ITMI20102071A1 - ELECTRODEPTISITION OF NANOMETRIC HYDROXYAPATITIS ON PROSTHETIC PLANTS AND ELECTROLYTIC PROCESS FOR ITS REALIZATION - Google Patents

Description

DESCRIPTION

Attached to a patent application for INDUSTRIAL INVENTION having the title

â € œ Electrodeposition of nanometric hydroxyapatite on prosthetic implants and electrolytic process for its realization "

The present invention relates to a process for coating at least one metal element of a prosthetic device, in order to obtain a high bone integration between the surface of the metal element and the receiving bone structure, and to the prosthetic device which includes this coated metal element.

Prosthetic devices are for example: implants, means of synthesis, external fixation systems, stabilization systems, fusion cages, dental implants, screws, to be used for clinical / surgical purposes in the orthopedic, maxillofacial and neurosurgical fields.

It is known that both orthopedic and dental metal prostheses are often treated superficially to improve their interface with the bone tissue in which they are implanted.

For example, titanium prostheses are superficially treated with electrochemical methods so that a titanium dioxide coating with anatase structure is formed on the surface, capable of being activated with appropriate UV-Vis lighting capable of generating free radicals. The surface thus takes on a marked antiseptic and hydrophilic characteristic. If suitably activated photochemically, this anatase coating makes the prosthesis sterile for implantation and maintains its hydrophilic characteristics for a certain period even after implantation, stimulating in situ a specific cellular action capable of favoring bone integration. According to some authors, the photosensitivity of the anatase ceases once the prosthesis is implanted with the cessation of UV-Vis activation. According to others, the antiseptic and antibacterial action of the anatase coating exerts a toxic action against osteoblasts, hindering the formation of new bone.

From anatase coatings, with characteristics far removed from those of biogenic materials, we have recently switched to strongly biomimetic coatings.

The biomimetic coatings of orthopedic and dental prostheses mimic the bone tissue in which they are implanted as much as possible, due to their composition, structure, morphology and mechanical properties. Recently, calcium phosphate, hydroxyapatite, gelatin, reconstituted collagen and hybrid coatings consisting of hydroxyapatite and reconstituted collagen have been proposed, electrodeposited simultaneously on the metal prosthesis to make the surface of the prosthesis more similar to natural bone. Hybrid collagen-hydroxyapatite coatings are certainly those that more than any other mimic bone tissue in composition and structure. In fact, the collagen fibers reconstituting themselves during the electrochemical process incorporate nanocrystals of hydroxyapatite within themselves, forming a coating of highly biomimetic calcified reconstituted collagen fibers that are deposited isotropically around the surface of the prosthesis, wrapping it like a sheath with a micrometric thickness. Thanks to its high mimicry, this hybrid coating certainly surpasses all the various protein coatings previously proposed such as those of gelatin, alginate, kyosan, fibrin and hyaluronic acid. They can be obtained very simply by spray-dry, but also by pure immersion of the prosthesis in a sol-gel suspension of the protein. However, normally these protein coatings are not well accepted by the cellular component that tends to engrave this type of material, disfavouring ossification. On the contrary, inorganic coatings such as bio-glasses have always been positively judged, of which the best known are those of Hench that undergo mineralization in vitro by simple immersion in SBF (Simulated Body Fluid) and in vivo induce a high cellular stimulation. to mineralization. More recently, bioglasses have been replaced by phosphate-based coatings, such as Î ± or β tricalcium phosphate Ca3PO4o Ca5 (PO4) 3-X (CO3) X (OH) 1 + X in which x is about 0.2 or inferior. Another widespread type of coating used in implantology is based on hydroxyapatite Ca10 (PO4) 6 (OH) 2.

Currently known hydroxyapatitic coatings have a thickness of the order of a few tens of microns and can be obtained with plasma spraying or sol-gel methods. With these two methods it is very difficult to achieve homogeneous, nanostructured coatings with a thickness lower than those mentioned so far. In fact, with these methods, it is possible to prepare hydroxyapatite (HA) coatings, possibly replaced with different ions, but it is not possible to obtain a uniform coating with a nanometric thickness.

Hydroxyapatite has well known properties of biocompatibility, bioabsorbability and osteoconductivity, inducing the formation of new bone. However, hydroxyapatite coatings with thicknesses of the order of microns have the drawback of integrating into the new bone at a very high speed which can often cause the coating to detach from the surface of the prosthesis. In other words, these coatings are integrated into the new bone without, however, the prosthesis itself being integrated as, during the osseoingration process, the coating detaches from the prosthesis. The dramatic consequence of this drawback is that an empty space (a pocket) is formed between the new bone that is formed (and which has incorporated the hydroxyapatite coating) and the prosthesis. The prosthesis therefore cannot be properly osseointegrated and remains mobile until a complete detachment from the new bone formed is determined with the consequences that can be imagined for the patient's recovery.

The above problem is solved by a process for coating at least one metal element of a prosthetic device with a nanometric thickness coating based on nanostructured biomimetic hydroxyapatite which adheres perfectly to the surface of the prosthesis and allows complete osseointegration, as outlined in the annexes. claims.

The present invention relates to a process for coating at least one metal element of a prosthetic device with a hydroxyapatite-based coating comprising the steps of:

a) providing an electrolytic bath comprising at least calcium ions and phosphate ions at a temperature between 5 ° C and 40 ° C, preferably between 10 ° C and 25 ° C;

b) immersing in said electrolytic bath at least one cathode and at least one anode, said at least one cathode comprising the metal element to be coated;

c) passing a direct electric current through said electrolytic bath so as to obtain on said surface an electrolytic deposition of a calcium-phosphate compound comprising nanometric crystals of hydroxyapatite;

d) subject the metal element coated with the calcium-phosphate compound based on hydroxyapatite to a heat treatment at a temperature between 70 ° C and 800 ° C

The duration of the thermal process is between 1 hour and 6 hours, preferably between 2 hours and 4 hours.

Before the heat treatment of point d), the metal element is extracted from the electrolytic bath and dried under a flow of hot air, at a temperature between 40 ° C and 100 ° C, preferably between 60 ° C and 80 ° C, or by immersion of the same plant in an alcohol bath for a time between 5 and 120 seconds, preferably between 15 and 50 seconds. According to a preferred embodiment, at the beginning of the deposition the electrolytic bath has a pH between 3.0 and 4.5, preferably between 3.5 and 4.0; the pH rises near the cathode to a value higher than 8, generally between 10 and 12, during the deposition process, without adding alkaline compounds. At the end of the electrolytic deposition process, the electrolytic bath has a pH generally comprised between 4.0 and 6.0, preferably between 4.5 and 5.5.

According to a preferred embodiment, the electrolytic deposition is carried out with a substantially constant direct current. Preferably the direct current is kept at relatively low values in order to avoid detachments of the deposited material caused by an excessive development of gaseous hydrogen at the cathode. Generally the direct current has a value between 10 and 100 mA, more preferably between 20 mA and 60 mA.

The potential of the applied current can vary between 5 V to 150 V, but preferably between 20 V and 80 V.

The duration of the electrochemical process is between 3 seconds and 15 minutes, preferably between 90 seconds and 6 minutes.

Preferably, the calcium ions are added to the electrolytic bath in the form of a salt soluble under the reaction conditions, for example Ca (NO3) 2 * 4H2O, Ca (NO3) 2 * 2H2O, Ca (CH3COO) 2 or their mixtures. The initial concentration of the calcium ions in the electrolytic bath is generally comprised between 0.01 and 0.1 mol / liter, preferably between 0.02 and 0.06 mol / liter. Preferably, the phosphate ions are added to the electrolytic bath in the form of a salt soluble under the reaction conditions, for example NH4H2PO4, K2HPO4, KH2PO4, H3PO4 or their mixtures.

The initial concentration of the phosphate ions in the electrolytic bath is generally comprised between 0.01 and 0.10 mol / liter, preferably between 0.02 and 0.05 mol / liter. In the context of the present invention, the term "phosphate ions" includes both the phosphate ions PO4 <3∠'>, and the hydrogen and dihydrogen-phosphate ions HPO4 <2âˆ'> and H2PO4 <∠'> possibly present in equilibrium with the ions PO4 <3∠'> in variable quantities depending on the pH.

In a particularly preferred embodiment of the invention, in addition to the calcium and phosphate ions, zinc, strontium, carbonate, sodium, potassium and fluoride ions are present in the electrolytic bath. The presence of these ions in suitable concentration ratios allows to obtain a coating based on substituted hydroxyapatite in a similar way to the biological one, (so-called biomimetic hydroxyapatite), thus obtaining a coating that simulates in chemical composition, size, morphology and structure of the crystals the hydroxyapatite constituting the bone and dentin.

The zinc, strontium, carbonate, sodium, potassium and fluoride ions are added to the electrolytic bath in the form of a soluble salt under the reaction conditions. For example, Zn (CH3COO) 2, Zn (NO3) 2, ZnCO3 or their mixtures are used as a source of zinc ions; strontium ions derive from Sr (OH) 2, SrO, Sr (OH) 2 * 8H2O, SrCO3o their mixtures; CaCO3, CO2 (gas), Na2CO3, K2CO3, or their mixtures are used as a source of carbonate ions; for sodium ions Na2CO3, CH3COONa, Na2NO3, NaF or their mixtures are used; K2CO3, CH3COOK, K2NO3, K2HPO4, KH2PO4 or their mixtures are used for potassium ions, while HF, NaF, KF or their mixtures are used for fluoride ions.

The concentrations of the solutions containing the above salts vary between 0.5 M and 0.000001 M.

In another preferred embodiment, in the electrolytic bath containing the calcium and phosphate ions, possibly together with the other ions, it is possible to add an aqueous solution of poly-L-lysine, preferably with a concentration between 0.0001 M and 0.5 M. In this way it is possible to obtain hydroxyapatite functionalized with poly-L-lysine, at the same time as the formation of the coating.

The use of lysine allows to obtain a coating consisting of hydroxyapatite nanocrystals functionalized on the surface with poly-L-lysine chains capable of offering the bone surface an interface that is not purely inorganic, but biologically hybrid capable of stimulating the cellular action and therefore to exhibit a specific bioreactivity. Poly-L-lysine can be inserted into the process of making the prosthetic implant together with the electrolytic solution. In this way the growth of hydroxyapatite nano-crystals on the metal surface is obtained, in the presence of lysine, which is incorporated in the coating itself.

Otherwise, it is possible to immerse the prosthetic implant in a solution containing poly-L-lysine after having carried out the coating of hydroxyapatite nano-crystals. In this way, the activation of hydroxyapatite by lysine will be more superficial.

Preferably, the metal element comprises titanium or an alloy thereof with Ta, Nb, V, Al, Pt, for example Ti6Al4V alloys or Ti6Al7Nb alloys.

By carrying out the process according to the present invention, it is possible to vary the thickness of the hydroxyapatite layer from 10 nm to 500 nm, preferably between 50 nm and 200 nm.

Preferably, the hydroxyapatite is present in the form of crystals having a flattened lanceolate morphology (biomimetic morphology), having average dimensions of the longer side of less than 400 nm, more preferably between 200 and 50 nm.

The heat treatment aims to increase the adhesion of the apatitic nanocrystals to the metal surface of the prosthesis, producing an additional effect to that of the nanometric thickness and the nanostructuring of the coating which represent the fundamental chemical-physical characteristics to avoid, once the prosthesis It is implanted, the unpleasant drawbacks of the known art in which the formation of pockets occurred between the osseointegrated coating and the metal prosthesis, with consequent detachment and failure to osseointegrate the prosthesis itself.

According to a further aspect, the present invention relates to a prosthetic device comprising at least one metal element, said metal element having at least one surface coated with at least one layer adhering to the metal surface obtainable by electrolytic deposition of a calcium-phosphate compound comprising hydroxyapatite. Preferably, the calcium-phosphate compound comprises hydroxyapatite substituted with zinc, strontium, carbonate, sodium, potassium, fluoride ions or mixtures thereof (biomimetic hydroxyapatite). The prosthetic device according to the present invention, being obtained with an electrodeposition method followed by heat treatment, has an advantage over known devices, which lies in the greater adherence of the coating to the metal surface. This determines a better osseointegration of the prosthetic device compared to previously known prostheses coated with micrometric non-nanostructured apatitic coatings obtained with processes that do not include a heat treatment. The present invention will now be illustrated by means of some embodiment examples, also referring to the attached figures, in which:

- Figure 1 shows a dental implant covered with a homogeneous coating of ion-substituted apatitic nanocrystals, obtained with the following experimental parameters: 25 ° C, 3.5 minutes of electrodeposition, 30 mA, 20 V, not heat treated, dried in absolute alcohol ;

- Figure 2 shows a coating of ion-substituted hydroxyapatite nanocrystals obtained with the following experimental parameters: 30 ° C, 3 minutes of electrodeposition, 34 mA, 30 V, not heat treated;

- Figure 3 shows a coating of ion-substituted hydroxyapatite nanocrystals obtained with the following experimental parameters: 25 ° C, 2 minutes of electrodeposition, 34 mA, 40 V, not heat treated;

- Figure 4 shows a coating of ion-substituted hydroxyapatite nanocrystals, obtained with the following experimental parameters: 30 ° C, 6 minutes of electrodeposition, 17 mA, 25 V, not heat treated;

- figure 5 shows a coating composed of hydroxyapatitic, ion-substituted nanocrystals, obtained with the following experimental parameters: 20 mA, 50 V, 25 ° C, 5 minutes of electrodeposition, then subsequently heat treated for 2 hours at 500 ° C; - Figure 6 shows ion-substituted hydroxyapatite nanocrystals of the invention with a flat morphology, of variable size between 50 - 60 nm in length and 60-70 nm in width;

- Figure 7 shows nanocrystals of ion-substituted hydroxyapatite according to the invention with acicular morphology, of variable size between 170 - 200 nm in length and 50-60 nm in width;

Figure 8 shows an X-ray diffraction spectrum of three different coatings composed of ion-substituted hydroxyapatite nanocrystals of the invention made at 20 ° C (red), 30 ° C (blue) and 40 ° C (green);

- Figure 9 shows the thermogram of the ion-substituted hydroxyapatite obtained by the method of the invention;

- Figure 10 shows the FT-IR spectrum of ion-substituted hydroxyapatite nanocrystals obtained electrochemically.

EXAMPLE 1

Introduce into the electrolytic cell: 47 mL of the Ca <2+> ion solution at a concentration of 42 mM, 47 mL of the PO4 <3-> ion solution at a concentration of 25 mM, 4 mL of the Zn <ion solution 2+> at 4.6 mM concentration, 4 mL of Sr ion solution <2+> at 4.6 mM concentration, 4 mL of Na <+> ion solution at 10 mM concentration, 4 mL of ion solution K <+> at the 9.4 mM concentration, 4 mL of the F <-> ion solution at the 9.0 mM concentration and 6 mL of the CO3 <2-> ion solution at the 4.8 mM concentration. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 28 mA is applied, a potential of 35 V. The electrodeposition reaction takes place at a temperature of 25 ° C for a total time of 3 minutes. At the end of the process, the plant is extracted from the electrochemical bath and dried in a bath of absolute alcohol for a time equal to 20 seconds. The result is an implant covered with ion-substituted hydroxyapatite nanocrystals which is immersed in an aqueous solution of lysine for a time equal to 30 seconds, then dried under the constant jet of a flow of air at 70 ° C.

EXAMPLE 2

Introduce into the electrolytic cell: 50 mL of the Ca <2+> ion solution at a concentration of 42 mM, 50 mL of the PO4 <3-> ion solution at a concentration of 25 mM, 4 mL of the Zn <ion solution. 2+> at 5.0 mM concentration, 4 mL of Sr ion solution <2+> at 5.0 mM concentration, 4 mL of Na <+> ion solution at 10 mM concentration, 4 mL of ion solution K <+> at 9.4 mM concentration, 4 mL of F <-> ion solution at 10.0 mM concentration, 4 mL of CO3 <2-> ion solution at 4.8 mM concentration and 4 mL of lysine solution. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 40 mA is applied, a potential of 20 V. The electrodeposition reaction takes place at a temperature of 30 ° C for a total time of 4 minutes. At the end of the electrochemical process, an implant is obtained covered with ion-substituted hydroxyapatite nanocrystals functionalized on the surface with lysine. This is dried under a constant flow of hot air at a temperature of 60 ° C.

EXAMPLE 3

Introduce into the electrolytic cell: 47 mL of the Ca <2+> ion solution at a concentration of 42 mM, 47 mL of the PO4 <3-> ion solution at a concentration of 25 mM, 4 mL of the Zn <ion solution 2+> at 4.6 mM concentration, 4 mL of Sr ion solution <2+> at 4.6 mM concentration, 4 mL of Na <+> ion solution at 10 mM concentration, 4 mL of ion solution K <+> at the 9.4 mM concentration, 4 mL of the F <-> ion solution at the 9.0 mM concentration and 6 mL of the CO3 <2-> ion solution at the 4.8 mM concentration. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 28 mA is applied, a potential of 35 V. The electrodeposition reaction takes place at a temperature of 25 ° C for a total time of 3 minutes. At the end of the electrochemical process, an implant is obtained covered with ion-substituted hydroxyapatite nanocrystals which is subjected to a heat treatment at 600 ° C for a total time of 3 hours. EXAMPLE 4

Introduce into the electrolytic cell: 45 mL of the Ca <2+> ion solution at a concentration of 42 mM, 45 mL of the PO4 <3-> ion solution at a concentration of 25 mM, 9 mL of the Zn <ion solution. 2+> at 4.6 mM concentration, 9 mL of Sr <2+> ion solution at 4.6 mM concentration, 4 mL of Na <+> ion solution at 10 mM concentration, 4 mL of ion solution K <+> at the 9.4 mM concentration and 4 mL of the F <-> ion solution at the 9.0 mM concentration. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 34 mA and a potential of 40 V are applied. The electroplating reaction takes place at a temperature of 25 ° C for a total time of 2 minutes. At the end of the electrochemical process, an implant is obtained covered with ion-substituted hydroxyapatite nanocrystals which is subjected to a heat treatment at 500 ° C for a total time of 4 hours.

EXAMPLE 5

Introduce into the electrolytic cell: 50 mL of the Ca <2+> ion solution at a concentration of 40 mM, 50 mL of the PO4 <3-> ion solution at a concentration of 20 mM, 5 mL of the Zn <ion solution. 2+> at 5.0 mM concentration, 5 mL of Sr <2+> ion solution at 4.6 mM concentration, 5 mL of Na <+> ion solution at 10 mM concentration and 5 mL of ion solution K <+> at a concentration of 9.4 mM. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 34 mA and a potential of 20 V are applied. The electroplating reaction takes place at a temperature of 30 ° C for a total time of 2 minutes. At the end of the electrochemical process, an implant is obtained covered with ion-substituted hydroxyapatite nanocrystals which is subjected to a heat treatment at 500 ° C for a total time of 2 hours.

EXAMPLE 6

Introduce into the electrolytic cell: 50 mL of the Ca <2+> ion solution at a concentration of 38 mM, 50 mL of the PO4 <3-> ion solution at a concentration of 20 mM, 10 mL of the Zn <ion solution. 2+> at the concentration of 4.8 mM and 10 mL of the Sr <2+> ion solution at the concentration 5.0 mM. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 20 mA is applied, a potential of 36 V. The electroplating reaction takes place at a temperature of 25 ° C for a total time of 3.5 minutes. At the end of the electrochemical process, an implant is obtained covered with ion-substituted hydroxyapatite nanocrystals which is subjected to a heat treatment at 400 ° C for a total time of 2.5 hours. EXAMPLE 7

Introduce into the electrolytic cell: 50 mL of the Ca <2+> ion solution at a concentration of 41 mM, 50 mL of the PO4 <3-> ion solution at a concentration of 22 mM, 20 mL of the Zn <ion solution. 2+> at a concentration of 4.8 mM. Once the listed solutions have been mixed, the two electrodes are introduced into the cell. Then a current intensity of 30 mA is applied, a potential of 30 V. The electrodeposition reaction takes place at a temperature of 20 ° C for a total time of 4 minutes. At the end of the electrochemical process, an implant is obtained covered with ion-substituted hydroxyapatite nanocrystals which is subjected to a heat treatment at 300 ° C for a total time of 3 hours.

Claims (13)

CLAIMS 1. Process for coating a surface of a metal element with a biomimetic and nanometric hydroxyapatite-based coating, which includes: a) providing an electrolytic bath comprising at least calcium ions and phosphate ions at a temperature between 5 ° C and 40 ° C; b) immersing in said electrolytic bath at least one cathode and at least one anode, said at least one cathode comprising the metal element to be coated; c) passing a direct electric current through said electrolytic bath so as to obtain on said surface an electrolytic deposition of a calcium-phosphate compound comprising nanometric crystals of hydroxyapatite; d) subjecting the metal element coated with the calcium-phosphate compound to a heat treatment at a temperature between 70 ° C and 800 ° C. 2. Process according to claim 1, in which at the beginning of the deposition the electrolytic bath has a pH between 3.0 and 4.5, preferably between 3.5 and 4.0, said pH rising in proximity of the cathode to a value higher than 8, preferably between 10 and 12 during the deposition process without adding alkaline compounds. Process according to claim 2, wherein at the end of the deposition process the electrolytic bath has a pH comprised between 4.0 and 6.0, preferably between 4.5 and 5.5. Process according to any one of the preceding claims, in which the electrolytic deposition is carried out with a substantially constant direct current, preferably having a value comprised between 10 and 100 mA, more preferably between 20 and 60 mA. 5. Process according to any one of the preceding claims, in which, before the heat treatment of point d), said metal element is extracted from the electrolytic bath and dried under a flow of hot air, at a temperature between 40 ° C and 100 ° C, preferably between 60 ° C and 80 ° C, or by immersion of said metal element in an alcohol bath for a time between 5 and 120 seconds, preferably between 15 and 50 seconds. 6. Process according to any one of the preceding claims, further comprising a step e) of immersion of said metal element coated with a hydroxyapatite-based coating in a solution containing poly-L-lysine. Process according to any one of the preceding claims, wherein the calcium ions are present in the electrolytic bath with an initial concentration of between 0.01 and 0.1 mol / liter, preferably between 0.02 and 0.06 mol / liter. Process according to any one of the preceding claims, in which the phosphate ions are present in the electrolytic bath with an initial concentration comprised between 0.01 and 0.10 mol / liter, preferably between 0.02 and 0.04 mol / liter. Process according to any one of the preceding claims, in which zinc, strontium, carbonate, sodium, potassium, fluoride and / or poly-L-lysine ions are further present in the electrolytic bath. 10. Process according to any one of the preceding claims, wherein the metal element comprises titanium or an alloy thereof with Ta, Nb, V, Al, Pt, preferably Ti6Al4V alloys or Ti6Al7Nb alloys. Process according to any one of the preceding claims, in which a layer having a thickness of between 10 nm and 500 nm, preferably between 50nm and 200 nm, is obtained from the deposition of the calcium-phosphate compound. Process according to any one of the preceding claims, in which the hydroxyapatite in the coating is present in the form of crystals having a flattened lanceolate morphology, having average dimensions of the longer side lower than 400 nm, preferably between 50 and 200 nm. 13. Prosthetic device comprising at least one metal element, said metal element having at least one surface coated with at least one layer obtainable by means of the electrolytic deposition process according to any one of the preceding claims.