Injectable biomaterial consisting of particles of a collagen inducer and a composition comprising at least two crosslinked hyaluronic acids in a mixture

Abstract

The present invention relates to an injectable biomaterial consisting of particles of a collagen inducer and a composition comprising at least two crosslinked hyaluronic acids in a mixture. It also relates to a biomaterial according to the invention, characterised in that the collagen inducer is chosen from the polyhydroxyalkanoates (PHA), hydroxyapatites, polycaprolactones, polylactic or polyglycolic acids, polydioxanone, poly(trimethylene carbonates) (PTMC) and / or polysaccharides and derivatives thereof, such as dextranomer in isolated form or in the form of copolymers and / or mixtures in particulate form.

Description

INJECTABLE BIOMATERIAL CONSISTING OF COLLAGEN INDUCER PARTICLES AND A COMPOSITION COMPRISING AT LEAST TWO RETICULATED HYALURONIC ACIDS IN MIXTURE

[0001] The invention relates to the field of biomaterial formulations, particularly in the medical and aesthetic fields. In these applications, the formulations must exhibit optimized rheological properties, taking into account the characteristics of the medical device used for injection, the characteristics of the treated area, and the desired therapeutic or cosmetic effect, as well as optimized residual properties to achieve the longest possible effect.

[0002] Human skin tissue is composed of fibrous proteins such as collagen and an extracellular matrix (ECM) containing fibronectin, laminin, and glycosaminoglycans (GAGs). When skin tissue is damaged—that is, when it has defects, for example, due to aging—a common method is to restore function and form by injecting a filler material made of synthetic polymers or biological tissues into the affected area. This technique can restore tissue, fill defects, improve wrinkles, or correct contours.

[0003] The raw materials for fillers used in facial plastic surgery include autologous dermal implants, collagen, or hyaluronic acid (HA).

[0004] To improve the performance of fillers, attempts have been made to manufacture fillers containing microspheres of collagen-inducing products such as hydroxyapatite, lactic acid-based polymers, polyhydroxyalkanoates and / or polycaprolactone-based polymers.

[0005] The disadvantage of these products containing particulate inducers is the alteration of injectability properties and even rheological properties by the incorporation of said particles.

[0006] It is therefore necessary to develop filling compositions based on a biomaterial which allows for the preparation of easily injectable compositions with improved rheological properties including a collagen inducer in particulate form.

[0007] Preparing collagen-inducing material particles for incorporation into fillers, which are by design aqueous formulations, presents numerous technical difficulties, ranging from the challenge of preparing particles with a size distribution compatible with the preparation of injectable formulations under conditions that meet the precision requirements necessary for wrinkle filling.

[0008] The present invention relates to an injectable biomaterial and more particularly to a filler or implant consisting of a composition comprising at least two cross-linked hyaluronic acids in a mixture and particles of a collagen inducer.

[0009] The present invention relates to a biomaterial consisting of collagen inducer particles and a composition comprising at least two cross-linked hyaluronic acids in a mixture

[0010] The invention relates to a biomaterial in which the composition comprising at least two cross-linked hyaluronic acids in mixture is in the form of a gel or hydrogel.

[0011] The invention therefore relates to a biomaterial comprising at least one gel or hydrogel made up of a mixture of at least two cross-linked hyaluronic acids and particles of a collagen inducer.

[0012] Surprisingly, the compositions according to the invention are easily injectable through fine needles (27G), while possessing remarkable viscoelastic properties and an inducing microparticle content adapted to obtain the desired filling effect.

[0013] Administering the compositions according to the invention requires a moderate and entirely acceptable injection force and does not lead to needle clogging. Furthermore, while fillers suitable for medical and aesthetic applications must be easily injectable, it is also essential that these products, containing solid particles dispersed in an injectable biomaterial, remain stable over time. This means they must remain homogeneous, and sedimentation or particle aggregation must be prevented.

[0014] The compositions according to the invention make it possible to limit, and even avoid, the static sedimentation of the incorporated microparticles.

[0015] In one embodiment, the collagen inducer is chosen from polyhydroxyalkanoates (PHA), hydroxyapatites, polycaprolactones, polylactic or polyglycolic acids, polydioxanone, poly(trimethylene carbonates) (PTMC) and / or polysaccharides and their derivatives such as dextranomer in isolated form or as copolymers and / or mixtures in particulate form.

[0016] Polyhydroxyalkanoates (PHAs) are diverse biopolyesters with a similar structure and different side-chain groups, synthesized by a variety of microorganisms. Due to their excellent biodegradability and biocompatibility, PHAs have been used in numerous applications, including medical implants, bioengineering, and regenerative medicine.

[0017] Hydroxyapatites (CaHA) are mineral species composed of calcium phosphate. The formula for hydroxyapatite is usually written CaIO(PO4)e(OH)2, where the OH- ion can be replaced by fluorine, chlorine, or carbonate. Hydroxyapatite is the main mineral component of bone and teeth. It can be used in numerous applications, such as a bone graft or in certain dental implants. Hydroxyapatites are also used in injectable fillers for facial plastic surgery, such as the RADIESSE product, which consists of calcium hydroxyapatite microspheres suspended in a vehicle containing carboxymethylcellulose.

[0018] Hydroxyapatite microspheres are marketed by SANGI Co., Ltd. (Japan) or by EPRUI Biotech Co., Ltd (China).

[0019] Polycaprolactone (PCL) is a biodegradable polyester that can be prepared by ring-opening polymerization of the ε-caprolactone monomer. PCL is used in the medical field for controlled-release drug delivery systems and medical devices such as biodegradable sutures. Degradable PCL collagen inducer microspheres are sold by Shenzhen Esun Industrial Co., Ltd. (China).

[0020] Polyethylene glycol and PCL copolymers (PEG-PCL) are copolymers composed of polycaprolactone and ethylene glycol. Degradable PEG-PCL collagen inducer microspheres are sold by Shenzhen Esun Industrial Co., Ltd. (China).

[0021] Polylactic acids (PLAs) are biodegradable polymers that can be obtained by two main synthesis methods: polycondensation or ring-opening polymerization. Two monomers can be used: (L)-lactic acid (LLA) and (D)-lactic acid (DLA). These monomers can be used to produce various polymers or copolymers such as poly-(L)-lactic acid (PLLA), poly-(D)-lactic acid (PDLA), and poly-D,L-lactic acid (PDLLA).

[0022] PLA is used in the medical field for controlled-release drug delivery systems and medical devices such as biodegradable sutures. PLA is also used in injectable fillers for facial plastic surgery, such as SCULPTRA, a product composed of PLLA microspheres and carboxymethylcellulose, which comes in the form of a dry powder that must be reconstituted. Degradable collagen-inducing microspheres of PLLA or PDLLA are sold by Shenzhen Esun Industrial Co., Ltd. (China).

[0023] Polyethylene glycol and PLA copolymers (PEG-PLA) are copolymers composed of lactic acid and ethylene glycol. Microspheres Degradable collagen inducer PEG-PLLA are sold by Shenzhen Esun Industrial Co., Ltd. (China).

[0024] Poly(L-lactic-co-caprolactone) (PLCL) is a biodegradable copolymer composed of lactic acid and caprolactone; it is notably used in absorbable suture threads.

[0025] BMG Incorporated (Japan) markets PLCL in powder form, with lactic acid:caprolactone ratios of 75:25 or 50:50.

[0026] Polyglycolic acid (PGA) is a biodegradable linear polyester obtained by polymerization of glycolide, which is the dimeric anhydride of glycolic acid. It is notably used in absorbable sutures.

[0027] Polylactic acid-polyglycolic acid (PLGA) copolymers are biodegradable polyesters that can be either random copolymers or block copolymers. Depending on the ratio of lactic acid to glycolic acid used during polymerization, different forms of PLGA can be obtained, such as PLGA 85:15, composed of 85% lactic acid and 15% glycolic acid. These polymers can be used in the medical field for controlled-release drug delivery systems and medical devices such as biodegradable sutures or surgical implants.

[0028] Polydioxanone (PLO), or poly-p-dioxanone, is a synthetic biodegradable polyester obtained by ring-opening polymerization from the p-dioxanone monomer. PLO is used in biomedical applications, particularly for suture preparation and in orthopedic surgery.

[0029] Poly(trimethylene carbonate) (PTMC) is a biodegradable polymer synthesized from cyclic trimethylene carbonate (CMC). It is used in controlled-release drug systems and tissue engineering applications.

[0030] Poly(L-lactide-co-trimethylene carbonate) is a degradable copolymer based on lactic acid and trimethylene carbonate used in medical devices such as sutures.

[0031] Poly(trimethylene carbonate-co-p-dioxanone-co-L-lactide) is a degradable copolymer based on lactic acid, trimethylene carbonate and p-dioxanone used in medical devices such as sutures.

[0032] The polysaccharides selected from hyaluronic acid and its derivatives, chitosan and its derivatives, dextran and its derivatives, particularly dextranomer, in isolated form or in the form of copolymers and / or mixtures in particulate form.

[0033] Dextranomers are cross-linked dextran-based polymers that can exist in the form of microspheres. Dextranomers can also be used as collagen inducers for injectable fillers for facial plastic surgery, such as the GENEFILL DX product which includes dextranomer microparticles and cross-linked hyaluronic acid.

[0034] In one embodiment, the collagen inducer is chosen from among the PHAs.

[0035] PHAs are chosen from first generation PHAs such as poly(3-hydroxybutyric acid) (PHB) and poly(4-hydroxybutyric acid) (P4HB), second generation poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), third generation poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx or PHBHx), fourth generation poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB or P3HB4HB) or fifth generation poly(3-hydroxybutyricacid-co-3-hydroxyvalericacid-co-3-hydroxyhexanoic acid) (PHBVHHx or PHBVHx), alone or in mixtures or as copolymers.

[0036] In one embodiment, PHA is P4HB.

[0037] In one embodiment, PHA is poly(3-hydroxybutyrate-co-4-hydroxybutyrate).

[0038] In one embodiment, PHA is P4HB mixed with poly(3-hydroxybutyrate-co-4-hydroxybutyrate.

[0039] In one embodiment, the collagen inducer is chosen from among the hydroxyapatites.

[0040] In one embodiment, hydroxyapatite is calcium hydroxyapatite.

[0041] In one embodiment, the collagen inducer is chosen from polycaprolactones.

[0042] In one embodiment, the collagen inducer is chosen from polylactic acids (PLA).

[0043] In one embodiment, the collagen inducer is selected from polymers or copolymers such as poly-(L)-lactic acid (PLLA), poly-(D)-lactic acid (PDLA), and poly-D,L-lactic acid PDLLA.

[0044] In one embodiment, the collagen inducer is chosen from lactic acid and polycaprolactone copolymers, such as poly(L-lactic-co-caprolactone) (PLCL).

[0045] In one embodiment, the collagen inducer is polyglycolic acid (PGA).

[0046] In one embodiment, the collagen inducer is chosen from polylactic acid and polyglycolic acid (PLGA) copolymers.

[0047] In one embodiment, the collagen inducer is polydioxanone (PLO) or poly-p-dioxanone.

[0048] In one embodiment, the collagen inducer is selected from polylactic acid and polytrimethylene carbonate copolymers

[0049] In one embodiment, the collagen inducer is chosen from polyglycolic acid, polydoxanone and polytrimethylene carbonate copolymers.

[0050] In one embodiment, the collagen inducer is chosen from dextran and its derivatives.

[0051] In one embodiment, the collagen inducer is chosen from among the dextranomers

[0052] The invention also relates to the method of preparing the injectable biomaterial consisting of a composition comprising at least a mixture of cross-linked hyaluronic acid and particles of a collagen inducer.

[0053] It also relates to the methods of implanting said injectable composition consisting of a composition comprising at least a mixture of cross-linked hyaluronic acid and particles of a collagen inducer.

[0054] In one embodiment, the composition according to the invention is in solvent-free form, in particular water-free, for example in lyophilized form.

[0055] In one embodiment, the composition is in the form of an injectable aqueous composition.

[0056] When the composition is in aqueous form, the biocompatible polymer, namely the mixture of at least two cross-linked hyaluronic acids, is in hydrogel form and the collagen inducer particles are suspended in the gel.

[0057] In one embodiment, the composition is in the form of a bipartite composition, one part of which comprises an aqueous polymeric phase, namely a mixture of at least two cross-linked hyaluronic acids, and the other part comprises particles suspended in an organic phase miscible in the aqueous polymeric phase.

[0058] In one embodiment, the composition is in the form of a bipartite composition, one part of which comprises an aqueous polymeric phase, namely a mixture of at least two cross-linked hyaluronic acids, and the other part comprises the particles in dry form.

[0059] In the context of this application, a "hydrogel" is defined as a polymeric gel consisting of a three-dimensional network made up of at least one polymer, capable of absorbing a large quantity of water or aqueous solution and exhibiting particular rheological properties, especially in terms of viscosity and viscoelasticity.

[0060] The said network can be formed by grafting and / or chemical crosslinking by creating bonds between polymer chains, these bonds being covalent bonds.

[0061] This network can also be obtained through transient physical interactions, for example ionic, hydrophobic or hydrogen bonds.

[0062] When the composition is in aqueous form, the aqueous phase consists of water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS or a biological type buffer used in cell culture of the HEPES type ((hydroxyethyl)piperazinyl]ethanesulfonic acid)

[0063] The dissolving of the biocompatible polymer, namely the mixture of at least two cross-linked hyaluronic acids or of the composition according to the invention or in solvent-free form, is carried out by the addition of water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS.

[0064] In one embodiment, the biocompatible polymer, namely the mixture of at least two cross-linked hyaluronic acids, is dissolved by adding water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS, further comprising at least one active ingredient, for example an antioxidant and / or a local anesthetic.

[0065] In this application, the term "filler" or "filler product" refers to a product intended to be injected into the dermal or subcutaneous layer of the skin in order to visually improve the wrinkled area of ​​the face, and to serve to maintain volume by itself without pharmacological action.

[0066] On the other hand, implants are biomaterials used to replace and repair damaged organs in the human body.

[0067] Therefore, although the filler and the implant have the same composition (biocompatible polymer, namely a mixture of at least two cross-linked hyaluronic acids and collagen-inducing particles), their application objectives and effects are different.

[0068] In one embodiment, said crosslinked mixture of hyaluronic acids, or one of their salts, is such as that described in patent application W02009 / 071697 in the name of the applicant.

[0069] In one embodiment, said mixture of hyaluronic acids or one of their salts, crosslinked, is a biodegradable, single-phase cohesive hydrogel consisting of a homogeneous mixture of x hyaluronic acids or one of their salts, identical or different, crosslinked prior to their interpenetration by mixing said cross-linked polymers being insoluble in water and miscible with each other and x being between 2 and 5.

[0070] The hyaluronic acids usable within the framework of the present invention have an average molecular mass by weight (Mw) of the hyaluronic acid before crosslinking of between about 0.02 and about 6 MDa, preferably between about 0.04 and about 4 MDa, preferably still between about 0.05 and about 3 MDa.

[0071] Hyaluronic acid salts are chosen from among physiologically acceptable salts, such as sodium, potassium, calcium salts, advantageously sodium salt.

[0072] In one embodiment, x is equal to 2.

[0073] In the hydrogel according to the present invention, the weight ratio between the crosslinked hyaluronic acids can vary in very large proportions, depending on the average molecular masses and the respective crosslinking rates according to the final properties sought.

[0074] When the mixture comprises a weakly crosslinked hyaluronic acid with a crosslinking ratio x2 and a strongly crosslinked one with a crosslinking ratio xl, and the weight proportion of the strongly crosslinked polysaccharide gel in the mixture is between about 0.1 and 99.9%, preferably 5 to 50% with a crosslinking ratio xl and 50 to 95% of gel with a crosslinking ratio x2, or even more preferably 10 to 40% of gel with a crosslinking ratio xl and 60 to 90% with a crosslinking ratio x2; xl being greater than x2.

[0075] In one embodiment the composition further comprises non-crosslinked hyaluronic acid.

[0076] In one embodiment, the concentration of non-crosslinked hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 50 mg / g.

[0077] In one embodiment, the concentration of non-crosslinked hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 25 mg / g.

[0078] In one embodiment, the concentration of non-crosslinked hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 25 mg / g.

[0079] In one embodiment, the composition further comprises a polysaccharide other than hyaluronic acid, selected from the group consisting of keratin, heparin, cellulose, cellulose derivatives (in particular methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose), alginic acid, xanthan gum, carrageenan, chitosan, chondroitin, heparosan, and their biologically acceptable salts, alone or in mixture.

[0080] In one embodiment, the concentration of polysaccharide other than hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 200 mg / g.

[0081] In the following text, hyaluronic acid concentrations are calculated by reference to the mass of biocompatible polymer composition used, before suspension of particles in the composition, i.e. by reference to the mass of the gel or hydrogel or the mass of the aqueous polymeric phase.

[0082] These concentrations include all the hyaluronic acids used, namely, the cross-linked hyaluronic acids and possibly the non-cross-linked hyaluronic acid.

[0083] If the composition also includes a polysaccharide other than hyaluronic acid, the concentrations are calculated relative to the total mass of the composition before the introduction of the particles.

[0084] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 2 mg / g and 200 mg / g.

[0085] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 2 mg / g and 75 mg / g.

[0086] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 5 mg / g and 50 mg / g.

[0087] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 2 mg / g and 50 mg / g.

[0088] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 4 mg / g and 40 mg / g.

[0089] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 5 mg / g and 30 mg / g.

[0090] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 10 mg / g and 30 mg / g.

[0091] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is between 10 mg / g and 40 mg / g.

[0092] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 2 mg / g.

[0093] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 4 mg / g.

[0094] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 5 mg / g.

[0095] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 6 mg / g.

[0096] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 8 mg / g.

[0097] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 10 mg / g.

[0098] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 14 mg / g.

[0099] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 20 mg / g. [000100] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 40 mg / g. [000101] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 60 mg / g. [000102] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 80 mg / g. [000103] In one embodiment, the concentration of hyaluronic acid in the injectable aqueous composition is 100 mg / g. [000104] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 2 mg / g and 200 mg / g. [000105] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 2 mg / g and 75 mg / g. [000106] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 5 mg / g and 50 mg / g. [000107] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 2 mg / g and 50 mg / g. [000108] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 4 mg / g and 40 mg / g. [000109] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 5 mg / g and 30 mg / g. [000110] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 10 mg / g and 30 mg / g. [000111] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is between 10 mg / g and 40 mg / g. [000112] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 2 mg / g. [000113] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 4 mg / g. [000114] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 5 mg / g. [000115] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 6 mg / g. [000116] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 8 mg / g. [000117] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 10 mg / g. [000118] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 14 mg / g. [000119] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 20 mg / g. [000120] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 40 mg / g. [000121] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 60 mg / g. [000122] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 80 mg / g. [000123] In one embodiment, the concentration of hyaluronic acid in the gel or hydrogel before suspension of the particles is 100 mg / g. [000124] In one embodiment, the concentration of non-crosslinked hyaluronic acid in the gel or hydrogel before suspension of the particles is between 0 mg / g and 50 mg / g. [000125] In one embodiment, the concentration of non-crosslinked hyaluronic acid in the gel or hydrogel before suspension of the particles is between 0 mg / g and 25 mg / g. [000126] In one embodiment, the concentration of non-crosslinked hyaluronic acid in the gel or hydrogel before suspension of the particles is between 0 mg / g and 25 mg / g. [000127] In one embodiment, the concentration of polysaccharides other than hyaluronic acid in the gel or hydrogel before suspension of the particles is between 0 mg / g and 200 mg / g [000128] In the following text, particle concentrations are given by reference to the total mass of the composition, namely the biomaterial after suspension of the particles. [000129] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 700 mg / g. [000130] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 600 mg / g. [000131] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 500 mg / g. [000132] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 400 mg / g. [000133] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 300 mg / g. [000134] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 10 mg / g and 300 mg / g. [000135] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 50 mg / g and 300 mg / g. [000136] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 50 mg / g and 400 mg / g. [000137] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 50 mg / g and 500 mg / g. [000138] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 50 mg / g and 600 mg / g. [000139] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 200 mg / g. [000140] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 75 mg / g. [000141] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 5 mg / g and 50 mg / g. [000142] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 2 mg / g and 50 mg / g. [000143] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 4 mg / g and 40 mg / g. [000144] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 5 mg / g and 30 mg / g. [000145] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 10 mg / g and 30 mg / g. [000146] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is between 10 mg / g and 40 mg / g. [000147] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 2 mg / g. [000148] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 4 mg / g. [000149] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 5 mg / g. [000150] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 6 mg / g. [000151] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 8 mg / g. [000152] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 10 mg / g. [000153] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 14 mg / g. [000154] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 20 mg / g. [000155] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 40 mg / g. [000156] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 60 mg / g. [000157] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 80 mg / g. [000158] In one embodiment, the content of collagen inducer particles in the injectable aqueous composition is 100 mg / g. [000159] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 200 mg / g. [000160] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 75 mg / g. [000161] In one embodiment, the PHA particle content in the injectable aqueous composition is between 5 mg / g and 50 mg / g. [000162] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 50 mg / g. [000163] In one embodiment, the PHA particle content in the injectable aqueous composition is between 4 mg / g and 40 mg / g. [000164] In one embodiment, the PHA particle content in the injectable aqueous composition is between 5 mg / g and 30 mg / g. [000165] In one embodiment, the PHA particle content in the injectable aqueous composition is between 10 mg / g and 30 mg / g. [000166] In one embodiment, the PHA particle content in the injectable aqueous composition is between 10 mg / g and 40 mg / g. [000167] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 700 mg / g. [000168] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 600 mg / g. [000169] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 500 mg / g. [000170] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 400 mg / g. [000171] In one embodiment, the PHA particle content in the injectable aqueous composition is between 2 mg / g and 300 mg / g. [000172] In one embodiment, the PHA particle content in the injectable aqueous composition is between 10 mg / g and 300 mg / g. [000173] In one embodiment, the PHA particle content in the injectable aqueous composition is between 50 mg / g and 300 mg / g. [000174] In one embodiment, the PHA particle content in the injectable aqueous composition is between 50 mg / g and 400 mg / g. [000175] In one embodiment, the PHA particle content in the injectable aqueous composition is between 50 mg / g and 500 mg / g. [000176] In one embodiment, the PHA particle content in the injectable aqueous composition is between 50 mg / g and 600 mg / g. [000177] In one embodiment, the PHA particle content in the injectable aqueous composition is 2 mg / g. [000178] In one embodiment, the PHA particle content in the injectable aqueous composition is 4 mg / g. [000179] In one embodiment, the PHA particle content in the injectable aqueous composition is 5 mg / g. [000180] In one embodiment, the PHA particle content in the injectable aqueous composition is 6 mg / g. [000181] In one embodiment, the PHA particle content in the injectable aqueous composition is 8 mg / g. [000182] In one embodiment, the PHA particle content in the injectable aqueous composition is 10 mg / g. [000183] In one embodiment, the PHA particle content in the injectable aqueous composition is 14 mg / g. [000184] In one embodiment, the PHA particle content in the injectable aqueous composition is 20 mg / g. [000185] In one embodiment, the PHA particle content in the injectable aqueous composition is 40 mg / g. [000186] In one embodiment, the PHA particle content in the injectable aqueous composition is 60 mg / g. [000187] In one embodiment, the PHA particle content in the injectable aqueous composition is 80 mg / g. [000188] In one embodiment, the PHA particle content in the injectable aqueous composition is 100 mg / g. [000189] In one embodiment, the PHA particle content in the injectable aqueous composition is 50 mg / g. [000190] In one embodiment, the PHA particle content in the injectable aqueous composition is 125 mg / g. [000191] In one embodiment, the PHA particle content in the injectable aqueous composition is 150 mg / g. [000192] In one embodiment, the PHA particle content in the injectable aqueous composition is 200 mg / g. [000193] In one embodiment, the PHA particle content in the injectable aqueous composition is 250 mg / g. [000194] In one embodiment, the PHA particle content in the injectable aqueous composition is 300 mg / g. [000195] In one embodiment, the PHA particle content in the injectable aqueous composition is 350 mg / g. [000196] In one embodiment, the PHA particle content in the injectable aqueous composition is 400 mg / g. [000197] In one embodiment, the PHA particle content in the injectable aqueous composition is 450 mg / g. [000198] In one embodiment, the collagen inducer particles have a size strictly less than 100 pm. [000199] In one embodiment, the collagen inducer particles have a size between 20 and 100 pm. [000200] In one embodiment, the collagen inducer particles have a size between 20 and 80 pm. [000201] In one embodiment, the collagen inducer particles have a size between 20 and 60 pm. [000202] Control of particle size distribution during the particle formation process is fundamental because collagen inducer particles are incorporated into a biomaterial which is an injectable composition. [000203] In one embodiment, the collagen inducer particles have a size strictly less than 100 pm. [000204] In one embodiment, the collagen inducer particles have a size strictly less than 80 pm. [000205] In one embodiment, the collagen inducer particles have a size strictly less than 60 pm. [000206] In one embodiment, the collagen inducer particles have a size between 5 and 100 pm. [000207] In one embodiment, the collagen inducer particles have a size between 5 and 80 pm. [000208] In one embodiment, the collagen inducer particles have a size between 5 and 60 pm. [000209] In one embodiment, the collagen inducer particles have a size between 20 and 100 pm. [000210] In one embodiment, the collagen inducer particles have a size between 40 and 100 pm. [000211] In one embodiment, the collagen inducer particles have a size between 20 and 90 pm. [000212] In one embodiment, the collagen inducer particles have a size between 40 and 90 pm. [000213] When the collagen inducer is chosen from PHAs or PLCLs, the particles are preferably prepared directly by a solvent evaporation technique, a double emulsion technique, or by microfluidization, using methods known from the literature. (Koosha, doctoral thesis, 1989, Univ. Nottingham, UK, Diss. Abstr. Int. B 51: 1206 (1990); Bruhn & Müeller, Proceed Intern. Symp. Control. Rel. Bioact. Mater. 18:668-69 (1991); Conti, et al, J Microencapsulation, 9: 153-66 (1992); Ogawa, et al., Chem. Pharm., 36: 1095-103 (1988); [000214] In one embodiment, the processes for preparing the collagen inducer particles are chosen from solvent evaporation techniques of a dispersed phase of an emulsion, said emulsion being obtained conventionally by mixing, by ultrasonic emulsification or by membrane emulsification, but also from conventional spray-drying techniques or possibly electrostatic spraying and / or microfluidization. [000215] In one embodiment, the particles are prepared by microfluidization using the droplet generation device described in patent application W02019 / 007965 in the name of ('UNIVERSITE LIBRE DE BRUXELLES', the contents of which are incorporated by reference. [000216] Otherwise, for other collagen inducers, the particles come directly from commercial suppliers such as those mentioned above. [000217] In one embodiment, the PHA particles are prepared by a membrane emulsification process. [000218] In one embodiment, PHA is solubilized in an organic solvent that is immiscible and / or soluble in water, such as dichloromethane, for example at a concentration of between 1 and 10% of collagen inducer in dichloromethane. [000219] Water is added to the emulsion generation system to form droplets which are then collected, rinsed to remove solvents and then dried to obtain collagen inducer particles. [000220] In one embodiment, a surfactant or film-forming agent such as polyvinyl alcohol is added to the aqueous phase. [000221] The dried and possibly calibrated particles by sieving are then incorporated according to various processes into the biocompatible polymer composition. [000222] Collagen inducer particles are suspended in water or in an aqueous saline solution, for example a phosphate buffer solution, for example PBS, and then this suspension is incorporated into a composition comprising a biocompatible polymer in solution or in the form of a gel or hydrogel in water or in an aqueous saline solution, for example a phosphate buffer solution, for example PBS, to obtain a composition according to the invention. [000223] To preserve this composition, it can be lyophilized and then rehydrated with water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS, before injection. [000224] The invention also relates to the composition comprising the biocompatible polymer and the PHA in lyophilized form. This composition must be rehydrated before use. [000225] In one embodiment, the collagen inducer particles are suspended in an organic liquid such as glycerol, preferably polyethylene glycol having an average molecular mass of less than 1000 g / mol -1 , or dimethyl sulfoxide [000226] In one embodiment, the collagen inducer particles are incorporated without having been suspended directly into an aqueous composition of biocompatible polymer in the form of a gel or hydrogel to obtain, by means of a mixing device, an injectable composition according to the invention. [000227] In one embodiment, the mixing device consists of two syringes connected at the time of incorporation, and the mixing is carried out by making several back-and-forth movements until a homogeneous suspension is obtained. [000228] In one embodiment, the mixing device is a conventional mixer and the incorporation of particles is carried out by mixing until a homogeneous composition is obtained. [000229] The incorporation can be carried out just before use by the practitioner. [000230] The incorporation can be carried out at the end of manufacturing and the resulting composition will then be subjected to a lyophilization process to be rehydrated before injection. [000231] In one embodiment, hyaluronic acid is in the form of sodium or potassium salt. [000232] In one embodiment, hyaluronic acid is in the form of sodium salt. [000233] In one embodiment, the crosslinking of hyaluronic acid is carried out by means of at least one crosslinking agent. [000234] In one embodiment, the crosslinking is carried out by means of at least one bi- or polyfunctional crosslinking agent. [000235] In one embodiment, the crosslinking is carried out using at least one bifunctional crosslinking agent being butanedioldiglycidyl ether (BDDE) or 1,2,7,8-diepoxyoctane or divinylsulfone. [000236] In one embodiment, the crosslinking is carried out using BDDE. [000237] In one embodiment, the crosslinking is carried out using sodium or potassium trimetaphosphate. [000238] When the polysaccharide, and more particularly hyaluronic acid, is crosslinked using a crosslinking agent, the degree of crosslinking (x) is calculated theoretically using the following formula: number of moles of crosslinking agent introduced into the reaction medium number of moles of repeating units introduced into the reaction medium [000239] With regard to hyaluronic acid, the repeating unit is a disaccharidic motif. [000240] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.001 and 0.4. [000241] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.001 and 0.3. [000242] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.001 and 0.2. [000243] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.001 and 0.5. [000244] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.01 and 0.4. [000245] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.01 and 0.5. [000246] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.01 and 0.3. [000247] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.1 and 0.35. [000248] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.1 and 0.2. [000249] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.1 and 0.25. [000250] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X between 0.1 and 0.3. [000251] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.06. [000252] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.07. [000253] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.08. [000254] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.09. [000255] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.1. [000256] In one embodiment, the cross-linked hyaluronic acids have cross-linking ratios X of 0.11. [000257] In one embodiment, the cross-linked hyaluronic acids have cross-linking ratios X of 0.12. [000258] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.13. [000259] In one embodiment, the cross-linked hyaluronic acids have cross-linking ratios X of 0.14. [000260] In one embodiment, the crosslinked hyaluronic acids have crosslinking ratios X of 0.15. [000261] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.001 and 0.4. [000262] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.001 and 0.3. [000263] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.001 and 0.2. [000264] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.001 and 0.5. [000265] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.01 and 0.4. [000266] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.01 and 0.5. [000267] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.01 and 0.3. [000268] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.1 and 0.35. [000269] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.1 and 0.2. [000270] In one embodiment, the cross-linked hyaluronic acid has a cross-linking ratio xl or x2 between 0.1 and 0.25 [000271] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.1 and 0.3. [000272] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.06. [000273] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.07. [000274] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.08. [000275] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.09. [000276] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.1. [000277] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.11. [000278] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.12. [000279] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.13. [000280] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.14. [000281] In one embodiment, the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 of 0.15. [000282] In one embodiment, the weight-average molecular mass Mw of hyaluronic acids before crosslinking is within a range of 0.01 MDa to 5 MDa (0.01 <Mw <5 MDa). [000283] In one embodiment, the weight-average molecular mass Mw of hyaluronic acids before crosslinking is within a range of 0.1 MDa to 3.5 MDa (0.1 <Mw <3,5 MDa). [000284] In one embodiment, the weight-average molecular mass Mw of hyaluronic acids before crosslinking is in the range of 1 MDa to 3 MDa (1 <Mw <3 MDa). [000285] In one embodiment, the average molecular mass by weight Mw of hyaluronic acids before crosslinking is 1 MDa. [000286] In one embodiment, the average molecular mass by weight Mw of hyaluronic acids before crosslinking is 3 MDa. [000287] In one embodiment, the composition according to the invention further comprises an active ingredient selected from the group consisting of local anesthetics, vitamin C derivatives, anti-inflammatories, antioxidants, antibiotics and mixtures thereof. [000288] In one embodiment, the composition according to the invention further comprises at least one local anesthetic. [000289] In one embodiment, the composition according to the invention further comprises a local anesthetic at a local anesthetic concentration of between 0.1 and 5%, relative to the total mass of said composition. [000290] In one embodiment, the composition according to the invention further comprises a local anesthetic at a local anesthetic concentration of between 0.1 and 4%, relative to the total mass of said composition. [000291] In one embodiment, the composition according to the invention further comprises a local anesthetic at a local anesthetic concentration of between 0.1 and 2%, relative to the total mass of said composition. [000292] In one embodiment, the composition according to the invention further comprises a local anesthetic to obtain a local anesthetic concentration of between 0.1 and 1%, relative to the total mass of said formulation. [000293] In one embodiment, the composition according to the invention further comprises a local anesthetic to obtain a local anesthetic concentration of between 0.1 and 0.5%, relative to the total mass of said composition. [000294] In one embodiment, the composition according to the invention further comprises local anesthetic at a local anesthetic concentration of approximately 0.3%, relative to the total mass of said composition. [000295] In one embodiment, the local anesthetic is chosen from the amino-ester group. [000296] In one embodiment, the amino ester is chosen from the group comprising procaine, benzocaine, chloroprocaine and tetracaine in base or salt form, for example in hydrochloride form. [000297] In one embodiment, the local anesthetic is chosen from the amino-amide group. [000298] In one embodiment, the amino-amide is selected from the group comprising lidocaine, mepivacaine, prilocaine, articaine, aptocaine, bupivacaine, etidocaine and ropivacaine in base or salt form, for example in hydrochloride form. [000299] In one embodiment, the local anesthetic is chosen from the amino-ether group. [000300] In one embodiment, the amino-ether is chosen from the group comprising diamocaine and pramocaine in base or salt form, for example in hydrochloride or cyclamate form. [000301] In one embodiment, the amino ether is selected from the group consisting of lidocaine, mepivacaine, and their salts and isolated isomers. [000302] In one embodiment, the amino ether is lidocaine. [000303] In one embodiment, the amino-ether is lidocaine or one of its pharmaceutically acceptable salts. [000304] In one embodiment, the amino ether is lidocaine hydrochloride. [000305] In one embodiment, the amino ether is mepivacaine. [000306] In one embodiment, the amino-ether is mepivacaine or one of its pharmaceutically acceptable salts. [000307] In one embodiment, the amino-ether is selected from the group consisting of racemic mepivacaine hydrochloride, racemic mepivacaine hydrochloride, (r)-mepivacaine hydrochloride, (s)-mepivacaine hydrochloride, (r)-mepivacaine and (s)-mepivacaine, or one of their pharmaceutically acceptable salts. [000308] In one embodiment, the amino-ether is mepivacaine hydrochloride. [000309] In one embodiment, the amino-ether is (r)-mepivacaine hydrochloride. [000310] In one embodiment, the amino-ether is (s)-mepivacaine hydrochloride. [000311] In one embodiment, the amino-ether is racemic mepivacaine hydrochloride. [000312] In one embodiment, the amino-ether is (r)-mepivacaine. [000313] In one embodiment, the amino-ether is (s)-mepivacaine. [000314] In one embodiment, the amino-ether is racemic mepivacaine. [000315] In one embodiment, the composition according to the invention further comprises at least one amino-ether local anesthetic selected from the group consisting of lidocaine, mepivacaine, and mixtures thereof. [000316] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine. [000317] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine, at a lidocaine concentration of between 0.1 and 5%, relative to the total mass of said composition. [000318] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine, at a lidocaine concentration of between 0.1 and 4%, relative to the total mass of said composition. [000319] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine, at a lidocaine concentration of between 0.1 and 2%, relative to the total mass of said composition. [000320] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine, at a lidocaine concentration of between 0.1 and 1%, relative to the total mass of said composition. [000321] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine, at a lidocaine concentration of between 0.1 and 0.5%, relative to the total mass of said composition. [000322] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely lidocaine, at a lidocaine concentration of approximately 0.3%, %, relative to the total mass of said composition. [000323] In one embodiment, the composition according to the invention further comprises at least one local anesthetic, namely mepivacaine. [000324] In one embodiment, the composition according to the invention further comprises a local anesthetic being mepivacaine at a concentration of mepivacaine between 0.1 and 5%, relative to the total mass of said composition. [000325] In one embodiment, the composition according to the invention further comprises a local anesthetic being mepivacaine at a concentration of mepivacaine between 0.1 and 4%, relative to the total mass of said composition. [000326] In one embodiment, the composition according to the invention further comprises a local anesthetic being mepivacaine at a concentration of mepivacaine between 0.1 and 2%, relative to the total mass of said composition. [000327] In one embodiment, the composition according to the invention further comprises a local anesthetic being mepivacaine at a concentration of mepivacaine between 0.1 and 1%, relative to the total mass of said composition. [000328] In one embodiment, the composition according to the invention further comprises a local anesthetic being mepivacaine at a concentration of mepivacaine between 0.1 and 0.5%, relative to the total mass of said composition. [000329] In one embodiment, the composition according to the invention further comprises a local anesthetic being mepivacaine at a mepivacaine concentration of about 0.3%, relative to the total mass of said composition. [000330] In one embodiment, the composition according to the invention further comprises at least one local anesthetic being diclonine in base or salt form, for example in hydrochloride form. [000331] In one embodiment, the composition according to the invention further comprises at least one local anesthetic selected from the group consisting of chlorobutanol, guafecainol and polidocanol. [000332] In one embodiment, the local anesthetic is chlorobutanol. [000333] In one embodiment, the local anesthetic is guafecainol. [000334] In one embodiment, the local anesthetic is polidocanol. [000335] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory. [000336] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory chosen from the group consisting of steroidal and non-steroidal anti-inflammatory drugs. [000337] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory chosen from the group consisting of non-steroidal anti-inflammatory drugs. [000338] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group comprising salicylate anti-inflammatories, propionic derivatives, indolic derivatives, pyrazole derivatives, oxicams and coxibs. [000339] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group comprising diclofenac, the nimesulfide, niflumic acid, mefenamic acid and nabumetone, alone or in mixture. [000340] In one embodiment, the composition according to the invention further comprises at least one salicylated anti-inflammatory selected from the group comprising diflunisal, benorilate and aspirin, alone or in mixture. [000341] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group of propionic derivatives including alminoprofen, ketoprofen, ibuprofen, naproxen, flurbiprofen and tiaprofenic acid, alone or in mixture. [000342] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group of indole derivatives including indomethacin, sulindac and etodolac, alone or in mixture. [000343] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group of pyrazole derivatives including in particular phenylbutazone. [000344] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group of oxicams comprising piroxicam, tenoxicam and meloxicam, alone or in mixture. [000345] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group of coxibs comprising celecoxib, etoricoxib and rofecoxib, alone or in mixture. [000346] In one embodiment, the concentration of non-steroidal anti-inflammatory drugs in the composition according to the invention is between 0.01 and 2000 mg / g. [000347] In one embodiment, the concentration of non-steroidal anti-inflammatory drugs in the composition according to the invention is between 0.1 and 1000 mg / g. [000348] In one embodiment, the concentration of non-steroidal anti-inflammatory drugs in the composition according to the invention is between 0.5 and 500 mg / g. [000349] In one embodiment, the composition according to the invention further comprises at least one steroidal anti-inflammatory. [000350] In one embodiment, the composition according to the invention further comprises at least one steroidal anti-inflammatory selected from the group comprising dexamethasone, prednisolone, corticosterone, budesonide, sulfasalazine, mesalamine, cetirizine, diphenhydramine, antipyrine, methyl salicylate, loratadine, thymol, carvacrol, bisabolol, allantoin, eucalyptol, phenazone (antipyrine), propyphenazone, alone or in mixture. [000351] In one embodiment, the concentration of steroidal anti-inflammatory drugs in the composition according to the invention is between 0.01 and 2000 mg / g. Tl [000352] In one embodiment, the concentration of steroidal anti-inflammatory drugs in the composition according to the invention is between 0.1 and 1000 mg / g. [000353] In one embodiment, the concentration of steroidal anti-inflammatory drugs in the composition according to the invention is between 0.5 and 500 mg / g. [000354] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group consisting of sucrose octasulfate and its salts. [000355] In one embodiment, the composition according to the invention further comprises at least one anti-inflammatory selected from the group consisting of sucrose octasulfate and its sodium and potassium salts. [000356] In one embodiment, the composition according to the invention further comprises at least one water-soluble anti-inflammatory salt of sucrose octasulfate selected from the group consisting of alkali metal salts, alkaline earth metal salts, silver salts, ammonium salts, amino acid salts. [000357] In one embodiment, the composition according to the invention further comprises at least one water-soluble anti-inflammatory salt of sucrose octasulfate selected from the group consisting of alkali metal salts or alkaline earth metal salts. [000358] In one embodiment, the composition according to the invention further comprises at least one water-soluble anti-inflammatory salt of sucrose octasulfate selected from the group consisting of sodium salt of sucrose octasulfate or potassium salt of sucrose octasulfate. [000359] In one embodiment, the composition according to the invention further comprises at least one antimicrobial. [000360] In one embodiment, the composition according to the invention further comprises at least one antimicrobial selected from the group comprising gentamicin, silver sulfadiazine, metronidazole, fucidin, bacitracin, eosin, povidone-iodine, copper gluconate, zinc gluconate, manganese gluconate or their salts, alone or in mixture. [000361] In one embodiment, the concentration of antimicrobials in the composition according to the invention is between 0.1 and 200 mg / g. [000362] In one embodiment, the concentration of antimicrobials in the composition according to the invention is between 0.5 and 100 mg / g. [000363] In one embodiment, the composition according to the invention further comprises at least one glycoside or a glycoside derivative. [000364] In one embodiment, the composition according to the invention further comprises at least one glycoside or glycoside derivative selected from the group comprising D-glucopyranose, 1,4 glycoside, esculin, hesperidin, diosmin, arbutin, skimmine or aloin, alone or in mixtures. [000365] In one embodiment, the concentration of glycosides in the composition according to the invention is between 0.1 and 200 mg / g. [000366] In one embodiment, the concentration of glycosides in the composition according to the invention is between 0.5 and 100 mg / g. [000367] In one embodiment, the composition according to the invention further comprises at least one antibiotic selected, for example, from the group of rifampicin, minocycline, gentamicin, fusidic acid, amoxicillin, azithromycin, benzathine, benzylpenicillin, cefaclor, cefadroxil, cephalexin, cefixime, cefotiam, cefpodoxime, ceftriaxone, cefuroxime, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, cotrimoxazole, doxycycline, erythromycin, fosfomycin, josamycin, levofloxacin, metronidazole, minocycline, moxifloxacin, the mupirocin, nitrofurantoin, norfloxacin, ofloxacin, ornidazole, phenoxymethylpenicillin (penicillin V), penicillin, pivmecillinam, pristinamycin, roxithromycin, spiramycin, sulfadiazine, tetracycline and trimethoprim, alone or in mixture. [000368] In one embodiment, the composition according to the invention further comprises at least one mixture of antibiotic, for example the combination of rifampicin and minocycline. [000369] In one embodiment, the composition according to the invention further comprises at least one mixture of antibiotic, for example the combination of gentamicin and minocycline. [000370] In one embodiment, the composition according to the invention further comprises at least antioxidant. [000371] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of polyols. [000372] In one embodiment, the composition according to the invention further comprises at least one polyol selected from the group consisting of mannitol, sorbitol, propylene glycol, xylitol, glycerol, maltitol, lactitol and erythritol. [000373] In one embodiment, the composition according to the invention further comprises at least one polyol selected from the group consisting of mannitol, sorbitol, maltitol and glycerol, alone or in mixture. [000374] In one embodiment, the composition according to the invention further comprises at least one polyol selected from the group consisting of mannitol, sorbitol and maltitol, alone or in mixture. [000375] In one embodiment, the composition according to the invention further comprises at least one polyol at a polyol concentration of between 0.1 mg / ml and 50 mg / ml, relative to the total mass of said composition. [000376] In one embodiment, the composition according to the invention further comprises at least one polyol at a polyol concentration of between 5 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000377] In one embodiment, the composition according to the invention further comprises at least one polyol at a polyol concentration of between 10 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000378] In one embodiment, the composition according to the invention further comprises at least one polyol at a polyol concentration of between 20 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000379] In one embodiment, the composition according to the invention further comprises at least one polyol at a polyol concentration of between 30 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000380] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being mannitol. [000381] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being mannitol at a concentration between 5 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000382] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being mannitol at a concentration between 10 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000383] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being mannitol at a concentration between 20 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000384] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being mannitol at a concentration of between 30 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000385] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being sorbitol. [000386] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being sorbitol at a concentration between 5 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000387] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being sorbitol at a concentration of between 10 mg / ml and 40 mg / ml, relative to the total mass of said composition [000388] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being sorbitol at a concentration of between 20 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000389] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being sorbitol at a concentration of between 30 mg / ml and 40 mg / ml, relative to the total mass of said composition. [000390] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being maltitol. [000391] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being glycerol. [000392] In one embodiment, the composition according to the invention further comprises at least one polyol, said polyol being a mixture of mannitol and sorbitol. [000393] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of vitamin C derivatives. [000394] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of vitamin C derivatives including magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl-2-glucoside, and mixtures thereof. [000395] In one embodiment, said at least one vitamin C derivative is magnesium ascorbyl phosphate. [000396] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of vitamin E derivatives and tocopherols. [000397] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of carotenoids and retinoids and their derivatives. [000398] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of carotenoids and retinoids and their derivatives including retinol, retinoic acid, retinal, retinol esters and carotene. [000399] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of pseudo-tripeptides. [000400] In one embodiment, the pseudo-tripeptide is glutathione. [000401] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group comprising the various forms of coenzyme Q10, ubiquinone or ubiquinol. [000402] In one embodiment, the composition according to the invention further comprises at least one vitamin. [000403] In one embodiment, the composition according to the invention further comprises at least one vitamin selected from the group comprising retinol, thiamine, riboflavin, nicotinamide, dexpenthenol, piridoxine, ascorbic acid, ergocalciferol, tocopherol, biotin and folic acid alone or in mixture. [000404] In one embodiment, the concentration of vitamins in the composition according to the invention is between 0.01 and 200 mg / g. [000405] In one embodiment, the composition according to the invention further comprises at least one vasoconstrictor. [000406] In one embodiment, the composition according to the invention further comprises at least one vasoconstrictor selected from the group comprising naphazoline, epinephrine, methoxamine, methylnorepinephrine, norepinephrine, oxymethazoline, phenylephrine, pseudoephedrine, synephrine, cirazolin and xylomethazoline. [000407] In one embodiment, the concentration of vasoconstrictors in the composition according to the invention is between 0.01 and 3 mg / g. [000408] In one embodiment, the composition according to the invention further comprises at least one vasodilator. [000409] In one embodiment, the composition according to the invention further comprises at least one vasodilator selected from the group comprising adenosine, nicotinic acid, minoxidil and diazoxide, alone or in mixture. [000410] In one embodiment, the concentration of vasodilators in the composition according to the invention is between 0.01 and 10 mg / g. [000411] In one embodiment, the composition according to the invention further comprises at least one anti-hemorrhagic or hemostatic agent. [000412] In one embodiment, the composition according to the invention further comprises at least one antihemorrhagic or hemostatic agent selected from the group comprising aminocaproic acid or tranexamic acid, alone or in mixture. [000413] In one embodiment, the concentration of antihemorrhagic or hemostatic agents in the composition according to the invention is between 0.01 and 5 mg / g. [000414] In one embodiment, the composition according to the invention further comprises at least one antioxidant and at least one local anesthetic. [000415] In one embodiment, the composition according to the invention further comprises at least one antioxidant selected from the group of polyols and at least one local anesthetic selected from the group of amino-amides. [000416] In one embodiment, the composition according to the invention is characterized in that it is injectable. [000417] In one embodiment, the composition according to the invention is characterized in that it is sterile. [000418] In one embodiment, the composition according to the invention is characterized in that it is injectable and sterile. [000419] The composition according to the invention has numerous applications. [000420] Medical applications include, for example, injections to replace deficient biological fluids, such as synovial fluid in joints, injections following surgery to prevent post-surgical adhesions, periurethral injections to treat incontinence, and injections following presbyopia surgery. Aesthetic applications include, for example, injections to fill wrinkles, fine lines, and skin imperfections, or to augment volume, such as that of the lips, cheekbones, etc. [000421] The applications targeted are more particularly those commonly used in the context of injectable viscoelastics and polysaccharides or collagen used or potentially usable in the following pathologies or treatments: aesthetic injections on the face: for filling wrinkles, skin defects or for volumizing (cheekbones, chin, lips); volumizing injections on the body: breast and buttock augmentation, G-spot augmentation, vaginoplasty, vaginal labia reconstruction, penis enlargement; in joint surgery and in dental surgery for filling periodontal pockets, for example; treatment of osteoarthritis, injection into the joint as a replacement or supplement for deficient synovial fluid; periurethral injection for the treatment of urinary incontinence due to sphincter insufficiency;Post-surgical injection to prevent peritoneal adhesions; injection following presbyopia surgery via scleral laser incisions; injection into the vitreous cavity; injection during cataract surgery; injection for the treatment of vaginal dryness; injection into tissue spaces; injection into the genital area. [000422] More particularly, in cosmetic surgery, depending on its viscoelastic and residual properties, the composition of the invention can be used: for filling fine, medium or deep wrinkles, and injected with fine diameter needles (27 Gauge for example); as a volumizer with injection using larger diameter needles, for example 22 to 26 gauge, and longer needles (for example 30 to 40 mm); in this case, its cohesive nature will ensure that it remains in place at the injection site. [000423] These examples of use are in no way limiting, and the composition of the invention can be used to: fill volumes; create spaces within certain tissues, thus promoting their optimal function; replace deficient physiological fluids. Examples Particle preparation Example A: Preparation of P4HB particles [000424] A solution of P4HB in dichloromethane with 5% P4HB is prepared and introduced into the device described in patent application W02019 / 007965 in the name of ('UNIVERSITE LIBRE DE BRUXELLES. [000425] Water comprising 1% polyvinyl alcohol is introduced as a continuous phase into the above-mentioned device. [000426] The flow rate is set at 50 pL / min and particles are obtained which are then washed with water to extract the solvent until it is eliminated and then dried under an airflow. [000427] There is no coalescence and the beads are sufficiently solid to be handled after 30 minutes. [000428] Drying is continued until completion and the particle size is measured, the diameter is 58 pm. Example 1: Preparation of Phosphate / NaCl buffer solution [000429] The buffer solution is prepared by introducing 0.225 g of NahbPC ^hbO, 1.115 g of Na2HPC>4, and 42.5 g of NaCl into a 5 L volumetric flask which is filled to the mark with water for injection (WFI). Example 7: Preparation of injectable compositions [000430] The following non-limiting examples present distinct embodiments for preparing injectable compositions comprising different polysaccharides mixed with P4HB microbeads. [000431] One embodiment consists of carrying out rehydration just before the injection of lyophilized mixtures, using water for injection (WFI). [000432] A second embodiment consists of carrying out a mixture just before the injection of an effective quantity of P4HB microbeads obtained in example A with an injectable composition comprising at least one polysaccharide. [000433] A third embodiment consists of carrying out a mixture just before the injection of a suspension in the injectable water comprising P4HB microbeads obtained in example A with an injectable composition comprising at least one polysaccharide. Example 7d [000434] Composition 7d comprising the product STYLAGE XXL, marketed by the company VIVACY, prepared according to the process described in the patent application W02009 / 071697, carboxymethylcellulose (CMC) and P4HB microbeads, 58 pm in diameter, obtained in Example A is prepared by mixing a lyophilized composition obtained from a composition containing carboxymethylcellulose (CMC) is prepared by solubilizing 454 mg of CMC (AQUALON product type 7MF PH BET or 7LF PH BET degree of substitution 0.7 with a viscosity at 2% between 20 and 700 mPa.sec) in 20 mL of buffer solution prepared according to the protocol of Example 1 of STYLAGE XXL in a mass ratio 1:1. [000435] This composition is introduced into a 1 mL syringe. Example 7th [000436] Compositions 7e comprising cross-linked hyaluronic acid and P4HB were made by mixing commercial products from the STYLAGE range, marketed by the company VIVACY, and P4HB in the form of solid microbeads having a diameter of 58 pm obtained in example A. [000437] Each of the compositions 7e.1 to 7e.4 was prepared by mixing 1 mL of STYLAGE XXL product prepared according to the process described in patent application W02009 / 071697, contained in a syringe, and a defined mass of P4HB microbeads having a diameter of 58 pm obtained in Example A, contained in a second syringe, to obtain compositions having varying concentrations of [P4HB]. [000438] The two components are mixed by connecting the two syringes end to end and making several back-and-forth movements until a homogeneous suspension is obtained. [000439] Each of the compositions 7e.5 to 7e.7 was prepared by mixing 0.8 mL of STYLAGE S product prepared according to the process described in patent application W02009 / 071697, contained in a syringe, and a defined mass of P4HB microbeads having a diameter of 58 pm obtained in Example A, contained in a second syringe, to obtain compositions having varying concentrations of [P4HB]. [000440] The two components are mixed by connecting the two syringes end to end and making several back-and-forth movements until a homogeneous suspension is obtained. [000441] The compositions and the various technical characteristics of compositions 7e.1 to 7e.7 are summarized in Table 1 below. [000442] Table 1 Example 7f [000443] A third embodiment consists of mixing, just before injection, a solution comprising P4HB microbeads obtained in example A with an injectable composition comprising at least one polysaccharide. [000444] Compositions 7f comprising crosslinked hyaluronic acid and P4HB in the presence of a biocompatible solvent were made by mixing commercial products from the STYLAGE range, marketed by the company VIVACY, and an organic solvent containing P4HB microbeads having a diameter of 58 pm obtained in example A. [000445] In a first step, a defined mass of P4HB microbeads is weighed and introduced into a defined volume of organic solvent and the resulting suspension is introduced into a syringe 1. [000446] Each of the compositions 7f.l and 7f.2 were made by mixing 0.8 mL of STYLAGE S product prepared according to the process described in patent application W02009 / 071697, contained in a syringe 2, and the suspension obtained previously, contained in syringe 1, by connecting the two syringes end to end and making several back-and-forth movements until a homogeneous suspension was obtained. [000447] The compositions and the various technical characteristics of compositions 7f.l and 7f.2 are summarized in Table 2 below. Table 2 Example 8: Injectability Tests Example 8d [000448] Composition 7d, comprising STYLAGE XXL Lido prepared according to the process described in patent application W02009 / 071697, marketed by VIVACY, carboxymethylcellulose (CMC), and P4HB microbeads with a diameter of 58 µm, divided and introduced into two 1 mL syringes, was tested to evaluate its injectability. The results of these tests are presented in Table 3 below. Table 3 [000449] The tests carried out show that composition 7d is injectable through a needle having a diameter of 27 G. Example 8 [000450] The injectability of compositions 7e.1 to 7e.3, comprising the STYLAGE XXL product prepared according to the process described in patent application W02009 / 071697, marketed by the company VIVACY, and varying concentrations of P4HB microbeads, having a diameter of 58 pm, was evaluated and the results of these tests are presented in Table 4 below. Table 4 [000451] Tests have shown that compositions 7e.1 to 7e.3, comprising cross-linked hyaluronic acid and varying concentrations of P4HB microbeads, are injectable through needles with a diameter of 27 G, even when the microbead concentration increases significantly up to 99.7 mg / g -1 . Example 8f [000452] The injectability of compositions 7f.l and 7f.2, comprising the STYLAGE S product prepared according to the process described in patent application W02009 / 071697, marketed by the company VIVACY, of P4HB microbeads, having a diameter of 58 pm, and a biocompatible solvent was evaluated and the results of these tests are presented in Table 5, below. Table 5 [000453] The tests carried out show that the compositions 7f.1 and 7f.2, comprising cross-linked hyaluronic acid and P4HB microbeads, at a concentration of approximately 100 mg.g -1 and an organic solvent are injectable through needles having a diameter of 27 G. Example 9 Example 9a: Preparation of a G1 cross-linked hyaluronic acid gel from 3 MDa sodium hyaluronate. Step a: Hydration of sodium hyaluronate. [000454] 114 g of sodium hyaluronate with an average molar mass by weight of approximately 3 MDa (injectable grade) and containing 12% residual moisture are dissolved at room temperature in an aqueous solution of 0.25 N sodium hydroxide under mechanical stirring. Step b: Crosslinking. [000455] 7.4 g of BDDE (99% purity) are diluted in a 0.25 N sodium hydroxide solution, then added to the sodium hyaluronate obtained in the previous step. The The mixture is then homogenized in a paddle mixer. The reaction mixture, consisting of 100 g of dry sodium hyaluronate, 7.3 g of BDDE, and 782 g of 0.25 N sodium hydroxide, is placed in a water bath at 50 °C for 3 hours. The degree of crosslinking (XI) is approximately 0.13. Step c: Neutralization, purification. [000456] After crosslinking, the reaction medium is neutralized with a solution containing 1 N HCl and phosphate buffer supplemented with mannitol overnight at +4 °C under orbital stirring, then homogenized at room temperature by mechanical stirring. [000457] The mannitol-supplemented phosphate buffer mentioned above was prepared by mixing the following compounds under mechanical stirring: The cross-linked hyaluronic acid gel obtained after mechanical agitation is loaded into a tubular dialysis membrane with a cutoff threshold of 12–14 kDa and dialyzed at +4 °C against mannitol-supplemented phosphate buffer as prepared above. The final sodium hyaluronate concentration is 27.5 mg / g, and the resulting gel exhibits physiological pH and osmolarity. Example 9b: Preparation of a G2 cross-linked hyaluronic acid gel from 1 MDa sodium hyaluronate. [000458] A cross-linked hyaluronic acid gel was prepared according to a protocol similar to that previously described for the Gl gel, but from sodium hyaluronate of lower average weight molar mass. [000459] In the crosslinking step, the reaction mixture composed of 100 g of dry sodium hyaluronate (of injectable grade and average molar mass by weight of approximately 1 MDa), 4.5 g of BDDE (99% purity), and 585 g of 0.25 N sodium hydroxide is placed in a water bath at 50 °C for 3 hours. The X2 crosslinking ratio is approximately 0.08. [000460] At the end of the neutralization / purification step, the final concentration of sodium hyaluronate is 27.5 mg / g and the resulting gel has a physiological pH and osmolarity. Example 9c: Preparation of a non-crosslinked hyaluronic acid gel SI [000461] 10.3 g of sodium hyaluronate with a weight-average molar mass of approximately 3 MDa and containing 12% residual moisture are weighed into a container and incubated in 290 g of phosphate buffer supplemented with mannitol, the composition of which is described above, at +4 °C overnight. The resulting gel is then homogenized at room temperature by alternating mechanical agitation and rest. This preparation has a total sodium hyaluronate concentration of 30 mg / g with a measured pH of 7.3 and an osmolarity of 298 mOsm / kg. Example 9d: Preparation of a Fl composition comprising a mixture of crosslinked and non-crosslinked gels Step a: Preparation of G3: Mixture of G1, G2 and SI [000462] Suitable equipment comprising a mixing bowl and an upper part consisting of a stirring paddle mounted on a motor is used. 200.0 g of G1 gel, 200.0 g of G2 gel, 54.0 g of SI solution, and 7.0 g of a 0.6% (w / w) sodium hydroxide solution are introduced into the mixing bowl. The mixture is stirred for 20 minutes at room temperature. Step b: Preparation of a local anesthetic solution [000463] A solution comprising a local anesthetic is prepared by solubilizing 5.3 g of lidocaine hydrochloride monohydrate (residual moisture of 9.6%) in 94.7 g of phosphate buffer supplemented with mannitol and 25 g of a 0.2% (w / w) sodium hydroxide solution. Step c: Fl Preparation [000464] 511.8 g of mannitol-supplemented phosphate buffer and 78.9 g of the lidocaine solution prepared in the previous step are added to 461 g of the previously obtained G3 gel. The mixture is homogenized by alternating agitation and resting periods for a total duration of approximately 155 minutes at room temperature. The mixture has a total HA concentration (crosslinked and non-crosslinked) of 12 mg / g, of which 12% is non-crosslinked hyaluronic acid, and an anesthetic concentration of 3 mg / g and a measured pH of 7.3. The mixture is extruded by passing it through a 100 µm stainless steel square-mesh sieve (Guérin, France). The sieved composition is degassed by centrifugation at a Relative Centrifugal Acceleration (RCA) of 846 (2500 rpm) for 10 minutes on a Rotina 380 centrifuge (Andreas Hettich GmbH & co., Germany) equipped with a 6-place angular rotor with a rotation radius of 121 mm, then packaged in 1 mL BD Hypak™ SCF glass syringes. Example 9e: Preparation of PI microspheres of poly-4-hydroxybutyrate (P4HB) [000465] Poly-4-hydroxybutyrate (P4HB) microspheres were prepared by a membrane emulsification process. [000466] 11.25 g of P4HB obtained by bacterial fermentation of molar mass by weight (M w ) of approximately 180 kDa were dissolved in 225 mL of dichloromethane to obtain a 5% (w / v) solution. In parallel, 4.275 L of a 2% (w / w) solution of polyvinyl alcohol (PVA 23-88) in deionized water was prepared. [000467] The emulsion was produced at a flow rate of 475 mL / min for the aqueous phase and 25 mL / min for the organic phase using a 5 x 100 µm membrane and a 9.5 mm insert. The sample was produced and collected on an AXF-1 instrument using a digital collection pump system, ensuring a 5% (w / v) concentration of the organic phase during emulsification through a closed-loop delivery system. [000468] During preparation, the emulsion was gradually collected in a beaker containing 1 L of 2% (w / w) PVA solution and kept under constant stirring at 200 rpm until the membrane extrusion process was complete. 4.5 L of emulsion were recovered before the addition of 4.5 L of deionized water for dilution. After the dilution step, the mixing speed was increased to 600 rpm and the height of the stirring paddle was adjusted to one-third of the height of the volume occupied by the mixture. Stirring was maintained for 96 hours before being stopped, sedimentation was performed, approximately 2 L of clear supernatant was removed, the mixture was filtered through an 8 µm membrane to remove particles smaller than the desired size range, and several rinses were performed with deionized water. The recovered particles were then lyophilized for approximately 24 hours.The lyophilized particles were then sieved through a 200 mm diameter Retsch® woven wire mesh sieve with a 75 µm mesh opening. The sieved microspheres were deposited onto a glass slide and dispersed in three drops of water before being observed under a light microscope. The appearance, size, and size distribution of the microspheres were determined using a ZEISS Axio Scope Al optical microscope with an Epiplan-Neofluar 20x / 0.50 DIC M27 EC objective. Size was determined from a sample of 50 microspheres by taking two diameter measurements per microsphere. [000469] The results are presented in Table 6 below. Table 6: Size and size distribution of PI microspheres. Example 9f: Composition comprising a mixture of crosslinked and non-crosslinked HA gels Fl (and PI microspheres of poly-4-hydroxybutyrate (P4HB) [000470] Compositions comprising a mixture of crosslinked and non-crosslinked HA gels and different contents of P4HB microspheres are prepared from composition Fl and lot PI of P4HB microspheres. [000471] Each composition 1.6.1 to 1.6.3 is made by mixing a defined mass of P4HB microspheres Pl, contained in a 2.5 mL syringe (Terumo®), with a defined mass of composition Fl, a mixture of crosslinked and non-crosslinked HA gels, contained in a second 2.5 mL syringe (Terumo®) to obtain a total composition mass of 2 g. [000472] The two components are mixed by connecting the two syringes end-to-end using a double Luer Lock fitting and performing 100 back-and-forth movements to obtain a homogeneous suspension. The final mixture is packaged in a 1 mL BD Hypak™ SCF glass syringe. Compositions 1.6.1 to 1.6.3 and their various technical characteristics are summarized in Table 7 below. Table 7: Composition of compositions 1.6.1 to 1.6.3. Example 9g: Composition comprising a mixture of crosslinked and non-crosslinked Fl HA gels and low and high density calcium hydroxyapatite P2 and P3 microspheres [000473] Two types of calcium hydroxyapatite microspheres were used to produce mixtures with the composition Fl: [000474] Low density P2 calcium hydroxyapatite microspheres with a size between 25 and 45 pm were obtained from EPRUI Biotech Co., Ltd. (China) and were used as is without further purification. [000475] High density P3 calcium hydroxyapatite microspheres with a size between 25 and 45 pm were obtained from SANGI Co., Ltd. (Japan) and were used as is without further purification. Table 8: Size of microspheres P2 and P3. [000476] A composition 1.7.1 comprising a mixture of crosslinked and non-crosslinked HA gels and a content of low density calcium hydroxyapatite microspheres of 30% (w / w) is prepared from composition Fl and lot P2 of low density calcium hydroxyapatite microspheres (CaHA Low Density). [000477] A composition 1.7.2 comprising a mixture of crosslinked and non-crosslinked HA gels and a high density calcium hydroxyapatite microsphere content of 30% (w / w) is prepared from composition Fl and lot P3 of high density calcium hydroxyapatite microspheres (CaHA High Density). [000478] The two components are mixed by connecting the two syringes end-to-end using a double Luer Lock fitting and performing 100 back-and-forth movements to obtain a homogeneous suspension. The final mixture is packaged in a 1 mL BD Hypak™ SCF glass syringe. Compositions 1.7.1 and 1.7.2 and their various technical characteristics are summarized in Table 9 below. Table 9: Composition of compositions 1.7.1 and 1.7.2. Example 9h: Composition comprising a mixture of crosslinked and non-crosslinked HA gels Fl and P4 microspheres of poly(lactic-co-caprolactone) acid (PLCL) [000479] Granules of a poly(lactic-co-caprolactone) acid copolymer (50:50) with an average molar mass by weight (M w ) of 290 kDa were obtained from from BMG Incorporated (Japan). Microspheres were produced from this copolymer using a conventional microfluidic process to obtain microspheres with a target average diameter of 40 pm. Table 10: Size of P4 microspheres. [000480] Compositions comprising a mixture of crosslinked and non-crosslinked HA gels and different contents of PLCL microspheres are prepared from composition Fl and lot P4 of PLCL microspheres. [000481] Each composition 1.8.1 and 1.8.2 is made by mixing a defined mass of PLCL P4 microspheres, contained in a 2.5 mL syringe (Terumo®), with a defined mass of composition Fl, a mixture of crosslinked and non-crosslinked HA gels, contained in a second 2.5 mL syringe (Terumo®), to obtain a total composition mass of 2 g. [000482] The two components are mixed by connecting the two syringes end-to-end using a double Luer Lock fitting and performing 100 back-and-forth movements to obtain a homogeneous suspension. The final mixture is packaged in a 1 mL BD Hypak™ SCF glass syringe. Compositions 1.8.1 and 1.8.2 and their various technical characteristics are summarized in Table 11 below. Table 11: Composition of compositions 1.8.1 and 1.8.2 Example 9i: Determination of the rheological properties of compositions [000483] The rheological properties of the compositions were measured at a temperature of 25 °C on a Kinexus Prime Pro+ rheometer (Netzsch Group, Germany) with a smooth planar geometry of 20 mm diameter and a gap of 1 mm, by performing a 10 strain sweep -3 % to 10 3 % at an oscillation frequency of 1 Hz. [000484] The rheological properties of the compositions are defined from the following parameters: Elastic modulus (G') in the Linear Viscoelastic Region (LVER) in Pa; Viscous modulus (G") in the LVER in Pa; - Damping factor (tan θ) in the LVER; LVER limit strain (yp) in % being defined as the strain for a 10% loss of the elastic modulus compared to the value measured in the LVER; Stress at the limit of the LVER (TP) in Pa; - Elastic modulus at the crossing point (G'c) in Pa; Threshold strain (yc) in %; Threshold constraint (TC) in Pa; Plastic domain in deformation (yc - yp) in %; Plastic domain in Stress (TC - TP) in Pa. [000485] The rheological properties of the compositions described above are summarized in Table 12 below. Table 12: Viscoelastic properties measured on the compositions. [000486] Compositions comprising a mixture of cross-linked hyaluronic acid gels and a tissue inducer in the form of microspheres exhibit an increased elastic modulus G' compared to the equivalent mixture of cross-linked hyaluronic acid gels, in the absence of microspheres (Fl). [000487] It should be noted that the values ​​of Tan(δ) vary little with increasing G'. This means that the overall viscoelasticity of the product (ratio between the viscous component and the elastic component) is only slightly affected by the addition of microspheres, even for very high values ​​of G'. In particular, for compositions 1.6.1 (P4HB 20%) and 1.7.2 (CaHA 30%), the elastic modulus is doubled for an equivalent tan(δ). [000488] Also, compositions comprising a mixture of cross-linked hyaluronic acid gels and a tissue inducer in the form of microspheres exhibit a larger plastic domain under stress compared to the equivalent hyaluronic acid gel without microspheres. Example 9j: Determining the injectability of compositions [000489] The tests are carried out using compositions contained in 1 mL BD Hypak™ SCF glass syringes fitted with 27 G x TSK needles 1 / 2" (13 mm) ETW. The injectability of each composition is determined on a Mecmesin Multitest li force test bench by measuring the average force required to maintain a syringe piston speed of 13 mm / min. The average extrusion force in Newtons is measured for a piston stroke between 5 mm and 20 mm. The injection forces correspond to the average values ​​of duplicate measurements. Table 13: Injectability properties measured on the compositions. [000490] Apart from composition 1.7.1, all the compositions are very easily injectable using a 27G needle, with injection forces lower than ION, which is remarkable considering the associated G' values. Example 10 Example 10a: Preparation of an F2 composition comprising a mixture of crosslinked and non-crosslinked HA gels [000491] Suitable equipment comprising a mixing bowl and an upper part consisting of a motor-driven stirring paddle is used. A quantity of G1, G2 gel and SI solution are introduced into the mixing bowl with phosphate buffer supplemented with mannitol to obtain a composition with a total HA concentration of 20.5 mg / mL, a G1 / G2 ratio of 1.4, and an uncrosslinked HA concentration of 1.44 mg / g. The mixture is homogenized by repeated stirring / resting cycles until a homogeneous composition is obtained. The mixture is then extruded under vacuum through a 200 µm stainless steel square-mesh sieve (Guérin, France), degassed, and then packaged into 1 mL Schott TOPPAC® rigid plastic syringes. The packaged gel is sterilized by autoclaving at 127°C with an F0 of 48. Example 10b: Preparation of P5 microspheres of poly-4-hydroxybutyrate (P4HB) [000492] Poly-4-hydroxybutyrate (P4HB) P5 microspheres are prepared by a membrane emulsion process similar to that used to produce PI microspheres. The process parameters are listed in Table 14 below. Table 14: Process parameters. Table 15: Size of P5 microspheres. Example 10c: Composition comprising a mixture of crosslinked and non-crosslinked HA gels F2 and poly-4-hydroxybutyrate (P4HB) microspheres P5 [000493] The P5 microspheres were used to prepare 3 g of the mixture with composition F2 to produce preparations with microsphere concentrations of 5% (w / w) for preparation 2.3.1, 10% (w / w) for preparation 2.3.2, 15% (w / w) for preparation 2.3.3, and 30% (w / w) for preparation 2.3.4. To do this, a mass of P5 microspheres was weighed directly into a 15 mL Falcon conical centrifuge tube. A mass of preparation F2 was then weighed and added to the microspheres to obtain a total composition mass of 3 g. The mixture was manually blended with a spatula using cycles of stirring / resting for a total of 10 minutes until a homogeneous composition was obtained. Table 16: Composition of compositions 2.3.1 to 2.3.4. [000494] After preparation, the compositions are directly centrifuged to evaluate their resistance to sedimentation. For this purpose, the compositions are centrifuged at a Relative Centrifugal Acceleration (RCA) of 846 (2500 rpm), 3382 (5000 rpm), and 7610 (7500 rpm) for 10 minutes each on a Rotina 380 centrifuge (Andreas Hettich GmbH & Co., Germany) equipped with a 6-position angular rotor with a rotation radius of 121 mm. Between each centrifugation, the compositions are manually mixed with a spatula using agitation / rest cycles at room temperature for a total of 10 minutes until a homogeneous composition is obtained. After the accelerated sedimentation study, the compositions are remixed before being packaged in 1 mL BD Hypak™ SCF glass syringes. Table 17: Resistance to sedimentation of the different compositions. [000495] Tests conducted under static storage conditions demonstrated that P4HB microspheres dispersed in a cross-linked hyaluronic acid composition do not sediment after at least 2 weeks of storage at 4 °C. No sedimentation is observed under harsh centrifugation conditions, which suggests good stability of the compositions under real storage conditions. Example lOd: Composition comprising a mixture of crosslinked and non-crosslinked HA gels F2 and P6 microspheres of L-poly-L-lactic acid (PLLA) [000496] P6 PLLA microspheres with a size between 20 and 40 pm were obtained from Shenzhen Esun Industrial Co., Ltd. (China) and were used as is without further purification. The starting L-polylactic acid has a weight-average molar mass (M w ) of approximately 100 kDa. [000497] Compositions comprising a mixture of crosslinked and non-crosslinked HA gels and different contents of PLLA microspheres are prepared from composition F2 and lot P6 of PLLA microspheres. [000498] Each composition 2.4.1 to 2.4.4 is made by mixing a defined mass of PLLA P6 microspheres, contained in a 15 mL Falcon® tube, with a defined mass of composition F2, a mixture of crosslinked and non-crosslinked HA gels added to the microspheres in the Falcon® tube, to obtain a final composition mass of 4 g. [000499] The mixture was manually blended with a spatula using agitation / rest cycles for a total duration of 10 minutes until a homogeneous composition was obtained. Compositions 2.4.1 to 2.4.4 and their various technical characteristics are summarized in Table 18 below. Table 18: Composition of compositions 2.4.1 to 2.4.4 [000500] After preparation, the compositions are directly centrifuged to evaluate their resistance to sedimentation. For this purpose, the compositions are centrifuged at a Relative Centrifugal Acceleration (RCA) of 846 (2500 rpm), 3382 (5000 rpm), and 7610 (7500 rpm) for 10 minutes respectively on a Rotina 380 centrifuge (Andreas Hettich GmbH & Co., Germany) equipped with a 6-position angular rotor with a rotation radius of 121 mm. Between each centrifugation condition, the compositions are manually mixed with a spatula using agitation / rest cycles at room temperature for a total of 10 minutes until a homogeneous composition is obtained. After the accelerated sedimentation study, the compositions are remixed before being packaged in 1 mL BD Hypak™ SCF glass syringes. Table 19: Resistance to sedimentation of the different compositions. Tests conducted under static storage conditions have demonstrated that PLLA microspheres dispersed in a cross-linked hyaluronic acid composition do not sediment after at least 2 weeks of storage at 4°C. Example 10e: Determination of the rheological properties of compositions [000501] The rheological properties of the compositions were determined using a method similar to that described in Example 1 and are summarized in Table 19 below: Table 20: Viscoelastic properties measured on the compositions. [000502] Compositions comprising a mixture of cross-linked hyaluronic acid gels and a tissue inducer in the form of microspheres exhibit an increased elastic modulus G' compared to the equivalent mixture of cross-linked hyaluronic acid gels, in the absence of microspheres. Also, compositions comprising a cross-linked hyaluronic acid gel and microspheres exhibit larger plastic domains (under stress and strain) compared to the equivalent cross-linked hyaluronic acid gel, without microspheres. Example lOf: Determining the injectability of compositions [000503] The injectability of the compositions was determined using a method similar to that described in Example 1 and is summarized in Table 21 below: Table 21: Injectability properties measured on the compositions [000504] All the compositions are easily injectable through a 27G needle, and exhibit injection forces of less than 20N. Example 11 Example lia: Preparation of a G4 cross-linked hyaluronic acid gel [000505] A cross-linked hyaluronic acid gel G4 was prepared at 20 mg / g by diluting gel G1 with phosphate buffer supplemented with mannitol at room temperature. To do this, 200 g of G1 gel at 27.5 mg / g were weighed into a container using a precision balance, and phosphate buffer supplemented with mannitol was added to the G1 gel to a quantity of 275 g. The mixture was then manually stirred with a spatula using cycles of stirring and resting for a total of 15 minutes until a homogeneous composition was obtained. The preparation is then degassed by centrifugation at a Relative Centrifugal Acceleration (RCA) of 846 (2500 rpm) for 10 minutes on a Rotina 380 centrifuge (Andreas Hettich GmbH & Co., Germany) equipped with a 6-place angular rotor with a rotation radius of 121 mm, and then packaged in BD Hypak™ SCF 1 mL glass syringes before being sterilized according to a FO of 18.5 minutes. Example 11b: Preparation of a G5 cross-linked hyaluronic acid gel [000506] A G5 crosslinked hyaluronic acid gel was prepared at 20 mg / g by diluting the G2 gel with phosphate buffer supplemented with mannitol according to a protocol and quantities identical to those described for the preparation of the G4 gel. It was then centrifuged, packaged and sterilized under the same conditions as the G4 gel (F0 18.5 minutes). Example 11c: Preparation of a non-crosslinked hyaluronic acid gel S2 [000507] A non-crosslinked hyaluronic acid S2 gel was prepared at 20 mg / g by diluting the SI gel with phosphate buffer supplemented with mannitol according to a protocol and quantities identical to those described for the preparation of the G4 gel. It was then centrifuged, packaged and sterilized under the same conditions as the G4 gel (F0 18.5 minutes). Example lld: Composition comprising a mixture of crosslinked HA gels (G4 and G5) and P5 poly-4-hydroxybutyrate (P4HB) microspheres with and without non-crosslinked gel (S2) [000508] Two compositions comprising a mixture of cross-linked HA gels and 15% (w / w) of P4HB microspheres are prepared from gels G4 and G5, and from batch P5 of P4HB microspheres. Composition 4.1 is obtained by mixing 1.2 g of gel G4, 1.2 g of gel G5, 0.22 g of gel S2, and 0.46 g from batch P5 of P4HB microspheres for a total mass of 3.08 g of composition. Composition 4.2 is obtained by mixing 1.2 g of gel G4, 1.2 g of gel G5, 0.22 g of phosphate buffer solution containing mannitol, and 0.46 g from batch P5 of P4HB microspheres for a total mass of 3.08 g of composition. Table 22: Composition of compositions 4.1 and 4.2 [000509] The compositions are prepared as follows: [000510] In a 5 ml plastic syringe, the G4 gel, G5 gel, S2 gel (composition 4.1) or buffer solution (composition 4.2), and then the P5 microspheres of P4HB are successively introduced. The mixture is blended with a spatula until a homogeneous mixture is obtained (3 minutes). [000511] After preparation, the compositions are directly centrifuged to evaluate their resistance to sedimentation. For this purpose, the compositions are centrifuged at a Relative Centrifugal Acceleration (RCA) of 846 (2500 rpm), 3382 (5000 rpm), 7610 (7500 rpm), and 13528 (10000 rpm) for 10 minutes respectively on a Rotina 380 centrifuge (Andreas Hettich GmbH & Co., Germany) equipped with a 6-position angular rotor with a rotation radius of 121 mm. Between each centrifugation, the compositions are manually mixed with a spatula using agitation / rest cycles at room temperature for a total of 10 minutes until a homogeneous composition is obtained. After accelerated sedimentation study the compositions are remixed before being packaged in 1 mL BD Hypak™ SCF glass syringes. Table 23: Resistance to sedimentation of the different compositions. Example related to: Determining the rheological properties of compositions [000512] The rheological properties of the compositions were determined according to a protocol similar to that described in Example 9i and are summarized in Table 24 below: Table 24: Viscoelastic properties measured on the compositions. [000513] Both compositions exhibit high elastic moduli (G'). Composition 4.2, which does not contain non-crosslinked hyaluronic acid, has a lower tan delta and more extensive plastic domains under stress and strain. Example llf: Determination of the injectability of compositions [000514] The injectability of the compositions was determined according to a protocol similar to that described in Example 1 and is summarized in Table 25 below: Table 25: Injectability properties measured on the compositions. [000515] Compositions 4.1 and 4.2 exhibit good rheological properties while being easily injectable through 27G needles. Furthermore, these compositions remain homogeneous over time when stored under static conditions in syringes.

Claims

1. Demands

1. Injectable biomaterial consisting of collagen inducer particles and a composition comprising at least two cross-linked hyaluronic acids in a mixture.

2. Biomaterial according to claim 1, characterized in that the at least two cross-linked hyaluronic acids in mixture are in gel or hydrogel form.

3. Biomaterial according to any one of claims 1 or 2, characterized in that the composition comprising at least two cross-linked hyaluronic acids in mixture is in aqueous form and the biocompatible polymer is in hydrogel form.

4. Biomaterial according to any one of claims 1, 2 or 3, comprising at least one gel or hydrogel made up of a mixture of at least two cross-linked hyaluronic acids and particles of a collagen inducer.

5. Biomaterial according to claim 1, characterized in that the composition is in solvent-free form, in particular water-free, for example in lyophilized form.

6. Biomaterial according to any one of the preceding claims, characterized in that the collagen inducer is selected from polyhydroxyalkanoates (PHA), hydroxyapatites, polycaprolactones, polylactic or polyglycolic acids, polydioxanone, poly(trimethylene carbonates) (PTMC) and / or polysaccharides and their derivatives such as dextranomer in isolated form or in the form of copolymers and / or mixtures in particulate form.

7. Biomaterial according to claim 6, characterized in that the collagen inducer is selected from PHAs.

8. Biomaterial according to claim 7, characterized in that the PHAs are selected from first generation PHAs such as poly(3-hydroxybutyric acid) (PHB) and poly(4-hydroxybutyric acid) (P4HB), second generation poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), third generation poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx or PHBHx), fourth generation poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB or P3HB4HB) or fifth generation poly(3-hydroxybutyricacid-co-3-hydroxyvalericacid-co-3-hydroxyhexanoic acid) (PHBVHHx or PHBVHx), alone or in mixtures or in the form of copolymers.

9. Biomaterial according to claim 8, characterized in that the PHA is the P4HB.

10. Biomaterial according to claim 8, characterized in that PHA is poly(3-hydroxybutyrate-co-4-hydroxybutyrate).

11. Biomaterial according to claim 6, characterized in that the collagen inducer is selected from hydroxyapatites.

12. Biomaterial according to claim 11, characterized in that the hydroxyapatite is calcium hydroxyapatite.

13. Biomaterial according to claim 6, characterized in that the collagen inducer is selected from polycaprolactones.

14. Biomaterial according to claim 6, characterized in that the collagen inducer is selected from polylactic acids (PLA).

15. Biomaterial according to claim 14, characterized in that the collagen inducer is selected from polymers or copolymers such as poly-(L)-lactic acid (PLLA), poly-(D)-lactic acid (PDLA), and poly-D,L-lactic acid PDLLA.

16. Biomaterial according to claim 6, characterized in that the collagen inducer is selected from lactic acid and polycaprolactone copolymers, such as poly(L-lactic-co-caprolactone) acid (PLCL).

17. Biomaterial according to claim 6, characterized in that the collagen inducer is polyglycolic acid (PGA).

18. Biomaterial according to claim 6, characterized in that the collagen inducer is selected from polylactic acid and polyglycolic acid (PLGA) copolymers.

19. Biomaterial according to claim 6, characterized in that the collagen inducer is polydioxanone (PLO) or poly-p-dioxanone.

20. Biomaterial according to any one of the preceding claims, characterized in that the composition is in aqueous form the biocompatible polymer, namely the mixture of at least two cross-linked hyaluronic acids is in hydrogel form and the collagen inducer particles are suspended in the gel.

21. Biomaterial according to any one of claims 1 to 19, characterized in that the composition is in the form of a bipartite composition of which one part comprises an aqueous polymeric phase, namely the mixture of at least two cross-linked hyaluronic acids and the other part comprises the particles suspended in an organic phase miscible in the aqueous polymeric phase.

22. A biomaterial according to any one of claims 1 to 19, characterized in that the composition is in the form of a bipartite composition, one part of which comprises an aqueous polymeric phase, namely a mixture of at least two cross-linked hyaluronic acids, and the other part comprises the particles in dry form.

23. A biomaterial according to any one of the preceding claims, characterized in that said cross-linked mixture of hyaluronic acids or one of their salts is a biodegradable, single-phase, cohesive hydrogel consisting of a homogeneous mixture of x identical or different hyaluronic acids or one of their salts, cross-linked prior to their interpenetration by mixing, said cross-linked polymers being insoluble in water and miscible with each other, and x being between 2 and 5.

24. Biomaterial according to claim 23, characterized in that x is equal to 2

25. Biomaterial according to any one of claims 23 or 24, characterized in that the mixture comprises a weakly crosslinked hyaluronic acid having a crosslinking ratio x2 and a strongly crosslinked hyaluronic acid having a crosslinking ratio xl, and that the weight proportion of the strongly crosslinked polysaccharide gel in the mixture is between about 0.1 and 99.9%, preferably 5 to 50% having a crosslinking ratio xl and 50 to 95% of gel having a crosslinking ratio x2 or even more preferably 10 to 40% of gel having a crosslinking ratio xl and 60 to 90% having a crosslinking ratio x2; xl being greater than x2.

26. Biomaterial according to any one of claims 1 to 25, characterized in that the composition further comprises non-crosslinked hyaluronic acid.

27. ​​Biomaterial according to any one of claims 1 to 26, characterized in that the composition further comprises a polysaccharide selected from the group consisting of keratan, heparin, cellulose, cellulose derivatives (in particular methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylmethylcellulose, carboxymethylcellulose), alginic acid, xanthan gum, carrageenan, chitosan, chondroitin, heparosan, and their biologically acceptable salts, alone or in mixture.

28. Biomaterial according to any one of claims 1 to 27, characterized in that the weight-average molecular mass (MW) of hyaluronic acid before crosslinking is between approximately 0.02 and approximately 6 MDa, of preferably between about 0.04 and about 4 MDa, preferably still between about 0.05 and about 3 MDa.

29. Biomaterial according to any one of claims 1 to 28, characterized in that the hyaluronic acid salts are selected from physiologically acceptable salts, such as sodium, potassium, calcium salts, advantageously sodium salt.

30. Biomaterial according to any one of the preceding claims, characterized in that the concentration of hyaluronic acid in the gel or hydrogel before suspension of particles is between 2 mg / g and 200 mg / g.

31. Biomaterial according to any one of the preceding claims, characterized in that the concentration of non-crosslinked hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 50 mg / g.

32. Biomaterial according to any one of the preceding claims, characterized in that the concentration of non-crosslinked hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 25 mg / g.

33. Biomaterial according to any one of the preceding claims, characterized in that the concentration of non-crosslinked hyaluronic acid in the injectable aqueous composition is between 0 mg / g and 25 mg / g.

34. Biomaterial according to any one of the preceding claims, characterized in that the concentration of polysaccharides other than hyaluronic acid in the gel or hydrogel before suspension of the particles is between 0 mg / g and 200 mg / g

35. Biomaterial according to any one of the preceding claims, characterized in that the crosslinked hyaluronic acids have crosslinking ratios X between 0.001 and 0.

4.

36. Biomaterial according to any one of the preceding claims, characterized in that the crosslinked hyaluronic acid has a crosslinking ratio xl or x2 between 0.001 and 0.

4.

37. Biomaterial according to any one of the preceding claims, characterized in that the content of collagen inducer particles in the biomaterial is between 2 mg / g and 700 mg / g.

38. Biomaterial according to any one of the preceding claims, characterized in that the PHA particle content in the biomaterial is between 2 mg / g and 700 mg / g.

39. Biomaterial according to any one of the preceding claims, characterized in that the average molecular mass Mw by weight of hyaluronic acids before crosslinking is within a range of 0.01 MDa to 5 MDa (0.01 <Mw <5 MDa).

40. Biomaterial according to any one of the preceding claims, characterized in that the average molecular mass Mw of hyaluronic acids before crosslinking is 1 MDa.

41. Biomaterial according to any one of the preceding claims, characterized in that the average molecular mass Mw of hyaluronic acids before crosslinking is 3 MDa.

42. Biomaterial according to any one of the preceding claims, characterized in that the collagen inducer particles have a size strictly less than 100 pm.

43. Biomaterial according to any one of the preceding claims, characterized in that the collagen inducer particles have a size between 20 and 100 pm.

44. Biomaterial according to any one of the preceding claims, characterized in that the PHA particles are prepared by microfluidization.

45. Biomaterial according to any one of the preceding claims, characterized in that the composition further comprises an active ingredient selected from the group consisting of local anesthetics, vitamin C derivatives, anti-inflammatories, antioxidants, antibiotics and mixtures thereof.

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