Biomaterials for use in dentistry

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, a biomaterial obtainable by photopolymerization of such a crosslinkable polymer composition, methods for preparing such a composition and such a biomaterial, and the use of such a biomaterial for various applications in the health sector.

Description

Detailed Description of the Invention

[0001] 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, methods for preparing such a composition and such a biomaterial, and the use of such a biomaterial for various applications in the health sector.

[0002] Currently, over 60% of the population in industrialized countries requires implant-based prosthetic rehabilitation. In Europe, approximately 1.5 million patients undergo bone reconstruction during maxillofacial surgery each year. Dental implants are an alternative treatment for replacing missing teeth. To achieve optimal results with these dental implants, sufficient bone must be available to accommodate and stabilize the implant. However, tooth loss, regardless of cause, is usually accompanied by varying degrees of alveolar bone resorption. Such bone resorption can be a contraindication to dental implant placement, which requires extremely precise positioning and perfect long-term stability. Consequently, having sufficient bone volume is essential for optimal results during dental implant placement. Reconstruction of alveolar bone through restorative / regenerative surgery has become standard practice: particularly when bone deficiencies exceed 3 mm in width and / or height, bone grafting, more specifically autologous bone grafting (bone harvested directly from the patient), is performed to restore a favorable anatomical condition for implant placement in terms of both quantity and density. In this case, a second surgical site is opened to harvest the bone needed to reconstruct the area to be augmented. However, augmentation requires skills only possessed by experienced professionals. Furthermore, autologous bone grafting is associated with increased morbidity, patient discomfort, and prolonged surgical procedures. Specifically, the surgical procedure is performed at two different surgical sites, making it very long and painful for the patient; and a waiting period of 4 to 6 months is usually required before the implant can be placed to allow the grafted bone to integrate with the host bone. Furthermore, after bone surgery, patients must take antibiotics to prevent infection. In fact, oral infections can pose a real health risk, especially for patients with autoimmune diseases or other medical conditions such as diabetes. In addition, the amount of bone graft available in the oral cavity is limited and may not be sufficient to meet the requirements. Another major drawback of autologous bone grafting is the variable degree of resorption that occurs over time. Resorption is particularly pronounced in cancellous bone, varying from 12 to 60% after implant placement (1 to 5 years).

[0003] Allogeneic (from an individual of the same species as the recipient), xenogeneic (from an individual of a different species than the recipient), and synthetic (synthetic) bone substitute biomaterials have been proposed to replace autologous bone grafts. Allogeneic and xenogeneic biomaterials require a potential donor and numerous processing and / or preparation steps before use. Synthetic biomaterials can also be used as bone substitutes in bone replacement and reconstruction. They are infinitely available, do not require bone banks, and do not pose the risk of pathogen transmission. Currently, several synthetic materials are used in oral dentistry: tricalcium phosphate, calcium carbonate, synthetic hydroxyapatite, biphasic ceramics, composites, and bioglass. Synthetic materials must be biocompatible, bioactive, and osteoconductive, and may or may not be resorbable.

[0004] In particular, hydroxyapatite is often used as an implant for artificial replacement of hard tissue in dental surgery. Its structural characteristics, such as its size and morphology, vary depending on the synthesis method used. Due to its high absorption capacity and its binding affinity with polyvalent molecules, hydroxyapatite is particularly used in the form of nanoparticles for gene and protein delivery and artificial bone regeneration. However, hydroxyapatite is a compound that is insufficient in terms of mechanical strength, fracture resistance, and fatigue strength.

[0005] Jeong HJ. et al. [Int. J. Mol. Sci., (Switzerland), 2020, Vol. 21, 1863, pp. 1-15] describe a three-dimensional (3D) hybrid material based on hydroxyapatite or tricalcium phosphate and polycaprolactone. The hybrid material is prepared as follows: a polycaprolactone structure sized to accept a metal implant is fabricated by 3D printing, and then particles of polycaprolactone, hydroxyapatite, tricalcium phosphate, poly(ethylene oxide), and sodium chloride are mixed. The resulting mixture is then injected into the structure. The assembly is then heated in an oven at 80°C for 10 minutes and then washed with deionized water to remove the poly(ethylene oxide) and sodium chloride. The resulting hybrid material is porous and possesses osteoconductive properties. It is reported that the material can regenerate alveolar bone during dental implant placement. However, this material does not eliminate the risk of oral infection. Furthermore, its mechanical properties remain weak.

[0006] Consequently, the goal of the present invention is to overcome the drawbacks of the prior art and, in particular, to provide a biocompatible and biodegradable biomaterial that has excellent mechanical and antibacterial properties, and that can be easily adapted to the patient's dental and / or maxillofacial morphology while ensuring excellent osteoconductive and resorbable properties. In particular, there is a need for a bone support or substitute for dental implant placement. A first object of the present invention is a crosslinkable polymer composition comprising: - at least one biocompatible, biodegradable organic polymer or at least one of its precursors, and preferably at least one of its precursors, at least one calcium phosphate; - at least zinc-zinc oxide core-shell particles; The composition is characterized by comprising:

[0007] The crosslinkable compositions of the present invention can readily provide biomaterials for use as bioactive bone substitutes for dental applications, particularly for treating patients with missing teeth. The crosslinkable compositions provide biocompatible and biodegradable biomaterials with improved mechanical properties, antibacterial properties, and the ability to easily conform to the patient's dental and / or maxillofacial morphology, particularly by 3D printing as described in more detail below, while ensuring excellent osteoconductive and resorbable properties. The biomaterials can then be used as bone substitutes for dental implant placement in a single operation using a technique that is easier for the practitioner and therefore more reliable for the patient.

[0008] In the present invention, the term "osteoconduction" refers to the ability of a biomaterial to act as a matrix onto which surrounding vascular and bone cells can attach, thereby allowing these cells to migrate to the implanted site, colonize it, vascularize it, and synthesize new bone matrix. The calcium phosphate provides the osteoconductive properties of the crosslinkable composition. In the present invention, calcium phosphate is understood to be an inorganic material containing phosphorus and calcium. The calcium phosphate used in the crosslinkable composition preferably has a calcium / phosphorus atomic ratio that is close to that of bone (about 1.6).

[0009] Preferably, the calcium phosphate is hydroxyapatite (Hap) (chemical formula Ca(PO)(OH) or Ca 10 (PO4)6(OH)2), tricalcium phosphate (of the formula Ca3(PO4)2 or TCP), monocalcium phosphate (of the formula Ca(H2PO4)2 or MCPM), dicalcium phosphate (DCP), or octacalcium phosphate. Hydroxyapatite is particularly preferred, particularly since it has a Ca / P ratio that gives it bone-like properties.

[0010] The calcium phosphate preferably represents about 0.1 to 10% by weight, more preferably about 0.5 to 2% by weight, based on the total weight of the crosslinkable composition, and particularly above 10% by weight, the crosslinkable composition becomes difficult to print, especially by 3D printing using photopolymerization. The calcium phosphate is preferentially in the form of particles with a size ranging from about 100 nm to 25 μm, particularly preferably from about 200 nm to 20 μm.

[0011] In the present invention, the size of the calcium phosphate particles is determined by methods well known to those skilled in the art, preferentially by dynamic light scattering, laser granulometry or scanning electron microscopy, preferably by dynamic light scattering or scanning electron microscopy. The zinc-zinc oxide particles of the crosslinkable composition of the present invention comprise a zinc core and a zinc oxide shell. The zinc-zinc oxide particles preferentially have a size in the range of about 0.1 to 200 μm, particularly preferably about 1 to 50 μm.

[0012] In the present 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, preferentially dynamic light scattering, in which case the present invention refers to the hydrodynamic diameter.

[0013] Zinc-zinc oxide preferably represents about 0.1 to 25% by weight, particularly preferably about 0.1 to 20% by weight, even more preferably about 1 to 15% by weight, and even more preferably about 1 to 10% by weight, based on the total weight of the crosslinkable composition.

[0014] According to a preferred embodiment of the present invention, the zinc-zinc oxide particles contain about 51 to 90% by weight of zinc oxide, particularly preferably about 60 to 80% by weight of zinc oxide, based on the total weight of the zinc-zinc oxide particles. The zinc oxide shell or layer may have a thickness in the range of about 1 to 1000 nm, particularly preferably about 300 to 800 nm. The thickness is measured in particular using a scanning electron microscope, a transmission electron microscope, or an atomic force microscope, preferably by a scanning electron microscope.

[0015] This zinc oxide layer or shell differs in particular in its thickness from the zinc oxide layer that may possibly form naturally around the zinc, for example by air oxidation, which may in fact have a maximum thickness of a few tenths of a nanometer.

[0016] The zinc-zinc oxide particles provide the antibacterial activity of the crosslinkable composition, which is then fully retained in the biomaterial obtained from the crosslinkable composition.

[0017] Unlike prior art techniques that use as germicides noble metals such as silver, which induce a certain degree of toxicity upon release, or photoactive materials that require radiation (e.g., ultraviolet light) to be activated, the zinc-zinc oxide particles used in the crosslinkable compositions of the present invention are non-toxic to patients, are slowly released by biomaterials, and have excellent germicidal activity without the need for external stimuli such as light irradiation. Finally, the combination of zinc and zinc oxide enhances bone cell differentiation and the mineralization properties of hydroxyapatite.

[0018] In the present invention, the term "biodegradable organic polymer" means an organic polymer that can be decomposed or digested by microorganisms (e.g. bacteria, fungi, algae), for example by the action of enzymes. The reaction involved in biodegradation in the human body is hydrolysis, i.e. the cleavage of covalent bonds by reaction with water (see current standard NF EN 13 432).

[0019] In the present invention, the term "biocompatible organic polymer" means an organic polymer that has the ability not to interfere with and not to disrupt the biological environment in which it is used. In particular, the polymer should not cause a strong inflammatory reaction (e.g., allergy) and / or be toxic to humans.

[0020] In the present invention, the term "organic polymer" refers to a polymer that contains at least a carbon atom covalently bonded to a hydrogen, oxygen, nitrogen, or sulfur atom. In other words, an organic polymer contains organic repeating units, i.e., repeating units that contain at least a carbon atom covalently bonded to a hydrogen, oxygen, nitrogen, or sulfur atom. Preferably, the organic polymer does not contain metals or metalloids. In other words, the organic polymer does not contain metals or metalloids such as silicon, is different from polysiloxane chains, or does not contain Si-O bonds.

[0021] The biocompatible, biodegradable organic polymers may be selected from aliphatic polyesters, polysaccharides, polyorthoesters, polyanhydrides, polyphosphazenes, polyacrylates and polyurethanes. In the present invention, polymers include both homopolymers and copolymers.

[0022] Examples of aliphatic polyesters include polyglycolide (i.e., poly(glycolic acid) or PGA), polylactide (i.e., poly(lactic acid) or PLA), glycolide-lactide copolymer (PLGA), polylactone (e.g., poly(ε-caprolactone)), polyhydroxyalkanoates (e.g., polyhydroxyvalerate, poly(hydroxybutyrate)), poly(aliphatic ester-urethane) copolymers, and preferably polyglycolide (i.e., poly(glycolic acid) or PGA), polylactide (i.e., poly(lactic acid) or PLA), and glycolide-lactide copolymer (PLGA). Examples of polysaccharides include cellulose or starch. Examples of polyanhydrides include poly(isophthalic anhydride) or poly(terephthalic anhydride). Examples of polyphosphazenes include polydichlorophosphazene. Examples of polyacrylates include polyethyl acrylate or polymethyl acrylate. Examples of polyorthoesters include Class I POE, Class II POE, Class III POE, or Class IV POE. According to a preferred embodiment of the present invention, the organic polymer is an aliphatic polyester, and particularly preferably a polylactide.

[0023] PLA is particularly suitable for bone tissue engineering due to its high dimensional stability and modularity. PLA is a biodegradable, bioabsorbable, and biocompatible thermoplastic aliphatic polyester that can be synthesized by various methods, allowing for tailoring of its mechanical properties, biodegradation, geometric shape, and structure. Precursors to one of the biodegradable, biocompatible organic polymers can also be used in the crosslinkable composition. The precursor may be an organic monomer or oligomer.

[0024] The organic monomers or oligomers can be used to form biodegradable, biocompatible organic polymers as defined herein by polymerization, preferentially by photopolymerization. The precursors may be selected from aliphatic esters, polyhydric alcohols and acrylates.

[0025] Examples of aliphatic esters include lactide, lactic acid, glycolic acid, glycolide, lactones (eg, ε-caprolactone) or hydroxyalkanoates (eg, hydroxyvalerate, hydroxybutyrate).

[0026] The precursors of the biodegradable, biocompatible organic polymers preferably have a molar mass in the range of about 100 to 10,000 g / mol, particularly preferably about 500 to 2,000 g / mol.

[0027] According to a preferred embodiment of the present invention, the biodegradable, biocompatible organic polymer (respectively, the precursor of the biodegradable, biocompatible organic polymer) represents approximately 20 to 70% by weight, particularly preferably approximately 25 to 65% by weight, and even more preferably approximately 30 to 60% by weight, of the total weight of the crosslinkable composition.

[0028] The viscosity of the crosslinkable composition is about 0.1 to 100 Pa·s (0.1 to 100 kg·m -1 ·s -1 ), and particularly preferably about 0.1 to 0.5 Pa s (0.1 to 0.5 kg m -1 ·s -1 ), which facilitates the formation of biomaterials by 3D printing. In the present invention, viscosity is measured using a rheometer at 25°C and 10 rad·s -1 It is measured at a shear rate of . The crosslinkable composition of the present invention is a liquid composition at room temperature (ie, 18 to 25°C).

[0029] The crosslinkable compositions of the present invention have the advantage of being 3D printable compositions, in particular printable by any 3D printing method involving photopolymerization, such as digital light processing (DLP), stereolithography (SLA printing) or UV-LCD printing (LCD screen). Preferably, the crosslinkable composition further comprises a photoinitiator (or photopolymerization initiator). The photoinitiator can be selected from Type I or II photoinitiators.

[0030] Examples of Type I photoinitiators include ethyl (2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L) or diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (BAPO).

[0031] 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.

[0032] Preferably, the crosslinkable composition further comprises at least one compound having one or more reactive functional groups, such as acrylate, methacrylate or epoxy functional groups. The reactive functional groups may be present directly on the precursors of the biodegradable, biocompatible organic polymer, for example in terminal positions.

[0033] A second object of the present invention is a method for preparing a crosslinkable composition according to the first object of the present 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 polar protic solvent to form a dispersion, and step ii) of adding to the dispersion of step i) a biocompatible and biodegradable organic polymer or one of its precursors, preferably one of its precursors.

[0034] The zinc-zinc oxide core-shell particles, calcium phosphate, biocompatible and biodegradable organic polymer and one of its precursors are as defined in the first object of the present invention. The polar protic solvent may be selected from C1-C5 alcohols. The polar protic solvent is preferably ethanol.

[0035] The polar protic solvent ensures good dispersion of the zinc-zinc oxide core-shell particles and calcium phosphate particles while ensuring easy removal in subsequent steps.

[0036] The zinc-zinc oxide core-shell particles preferably represent about 0.1 to 20% by weight, particularly preferably about 1 to 5% by weight, of the total weight of the dispersion obtained in step i).

[0037] The calcium phosphate particles preferably account for about 0.1 to 10% by weight, particularly preferably about 0.5 to 2% by weight, of the total weight of the dispersion obtained in step i). Preferably, step i) is carried out using ultrasound. Step i) may include mechanical agitation, preferably followed by ultrasound. Step ii) forms a crosslinkable composition according to the first object of the present invention. Step ii) can be carried out using mechanical stirring, which makes it possible to obtain a homogeneous composition. Mechanical stirring can be followed by magnetic stirring, which allows the polar protic solvent to evaporate. After the polar protic solvent has evaporated, step ii) may involve homogenizing the composition using ultrasound.

[0038] A photoinitiator and / or a compound having one or more reactive functional groups as defined in the first object of the present invention is preferentially added in step ii), advantageously simultaneously with the biodegradable, biocompatible organic polymer. The zinc-zinc oxide core-shell particles are preferentially:

[0039] u) contacting a salt of Zn(II) ions, such as zinc(II) nitrate, sulfate, acetate or chloride, preferably in an aqueous solution, with a strong base, such as potassium hydroxide or sodium hydroxide, preferably in an aqueous solution; and v) adding zinc metal particles (i.e., zinc(0)) to form a resulting composition (which changes color from clear to black); is obtained by The zinc(0) can be pre-washed before use in an acidic medium (for example a 1% by volume hydrochloric acid solution), preferably with stirring, for example by centrifugation.

[0040] The resulting solids formed in the composition can then be washed, preferably with water and / or a C1-C3 alcohol, and optionally dried. At the end of step u), the pH of the resulting solution is 14 or greater. The zinc metal particles are preferentially in the size range of about 0.04 μm to 10 μm, particularly preferably about 1 to 10 μm. The molar ratio of zinc(0) / zinc(II) salt in step v) can be in the range of 0.1-90, preferably 0.6-70.

[0041] This ratio depends on the size of the zinc-zinc oxide core-shell particles that one wishes to obtain: specifically, the higher the ratio, the larger the size of the zinc-zinc oxide core-shell particles.

[0042] This simple, economical and easy to implement method differs from methods known in the prior art, such as laser ablation of zinc particles, which are expensive, complex and / or do not allow fine tuning of the amount of ZnO relative to Zn in the particles. A third object of the invention is a biomaterial, characterized in that it is obtained by photopolymerization of one or more layers of a crosslinkable composition according to the first object of the invention.

[0043] In the present invention, the term "biomaterial" means a material intended to come into contact with biological tissues and / or biological fluids in order to evaluate, treat, modify or substitute for any tissue, organ or function of the body (Consensus de Chester, UK, 1991).

[0044] The biomaterial of the present invention can have a Young's modulus of at least about 1 GPa, preferably at least 2 GPa, and particularly preferably in the range of about 2 to 3 GPa. The biomaterial of the present invention can have an elongation at break of at least about 5%, preferably at least about 6%, and particularly preferably in the range of about 5 to 15%.

[0045] The biomaterial of the present invention can have a breaking stress of at least about 100 MPa, preferably at least about 120 MPa, and particularly preferably in the range of about 100 to 200 MPa. The biomaterial is formed by photopolymerizing one or more layers of a crosslinkable composition according to the first object of the present invention.

[0046] Photopolymerization ensures that the bactericidal and osteoconductive properties of the crosslinkable composition are maintained. Furthermore, the addition of zinc-zinc oxide and calcium phosphate particles does not reduce or even maintain the mechanical properties of the biocompatible and biodegradable organic polymer used in the crosslinkable polymer composition.

[0047] Photopolymerization or radiation curing of crosslinkable compositions is carried out with light, especially UV light. Radiation curing is much faster than thermal processing, allowing for faster production speeds and reduced facility space. Preferably, the photopolymerization is carried out at a wavelength in the range of about 385 nm to 405 nm, advantageously at about 405 nm.

[0048] Photopolymerization is preferably carried out by 3D printing, particularly preferably by any 3D printing that performs photopolymerization, such as digital light processing (DLP printing), stereolithography (SLA printing), or UV-LCD printing. In this embodiment, the crosslinkable composition is polymerized using a UV light projector and an adjustable reflector. In this way, the crosslinkable composition can be solidified over the entire surface, one layer at a time. The biomaterial is thus formed layer by layer. 3D printing makes it fast and easy to create complex shapes and desired patient-specific geometries from medical images.

[0049] As a result, this allows more practitioners to perform dental implant placement using simpler, more reliable techniques and without causing inflammatory and infectious reactions. The practitioner can obtain the implanted biomaterial immediately after scanning the patient, either by printing the bone substitute itself or through a fellow dental technician. Furthermore, by reducing the number of surgeries, dental implant placement can become more affordable and the procedure less painful for the patient. The biomaterial preferably comprises zinc-zinc oxide core-shell particles, calcium phosphate, and a photocrosslinked polymeric material.

[0050] A fourth object of the present invention is a method for producing a biomaterial, characterized in that it comprises at least one step A) of photopolymerizing one or more layers of a crosslinkable composition according to the first object of the present invention.

[0051] According to a preferred embodiment of the invention, step A) is carried out by 3D printing, advantageously by Digital Light Processing (DLP printing). The layer of the crosslinkable composition may have a thickness in the range of about 5 to 100 μm, particularly preferably about 25 to 100 μm. Step A) can be carried out at a temperature in the range of about 10 to 40°C. Step A) can be carried out for a period of time ranging from about 5 to 720 minutes per layer. Step A) can be carried out at a speed ranging from about 5 to 50 mm / h per layer. Step A) is approximately 20-50mW / cm per layer. 2 It can be performed in a range of light intensities. At the end of step A), a biomaterial according to the third object of the invention is preferably obtained. A fifth object of the present invention is a biomaterial for medical use, obtained by the method according to the third object of the present invention or according to the fourth object of the present invention.

[0052] A sixth object of the present invention is a biomaterial obtained by a method according to the third object of the present invention or according to the fourth object of the present invention, for use in bone regeneration and in the prevention and / or treatment of implant-related oral infections.

[0053] The biomaterial has excellent biocompatibility and resorption properties, as well as osteoinductive and osteoconductive properties that allow natural bone tissue to return to the implanted site. Thus, the biomaterial can be used as a bone substitute in dental applications, particularly for the placement of dental implants. In particular, the biomaterial allows for the gradual, controlled, and localized release of bactericidal zinc-zinc oxide particles at the treatment site, thereby avoiding the risk of infection during dental implant treatment.

[0054] In the present invention, the term "bone substitute" refers to a synthetic-derived biomaterial for implantation intended to reconstitute bone stock by reinforcing bone structure or filling bone loss.

[0055] The biomaterial of the present invention thus houses a dental implant in place of a natural graft. This type of biomaterial should be distinguished from prior art biomaterials, e.g. in the form of cages, which are used to hold an implant, and which are not then used to replace the natural graft.

[0056] A seventh object of the present invention is a bone substitute capable of accommodating a dental implant, characterized in that it contains a biomaterial obtained by the method according to the third object of the invention or according to the fourth object of the invention. The accompanying drawings illustrate the invention. [Brief explanation of the drawings]

[0057] [Figure 1]1 shows scanning electron microscope (SEM) images of nanometer or micrometer sized zinc particles not according to the invention and zinc-zinc oxide core-shell particles according to the invention. [Figure 2] FIG. 1 shows X-ray diffraction (XRD) spectra of nanometer or micrometer sized zinc particles not according to the invention, zinc oxide particles not according to the invention, and zinc-zinc oxide core-shell particles according to the invention. [Figure 3] FIG. 1 shows an image of a biomaterial according to the invention obtained by 3D printing. [Figure 4] 1 shows Young's modulus, stress at break, elongation at break, and standard force-tensile elongation at break curves for biomaterials according to the present invention and biomaterials not according to the present invention. [Figure 5] 1 shows Young's modulus, stress at break, elongation at break, and standard force-compression elongation at break curves for biomaterials according to the present invention and biomaterials not according to the present invention. [Figure 6] FIG. 1 illustrates the presence of carbon, oxygen, calcium and zinc on the surface of a biomaterial according to the present invention. [Figure 7] FIG. 1 shows the presence of carbon, oxygen, calcium and zinc in the core of a biomaterial according to the present invention. [Figure 8] FIG. 1 shows the antibacterial properties of the biomaterial according to the present invention.

[0058] Further features and advantages of the present invention will become apparent in light of the description of the non-limiting examples of crosslinkable compositions and biomaterials according to the present invention, and methods for their manufacture. [Example] Example 1: Method for producing zinc-zinc oxide core-shell particles 1.1 Zn-ZnO particles obtained from nanometer-sized zinc particles (Zn-ZnO nano )

[0059] In a first container (beaker), dissolve 1.48 g of zinc nitrate hexahydrate Zn(NO) 6H0 (98% purity, CAS 101966‐18‐6, Sigma-Aldrich) in 10 mL of distilled water to form a zinc nitrate solution.

[0060] In a second container (beaker), dissolve 2.75 g of potassium hydroxide KOH (90%, CAS 1310-58-3, Sigma-Aldrich) in 10 mL of distilled water to form potassium hydroxide solution. The zinc nitrate solution is then added to the potassium hydroxide solution and the resulting solution is magnetically stirred for several minutes.

[0061] Meanwhile, 0.2 g of nanometer-sized zinc particles (approximately 50 nm in diameter, >99% purity, CAS 7440-66-6, Sigma-Aldrich) are washed with 0.3 mL of a 1% by volume solution of hydrochloric acid (HCl) (35% by volume HCl, CAS 7647-01-0, Sigma-Aldrich) using a centrifuge (speed: 8500 rpm for 5 minutes). The washed zinc is then dissolved in the previously prepared solution to form a composition, which is maintained under magnetic stirring for 2 hours. The composition changes from transparent to black. 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. Zn-ZnO particles (Zn-ZnO) obtained from 1.2 micrometer-sized zinc particles micro )

[0062] In a first container (beaker), dissolve 1.48 g of zinc nitrate hexahydrate Zn(NO) 6H0 (98% purity, CAS 101966‐18‐6, Sigma-Aldrich) in 10 mL of distilled water to form a zinc nitrate solution.

[0063] In a second container (beaker), dissolve 3 g of potassium hydroxide KOH (90%, CAS 1310‐58‐3, Sigma‐Aldrich) in 10 mL of distilled water to form an aqueous potassium hydroxide solution. The potassium hydroxide solution is then added to the zinc nitrate solution and the resulting solution is magnetically stirred for several minutes.

[0064] Meanwhile, 2 g of micrometer-sized zinc particles (particle size approximately 10 μm, purity >98%, CAS 7440-66-6, Sigma-Aldrich) are washed with 2.6 mL of a 1% by volume solution of hydrochloric acid (HCl) (35% by volume HCl, CAS 7647-01-0, Sigma-Aldrich) using a centrifuge (speed 8500 rpm for 5 minutes). The washed zinc is then dissolved in the previously prepared solution obtained above to form a composition, which is maintained under magnetic stirring for 2 hours. The composition changes from transparent to gray. 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. 1.3 Characterization of Zn-ZnO core-shell particles

[0065] FIG. 1 shows the nanometer-sized zinc particles used in Example 1.1 (FIG. 1-a), the micrometer-sized zinc particles used in Example 1.2 (FIG. 1-b), and the Zn-ZnO particles prepared in Example 1.1. nano Zinc-zinc oxide core-shell particles (Fig. 1c) and Zn-ZnO prepared in Example 1.2 micro Scanning electron microscopy (SEM) images of zinc-zinc oxide core-shell particles (Figure 1-d) are shown. Scanning electron microscopy images were acquired using a scanning electron microscope sold by Hitachi under the trade name Hitachi S4800 SEM system.

[0066] SEM images reveal various structures: the original nanometer-sized zinc is in the form of slightly distorted spheres, with particle sizes less than 1 μm; the original micrometer-sized zinc is in the form of regular spheres with a diameter of about 2 μm; Zn-ZnO obtained from the original nanometer-sized zinc nano The particle morphology is sea-urchin-shaped spheres slightly smaller than 2 μm. Zn-ZnO obtained from the original micrometer-sized zinc. microThe particles are in the form of spheres ranging in size from 2 to 4 μm with a shell of ZnO nanopillars surrounding and covering the Zn surface. Dynamic light scattering analysis was performed using an instrument sold by MALVERN under the trade name ZetaSizer NS. The results obtained are shown in Table 1 below.

[0067] [Table 1]

[0068] The results in Table 1 show similar sizes to those obtained by scanning electron microscopy, except for the zinc-zinc oxide particles prepared in Example 1.1, which may be due to the large particle size variability and / or the fact that the zinc-zinc oxide core-shell particles prepared in Example 1.1 are largely agglomerated.

[0069] X-ray diffraction (XRD) analysis was performed using a Philips X'Pert diffractometer equipped with a PANalytical X'Pert Powder XRD System using CuKα radiation over the 2Θ angle range of 10° to 90°. Diffractograms were collected and integrated using X'Pert Data Collector software.

[0070] FIG. 2 shows the micrometer-sized zinc particles used in Example 1.2 (FIG. 2-a), the nanometer-sized zinc particles used in Example 1.1 (FIG. 2-b), commercially available zinc oxide particles (CAS number 1314-13-2) with a size of approximately 100 nm (FIG. 2-c), and the zinc-zinc oxide particles, Zn-ZnO, prepared in Example 1.2. micro (Fig. 2-d), and zinc-zinc oxide particles Zn-ZnO prepared in Example 1.1 nano (Figure 2-e) shows the XRD spectrum. The results indicate that the Zn-ZnO particles prepared in Examples 1.1 and 1.2 contain zinc and zinc oxide. Energy dispersive X-ray spectroscopy (EDX) analysis was performed using an instrument sold by Zeiss under the trade name Zeiss Evo ED15. Table 2 below lists the chemical composition of the resulting Zn-ZnO particles.

[0071] [Table 2]

[0072] SEM analysis of ultrathin sections cut from resin-embedded particles revealed that Zn-ZnO nano Zn-ZnO micro showed an average ZnO shell thickness of approximately 570 nm. Example 2: Method for preparing a crosslinkable composition according to the present invention

[0073] In a 250 mL container (beaker), 1.5 g of hydroxyapatite (Hap) (purity ≥ 97%, CAS 12167-74-7, Sigma-Aldrich, particle size approximately 200 nm) and 3 g of the Zn-ZnO prepared in Example 1 were added. nano or Zn-ZnO micro The core-shell particles are dispersed in 150 mL of ethanol (EtOH) to form a dispersion, which is subjected to an ultrasonic bath for 1 hour and then poured into a 500 mL vessel (flask) fitted with a mechanically controlled stirrer sold under the trade name Ika Labortechnik RW 20.n. The dispersion is stirred at 500 rpm for 30 minutes using the mechanically controlled stirrer.

[0074] 150 mL of a polylactic acid (PLA)-based solution (eSun, "eResin-PLA transparent") is added to the dispersion, and the resulting composition is maintained under mechanical stirring overnight. The resulting composition is then placed under magnetic stirring at 300 rpm for several days to evaporate the solvent. Finally, the composition is sonicated for 40 minutes at 60% amplitude using an ultrasonic homogenizer sold under the trade name Sonopuls, and then filtered to obtain the PLA, Zn-ZnO. nano A crosslinkable composition CR1 is formed containing PLA, Zn-ZnO, and hydroxyapatite. micro and a composition CR2 comprising hydroxyapatite.

[0075] The procedure detailed herein above was replicated using various amounts of hydroxyapatite and Zn-ZnO to form various crosslinkable compositions. Table 3 below lists the various crosslinkable compositions obtained using the appropriate ratios of hydroxyapatite and Zn-ZnO particles.

[0076] [Table 3]

[0077] To analyze the crosslinkable compositions, a rheometer sold by Anton Paar under the trade name Anton Paar MCR 302 was used.

[0078] To perform the analysis, 1 mL of sample is placed in the sample holder. The temperature of the rheometer is set at room temperature, i.e., 25 °C, for all measurements. Measurements are taken using a cone-plate geometry. 1–100 rad·s -1 The change in viscosity is monitored over time by varying the shear rate at . The shear rate selected for the measurements is 10 rad·s -1 Table 4 below shows the viscosity results (Pa·s or kg·m) obtained for the various crosslinkable compositions prepared below. -1 s -1) is a summary of

[0079] [Table 4] Comparative Example 3: Method for preparing a crosslinkable composition not according to the invention 3.1 Crosslinkable compositions without Zn-ZnO core-shell particles

[0080] In a first 500 mL beaker, dissolve 1.5 g of hydroxyapatite (Hap) (purity ≥ 97%, CAS 12167-74-7, Sigma-Aldrich, particle size approximately 200 nm) in 150 mL of ethanol (EtOH) to form a solution, which is subjected to an ultrasonic bath for 1 h and then magnetically stirred for 1 h.

[0081] In a second container (beaker), 150 mL of a polylactic acid (PLA)-based solution (eResin, "eResin-PLA transparent") is poured into 50 mL of EtOH, and the resulting solution is magnetically stirred for 1 hour. The resulting solution is added to the previously prepared hydroxyapatite solution. The resulting composition is then placed under magnetic stirring at 300 rpm for several days to evaporate the solvent. Finally, the composition is filtered to form a crosslinkable composition CR0-A comprising PLA and hydroxyapatite. 3.2 Hydroxyapatite-free crosslinkable compositions

[0082] In a 150 mL beaker, 2 g of Zn-ZnO prepared in Example 1) nano Disperse particles in 100mL of ethanol (EtOH) to form dispersion, which is placed in an ultrasonic bath for 1 hour.Then, pour this dispersion into a 500mL container (flask) that is attached to a mechanically controlled stirrer, which is sold under the trade name Ika Labortechnik RW 20.n.Use this mechanically controlled stirrer to stir this dispersion at 500 rpm for 30 minutes.

[0083] 100 mL of a polylactic acid (PLA)-based solution (eResin, "eResin-PLA transparent") is added to the dispersion, and the resulting composition is maintained under mechanical stirring at 60 rpm overnight. The resulting composition is then placed under magnetic stirring at 300 rpm for several days to evaporate the solvent. Finally, the composition is sonicated for 40 minutes at 60% amplitude using an ultrasonic homogenizer sold under the trade name Sonopuls, followed by magnetic stirring for 1 hour. Finally, the composition is filtered to form a crosslinkable composition CR0-B comprising PLA and Zn-ZnO. Example 4: Method for preparing crosslinked biomaterials according to the present invention

[0084] The crosslinkable composition CR1 prepared in Example 2 is 3D printed in the form of layers using a device sold by Shining 3D under the trade name "Accufab-D1", under the following conditions: - Layer thickness (mm): 0.1 - Exposure time (s): 4.10 - Exposure level: High power - Top pause time (s): 0.00 - Pause time at bottom (s): 2.00 - Extended exposure time (s): 15.00 - Extended exposure level: Medium power - Extended pause time at top (s): 0.00 - Extended pause time at bottom (s): 2.00 - Extended exposure layer: 3 - Extended exposure layer offset (mm): 0.05 - Contour offset (mm): 0.00 - X-axis scale offset rate (%): 100 - Y-axis scale offset rate (%): 100 - Exposure Time Offset (s): 0.00 - Extended Exposure Time Offset (s): 0.00 - Viscosity (%): 50 - Peeling speed: 6 - Different first layer thickness: No - Air bubble removal: No - Rapid printing: No - Basic printing time: 5.50 - Color: Red 128 / Green 128 / Blue 128 / Alpha 255 - Constant rotation angle around X axis (°): 0.00 - Constant rotation angle around Y axis (°): 0.00 - Constant rotation angle around Z axis (°): 0.00 - Constant resize of parts (%): 100 is used. The results showed that hydroxyapatite and Zn-ZnO nano 1 is a first biomaterial BM1 of the present invention comprising core-shell particles. FIG. 3 shows an image of the biomaterial according to the invention obtained after 3D printing. Example 5: Characterization of crosslinked biomaterials 5.1 Mechanical property characterization

[0085] The mechanical properties of various biomaterials were obtained using a 5 kN load cell connected to a tension-compression system sold by Zwick Roell under the trade name Zwick Roell Proline Z005. Samples of the crosslinkable compositions were printed in the form of test specimens marked "E" (40 mm long, 4 mm wide, and 1 mm thick) and cylinders marked "C" (12 mm long and 6 mm diameter). The test specimens were then clamped between the jaws and subjected to a force of 0.05 mm s -1 The cylinder itself was pulled by two platforms at a rate of 0.1 mm s until it broke. This provides an indication of the mechanical properties under tension. -1 The material is compressed at a rate of 1 / 300 sq. m / s. This provides an indication of the mechanical properties under compression. ZwickRoell software can calculate Young's modulus, maximum applied force, maximum breaking force, and breaking elongation. To obtain statistical measurements of each parameter, several test samples are printed using the same crosslinkable composition. The biomaterials tested for these mechanical properties were:

[0086] - printed biomaterials in the form of test samples (E1) and cylinders (C1) derived from the crosslinkable composition CR1 prepared in Example 2 hereinbefore,

[0087] - a test sample (E0-A) and a printed biomaterial in the form of a cylinder (C0-A) derived from the crosslinkable composition CR0-A prepared in Comparative Example 3 hereinbefore,

[0088] - printed biomaterials in the form of test samples (E0-B) and cylinders (C0-B) derived from the crosslinkable composition CR0-B prepared in Comparative Example 3 hereinbefore, and

[0089] - Test samples (E0) and printed biomaterials in the form of cylinders (C0) derived from 150 mL of a polylactic acid (PLA)-based solution (Esun, "eResin-PLA transparent") is.

[0090] Figure 4 shows the Young's modulus (GPa) of biomaterials E0, E0-A, E0-B, and E1 (Figure 4-a); the stress at break (MP) of biomaterials E0, E0-A, E0-B, and E1 (Figure 4-b); the elongation at break (%) of biomaterials E0, E0-A, E0-B, and E1 (Figure 4-c); and the standard force curve (Newton, N) based on the elongation at break (%) (Figure 4-d).

[0091] Figure 5 shows the Young's modulus (GPa) of biomaterials C0, C0-A, C0-B, and C1 (Figure 5-a); the stress at break (MP) of biomaterials C0, C0-A, C0-B, and C1 (Figure 5-b); the elongation at break (%) of biomaterials C0, C0-A, C0-B, and C1 (Figure 5-c); and the standard force curve (Newton, N) based on the elongation at break (%) of biomaterials C0, C0-A, C0-B, and C1 (Figure 5-d). 5.2 Characterization of Chemical Composition

[0092] To characterize the biomaterial of the present invention, flat cylindrical pellets marked with a "P" (2 mm thick and 10 mm diameter) are 3D printed from the crosslinkable composition. The printed biomaterial pellets were subjected to energy dispersive X-ray spectroscopy (EDX) analysis using the equipment described in Example 1.

[0093] For this purpose, three pellets P5 obtained from the crosslinkable composition CR5 were analyzed on the surface and in the core and compiled in three different spectra. Table 5 below shows the average of the three present weight percentages in the different spectra on the surface and in the core.

[0094] [Table 5]

[0095] Mapping of the various elements present in the biomaterial of the invention, zinc, oxygen, carbon and calcium, was carried out on the surface and in the core of pellet P5 using energy dispersive X-ray spectroscopy (EDX). FIG. 6 shows the presence of carbon (FIG. 6-a), oxygen (FIG. 6-b), calcium (FIG. 6-c) and zinc (FIG. 6-d) on the surface of biomaterial P5. Figure 7 shows the presence of carbon (Figure 6-a), oxygen (Figure 6-b), calcium (Figure 6-c) and zinc (Figure 6-d) within the core of biomaterial P5. These figures clearly show the homogeneity of the biomaterial of the present invention, especially the homogeneous restoration of calcium and zinc. 5.3 Investigation of the antibacterial properties of the biomaterial according to the present invention

[0096] To characterize the biomaterial of the invention, several flat cylindrical pellets marked "P1" (2 mm thick and 6 mm in diameter, weighing 40 mg) are 3D printed from the crosslinkable composition CR1.

[0097] A strain of Escherichia coli (-) and a strain of Staphylococcus aureus (+) were plated on blood agar, and the next day the pellets were transferred to a 10 ml broth of the commercial reference name "tryptone-salt" and diluted to 10 ml. 6 The pellets were distributed in a fixed volume of bacterial suspension at a concentration of CFU / mL, ranging from 0.002 g / mL to 0.2 g / mL for each bacterial strain. Table 6 below shows the concentration of the various tubes containing pellets in a given volume of bacterial suspension (mL). Duplicates were run for each bacterial strain. The negative control, T(-), corresponds to pellet P1 in "tryptone-salt" broth without bacteria. The positive control, T(+), corresponds to the bacterial suspension without pellets.

[0098] [Table 6]

[0099] FIG. 8 shows the optical density (OD) of each tube measured at 620 nm for E. coli and S. aureus bacterial strains at time 0 (gray graph, "Control") and after 24 hours of incubation at 37°C with agitation at 150 rpm (black graph, "T24h"). The antibacterial activity of the biomaterial corresponding to pellet P1 is effective against Escherichia coli and Staphylococcus aureus from a concentration of 0.01 g / mL. Example 6: Methods for preparing crosslinkable compositions according to the present invention and crosslinked biomaterials according to the present invention

[0100] 58 mL of polylactide diol monomer (commercially available from Esun as 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-ZnO prepared in Example 1.1 nano The particles are placed in a 250 mL flask to form a first composition.

[0101] In parallel, in a 100 mL beaker, 3 g of diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure® 819, 97% purity, CAS 162881-26-7, Sigma-Aldrich) as a photoinitiator is added to 39 mL of triethylene glycol dimethacrylate (TEGDMA) (containing 80-120 ppm methylhydroquinone as an inhibitor, 95% purity, CAS 109-16-0, Sigma-Aldrich) as a diluent to form a photoinitiator solution. This photoinitiator solution is magnetically stirred at 30 °C for 40 min. It is then added to the previously prepared first composition to form the resulting composition.

[0102] The composition is mechanically stirred at 400 rpm for 3 hours, then ultrasonically stirred for 40 minutes at 60% amplitude using an ultrasonic homogenizer sold under the trade name Sonopuls, and then magnetically stirred for 1 hour. In order to remove any air bubbles that may have formed in the crosslinkable composition, the composition is subjected to an ultrasonic bath for 10 minutes.

[0103] The prepared crosslinkable composition is 3D printed in the form of a layer using the equipment sold by Shining 3D under the trade name "Accufab-D1" and the conditions as described in Example 4. Example 7: Methods for preparing crosslinkable compositions according to the present invention and crosslinked biomaterials according to the present invention

[0104] 58 mL of polylactic acid α,ω-bis(methacrylate) (Specific Polymers, CAS 488834-04-4, internal reference number SP-2P-7-004), 1 g of hydroxyapatite, and 1 g of Zn-ZnO prepared in Example 1.1 nano The particles are placed in a 250 mL flask to form a first composition.

[0105] In parallel, in a 100 mL beaker, add 3 g of diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819, 97% purity, CAS 162881-26-7, Sigma-Aldrich) as a photoinitiator to 39 mL of triethylene glycol dimethacrylate (TEGDMA) (containing 80-120 ppm methylhydroquinone as an inhibitor, 95% purity, CAS 109-16-0, Sigma-Aldrich) as a diluent to form a photoinitiator solution. This photoinitiator solution is magnetically stirred at 30 °C for 40 min. It is then added to the previously prepared first composition to form the resulting composition.

[0106] The composition is mechanically stirred at 400 rpm for 3 hours, then ultrasonically stirred for 40 minutes at 60% amplitude using an ultrasonic homogenizer sold under the trade name Sonopuls, and then magnetically stirred for 1 hour. In order to remove any air bubbles that may have formed in the crosslinkable composition, the composition is subjected to an ultrasonic bath for 10 minutes.

[0107] The prepared crosslinkable composition is 3D printed in the form of a layer using the equipment sold by Shining 3D under the trade name "Accufab-D1" and the conditions as described in Example 4. Example 8: Methods for preparing crosslinkable compositions according to the present invention and crosslinked biomaterials according to the present invention

[0108] 58 mL of poly(lactic acid-co-caprolactone) α,ω-bis(methacrylate) (manufactured by Specific Polymers, in-house reference number SP-POL-182), 1 g of hydroxyapatite, and 1 g of Zn-ZnO prepared in Example 1.2 micro The particles are added to a 250 mL flask to form a first composition.

[0109] In parallel, in a 100 mL beaker, add 3 g of diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (Irgacure 819, 97% purity, CAS 162881-26-7, Sigma-Aldrich) as a photoinitiator to 39 mL of triethylene glycol dimethacrylate (TEGDMA) (containing 80-120 ppm methylhydroquinone as an inhibitor, 95% purity, CAS 109-16-0, Sigma-Aldrich) as a diluent to form a photoinitiator solution. This photoinitiator solution is magnetically stirred at 30 °C for 40 min. It is then added to the previously prepared first composition to form the resulting composition.

[0110] The composition is mechanically stirred at 400 rpm for 3 hours, then ultrasonically stirred for 40 minutes at 60% amplitude using an ultrasonic homogenizer sold under the trade name Sonopuls, and then magnetically stirred for 1 hour. In order to remove any air bubbles that may have formed in the crosslinkable composition, the composition is subjected to an ultrasonic bath for 10 minutes.

[0111] The prepared crosslinkable composition is 3D printed in the form of a layer using the equipment sold by Shining 3D under the trade name "Accufab-D1" and the conditions as described in Example 4.

Claims

1. 1. A crosslinkable polymer composition comprising: - at least one biodegradable, biocompatible organic polymer, or at least one of its precursors, at least one calcium phosphate, and - at least zinc-zinc oxide core-shell particles A composition comprising:

2. 2. The composition according to claim 1, wherein the calcium phosphate is present in an amount ranging from 0.1 to 10% by weight relative to the total weight of the crosslinkable composition.

3. 3. The composition according to claim 1, wherein the calcium phosphate is hydroxyapatite.

4. A composition according to any one of claims 1 to 3, characterized in that the size of the zinc-zinc oxide core-shell particles ranges from 0.1 to 200 µm.

5. Polymer composition according to any one of claims 1 to 4, characterized in that the zinc-zinc oxide is present in a weight ratio of 0.1 to 25% by weight relative to the total weight of the crosslinkable composition.

6. 6. The composition according to claim 1, wherein the biodegradable, biocompatible organic polymer is selected from aliphatic polyesters, polysaccharides, polyorthoesters, polyanhydrides, polyphosphazenes, polyacrylates and polyurethanes.

7. The composition according to any one of claims 1 to 6, characterized in that the organic polymer is a polylactide.

8. The composition according to any one of claims 1 to 7, further comprising a photoinitiator.

9. The composition according to any one of claims 1 to 8, further comprising at least one compound containing one or more reactive functional groups.

10. 10. A method for preparing a composition as defined in any one of claims 1 to 9, characterized in that it comprises at least one step i) of mixing zinc-zinc oxide core-shell particles and calcium phosphate particles in a polar protic solvent to form a dispersion, and 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 is obtainable by photopolymerization of one or more layers of a crosslinkable composition as defined in any one of claims 1 to 9.

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

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

14. A biomaterial for medical use as defined in claim 11 or obtainable by the method as defined in claim 12 or 13.

15. 14. A biomaterial as defined in claim 11 or obtainable by a method as defined in claim 12 or 13, for use in bone regeneration and in the prevention and / or treatment of implant-related oral infections.

16. A bone substitute capable of accommodating a dental implant, characterized in that it comprises a biomaterial as defined in claim 11 or obtainable by the method as defined in claim 12 or 13.

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