Biomaterial for use in the dental field

Abstract

The present invention relates to a crosslinkable polymer composition comprising at least one calcium phosphate, at least one biocompatible and biodegradable organic polymer or one of its precursors, and Zn-ZnO core-shell particles, to a biomaterial obtainable by photopolymerization of such a crosslinkable polymer composition, to a process for preparing such a composition and such a biomaterial, and to the use of such a biomaterial for various applications in the field of health.

Description

[0001] Biomaterial for use in the dental field

[0002] The present invention relates to a crosslinkable polymer composition comprising at least one calcium phosphate, at least one biocompatible and biodegradable organic polymer or one of its precursors, and Zn / ZnO core / shell particles, a biomaterial obtainable by photopolymerization of such a crosslinkable polymer composition, a method for preparing such a composition and such a biomaterial, as well as the use of such a biomaterial for various applications in the field of health.

[0003] Currently, more than 60% of the population in industrialized countries requires implant-prosthetic rehabilitation. In Europe, approximately 1.5 million patients undergo bone reconstruction each year during maxillofacial surgery. Dental implants represent an alternative treatment for replacing missing teeth. To achieve the best results with these dental implants, sufficient bone must be available to accommodate and stabilize them. However, tooth loss, whatever the cause, is usually accompanied by more or less marked resorption of the alveolar bone. Such bone resorption can then constitute a contraindication to the placement of dental implants, which require very precise positioning and perfect long-term stability.To achieve optimal results when placing dental implants, it is therefore essential to have sufficient bone volume. Reconstruction of alveolar bone through restorative / regenerative surgery procedures has become common practice: in particular, when bone deficits are greater than 3 mm in width and / or height, a bone graft, and more specifically an autogenous bone graft (bone taken directly from the patient), is performed to restore favorable anatomical conditions for implant placement, both in volume and density. A second surgical site is then opened to harvest the bone necessary for the reconstruction of the site intended for augmentation. However, augmentation procedures are demanding techniques and reserved for experienced specialists.Additionally, autogenous bone grafting is associated with increased morbidity, patient discomfort, and prolonged surgical procedures. In particular, the surgery is quite long and painful for the patient because it is performed at two different surgical sites; and a waiting period of 4 to 6 months is usually required before implant placement for the graft to fuse to the recipient bone. Furthermore, after bone surgery, patients are required to follow an antibiotic treatment to prevent infections. Indeed, oral infections can pose a real health risk, especially for patients with other pathologies such as autoimmune diseases or diabetes. In addition, the volume of bone graft available in the oral cavity is limited and may prove insufficient for the needs.Another major disadvantage of autogenous bone grafting is its more or less significant resorption in the long term. Resorption is particularly pronounced for cancellous bone, varying between 12 and 60% (1-5 years) after implant placement.

[0004] To replace autogenous bone grafts, allogenic (another individual of the same species as the recipient), xenogeneic (an individual of a different species than the recipient), and alloplastic (synthetic) bone substitute biomaterials have been proposed. Allogenic and xenogeneic biomaterials require potential donors and numerous processing and / or conditioning steps before use. Alloplastic biomaterials can also serve as bone substitutes in bone fillings and reconstructions. Their availability is unlimited, there is no need for a bone bank, and they pose no risk of pathogen transmission. Several alloplastic materials are currently used in dentistry: tricalcium phosphates, calcium carbonates, synthetic hydroxyapatites, biphasic ceramics, composite materials, and bioglasses.Alloplastic materials must be biocompatible, bioactive, osteoconductive and may or may not be resorbable.

[0005] In particular, hydroxyapatite is often used as an implant in the artificial replacement of hard tissues in dental surgery. Its structural properties, such as size and morphology, differ depending on the synthesis method used. Hydroxyapatite is notably used in the form of nanoparticles in the transport of genes, proteins and for artificial bone regrowth due to its very high absorption capacity and its binding affinity with polyvalent molecules. However, it is a limited compound in terms of mechanical strength, fracture toughness and fatigue resistance.

[0006] Jeong HJ. et al. [Int. J. Mol. Soi., 2020, 21, 1863, 1-15] describe a 3-dimensional (3D) hybrid material based on hydroxyapatite or tricalcium phosphate, and polycaprolactone. The hybrid material is prepared as follows: a polycaprolactone structure sized to receive a metal implant is prepared by 3D printing, then particles of polycaprolactone, hydroxyapatite, tricalcium phosphate, poly(ethylene oxide) and sodium chloride are mixed, the resulting mixture is introduced into the structure, the assembly is then heated in an oven for 10 minutes at 80°C, and then washed in deionized water to remove the poly(ethylene oxide) and sodium chloride. The resulting hybrid material is porous and has osteoconductive properties. It is described as being able to regenerate alveolar bone during the installation of a dental implant. However, this material does not eliminate the risk of oral infection.Furthermore, its mechanical properties remain weak.

[0007] The aim of the present invention is therefore to overcome the drawbacks of the prior art, and in particular to provide a biocompatible and biodegradable biomaterial having good mechanical and antibacterial properties, and which can easily adapt to the dental and / or maxillofacial morphology of a patient, while guaranteeing good osteoconductive and resorbability properties. In particular, there is a need for a bone support or substitute for the placement of dental implants.

[0008] The first subject of the invention is a crosslinkable polymer composition, characterized in that it comprises:

[0009] - at least one biocompatible biodegradable organic polymer or at least one of its precursors, and preferably at least one of its precursors,

[0010] - at least one calcium phosphate, and

[0011] - at least zinc core / shell / zinc oxide particles.

[0012] The crosslinkable composition of the invention makes it possible to easily produce a biomaterial that can be used as a bioactive bone substitute for dental applications, in particular for treating patients suffering from tooth loss. The crosslinkable composition leads in particular by 3D printing as detailed below to a biocompatible and biodegradable biomaterial having improved mechanical properties, antibacterial properties, and being able to easily adapt to the dental and / or maxillofacial morphology of a patient, while guaranteeing good osteoconductive and resorbability properties. The biomaterial can then be used as a bone substitute for the placement of dental implants in a single operation with a technique that is simpler for the practitioner and therefore more reliable for the patient.

[0013] In the invention, the term "osteoconduction" means the ability of a biomaterial to serve as a matrix to which surrounding vascular and bone cells can adhere, so that they can migrate to the recipient site, colonize it, revascularize it and synthesize the new bone matrix.

[0014] Calcium phosphate provides the osteoconductive properties of the crosslinkable composition.

[0015] In the invention, calcium phosphate means an inorganic material comprising phosphorus and calcium.

[0016] The calcium phosphate used in the crosslinkable composition preferably has a calcium / phosphorus atomic ratio close to that of bone (approximately 1.6).

[0017] Preferably, the calcium phosphate is selected from hydroxyapatite (Hap) (of formula Cas(PO4)3(OH) or Caio(P04)e(OH)2), tricalcium phosphate (of formula Cas(PO4)2) or TCP), monocalcium phosphate (of formula Ca(H2PO4)2 or MCPM), dicalcium phosphate (DCP), or octa calcium phosphate.

[0018] Hydroxyapatite is particularly preferred, especially because of its Ca / P ratio which gives it properties similar to those of bone.

[0019] The calcium phosphate preferably represents from 0.1 to 10% by mass approximately, and particularly preferably from 0.5 to 2% by mass approximately, relative to the total mass of the crosslinkable composition. In particular, beyond a concentration of 10% by mass, the crosslinkable composition then becomes difficult to print, in particular by 3D printing using photopolymerization.

[0020] The calcium phosphate is preferably in the form of particles with a size ranging from approximately 100 nm to 25 pm, and particularly preferably from approximately 200 nm to 20 pm.

[0021] In the invention, the size of the calcium phosphate particles is determined using methods well known to those skilled in the art, and preferably by dynamic light scattering, laser granulometry, or scanning electron microscopy, and preferably by dynamic light scattering, or scanning electron microscopy.

[0022] The zinc / zinc oxide particles of the crosslinkable composition of the invention comprise a zinc core and a zinc oxide shell.

[0023] The zinc / zinc oxide particles preferably have a size ranging from approximately 0.1 to 200 pm, and particularly preferably from approximately 1 to 50 pm.

[0024] In the invention, the size of the zinc / zinc oxide particles is determined using methods well known to those skilled in the art such as dynamic light scattering (DLS), laser granulometry, or scanning electron microscopy, and preferably dynamic light scattering. In DLS, the invention refers to the hydrodynamic diameter.

[0025] The zinc / zinc oxide preferably represents from 0.1 to 25% by mass approximately, particularly preferably from 0.1 to 20%, more particularly preferably from 1 to 15% by mass approximately, and even more particularly preferably from 1 to 10% by mass approximately, relative to the total mass of the crosslinkable composition.

[0026] According to a preferred embodiment of the invention, the zinc / zinc oxide particles comprise from 51 to 90% by mass approximately of zinc oxide, and particularly preferably from 60 to 80% by mass approximately of zinc oxide, relative to the total mass of the zinc / zinc oxide particles.

[0027] The zinc oxide shell or layer or envelope may have a thickness ranging from approximately 1 to 1000 nm, and particularly preferably from approximately 300 to 800 nm.

[0028] The thickness is determined in particular using a scanning electron microscope, a transmission electron microscope, or an atomic force microscope, and preferably by scanning electron microscope.

[0029] This zinc oxide layer or shell differs from a zinc oxide layer that could possibly form around zinc naturally, for example by air oxidation, in particular by its thickness. Indeed, a natural zinc oxide layer will have a maximum thickness of a few tenths of a nm. The zinc / zinc oxide particles provide the antibacterial activity of the crosslinkable composition. This activity is then completely preserved in the biomaterial obtained from the crosslinkable composition.

[0030] Unlike the prior art which uses noble metals such as silver as bactericides which induce a certain toxicity when it is released, or photoactive materials which require radiation (e.g. UV radiation) to be activated, the zinc / zinc oxide particles used in the crosslinkable composition of the invention are not toxic for the patient, they are released gradually by the biomaterial and they have good bactericidal activity without requiring an external stimulus such as photo-irradiation.

[0031] Finally, the combination of zinc and zinc oxide helps to strengthen the differentiation properties of bone cells and the mineralization of hydroxyapatite.

[0032] In the invention, the expression "biodegradable organic polymer" means an organic polymer that can be degraded or digested by microorganisms (e.g. bacteria, fungi, algae), for example by the action of enzymes. The reactions occurring during biodegradation in humans are hydrolysis reactions, i.e. cleavage of covalent bonds by reaction with water (see current standard NF EN 13 432.

[0033] In the present invention, the expression "biocompatible organic polymer" means an organic polymer having the capacity not to interfere with and not to degrade the biological environment in which they are used. In particular, they must not cause a strong inflammatory reaction (e.g. allergies) and / or must not be toxic to humans.

[0034] In the present invention, the expression "organic polymer" means a polymer comprising at least carbon atoms covalently bonded to hydrogen, oxygen, nitrogen, or sulfur atoms. In other words, the organic polymer comprises organic recurring units, i.e. recurring units comprising at least carbon atoms covalently bonded to hydrogen, oxygen, nitrogen, or sulfur atoms. The organic polymer is preferably free of metal and metalloid. In other words, the organic polymer preferably does not comprise a metal or metalloid such as silicon, or is different from a polysiloxane-type polymer, or does not comprise a Si-O bond.

[0035] The biodegradable biocompatible organic polymer may be selected from aliphatic polyesters, polysaccharides, polyorthoesters, polyanhydrides, polyphosphazenes, polyacrylates, and polyurethanes.

[0036] In the invention, a polymer includes both homopolymers and copolymers.

[0037] Examples of aliphatic polyesters include polyglycolides (i.e. poly(glycolic acid) or PGA), polylactides (i.e. poly(lactic acid) or PLA), glycolide and lactide copolymers (PLGA), polylactones (e.g. poly(s-caprolactone)), polyhydroxyalkanoates (e.g. polyhydroxyvalerate, poly(hydroxybutyrate)), poly(aliphatic ester-urethane) copolymers, and preferably polyglycolides (i.e. poly(glycolic acid) or PGA), polylactides (i.e. poly(lactic acid) or PLA), and glycolide and lactide copolymers (PLGA).

[0038] Examples of polysaccharides include cellulose or starch.

[0039] Examples of polyanhydrides include poly(isophthalic anhydride) or poly(terephthalic anhydride).

[0040] Examples of polyphosphazenes include polydichlorophosphazene.

[0041] Examples of polyacrylates include polyethyl acrylate or polymethyl acrylate.

[0042] Examples of polyorthoesters include class I POE, class II POE, class III POE, or class IV POE.

[0043] According to a preferred embodiment of the invention, the organic polymer is an aliphatic polyester, and particularly preferably a polylactide.

[0044] PLA exhibits high dimensional stability and modulatable properties, making it particularly suitable for bone tissue engineering. It is a biodegradable, bioresorbable, and biocompatible thermoplastic aliphatic polyester that can be synthesized by different methods. Thus, its mechanical properties, biodegradation, geometry, and architecture can be modulated. A precursor of one of the biodegradable biocompatible organic polymers can also be used in the crosslinkable composition.

[0045] The precursor can be an organic monomer or oligomer.

[0046] The organic monomer or oligomer makes it possible to form a biocompatible biodegradable organic polymer as defined in the invention by polymerization, and preferably by photopolymerization.

[0047] The precursor may be chosen from aliphatic esters, polyols, and acrylates.

[0048] Examples of aliphatic esters include lactide, lactic acid, glycolic acid, glycolide, lactones (e.g. s-caprolactone), or hydroxyalkanoates (e.g. hydroxyvalerate, hydroxybutyrate).

[0049] The precursor of the biodegradable biocompatible organic polymer preferably has a molar mass ranging from approximately 100 to 10,000 g / mol, and particularly preferably from approximately 500 to 2,000 g / mol.

[0050] According to a preferred embodiment of the invention, the biodegradable biocompatible organic polymer (respectively the precursor of the biodegradable biocompatible organic polymer) represents from 20 to 70% by mass approximately, particularly preferably from 25 to 65% by mass approximately, and more particularly preferably from 30 to 60% by mass approximately, relative to the total mass of the crosslinkable composition.

[0051] The viscosity of the crosslinkable composition can range from approximately 0.1 to 100 Pa.s (0.1 to 100 kg nr 1 s -1 ), and particularly preferably from 0.1 to 0.5 Pa.s approximately (0.1 to 0.5 kg nr 1 s -1 ). This makes it easier to form a biomaterial by 3D printing.

[0052] In the present invention, the viscosity is measured using a rheometer, at 25°C, and with a shear rate of 10 rad.s -1 .

[0053] The crosslinkable composition of the invention is a liquid composition at room temperature (i.e. 18-25°C).

[0054] The crosslinkable composition of the invention has the advantages of being a 3D printable composition, in particular printable using any 3D printing process using photopolymerization, such as by digital light processing (well known as "Digital Light Processing" or DLP), by stereolithography (SLA printing) or by UV-LCD printing (LCD screen).

[0055] The crosslinkable composition preferably further comprises a photoinitiator (or a photopolymerization initiator).

[0056] The photoinitiator can be chosen from type I or II photoinitiators.

[0057] Examples of type I photoinitiators include ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L) or diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO).

[0058] Examples of type II photoinitiators include 1-hydroxycyclohexyl phenyl ketone, 2-ethylhexyl-(4-N,N-dimethylamino)benzoate or 2-ethyl-(4-N,N-dimethylamino)benzoate.

[0059] The crosslinkable composition preferably further comprises at least one compound comprising one or more reactive functions, such as acrylate, methacrylate or epoxide functions.

[0060] The reactive function(s) may be directly on the precursor of the biocompatible biodegradable organic polymer, for example in terminal position(s).

[0061] The second subject of the invention is a process for preparing a crosslinkable composition in accordance with the first subject of the invention, characterized in that it comprises at least one step i) of mixing zinc / zinc oxide core / shell particles and calcium phosphate particles in a protic polar solvent, to form a dispersion, and a step ii) of adding a biocompatible and biodegradable organic polymer or one of its precursors, and preferably one of its precursors, to the dispersion of step i).

[0062] The zinc core / shell / zinc oxide particles, the calcium phosphate, the biocompatible and biodegradable organic polymer and one of its precursors are as defined in the first subject of the invention.

[0063] The protic polar solvent can be selected from C1-C5 alcohols. The protic polar solvent is preferably ethanol. The protic polar solvent allows good dispersion of the zinc core / shell / zinc oxide particles and the calcium phosphate particles, while ensuring easy removal in subsequent steps.

[0064] The zinc core / shell / zinc oxide particles preferably represent from 0.1 to 20% by mass approximately, and particularly preferably from 1 to 5% by mass approximately, relative to the total mass of the dispersion of step i).

[0065] The calcium phosphate particles preferably represent from 0.1 to 10% by mass approximately, and particularly preferably from 0.5 to 2% by mass approximately, relative to the total mass of the dispersion of step i).

[0066] Step i) is preferably carried out using ultrasound.

[0067] Step i) may comprise mechanical agitation, preferably after ultrasound.

[0068] Step ii) makes it possible to form a crosslinkable composition in accordance with the first subject of the invention.

[0069] Step ii) can be carried out with mechanical stirring. This allows a homogeneous composition to be obtained.

[0070] Mechanical stirring can be followed by magnetic stirring. This allows the protic polar solvent to evaporate.

[0071] After evaporation of the protic polar solvent, step ii) may include homogenization of the composition using ultrasound.

[0072] The photoinitiator and / or the compound comprising one or more reactive functions as defined in the first subject of the invention are preferably added during step ii), advantageously at the same time as the biocompatible biodegradable organic polymer.

[0073] The zinc core / shell / zinc oxide particles are preferably obtained by: u) contacting a Zn(II) ion salt such as a zinc(II) nitrate, sulfate, acetate or chloride, preferably in aqueous solution, with a strong base such as potassium hydroxide or sodium hydroxide, preferably in aqueous solution; and v) adding zinc metal particles (i.e. zinc(0)) to form a resulting composition (which changes from transparent to black).

[0074] Zinc (0) can be pre-washed in an acid medium (e.g. 1% hydrochloric acid solution by volume) before use, preferably with stirring, for example by centrifugation.

[0075] A solid formed in the resulting composition can then be washed, preferably with water and / or a C1-C3 alcohol, and then optionally dried.

[0076] At the end of step u), the pH of the resulting solution is greater than or equal to 14.

[0077] The zinc metal particles preferably have a size ranging from approximately 0.04 pm to 10 pm, and particularly preferably from approximately 1 to 10 pm.

[0078] The zinc (0) / zinc (II) salt molar ratio in step v) can range from 0.1 to 90, and preferably from 0.6 to 70.

[0079] This ratio varies depending on the desired zinc core / zinc oxide particle size. In particular, the higher the ratio, the larger the zinc core / zinc oxide particle size.

[0080] This simple, economical and easy to implement process differs from known processes of the prior art such as laser ablation of zinc particles which are expensive and complex, and / or do not allow fine control of the quantity of ZnO vs Zn in the particles.

[0081] The third subject of the invention is a biomaterial, characterized in that it is capable of being obtained by photopolymerization of one or more layers of a crosslinkable composition in accordance with the first subject of the invention.

[0082] In the invention, the expression "biomaterial" means a material intended to be in contact with living tissues and / or biological fluids to evaluate, treat, modify the shapes of or replace any tissue, organ or function of the body (Chester consensus, UK, 1991).

[0083] The biomaterial of the invention may have a Young's modulus of at least about 1 GPa, preferably at least about 2 GPa, and particularly preferably ranging from about 2 to 3 GPa. The biomaterial of the invention may have an elongation at break of at least about 5%, preferably at least about 6%, and particularly preferably ranging from about 5 to 15%.

[0084] The biomaterial of the invention may have a breaking stress of at least approximately 100 MPa, preferably at least approximately 120 MPa, and particularly preferably ranging from approximately 100 to 200 MPa.

[0085] The photopolymerization of one or more layers of a crosslinkable composition in accordance with the first subject of the invention makes it possible to form the biomaterial.

[0086] Photopolymerization ensures that the bactericidal and osteoconduction properties of the crosslinkable composition are preserved. Furthermore, the addition of zinc / zinc oxide and calcium phosphate particles does not degrade or even maintain the mechanical properties of the biocompatible and biodegradable organic polymer used in the crosslinkable polymer composition.

[0087] Photopolymerization or radiation curing of the crosslinkable composition is carried out using light, particularly UV light. Radiation curing is much faster than heat treatment, and allows for higher manufacturing speeds and reduced installation space.

[0088] Preferably, the photopolymerization is carried out at a wavelength ranging from about 385 nm to about 405 nm, and advantageously at about 405 nm.

[0089] The photopolymerization is preferably carried out by 3D printing, and particularly preferably by any 3D printing that implements photopolymerization, such as by digital light processing (DLP printing), by stereolithography (SLA printing), or by UV-LCD printing. In this embodiment, the crosslinkable composition is polymerized using a UV light projector and orientable mirrors. This thus makes it possible to solidify the crosslinkable composition over the entire surface of one layer at a time. The biomaterial is thus formed layer by layer.

[0090] 3D printing makes it easy and quick to produce complex shapes and patient-specific desired geometry from medical images.

[0091] This may therefore allow a greater number of practitioners to perform dental implant placement using a simpler, more reliable technique, and without causing an inflammatory and infectious reaction. The practitioner can obtain the biomaterial to be implanted directly after the patient's scan, either by printing the bone substitute himself or through his prosthetist. Furthermore, by reducing the number of operations, the conditions for accessing dental implant placement may be less expensive and the procedure may be less painful for the patient.

[0092] The biomaterial preferably comprises zinc / zinc oxide core / shell particles, calcium phosphate, and a photocrosslinked polymer material.

[0093] The fourth subject of the invention is a method for manufacturing a biomaterial, characterized in that it comprises at least one step A) of photopolymerization of one or more layers of a crosslinkable composition in accordance with the first subject of the invention.

[0094] According to a preferred embodiment of the invention, step A) is carried out by 3D printing, and advantageously by digital light processing (DLP printing).

[0095] The layer(s) of crosslinkable composition may have a thickness ranging from approximately 5 to 100 μm, and particularly preferably from approximately 25 to 100 μm.

[0096] Step A) can be carried out at a temperature ranging from approximately 10 to 40°C.

[0097] Step A) can be carried out for a period of time ranging from approximately 5 to 720 min per layer.

[0098] Step A) can be carried out at a speed of approximately 5 to 50 mm / h per layer.

[0099] Step A) can be carried out at a light intensity ranging from 20 to 50 mw / cm 2 approximately per layer.

[0100] At the end of step A), a biomaterial is obtained which preferably conforms to the third subject of the invention.

[0101] The fifth subject of the invention is a biomaterial in accordance with the third subject of the invention or obtained according to a process in accordance with the fourth subject of the invention, for its medical use.

[0102] The sixth subject of the invention is a biomaterial in accordance with the third subject of the invention or obtained according to a process in accordance with the fourth subject of the invention, for its use in bone regeneration and the prevention and / or treatment of oral infections linked to implantation.

[0103] The biomaterial exhibits excellent biocompatibility, resorption properties, but also osteoinduction and osteoconduction properties to allow natural bone tissue to return to its place at the implantation site. The biomaterial can thus be used as a bone substitute in dental applications, particularly for the placement of dental implants. In particular, the biomaterial allows for a progressive, controlled, and localized release of bactericidal zinc / zinc oxide particles at the treated site, thus avoiding any risk of infection during dental implantation.

[0104] In the invention, the expression "bone substitute" means a biomaterial of synthetic origin intended for implantation, with a view to reconstituting bone stock by reinforcing a bone structure or filling a loss of bone substance.

[0105] The biomaterial of the invention then makes it possible to replace the natural graft to accommodate the dental implant. This type of biomaterial should be distinguished from prior art biomaterials which are used to retain the graft and which are, for example, in the form of a cage. They are not then used to replace the natural graft.

[0106] The seventh subject of the invention is a bone substitute capable of receiving a dental implant, characterized in that it comprises a biomaterial in accordance with the third subject of the invention or obtained according to a process in accordance with the fourth subject of the invention.

[0107] Brief description of the drawings

[0108] The accompanying drawings illustrate the invention.

[0109] Figure 1 represents scanning electron microscopy (SEM) images of nanometric or micrometric zinc particles not in accordance with the invention, and of zinc core / shell / zinc oxide particles in accordance with the invention.

[0110] Figure 2 represents the X-ray diffraction (XRD) spectrum of nanometric or micrometric zinc particles not in accordance with the invention, of zinc oxide particles not in accordance with the invention, and of zinc core / shell / zinc oxide particles in accordance with the invention.

[0111] Figure 3 represents an image of a biomaterial in accordance with the invention obtained by 3D printing.

[0112] Figure 4 represents the Young's moduli, the breaking stresses, the elongations at break, the curves of the standard force as a function of the elongation at break in tension of a biomaterial in accordance with the invention and of biomaterials not in accordance with the invention.

[0113] Figure 5 represents the Young's moduli, the stresses at break, the elongations at break, the curves of the standard force as a function of the elongation at break in compression of a biomaterial in accordance with the invention and of biomaterials not in accordance with the invention.

[0114] Figure 6 illustrates the presence of carbon, oxygen, calcium and zinc on the surface of a biomaterial according to the invention.

[0115] Figure 7 illustrates the presence of carbon, oxygen, calcium and zinc in the core of a biomaterial in accordance with the invention.

[0116] Figure 8 shows the antibacterial properties of a biomaterial according to the invention.

[0117] Other characteristics and advantages of the present invention will appear in light of the description of non-limiting examples of the crosslinkable composition and the biomaterial according to the invention, as well as their manufacturing process.

[0118] Examples

[0119] Example 1: Zinc core / shell / zinc oxide particle manufacturing process

[0120] 1.1 Zn / ZnO particles obtained from nanometric zinc particles (Zn / ZnO nano)

[0121] In a first container (beaker), 1.48 g of zinc nitrate hexahydrate Zn(NOs)2.6H20 (98% purity, CAS 101966-18-6, Sigma Aldrich) are dissolved in 10 ml of distilled water to form a zinc nitrate solution. In a second container (beaker), 2.75 g of potassium hydroxide KOH (90%, CAS 1310-58-3, Sigma Aldrich) are dissolved in 10 ml of distilled water to form a potassium hydroxide solution.

[0122] The zinc nitrate solution is then added to the potassium hydroxide solution to form a resulting solution which is left under magnetic stirring for a few minutes.

[0123] Meanwhile, 0.2 g of nanosized zinc particles (particle size about 50 nm, purity >99%, CAS 7440-66-6, Sigma Aldrich) are washed with 0.3 ml of 1% by volume hydrochloric acid (HCl) solution (35% by volume HCl, CAS 7647-01-0, Sigma Aldrich) using a centrifuge (speed of 8500 rpm for 5 min). The washed zinc is then dissolved in the resulting solution prepared previously to form a composition which is kept for 2 h under magnetic stirring. The composition changes from transparent to a black color. The solid dispersed in the resulting composition is washed three times with distilled water and twice with ethanol and then dried in an oven at 100 °C.

[0124] 1.2 Zn / ZnO particles obtained from micrometric zinc particles (Zn / ZnOmicro)

[0125] In a first container (beaker), 1.48 g of zinc nitrate hexahydrate Zn(NO3)2.6H2O (98% purity, CAS 101966-18-6, Sigma Aldrich) are dissolved in 10 ml of distilled water to form a zinc nitrate solution.

[0126] In a second container (beaker), 3 g of potassium hydroxide KOH (90%, CAS 1310-58-3, Sigma Aldrich) are dissolved in 10 ml of distilled water to form a potassium hydroxide solution.

[0127] The potassium hydroxide solution is then added to the zinc nitrate solution to form a resulting solution which is left under magnetic stirring for a few minutes.

[0128] Meanwhile, 2 g of micrometric zinc particles (particle size about 10 pm, purity >98%, CAS 7440-66-6, Sigma Aldrich) are washed with 2.6 ml of 1% by volume hydrochloric acid (HCl) solution (35% by volume HCl, CAS 7647-01-0, Sigma Aldrich) using a centrifuge (speed of 8500 rpm for 5 min). The washed zinc is then dissolved in the resulting solution prepared previously to form a composition which is kept for 2 h under magnetic stirring. The composition changes from transparent to a gray color. The solid dispersed in the resulting composition is washed three times with distilled water and twice with ethanol and then dried in an oven at 100 °C.

[0129] 1.3 Characterization of Zn / ZnO core / shell particles

[0130] Figure 1 shows scanning electron microscopy (SEM) images of the nanosized zinc particles used in Example 1.1 (Figure 1-a), the microsized zinc particles used in Example 1.2 (Figure 1-b), the Zn / ZnOano zinc core / shell particles prepared in Example 1.1 (Figure 1-c), and the Zn / ZnOmicro zinc core / shell particles prepared in Example 1.2 (Figure 1-d).

[0131] Scanning electron microscopy images were taken using a scanning electron microscope sold under the trade name Hitachi S4800 SEM system by HITACHI.

[0132] SEM images reveal different structures: the initial nanometric zinc appears as rather deformed spheres and the particles are smaller than 1 pm. The initial micrometric zinc appears as beautiful spheres of about 2 pm in diameter. The Zn / ZnOnano particles obtained from the initial nanometric zinc have a morphology of sea urchin-shaped microspheres slightly smaller than 2 pm. The Zn / ZnOmicro particles obtained from the initial micrometric zinc are in the form of spheres ranging in size from 2 to 4 pm, comprising a shell of ZnO nanopillars surrounding and covering the Zn surface.

[0133] Dynamic light scattering analyses were performed using a device sold under the trade name ZetaSizer NS by the company MALVERN.

[0134] The results obtained are presented in Table 1 below.

[0135] TABLE 1

[0136] The results in Table 1 show sizes of the same order of magnitude as those obtained by scanning electron microscopy, except for the zinc / zinc oxide particles prepared in Example 1.1. This may be explained by a high dispersity in particle sizes, and / or that the zinc / zinc oxide core / shell particles prepared in Example 1.1 are largely agglomerated.

[0137] X-ray diffraction (XRD) analysis was performed using a diffractometer sold under the trade name Philips X'Pert by Philips company equipped with PANalytical Xpert powder XRD system with Cu Ka radiation allowing access to an angle 20 in the range of 10° to 90°. The diffractograms are collected and integrated with the X'Pert Data Collector software.

[0138] Figure 2 shows the XRD spectrum of micron-sized zinc particles used in Example 1.2 (Figure 2-a), nano-sized zinc particles used in Example 1.1 (Figure 2-b), commercial zinc oxide particles (CAS No. 1314-13-2) of size about 100 nm (Figure 2-c), zinc / zinc oxide Zn / ZnOmicro particles prepared in Example 1.2 (Figure 2-d), and zinc / zinc oxide Zn / ZnOnano particles prepared in Example 1.1 (Figure 2-e).

[0139] The results show that the Zn / ZnO particles prepared in Examples 1.1 and 1.2 comprise zinc and zinc oxide.

[0140] Energy-dispersive X-ray spectroscopy (EDX) analyses were performed using a device sold under the trade name Zeiss Evo ED15 by Zeiss.

[0141] Table 2 below lists the chemical compositions of the obtained Zn / ZnO particles.

[0142] TABLE 2

[0143] SEM analyses from cut microslides of resin-embedded particles showed an average ZnO shell thickness of about 650 nm in Zn / ZnOnano and about 570 nm in Zn / ZnOmicro.

[0144] Example 2: process for preparing a crosslinkable composition in accordance with the invention

[0145] In a 250 ml container (beaker), 1.5 g of hydroxyapatite (Hap) (purity > 97%, CAS 12167-74-7, Sigma-Aldrich, particle size about 200 nm) and 3 g of Zn / ZnOnano or Zn / ZnOmicro core / shell particles as prepared in Example 1 are dispersed in 150 ml of ethanol (EtOH) to form a dispersion which is placed in an ultrasonic bath for 1 h, then poured into a 500 ml container (flask) attached to a mechanical stirrer sold under the trade name Ika Labortechnik RW 20. n. The dispersion is stirred using this mechanical stirrer for 30 minutes at 500 rpm.

[0146] 150 ml of a polylactic acid (PLA)-based solution (eSun, “transparent eResin-PLA”) is added to the previous dispersion and the resulting composition is kept under mechanical stirring overnight. The resulting composition is then left under magnetic stirring for several days, at 300 rpm, in order to allow the solvent to evaporate. Finally, the composition is placed under ultrasound for 40 min, at an amplitude of 60% using an ultrasonic homogenizer sold under the trade name Sonopuls, then filtered to form a crosslinkable composition CR1 comprising PLA, Zn / ZnOnano, and hydroxyapatite. A composition CR2 comprising PLA, Zn / ZnOmicro, and hydroxyapatite is also obtained.

[0147] The procedure detailed above was reproduced with different amounts of hydroxyapatite and Zn / ZnO to form different crosslinkable compositions. Table 3 below lists the different crosslinkable compositions obtained with the corresponding proportions of hydroxyapatite and Zn / ZnO particles.

[0148] TABLE 3

[0149] To analyze the crosslinkable compositions, a rheometer sold under the trade name Anton Paar MCR 302 by the company ANTON PAAR was used.

[0150] To do this, 1 ml of a sample is placed in a sample holder. The rheometer temperature is set at room temperature, i.e. 25°C for all measurements. The measurements are carried out using a conical plate geometry. The evolution of the viscosity is monitored over time by varying the shear rate between 1 and 100 rad.s -1The measurements taken have a shear rate of 10 rad.s -1 . The following table 4 brings together the viscosity results (in Pa.s or in kg nr 1 s -1 ) obtained for the different crosslinkable compositions prepared below.

[0151] TABLE 4

[0152] Comparative Example 3: Process for preparing a crosslinkable composition not in accordance with the invention

[0153] 3.1 Crosslinkable composition free of Zn / ZnO core / shell particles

[0154] In a first 500 ml container (beaker), 1.5 g of hydroxyapatite (HAP) (purity > 97%, CAS 12167-74-7, Sigma-Aldrich, particle size approximately 200 nm) are dissolved in 150 ml of ethanol (EtOH) to form a solution which is placed in an ultrasonic bath for 1 h, then magnetically stirred for 1 h. In a second container (beaker), 150 ml of a polylactic acid (PLA)-based solution (eSun, “eResin-PLA transparent”) are poured into 50 ml of EtOH and the resulting solution is magnetically stirred for 1 h. The resulting solution is added to the previously prepared hydroxyapatite solution. The resulting composition is then left under magnetic stirring for several days, at 300 rpm, in order to allow the solvent to evaporate. Finally, the composition is filtered to form a crosslinkable composition CR0-A comprising PLA and hydroxyapatite.

[0155] 3.2 Crosslinkable composition free of hydroxyapatite

[0156] In a 150 ml container (beaker), 2 g of Zn / ZnOnano particles as prepared in Example 1) are dispersed in 100 ml of ethanol (EtOH) to form a dispersion which is placed in an ultrasonic bath for 1 h. The dispersion is then poured into a 500 ml container (flask), attached to a mechanical stirrer sold under the trade name Ika Labortechnik RW 20. n. The dispersion is stirred using this mechanical stirrer for 30 minutes at 500 rpm.

[0157] 100 ml of a polylactic acid (PLA)-based solution (eSun, “transparent eResin-PLA”) is added to the previous dispersion and the resulting composition is kept under mechanical stirring overnight at 60 rpm. The resulting composition is then left under magnetic stirring for several days, at 300 rpm, in order to allow the solvent to evaporate. Finally, the composition is placed under ultrasound for 40 min, at an amplitude of 60% using an ultrasonic homogenizer sold under the trade name Sonopuls, then placed under magnetic stirring for 1 h. Finally, the composition is filtered to form a crosslinkable composition CR0-B comprising PLA, and Zn / ZnO.

[0158] Example 4: Process for preparing a crosslinked biomaterial in accordance with the invention

[0159] The crosslinkable composition CR1 prepared in Example 2 is 3D printed in the form of layers using a device sold under the trade name “Accufab-D1” by Shinning 3D with the following conditions:

[0160] - layer thickness (in mm): 0.1

[0161] - exposure time (in s): 4.10 - exposure level: high power

[0162] - top stop time (in s): 0.00

[0163] - downtime (in s): 2.00

[0164] - improved exposure time (in s): 15.00

[0165] - improved exposure level: medium power

[0166] - improved downtime at top (in s): 0.00

[0167] - improved downtime (in s): 2.00

[0168] - improved exposure layer: 3

[0169] - enhanced exposure layer offset (in mm): 0.05

[0170] - contour offset (in mm): 0.00

[0171] - X-axis percentage scale offset (in %): 100

[0172] - Y-axis percentage scale offset (in %): 100

[0173] - exposure time offset (in s): 0.00

[0174] - improved exposure time shift (in s): 0.00

[0175] - viscosity (in %): 50

[0176] - peeling speed: 6

[0177] - thickness of the first layer different: no

[0178] - wipe away bubbles: no

[0179] - fast printing: no

[0180] - basic printing time: 5.50

[0181] - color: 128 red / 128 green / 128 blue / 255 alpha

[0182] - always rotate around the X axis for (°) degrees: 0.00

[0183] - always rotate around the Y axis for (°) degrees: 0.00

[0184] - always rotate around the Z axis for (°) degrees: 0.00

[0185] - always resize the parts for (%): 100. We thus obtain a first biomaterial in accordance with the invention BM1 comprising hydroxyapatite and core / shell particles of Zn / ZnOnano.

[0186] Figure 3 represents an image of a biomaterial in accordance with the invention obtained following 3D printing.

[0187] Example 5: characterization of crosslinked biomaterials

[0188] 5.1 Characterization of mechanical properties

[0189] The mechanical properties of different biomaterials were obtained using a traction and compression system sold under the trade name Zwick Roell Proline Z005 by the company Zwick Roell, coupled with a 5 kN load cell. The crosslinkable composition samples were printed in the form of test pieces marked "E" (40 mm long, 4 mm wide and 1 mm thick) and cylinders marked "C" (12 mm long and 6 mm in diameter). The test pieces were then clamped between jaws and pulled at a speed of 0.05 mm. s -1 until they break. This provides an indication of the tensile mechanical properties. The cylinders are compressed by two platforms at a speed of 0.1 mm. s -1This provides an indication of the mechanical properties in compression. Zwick Roell software is capable of calculating Young's modulus, maximum force exerted, maximum force at break and elongation at break. Several specimens are printed with the same crosslinkable composition in order to make a statistical measurement of each of the parameters.

[0190] The biomaterials tested for their mechanical properties are as follows:

[0191] - a biomaterial printed in the form of test pieces (E1) and cylinders (C1) from the crosslinkable composition CR1 as prepared in example 2 above,

[0192] - a biomaterial printed in the form of test pieces (EO-A) and cylinders (CO-A) from the crosslinkable composition CRO-A as prepared in comparative example 3 above,

[0193] - a biomaterial printed in the form of test pieces (EO-B) and cylinders (CO-B) from the crosslinkable composition CRO-B as prepared in comparative example 3 above, and - a biomaterial printed in the form of test pieces (EO) and cylinders (CO) from 150 ml of a polylactic acid (PLA) based solution (eSun, “transparent eResin-PLA”).

[0194] Figure 4 illustrates the Young's moduli (in Gpa) of biomaterials EO, EO-A, EO-B, and E1 (Figure 4-a); the stresses at break (in MP) of biomaterials EO, EO-A, E0-B, and E1 (Figure 4-b); the elongations at break (in %) of biomaterials EO, E0-A, EO-B, and E1 (Figure 4-c); and the curves of standard force (in Newton, N) as a function of elongation at break (in %) (Figure 4-d).

[0195] Figure 5 illustrates the Young's moduli (in Gpa) of the biomaterials CO, CO-A, CO-B, and C1 (Figure 5-a); the stresses at break (in MP) of the biomaterials CO, CO-A, CO-B, and C1 (Figure 5-b); the elongations at break (in %) of the biomaterials CO, CO-A, CO-B, and C1 (Figure 5-c); and the standard force (in Newton, N) versus elongation at break (in %) curves of the biomaterials CO, CO-A, CO-B, and C1 (Figure 5-d).

[0196] 5.2 Characterization of chemical compositions

[0197] In order to be able to characterize the biomaterials of the invention, a flat cylinder-shaped pellet, denoted “P” (2 mm thick and 10 mm in diameter), is 3D printed from a crosslinkable composition.

[0198] Energy dispersive X-ray spectroscopy (EDX) analyses were performed using an apparatus described in Example 1 on this printed biomaterial pellet.

[0199] To do this, three parts of a P5 pellet obtained from the crosslinkable composition CR5 were analyzed and grouped, under three different spectra, on the surface and in the core. Table 5 below shows the average of the three mass percentages present on the different spectra, on the surface and in the core.

[0200] TABLE 5 A mapping of the different elements zinc, oxygen, carbon and calcium present in the biomaterial of the invention was carried out on the surface and in the heart of the P5 pellet using energy dispersive X-ray spectroscopy (EDX).

[0201] Figure 6 illustrates the presence of carbon (Figure 6-a), oxygen (Figure 6-b), calcium (Figure 6-c) and zinc (Figure 6-d) on the surface of the P5 biomaterial.

[0202] Figure 7 illustrates the presence of carbon (Figure 6-a), oxygen (Figure 6-b), calcium (Figure 6-c) and zinc (Figure 6-d) in the core of the P5 biomaterial.

[0203] These figures reveal the homogeneity of the biomaterial of the invention, in particular the homogeneous repair of calcium and zinc.

[0204] 5.3 Study of the antibacterial properties of the biomaterials in accordance with the invention

[0205] In order to be able to characterize the biomaterials of the invention, several flat cylinder-shaped pellets, noted “P1” (2 mm thick and 6 mm in diameter, 40 mg in mass), are 3D printed from the crosslinkable composition CR1.

[0206] Strains of Escherichia Coli (-), and Staphylococcus aureus (+) were subcultured onto blood agar, then the next day the pellets were distributed in a certain volume of bacterial suspension having a concentration of 10 6CFU / ml in a broth under the commercial reference “Tryptone-salt”, so as to obtain a range of concentrations from 0.002 g / ml to 0.2 g / ml for each bacterial strain. Table 6 below shows the concentration of the different tubes containing the pellets in a given volume of bacterial suspension (in ml). A duplicate is made for each of the strains. The negative control T(-) corresponds to a pellet P1 which is placed in a “Tryptone-salt” broth without bacteria. The positive control T(+) corresponds to the bacterial suspension without pellet.

[0207] TABLE 6

[0208] Figure 8 shows the optical density (OD) of each tube, measured at 620 nm at time zero (gray diagrams, “control”) and after incubation at 37°C for 24 hours with shaking at 150 rpm (black diagrams, “T24h”) for the bacterial strains E. Coli and S. Aureus.

[0209] The antibacterial activity of the biomaterial corresponding to the P1 pellet is effective against E. Coli and S. Aureus from a concentration of 0.01 g / ml.

[0210] Example 6: Process for preparing a crosslinkable composition in accordance with the invention and a crosslinked biomaterial in accordance with the invention

[0211] 58 ml of a polylactide diol monomer (marketed by eSun under the reference PLA205B when the diol is 1,4-butanediol or PLA205M when the diol is ethylene glycol), 1 g of hydroxyapatite and 1 g of Zn / ZnOnano particles as prepared in Example 1.1, are added to a 250 ml flask to form a first composition.

[0212] In parallel, in a 100 ml beaker, 3 g of diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819, purity 97%, CAS 162881-26-7, Sigma-Aldrich), as a photoinitiator, are added to 39 ml of triethylene glycol dimethacrylate (TEGDMA) (contains 80-120 ppm of methyl hydroquinone as an inhibitor, purity 95%, CAS 109-16-0, Sigma-Aldrich), as a diluent, to form a photoinitiator solution. This photoinitiator solution is stirred magnetically for 40 min at 30°C. Then, it is added to the first composition previously prepared to form a resulting composition.

[0213] The resulting composition is placed under mechanical stirring at 400 rpm for 3 hours, then under ultrasound for 40 minutes, at an amplitude of 60% using an ultrasonic homogenizer sold under the trade name Sonopuls, then under magnetic stirring for 1 hour. To eliminate any bubbles that may have formed in the crosslinkable composition, it is placed in an ultrasonic bath for 10 minutes.

[0214] The as-prepared crosslinkable composition is 3D printed in the form of layers using a device sold under the trade name “Accufab-D1” by Shinning 3D with the conditions as described in Example 4.

[0215] Example 7: Process for preparing a crosslinkable composition in accordance with the invention and a crosslinked biomaterial in accordance with the invention T1

[0216] 58 ml of polylactic acid, a,co-bis(methacrylate) (marketed by Specific Polymers, CAS 488834-04-4, internal reference SP-2P-7-004), 1 g of hydroxyapatite and 1 g of Zn / ZnOnano particles as prepared in Example 1.1, are added to a 250 ml flask to form a first composition.

[0217] In parallel, in a 100 ml beaker, 3 g of diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819, purity 97%, CAS 162881-26-7, Sigma-Aldrich), as a photoinitiator, are added to 39 ml of triethylene glycol dimethacrylate (TEGDMA) (contains 80-120 ppm of methyl hydroquinone as an inhibitor, purity 95%, CAS 109-16-0, Sigma-Aldrich), as a diluent, to form a photoinitiator solution. This photoinitiator solution is stirred magnetically for 40 min at 30°C. Then, it is added to the first composition previously prepared to form a resulting composition.

[0218] The resulting composition is placed under mechanical stirring at 400 rpm for 3 hours, then under ultrasound for 40 minutes, at an amplitude of 60% using an ultrasonic homogenizer sold under the trade name Sonopuls, then under magnetic stirring for 1 hour. To eliminate any bubbles that may have formed in the crosslinkable composition, it is placed in an ultrasonic bath for 10 minutes.

[0219] The as-prepared crosslinkable composition is 3D printed in the form of layers using a device sold under the trade name “Accufab-D1” by Shinning 3D with the conditions as described in Example 4.

[0220] Example 8: Process for preparing a crosslinkable composition in accordance with the invention and a crosslinked biomaterial in accordance with the invention

[0221] 58 ml of poly(lactic-co-caprolactone) a,cü-bis(methacrylate) acid (marketed by Specific Polymers, internal reference SP-POL-182), 1 g of hydroxyapatite and 1 g of Zn / ZnOmicro particles as prepared in Example 1.2, are added to a 250 ml flask to form a first composition.

[0222] In parallel, in a 100 ml beaker, 3 g of diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819, purity 97%, CAS 162881-26-7, Sigma-Aldrich), as a photoinitiator, are added to 39 ml of triethylene glycol dimethacrylate (TEGDMA) (contains 80-120 ppm of methyl hydroquinone as an inhibitor, purity 95%, CAS 109-16-0, Sigma-Aldrich), as a diluent, to form a photoinitiator solution. This photoinitiator solution is stirred magnetically for 40 min at 30°C. Then, it is added to the first composition previously prepared to form a resulting composition.

[0223] The resulting composition is placed under mechanical stirring at 400 rpm for 3 hours, then under ultrasound for 40 minutes, at an amplitude of 60% using an ultrasonic homogenizer sold under the trade name Sonopuls, then under magnetic stirring for 1 hour. To eliminate any bubbles that may have formed in the crosslinkable composition, it is placed in an ultrasonic bath for 10 minutes. The crosslinkable composition as prepared is 3D printed in the form of layers using a device sold under the trade name “Accufab-D1” by Shinning 3D with the conditions as described in Example 4.

Claims

Claims 1. Crosslinkable polymer composition, characterized in that it comprises: - at least one biodegradable biocompatible organic polymer or at least one of its precursors, - at least one calcium phosphate, and - at least zinc core / shell / zinc oxide particles.

2. Composition according to claim 1, characterized in that the calcium phosphate represents from 0.1 to 10% by mass, relative to the total mass of the crosslinkable composition.

3. Composition according to claim 1 or 2, characterized in that the calcium phosphate is hydroxyapatite.

4. Composition according to any one of the preceding claims, characterized in that the zinc core / shell / zinc oxide particles have a size ranging from 0.1 to 200 μm.

5. Composition according to any one of the preceding claims, characterized in that the zinc / zinc oxide represents from 0.1 to 25% by mass, relative to the total mass of the crosslinkable composition.

6. Composition according to any one of the preceding claims, characterized in that the biocompatible biodegradable organic polymer is chosen from aliphatic polyesters, polysaccharides, polyorthoesters, polyanhydrides, polyphosphazenes, polyacrylates, and polyurethanes.

7. Composition according to any one of the preceding claims, characterized in that the organic polymer is a polylactide.

8. Composition according to any one of the preceding claims, characterized in that it further comprises a photoinitiator.

9. Composition according to any one of the preceding claims, characterized in that it further comprises at least one compound comprising one or more reactive functions.

10. Process for the preparation of a composition as defined in any one of the preceding claims, characterized in that it comprises at least one step i) of mixing zinc / zinc oxide core / shell particles and calcium phosphate particles in a protic polar solvent, to form a dispersion, and one step ii) of adding a biocompatible and biodegradable organic polymer or one of its precursors to the dispersion of step i).

11. Biomaterial, characterized in that it can be obtained by photopolymerization of one or more layers of a crosslinkable composition as defined in any one of claims 1 to 9.

12. Method for manufacturing a biomaterial, characterized in that it comprises at least one step A) of photopolymerization of one or more layers of a crosslinkable composition as defined in any one of claims 1 to 9.

13. Method according to claim 12, characterized in that the photopolymerization A) is carried out by 3D printing.

14. Biomaterial as defined in claim 11 or obtained according to a process as defined in claim 12 or 13, for its medical use.

15. Biomaterial as defined in claim 11 or obtained according to a method as defined in claim 12 or 13, for its use in bone regeneration and the prevention and / or treatment of oral infections linked to implantation.

16. Bone substitute capable of receiving a dental implant, characterized in that it comprises a biomaterial as defined in claim 11 or obtained according to a process as defined in claim 12 or 13.

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