KR20070100230A - Bone implant device coated with hyaluronic acid - Google Patents

Abstract

The present invention relates to a bone implant device, particularly for dental and orthopaedic prosthesis on the vertebral column, having a quicker osteo-integration compared to the prior art devices. Particularly, the present invention relates to an implant device, of metal or polymer nature, a layer of hyaluronic acid being chemically bound on the surface thereof, for use in applications in contact with the bone, with activity of stimulating the bone tissue growth, as well as a process for preparing the same.

Description

HYALURONIC ACID COATED BONE IMPLANT DEVICE coated with hyaluronic acid

The present invention relates to orthopedic prostheses and dental prostheses in the spinal column that provide osteo-integration faster than bone implant devices, especially those of the previous literature.

Metal devices permanently implantable into bone tissue are widely used in medicine in a variety of fields. For example, dental implant surgery generally uses screws made of titanium in the mandible or maxilla to artificially replace the root that lost or no longer functions. In orthopedic surgery, some devices for use in fracture fixation, reduced spinal motility, and spinal surgery are generally implanted into bone tissue.

In this use, the implanted device is firmly anchored to the implant site so that it is in direct contact with the implanted device due to the growth of newly formed bone tissue. This phenomenon, known as osteo-integration, is a phenomenon in which the implanted implant device is perceived as the bones of the surrounding human body itself, particularly in the technical and scientific literature related to bone implant surgery via titanium devices. Is widely researched and described in. In contrast to other processes of implanting foreign material into tissues, the device is firmly fixed due to the growth of bone tissue in direct contact with the device, encapsulating into fibrous material, ie fiber integration, This makes the device suitable to withstand the load and performs structural tasks.

While the field based on bone-fusion has been a great success in recent years and is increasingly being used, there are still many problems to be solved. In particular, it is important to accelerate the bone-fusion process as much as possible, which reduces the time between the insertion of the implant and the actual load on the implant. For example, in dentistry, implants are generally not "loaded", thereby allowing for bone tissue treatment and inducing bone-fusion for a period of one to four months after intervention. The patient cannot perform chewing function through the implant. Moreover, healthy and young people are usually treated with bones easily, while older and osteoporotic people are usually treated slowly, that is, these people need more of this intervention and a significant number of patients There is a need for implant surgery to fix trauma or spinal motility.

Since it is generally known that the surface properties of the implant device play a fundamental role in tissues that respond to the implant, many studies have been conducted to improve the bone-fusion process by modifying the surface of the implantable device. Detailed photographs of these studies can be found in Puleo and Nancy, Biomaterials 1999; 20: 2311-2321, "The bone-biomaterial interface", or Davies, the textbook Bone Engineering, published by EM SQUARED, Toronto 2000. By studying these books and evaluating commercially available devices, the surface properties can be characterized by surface roughening (eg, sandblasting, plasma-spray deposition or acid treatment). Is often understood to improve. Layer deposition of ceramic materials with high bone affinity, such as hydroxyapatite or so-called bioglass, is also being studied and used.

In addition to these methods, interest is focused on introducing biological molecules that can promote bone growth on the surface of the implant device. Among most of the molecules studied, it has been reported that collagen can increase the rate of bone-fusion when anchored to the surface of implant titanium screws. It has also been proven to be effective when tested in vivo for specific peptides, in particular small molecule fragments that make up proteinaceous molecules that can interact with bone cells. In the publications of Puleo and Nancy, several molecules used to biologically modify the implant surface have been studied.

Although biologically modifying the implant surface is an area of scientific and theoretical interest, there is still a problem in the practical application of biologically modifying the implant surface. For example, collagen has a contamination problem because it originates from animals of unknown origin (especially bovine collagen) or because rejection is caused by possible incompatible reactions between different species. Since the peptides described above are expensive and inferior in stability from a chemical point of view, it is very difficult to rely on general methods in the field, such as, for example, sterilization, in treating the implant surface.

Hyaluronic acid is a glycosaminoglycan that spreads in all tissues of life and does not vary from species to species. The hyaluronic acid has very interesting biological and hydrating properties, and for this reason it has been extensively studied in the biomedical field and used in various special products. The latter case is outlined in several documents, including, for example, the major congressional newsletter on hyaluronic acid: "The Biology of Hyaluronan", D. Evered and J. Whelan, Eds. Wiley, Chichester, 1989, "The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatives", T. C Laurent, Ed., Portland Press Ltd, London, 1998, "Redefining Hyaluronan", G. Abatangelo and PH Weigel, ( Eds.), Elsevier, Amsterdam, 2000, "Hyaluronan", JF Kennedy, GO Phillips, PA Williams, V. Hascall, Eds., Woddhead Publishing Limited, 2002.

For example, as described in Bernard et al., "Redefining Hyaluronan", G. Abatangelo and PH Weigel, (Eds.), Elsevier, Amsterdam, 2000, p.215, hyaluronic acid as a molecule in a homogeneous phase Plays an important role in the process of bone formation.

For this reason, absorbed hyaluronic acid-based gels of bone forming proteins or growth factors have been used successfully for bone stimulation testing. Furthermore, hyaluronic acid solutions that selectively bind to dexamethasone drugs with osteogenic properties are described in Zou et al., Biomaterials, 2004; It has been demonstrated that it has a positive effect on the differentiation of stromal cells in bone cells as described in 5375-5385, 25.

However, the interesting osteogenic potential of hyaluronic acid in gel form or in solution form, or hyaluronic acid present in tissues, is not readily available for bone tissue transplantation devices as described above. In fact, hyaluronic acid is well soluble in aqueous solutions and has a very short winch duration. Chemical techniques that persist the hyaluronic acid persistence at the site of implantation, such as cross-linking, chemical modification, or surface immobilization, can alter the structure and molecular conformation of hyaluronic acid and negatively affect receptor-ligand specific interactions. This can reduce the bioactive activity of the molecule. In fact, the bioactive properties of hyaluronic acid are due to their ability to interact with specific receptors located on cell walls such as CD44 or RHAMM. J. Biol Chem. J. Lesley et al. 2000, Sep 1; As described in 275 (35): 26967-75, this type of interaction is very cooperative and requires very repetitive simultaneous interaction of hyaluronic acid with a single receptor to be effective. The cooperative nature of the interactions imparts typical motility of the molecules in solution, resulting in immobilization of hyaluronic acid on the material surface even on surfaces where no sufficiently strong specific interactions could be established, resulting in no cell adhesion. Morra and Cassinelli, Journal of Biomaterials Science, Polymer Edition, 1999; 10 (10): 1107-24. Reduction of adhesion of cells or biomolecules on surfaces to which hyaluronic acid is immobilized has been described in various scientific literature and described by Witt et al., "Hyaluronan", J. F. Kennedy, G. O. Phillips, P. A. Williams, V. Hascall, Eds ,. Woddhead Publishing Limited, 2002, volume 2, p. As described in 27, this property is used to reduce the adhesions resulting from surgical operations. Immobilization of hyaluronic acid on metal substrates and devices is described in Journal of Biomedical Materials Research, vol. 68, p. 95, 2004, Pitt et al., "Attachement of hyaluronan to metallic surfaces." According to the general knowledge as described in such a citation, the surface on which hyaluronic acid is immobilized shows "biopassive" or has insufficient cell adhesion. The authors of the above document describe a method in which insufficient biological attachment conferred by a fixed layer of hyaluronic acid can be used to prevent non-specific attachment; Emphasis was placed on the necessity of binding such non-adhesive matrices with attachment peptides to obtain specific bio-adhesive effects.

In essence, it is generally known that a layer of hyaluronic acid immobilized on a solid surface has resistance to biological adhesion, but in contrast, biological attachment is achieved by the bioactive action of hyaluronic acid immobilized on an implantation device. It is desirable to obtain, in which case the specific cell attachment of the implant to bone tissue is very important for bone-fusion.

It is also known that bone angiogenesis requires a mineralization step that is facilitated by calcium ions binding to the surface. As described in Bernard et al., In fact, hyaluronic acid has an active effect at this stage, which contributes significantly to the calcification process. In fact, hyaluronic acid carboxylate groups can chelate or complex calcium ions by having a positive effect on the mineral deposition process. However, the immobilization of hyaluronic acid on the surface of the implant device generally means that the amine groups or amine functional groups present on the substrate are consequently removed from the carboxyl groups of the bound hyaluronic acid, which can chelate with calcium ions. It means that the hyaluronic acid carboxyl group is bonded. Thus, immobilizing hyaluronic acid on the surface of such devices in a known manner does not improve the bone-fusion process.

In contrast, the present application, as described in the appended claims, hyaluronic acid immobilized on an implant screw, can exert an active effect on the bone-fusion process in vivo without any additional peptide fixation required, and the present invention It has been found that this property of the implantable device has been significantly improved over the properties exhibited by conventional devices by contact with bone tissue having a fixed hyaluronic acid layer of.

In a broad embodiment of the invention, the invention is a bone tissue consisting of a layer having metal or polymer properties of hyaluronic acid chemically bound on the surface of an implant device, as claimed in the appended claims. An implant device (hereinafter referred to as an "implant device"). There is no limit to the design or shape of the device when it is designed for use to provide growth or general bone tissue growth stimulation in contact with the device.

In a particularly advantageous embodiment of the invention, the device consists of or preferably is a dental implant screw, preferably made of titanium or an alloy thereof, or preferably made of titanium or an alloy thereof, for securing the spinal cord or skeleton. It consists of an intervertebral disc made of titanium, an alloy thereof or a cobalt-chromium alloy or a metal alloy, or a cage made of titanium or an alloy thereof.

A thin layer of hyaluronic acid, preferably having a thickness of 0.5 nm to 10000 nm, more preferably 1 nm to 1000 nm, more preferably 1.5 nm to 100 nm, is immobilized on the surface made of this alloy.

The method of immobilizing hyaluronic acid on the implant device of the present invention introduces an amine functional group on the surface of the device and consequently binds the hyaluronic acid and the amine group by functionalization of the hyaluronic acid hydroxy group. In fact, hyaluronic acid is a mucopolysaccharide having a molecular weight between 50,000 and 8,000,000 and containing a functional primary alcohol group, which compound is represented by the following formula:

Accordingly, the present invention relates to an implant device coated with a substrate having an amine group, wherein hyaluronic acid is bound to the substrate by functionalization of the hydroxyl group of the hyaluronic acid.

Substrates comprising amine groups can be coated on the surface of an implant device according to methods well known in the art. Particularly useful are techniques that provide for the introduction of a substrate with amine functional groups on the surface of an implant device by plasma deposition of molecules containing amine groups. General examples of molecules used for the purposes of the present invention are alkylamines such as allylamine, hexyl- or heptyl-amine, and organic molecules with amine functionalities which generally have the volatile properties required on the plasma. Plasma deposition of amines is carried out under the following conditions: pressure between 80 mTorr and 300 mTorr, input power between 5 W and 200 W, deposition time between 1 ms and 300 s. Plasma deposition may also be performed under pulsed plasma conditions with a cycle of active and inactive plasma between 1 ms and 100 ms to minimize molecular fragmentation and maintain maximum concentrations of amine groups. Plasma deposition treatment of amines may be performed by other plasma treatments, such as, for example, air or oxygen plasma, to clean the surface and increase its adherence to the substrate.

Hyaluronic acid may be added to an aqueous solution or a suitable solvent solution such as dimethyl sulfoxide or mixtures thereof containing water, dimethylformamide or mixtures thereof containing water, N-methyl pyrrolidone or mixtures thereof containing water. Or to the amine layer by methods known in the art for the functionalization of the hydroxy group and in particular for the substitution of the hydroxy group with an amine-type bond as follows: Ial-OH + Sub -NH2-> R-NH-R 'wherein Ial is a residue of hyaluronic acid and Sub is a residue of a substrate having amine functionality. As mentioned above, the process of the present invention provides functionalization of all hydroxyl groups as well as some of the hydroxyl groups of the reactive hyaluronic acid, depending on the reaction used and the reaction conditions applied. However, due to the functionalization reaction of the hydroxyl group of hyaluronic acid, it is bound by partial coverage indicating that the surface portion occupied by hyaluronic acid is greater than 0.6, evaluated by X-ray photoelectron spectroscopy known as XPS or ESCA. It is essential that a hyaluronic acid layer is formed. The test method is described in Marco Morra and Clara Cassinelli, "Simple model for the XPS analysis of polysaccharide-coated surfaces," published by the Surface and Interface Analysis magazine, 26, 742-746 (1998).

The functionalization reaction of the amine substrate with the hydroxyl group of the hyaluronic acid can be carried out according to various methods known to those skilled in the art, such as the following (listed as schematic examples): mesylate, tosylate or similar free groups. Reaction of an activated hydroxy group with an amine group that occurs after activation of a hydroxy group by formation of, for example, a reaction of hyaluronic acid with mesyl or tosyl chloride; Reactions of, for example, hyaluronic acid and halogenated hyaluronic acid and amines which occur after substitution of hydroxy with halo such as chlorine, bromine or iodine by reaction with thionyl chloride or carbon tetrabromide and triphenylphosphine ; The Mitsunobu reaction of hyaluronic acid with amines in the presence of diethylazadicarboxylate and triphenylphosphine; Reductive amination reactions which occur after oxidizing primary hydroxy groups to aldehydes.

Among the methods cited above, a synthetic route is preferred in which the hyaluronic acid hydroxy group is subjected to aldehyde oxidation and then provides a reductive amination reaction of the aldehyde formed.

The reaction of aldehyde oxidizing the primary alcohol group can be carried out using all selective oxidants of the alcohol group such as chromium trioxide, sodium perate or potassium perate. Sodium peridate is the preferred reagent in this reaction.

The aldehyde groups formed by alkyl-amine or aryl-amine amine groups were reacted by a reducing amination reaction in the presence of a suitable reducing agent such as the following non-limiting examples: a suitable catalyst such as Raney nickel or PtO _2. Hydrogen in the presence of; Aluminum, aluminum amalgam or Al / HgCl ₂ ; Boranes such as decaborane; Sodium cyanide such as MP-cyanoborohydride, MP-triacetoxyborohydride, immobilized on a resin for solid phase synthesis in the presence of a suitable scavenger such as, for example, PS-isocyanate, PS-benzaldehyde or MP-TsOH Noborohydride or sodium borohydride.

A preferred reagent for reductive amination reactions is sodium cyanoborohydride.

The reaction conditions used for the oxidative reaction of hydroxy groups with the aldehyde and the reductive amination of aldehydes are the conditions generally used in this type of reaction as illustrated in the examples below.

An advantage of the functionalization of hyaluronic acid hydroxy groups instead of carboxyl groups is that this method leaves the carboxyl groups capable of sufficient interaction with calcium ions, thereby maximizing the activity of hyaluronic acid to promote bone mineral deposition.

According to a preferred embodiment of the present invention, in addition to the bound hyaluronic acid layer, the implant device may comprise a releasable drug or bioactive agent that promotes the growth of bone tissue. In this embodiment, the device is preferably first coated with a polymer or ceramic layer capable of enveloping, absorbing or adsorbing the drug or bioactive component, and then according to the techniques described above. The hyaluronic acid can be fixed on the layer of.

Of the drugs or bioactive ingredients used according to the invention, substances which serve as bone growth stimulants are particularly preferred. Among them, dexamethasone drugs, dexamethasone-phosphate or acetate soluble forms thereof, various forms of vitamin D, growth factors, a family of proteins known as osteogenic proteins, molecules in the form of polysaccharides such as eparine, chondroitin Particular preference is given to sulfate (condroitin sulphate) and hyaluronic acid.

In addition to the absence of inherent toxicity, it is not possible to chemically limit the properties of the layer in which the drug or bioactive component is obtained, and its composition can be tailored according to the properties and desired kinetic release of the drug or bioactive component. Schematic examples include silicones, olefins or polymethyldisiloxanes, polybutadienes, polymethylmethacrylates, polyethylmethacrylates, polybutylmethacrylates, polyurethanes, fluorinated polymers, polyesters, poly-hydroxyethylmethacrylates Polymers of the acrylic type such as hydrophilic acrylates such as late or poly-hydroxybutyl methacrylate; Any ceramic layer may be composed of an alumine based inert ceramic, a silicate based inert ceramic or a silico-aluminate based inert ceramic, or a bioactive ceramic such as calcium phosphate or hydroxyapatite. This layer can be either compact form or porous form depending on the needs of controlling the kinetic release.

The polymer or ceramic layer was deposited according to conventional techniques, such as immersion, spraying by conventional spray guns and ultrasonic sprays, vapor-phase or plasma deposition. In the case of ceramic layers, sol-gel techniques may also be used.

General techniques, such as spraying from common solutions, suspensions or emulsions, or by the general procedure of immersion in solutions, suspensions or emulsions to deposit, devour, or absorb a drug or active ingredient in a support layer Or adsorbed.

Within the nature of the present invention, a substrate carrying an amine group can be deposited according to the method described above, followed by covalent bonding of hyaluronic acid to the substrate, which in turn can modify the layer in which the drug or active ingredient is devised. For example, after applying a layer devoid of drug or active ingredient, a plasma deposition process of allylamine or alkylamine, and hyaluronic acid in an aqueous solution was performed. By incorporating excess drug or bioactive components into the polymer or ceramic matrix, the initially measured excess dose can be balanced against any release and loss of drug at this stage. Such excess dosage will generally be a stoichiometrical amount of up to 30%, more preferably up to 10%.

As can be understood from the experimental tests made herein below, surprisingly, the fact that hyaluronic acid immobilized on an implant device implanted into a bone performs a significant osteointegrative action, as expected, according to literature data. Found. Accordingly, it is also an object of the present invention to use hyaluronic acid, such as a bone-fusion enhancer, to fix hyaluronic acid to the surface of the implant device in making a bone-contact implant device.

Example One Fixed Hyaluronic acid layer Having titanium sample Plasma deposition of allylamine was carried out using a Gambetti Kenologia reactor for plasma treatment with 99.7% titanium samples (obtained from Sigma-Aldrich) in the form of three 1 cm-sided squares. In particular, the deposition process was performed with pulsed plasma using a 10 ms cycle at 100 mTorr pressure. The input power is 50 W and the processing time is 30 seconds. At the end of the treatment, the screw was placed in a hyaluronic acid solution pre-treated with 0.5% concentration of water. Hyaluronic acid was manufactured by Lifecore Biomedical, Chesca, Minnesota, USA, and identified under batch number B22157. The aqueous hyaluronic acid solution was pre-treated in phosphate buffer with sodium perirate (16 mg / 100 cc) for 16 hours and the same volume of acetic acid buffer containing 1 mg / cc sodium cyanoborohydride was mixed into the reaction. It was. Samples were placed in solution overnight then washed with water and dried in a laminar flux hood.

Example 2 Evaluation of Cell Non-adherence of Samples Titanium samples not coated with three similarly sized hyaluronic acid and three samples of Example 1 were tested for cell adhesion with osteoblast type cells (MG-63) supplied from the Brescia Institute of Zooprophylaxis. Cells cultured according to the general method were inoculated into two samples consisting of two samples coated with hyaluronic acid and an uncoated titanium. After 3 days incubation, the samples were carefully washed with phosphate buffer and attached cells were removed with trypsin and counted by hemocytometer. The following results were obtained:

The data indicated that the number of cells present on the surface coated with hyaluronic acid was significantly reduced according to the literature data cited above.

Example 3 Fixed Hyaluronic acid layer Having titanium screws The experiment of Example 1 was repeated on a titanium implant screw made from Agliati s.r.l. The screws were tested by X-ray photoelectron spectroscopy (XPS), a surface testing technique that provides the chemical composition of the material to a depth of about 8 nm. The following results were obtained (data expressed in atomic%):

The stoichiometry observed, in particular nitrogen, C / O and C / N ratios, was consistent with the proportion of thin surface layers of hyaluronic acid as predicted by the typology of the binding reaction according to literature data.

Example 4 Enhanced in vivo Bone fusion Identification of characteristic To test the properties of the implantable titanium device in vivo obtained according to the present invention, rabbits were subjected to several tests. In particular, the cortical bones of the femoral bones of 10 adult rabbits were implanted with a total of 10 coated screws and 10 uncoated controls, 2 mm in diameter and 10 mm in length. The animals were sacrificed after 4 weeks and the femurs were histologically and mechanically tested. In particular, the measured parameters are as follows:-the affinity index, i.e. the ratio of the total length of the interface multiplied by 100 for the direct bone length opposite the interface without fibrotic mediation. Bone growth rate, ie the percentage of bone-filled area to the total area enclosed between the screws and the vertexes of a spire as observed in the histological examination. Pull out force, ie the measured maximum force required to pull the screw from the bone by means of a pull out test machine.

The following results were obtained:

As predicted according to current knowledge of immobilized hyaluronic acid, screws implanted into bone coated with hyaluronic acid do not show biopassive and anti-adhesive effects, but the threads coated with hyaluronic acid are not coated. It can be clearly seen from both histological data and mechanical tests that they have clearly enhanced bone-fusion characteristics compared to unscrewed screws.

Example 5 Drug release and hyaluronic acid Fixed Titanium screws with layers The plasma deposition process of propylene was initially performed using the reactor described in Example 1 with several titanium screws. The thin polymer layer was then coated on the screw and dexamethasone was coated on the screw using a spray gun with the solution described below (obtained from Conrad-Bartoli): dissolved in a 50-50 mixture of acetone and methyl alcohol. 0.5% polybutyl methacrylate and 0.1% dexamethasone (both obtained from Sigma Aldrich).

The method described in Examples 1 and 3 was carried out with the screws obtained to produce titanium screws combining the properties of releasing drugs that promote bone growth and of having a bioactive surface coated with hyaluronic acid.

Example 6 Release of Dexamethasone from a Titanium Device with a Fixed Hyaluronic Acid Layer The screws obtained as described in Example 5 were immersed in 2 cc of physiological saline and placed in a thermostat at 37 ° C. At a given time, the solution was removed and measured by UV-Vis absorbance spectrum at 242.4 nm, the maximum absorbance wavelength of dexamethasone. As shown in FIG. 1 the emission curve is expressed as a function of time.

The resulting bone tissue implant device is a device that exhibits the bioactivity of the surface coated with hyaluronic acid and the release of drugs that affect the bone formation process as described above.

Among the possible variants that can provide the implant device without departing from the scope of the present invention, the implant device can be made of a material of cobalt-chromium or alloys thereof, in addition to titanium, for example stainless steel in general. This is tolerated by the specific osteofusion effects obtainable with the device of the invention.

Claims (34)

An implant device for use in bone-contact, which stimulates activity on the growth of bone tissue and consists of a layer having metal or polymer properties of hyaluronic acid chemically bound on the surface of the implant device. The implant device of claim 1, wherein the device is a dental implant screw, a spinal or skeletal fixation screw, an intervertebral disc, or a cage. The implant device of claim 2, wherein the screw and cage are made of titanium or an alloy thereof. The implant apparatus of claim 2, wherein the intervertebral disc is made of titanium, an alloy thereof, or a cobalt-chromium alloy. The implant device of claim 1, comprising a coating of a substrate having an amine group, wherein hyaluronic acid is bound to the substrate by functionalization of the hydroxyl group of the hyaluronic acid. 6. The implant device of claim 5, wherein the substrate having an amine group comprises allylamine or preferably an alkylamine unit selected from hexyl-amine or heptyl-amine. 7. The implant device of claim 5 or 6, wherein the layer of hyaluronic acid has a thickness between 0.5 nm and 10000 nm. 7. The implant device of claim 5 or 6, wherein the layer of hyaluronic acid has a thickness between 1 nm and 1000 nm. 7. The implant device of claim 5 or 6, wherein the layer of hyaluronic acid has a thickness between 1.5 nm and 100 nm. The implant device of claim 1, wherein the layer of hyaluronic acid has a fractional coverage of greater than 0.6, as assessed by X-ray photoelectron spectroscopy techniques. The implant device of claim 1, wherein the device further comprises a releasable drug or bioactive agent capable of enhancing the growth of bone tissue. The implant device of claim 11, wherein the drug or bioactive agent is entrapped, absorbed or adsorbed to the polymer or ceramic layer. 13. The implant device of claim 12, wherein the substrate to which hyaluronic acid is immobilized is deposited on a polymer or ceramic layer onto which the drug or bioactive component is devoured, absorbed or adsorbed. The implant device of claim 12 or 13, wherein the drug or bioactive agent is selected from Dexamethasone, dexamethasone-phosphate or acetate soluble forms thereof, various forms thereof, vitamin D, growth factors, a group of proteins known as osteogenic proteins, molecules in the form of polysaccharides such as eparine, chondroitin sulfate and hyaluronic acid. 14. An implant device according to claim 12 or 13, wherein said polymer matrix comprises a polymer in the form of silicone, olefin or acrylic, said polymer preferably being selected from Polymethyldisiloxane, polybutadiene, polymethylmethacrylate, polyethylmethacrylate, polybutylmethacrylate, polyurethane, fluorinated polymer, polyester, polyhydroxyethylmethacrylate or polyhydroxybutyl-meth Hydrophilic polyacrylates preferably selected from acrylates. 15. The method of claim 12 or 13, wherein the ceramic layer comprises alumina-based inert ceramics, silicate-based inert ceramics or silica-aluminate-based inert ceramics, or bioactive ceramics such as calcium phosphate or hydroxyapatite. An implant device characterized in that. 18. The implant device of claim 16 wherein the ceramic layer is compact or porous. 18. A method of manufacturing the implant device of any one of claims 1 to 17, comprising the following steps: Providing a metal or polymer implant device; Coating the surface of the implant device with a substrate having an amine group; Binding the hyaluronic acid to the amine group of the substrate by functionalization of the hydroxyl group of hyaluronic acid. 19. The method of claim 18, wherein coating the surface of the implant device with a substrate having an amine group comprises the following steps: Selecting an amine having the property of volatility in the plasma-phase; Depositing the amine on the plasma-phase on the surface of the implant device to form a substrate layer containing a functionalizable amine group. 20. The method of claim 19, wherein said plasma deposition of amines is carried out under the following conditions. Pressure between 80 mTorr and 300 mTorr, input power between 5 W and 200 W, and deposition time between 1 ms and 300 s. 21. The method of claim 20, wherein said plasma deposition of amines is carried out under conditions of a pulsed plasma with a cycle of active and inert plasma comprised between 1 ms and 100 ms. 22. The process of any of claims 19 to 21, wherein the treatment of plasma deposition of amines proceeds by treating the surface of the implant device with an air or oxygen plasma to increase adhesion to the substrate. Way. 23. The method of any of claims 19 to 22, wherein the amine is selected from allylamine, hexylamine and heptylamine. 24. The method of any one of claims 18 to 23, wherein the step of binding the hyaluronic acid to the amine group of the substrate by functionalizing the hydroxyl group of hyaluronic acid comprises the following steps. Selectively oxidizing the alcohol group of hyaluronic acid to an aldehyde group; Bonding said aldehyde group of hyaluronic acid to said amine group of a substrate by a reductive amination reaction. 25. The method of claim 24, wherein the step of selectively oxidizing the hydroxy group to the aldehyde group is carried out in the presence of sodium periodate. 26. The method of claim 24 or 25, wherein the reductive amination reaction is carried out in the presence of sodium cyanoborohydride. 27. The method of any one of claims 24 to 26, wherein the hyaluronic acid comprises dimethyl sulfoxide or mixtures thereof comprising water, dimethylformamide or mixtures thereof comprising water and N-methyl pyrrolidone comprising water. Or by an aqueous solution such as a mixture thereof, or a suitable solvent solution. 28. The method of any one of claims 18 to 27, comprising the following steps: Providing a metal or polymer implant device; The surface of the implant device with a polymer or ceramic layer   Coating step; -A releasable drug that can promote the growth of bone tissue or   A bioactive component is incorporated into the polymer or ceramic layer,   Absorbed or adsorbed; The drug or bioactive compound is devoured, absorbed or   Having an amine group on the polymer or ceramic layer adsorbed   Depositing a substrate; Binding the hyaluronic acid to the amine group of the substrate by functionalizing the hydroxyl group of hyaluronic acid. 29. The method of claim 28, wherein coating the surface of the implant device with a polymer or ceramic layer comprises immersion, spraying with both conventional spray guns and ultrasonic sprays, and vapor-phase. Or plasma deposition, or sol-gel techniques in the case of ceramic layers. 30. The method of claim 28 or 29 wherein the drug or bioactive component is entrained in and absorbed by the polymer or ceramic layer by spraying from a common solution, suspension, emulsion, or by immersion in a common solution, suspension, emulsion. And / or adsorbed. 31. The method of any of claims 28-30, wherein the step of enveloping, absorbing or adsorbing a drug or bioactive component to the polymer or ceramic layer is a stoichiometrical amount, preferably up to 30%. Preferably in the presence of an excess of stoichiometric amount of drug or bioactive component. The implant device according to any one of claims 1 to 17, wherein the implant device is obtainable by the method according to any one of claims 18 to 31. Use of hyaluronic acid to produce an implant device for promoting osteo-integration of an implant device in contact with bone tissue, wherein the hyaluronic acid is immobilized on the implant device. 34. Use according to claim 33, wherein the device is as described in any one of claims 1 to 17.

Images