1575 cm -1 , and the groups -COO esters at 1164 cm -1 .
• the porous biomaterial according to the invention thus has a surface hydrophilicity more suitable for the adhesion of fibroblasts, the latter having greater adhesion on surfaces having a contact angle with water between 60 ° and 80 °.
• the water absorption rate obtained by immersing the materials in distilled water for 15 days, increases from about 400% for the poly (caprolactone-urea-urethane) elastomer matrix alone vs. about 700% for the porous biomaterial including hyaluronic acid. This shows that the porous biomaterial according to the invention will be more suitable for the penetration of liquids and therefore cell infiltration.
• the average molar mass between crosslinking nodes (Mc) was determined by measurements of swelling in toluene.
• the elastomeric matrix based on poly (caprolactone-urea-urethane) alone has a Mc value of 4860 +/- 240 g / mol, which makes it possible to evaluate the Young's modulus Ei * of the porous material.
• the value of 220 +/- 25 kPa attests to the elastomeric nature of the material.
• the porous biomaterial according to the invention comprising hyaluronic acid (of porosity and pore size equivalent to the elastomeric matrix based on poly (caprolactone-urea-urethane) alone) has a Mc value of 5380 +/- 1460 g / mol, which makes it possible to estimate the value of Ei * at 123 +/- 11 kPa.
• hyaluronic acid participates in a slight decrease in the modulus of the porous biomaterial according to the invention, while retaining the elastomeric nature of the polymer matrix, which will allow the biomaterial according to the invention to resist the contraction forces exerted by the fibroblasts. during cell migration within the material.
• the biomaterial according to the invention comprising hyaluronic acid degrades very slightly more rapidly than the elastomeric matrix based on poly (caprolactone-urea-urethane) alone. This is due to a increase in the hydrophilicity of materials.
• the biomaterial according to the invention is stable for more than 6 months at 37 ° C. The lifespan of a biomaterial is considerably reduced in vivo due to more drastic conditions; nevertheless, the biomaterial according to the invention is sufficiently stable to be used in tissue engineering applications.
• Example 3 Interactions between the porous biomaterial according to the invention and the cells (gingival fibroblasts) - In vitro study
• Example 4 In vivo study of the potential of the porous biomaterial according to the invention for the regeneration of soft tissues in a subcutaneous pocket model in rats
• porous biomaterial according to the invention comprising hyaluronic acid relative to the elastomeric matrix based on poly (caprolactone-urea-urethane) alone
• several batches of animals were monitored up to 36 days post-implantation of said matrices subcutaneously.
• the effectiveness of the material according to the invention was evaluated by histological study of the materials taken after sacrifice of the animals.
• groups of 5 rats were formed (20 rats): - group of animals elastomeric matrix based on poly (caprolactone-urea-urethane) only - group of animals poly (caprolactone-urea-urethane) elastomeric matrix comprising the unsulfated polysaccharide.
• the subcutaneous pocket model consists of making a midline incision in the back of the rat and creating a subcutaneous pocket in which the material to be evaluated will be inserted.
• the animals are anesthetized by intramuscular injection of 1.2 ml / kg of ketamine / xylazine (50/15 mg / kg). The dorsal part of the animals is shaved and then disinfected with Betadine®. A midline incision is made on the back of the rats and the skin flaps are lifted bilaterally. Polymer matrices (1cm in diameter by 2 to 3mm thick) are inserted on either side of the midline and stabilized. The skin planes are then sutured with absorbable 5.0 sutures.
• the animals are monitored daily, their general condition and their behavior are observed. Throughout the experiment, the animals did not show any loss of mobility, did not show signs of aggression. The weight curves have evolved steadily. There was no sign of inflammation or necrosis in the wound.
• the elastomeric matrices based on poly are removed from their storage medium (70% ethanol), rinsed with stirring for 5 minutes with physiological saline. They are then placed in the subcutaneous pockets.
• hemalun eosin hemalun: 0.2% hematein in a 5% aqueous solution of potassium alum / 2% aqueous eosin
• picrosirius red 0.1% picrosirius red in a saturated picric acid solution
• This surface appears to be colonized by numerous cells with round nuclei which may be inflammatory cells as well as erythrocytes.
• the pores of the porous biomaterial according to the invention comprising hyaluronic acid are invaded by a fibrous connective tissue remaining in contact with the surface of the pores.
• the number of cells with a round nucleus appears to be greatly reduced compared to the elastomeric matrix alone indicating a decrease in the inflammatory component.
• Perfectly formed vessels are present in the connective tissues, the red blood cells are well restricted there with no sign of effusion.
• Multi-nucleated 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.
• the hyaluronic acid assay is performed by a colorimetric assay technique using Alcian Blue. Briefly, the elastomer matrices based on poly (caprolactone-urea-urethane) alone (Elastomer) and on the porous biomaterial according to the invention comprising hyaluronic acid (Elastomer-AH) are cut, weighed and then incubated for 2 H in a solution of Blue. Alcian. The excess dye is removed and then substituted with a sodium acetate buffer solution (50mM / MgCl250mM at pH5.8). The materials are then incubated in a 60% ethanol solution, followed by an 80% acetic acid solution. Optical density is measured at 675 nm.
• the hyaluronic acid assays were carried out at different stages of the manufacturing process and made it possible to determine an average concentration of 425 pg of HA / g of porous biomaterial according to the invention (see Figure 11).
• Example 6 Sterilization by beta and gamma radiation
• the beta treatment sterilization was carried out by an ionization process consisting of continuously scrolling, at a regulated speed, the biomaterial with the beta radiation emitted by an electron accelerator. Doses of 15, 25 and 45 Gy were tested. For example, the dose performed at 25kGy +/- 10% was carried out under the following treatment conditions: frequency of 640 Hz / sweep setpoint at 2.6 / number of revolutions: 1 / speed: 0.898 m / min
• Sterilization by gamma treatment was carried out by an ionization process of exposing the biomaterial to gamma radiation emitted by a source of Cobalt 60 for a limited period of time.
• the dose performed was 25kGy +/- 10%
• the images obtained by 3D microscopy show for sterilization by beta radiation at 15 kGy that the elastomeric matrix based on poly (caprolactone-urea-urethane) alone (Elastomer) and porous biomaterial according to the invention comprising the hyaluronic acid (Elastomer-AH) does not show any structural alteration.
• the same results were obtained for the doses of beta and gamma radiation, from 15 to 45 kGy, whether the biomaterial according to the invention is dry or in an aqueous medium.

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