Specification of Patent of Invention for

"BIOCOMPATIBLE MATERIAL, PROCESS FOR

OBTAINING SAID BIOCOMPATIBLE MATERIAL AND USE

OF SAID BIOCOMPATIBLE MATERIAL IN IMPLANTS AND PROSTHESES"

The present invention discloses the obtainment of biocompatible prosthesis and/or implant materials from alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxides and/or metallic aluminum which allow the spontaneous formation of a calcium phosphate coating on the surface thereof.

Description of the prior art

Components comprised of alumina (AI ₂ O ₃ ) and sapphire (monocrystalline alumina) are widely used as prostheses, implants, and fixers for prostheses and implants (bone screws, plates, etc.) with the purpose of replacing or enabling the restoration of bones and teeth. The employment of this material is known in medical practice, particularly in orthopedics and odontology. Alumina is used in prostheses and implants due to its hardness, mechanical strength, and chemical inertia.

Alumina components, when implanted in the human body, are fixed by physical adhesion to the bone in which they were implanted. The implantation of alumina components in bones results, as a consequence of the bio-inertia associated with this material, in the

formation of a fibrous tissue in the interstice between the bone cavity into which the implant was inserted and the surface of the material. The fibrous tissue fixes the physically embedded implant to the rough surface of the implant and the bone.

Although the formation of the fibrous tissue results in the fixation of the implant, mechanical stresses upon the implants, such as those resulting from chewing in the case of odontological implants, may result, over time, in the destruction or settlement of this fibrous tissue, leading to a failure in the fixation and the need of restoring the implant by means of a new surgical procedure and the placement of a new implant.

On the other hand, ceramics formed of calcium phosphate, such as hydroxyapatite, tricalcium phosphate, phosphate- based cements, etc., when implanted in bones, are recognized by the living organism as biocompatible. The biocompatible behavior of these ceramics results in the fixation of the implants by the bone tissue growth as a function of the osteoconduction and osteoinduction phenomena, making the implant osteointegrated while avoiding the occurrence of a fibrous tissue interface between the implant and the bone wall.

The biointegration of materials composed of calcium phosphate is used for fixing not only implants formed uniquely of these materials; prostheses coated with calcium phosphate (hydroxyapatite, etc.) and formed by metallic titanium, as well as other

surgical metal alloys, have been fixed to bones by means of this process. In order to become more biocompatible, the prostheses are subjected to treatments which coat them with calcium phosphate or sintering processes which include these salts in the composition of the prosthesis itself. Many of these processes are known in the state of the art and described herein, however, in addition to not being able to render the prosthesis totally biocompatible, these processes also impair the physical characteristics of the same.

Among known methods for coating metal prosthesis with calcium phosphate, one could mention "Plasma Spray", "Ion Implantation", "Deep Coating", etc.

In "Plasma Spray", metal prosthesis coats are produced by introducing particles of the powder of a certain material into the plasma spray. These particles are fused and, through the plasma directed into the substrate, scattered along its surface. The coat formation depends upon the interaction between the droplets present in the plasma and the substrate or between previously deposited layers, i.e. the steps consist in scattering the droplets on the surface, forming lamellae, and solidifying the same.

The "Ion Implantation" technique allows the surface of the material and its surroundings to be modified without changing any property of its interior. However, this does not always happen. Physical changes induced by this method are the result of atomic and

nuclear collisions, which can lead to the formation of disordered and amorphous structures.

In the "Deep coating" technique, the substrate is immersed in a solution containing the material which will coat the surface. Thereafter, the solvent is evaporated, the substrate is removed and the surface becomes coated.

Although the coating with calcium phosphates is usual for metal prostheses and implants, the described methods for coating of prosthesis and implants with calcium phosphate involve the treatment of the prostheses and implants at high temperatures, advanced systems, and are not applicable to prostheses and implants having shapes which include recesses and protrusions. Another aspect is that the high temperature, typical of these methods, sinters and modifies the composition of calcium phosphate.

These techniques have the drawback of often not promoting a modification of the surface through a chemical reaction, in addition to the fact that, in many times, they result in changes on the mechanical properties of the substrate, which can lead to formation of stress points at the material. It should also be pointed out that the apparatus required for the plasma spray technique, which among previously mentioned techniques is the one that shows better results, is very costly.

Document US 6207130 discloses a process of metallic exchange in solution, wherein metal cations can be exchanged

for aluminum cations in the boehmite phase of materials known as carboxylate-alumoxanes. Carboxylate alumoxanes are prepared by reacting boehmite (or pseudoboehmite) with carboxylic acids in a suitable solvent, wherein aqueous solvents are preferably used. The metallic exchange process results in the formation of aluminum oxides through temperatures which are dependent upon the exchanged cations and which are comprised in the range of 800 ⁰ C to 1700 ⁰ C (1,472 ⁰ F to 3,092 ⁰ F).

Document WO0009578 discloses compositions and methods for preparing these compositions wherein at least one of the components is a chemically-modified carboxylate-alumoxane. Carboxylate-alumoxanes are chemically bound in the polymeric structure by reacting specific functional groups of a polymer precursor with carboxylate-alumoxane. The described method can be used for the production of polymers having organic and inorganic skeletons. Among polymer precursors which can be used are epoxides, phenol- formaldehyde resins, polyamides, polyesters, polyimides, polycarbonates, polyurethanes, amino-quinone polymers, and acrylates.

Document US6322890 discloses the obtainment of supramolecular solid alkyl-alumoxanes. The supramolecular alkylalumoxane structure comprises a) an aluminum oxide nanoparticle, b) a bonding unit, and c) an alkylalumoxane. Supramolecular alkylalumoxanes are prepared by reacting a

chemically-modified aluminum oxide nanoparticle with a pre-formed alkylalumoxane and subsequent hydrolysis. Supramolecular alkylalumoxanes act as a catalyst in the polymerization of organic monomers and as cocatalysts in the polymerization of olefins.

Object of the invention

The main objective of the present invention is to provide implant and/or prosthesis materials which are biocompatible and which allow the spontaneous formation of a calcium phosphate coating on the surface thereof.

Summary of the invention

The present invention discloses a process for obtaining a biocompatible material through the modification of a material formed by alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxides and/or metallic aluminum, wherein such modification occurs by reacting this material with dicarboxylic acid dissolved in an organic solvent.

The subject invention also refers to a process for obtaining a biocompatible material which comprises the process for obtaining a biocompatible material described in the invention.

The subject invention still refers to a biocompatible material composed of alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxides and/or metallic aluminum, said

biocompatible material being obtained according to the process for obtaining a biocompatible material described in the invention.

This invention also refers to a biocompatible material comprising said biocompatible material described in the invention.

This invention still refers to the use of said biocompatible material described in the invention, in orthopedic and odontological implants and/or prostheses.

Brief description of the drawings

Figure 1 - Reaction for forming of oxalate alumoxane

Figure 2 - Comparative view of electron micrograph from γ-alumina surfaces after immersion in SBF without surface modification (2A) and with surface modification (2B).

Figure 3 - Comparative view of electron micrograph from commercial alumina surfaces after immersion in SBF without surface modification (3A) and with surface modification (3B).

Figure 4 - Graph showing the elemental composition of modified γ- alumina surfaces.

Figure 5 - Graph showing the elemental composition of commercial alumina surfaces.

Detailed description of the invention

The present invention discloses a process for obtaining a biocompatible material through the modification of a material formed by alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxides and/or metallic aluminum, wherein such modification occurs by reacting this material with dicarboxylic acid dissolved in an organic solvent.

In the present invention, dicarboxylic acids are used as reagents for the formation of the carboxylate alumoxane on the surfaces of materials formed by all phases of alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxides and/or metallic aluminum, with the purpose of modifying them and making them biocompatible. Carboxylic acids which are used are selected from oxalic acid, propanediol acid, and butanedioic acid, although other dicarboxylic acids may also be used. Since acids are dicarboxilyc, one of the carboxylic groups is responsible for the formation of the alumoxane group, fixing the compound on the surface of alumina. The second carboxylic or carboxylate-ionized group (carboxylic/carboxylate) will remain free and directed outwards the surface of modified alumina. In the present invention, the organic solvent used is selected from ethanol, xylol, or any other organic solvent in which dissolution of dicarboxylic acid occurs.

The modification of all surfaces formed by all phases of alumina, sapphire, boehmite, aluminum oxidehydroxides,

and metallic aluminum is made by the reaction with carboxylic acids which react as the Al-OH groups present on the surface of the material resulting in the formation of a compound known as carboxylate alumoxane. The subject invention refers to the process for obtaining a biocompatible material, wherein said process results in the formation of carboxylate alumoxane on the surface of materials comprised of alumina and/or sapphire and/or boehmite and/or aluminum oxyhydroxides and/or metallic aluminum.

The surfaces of the various phases of alumina, sapphire, boehmite, aluminum oxyhydroxides, as well as metallic aluminum, show Al-OH groups resulting from the composition of the material or which may be formed by hydrolysis reactions. The process for obtaining a biocompatible material of the present invention may still comprise a step of treatment with NaOH in order to allow OH groups to be formed on its surface.

The present invention refers to a biocompatible material comprised of alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxydes and/or metallic aluminum, obtained according to a process wherein the surface of materials comprised of alumina and/or sapphire and/or boehmite and/or aluminum oxidehydroxydes and/or metallic aluminum is modified through reaction with a dicarboxylic acid. As a consequence of the reaction with a dicarboxylic acid, carboxylate alumoxane is formed on the

surface of these materials. The surface of the biocompatible material of this invention comprises carboxylate alumoxane.

The modification of the surfaces formed by all phases of alumina, sapphire, boehmite, aluminum oxidehydroxydes, and metallic aluminum by dicarboxylic acids, as proposed in this invention, enables, in addition to modifying the same, to induce precipitation and adhesion of calcium phosphates over the surface.

The formation of calcium phosphate on the modified surfaces may be carried out by immersing the materials in solutions having a composition similar to the composition of human body fluids (Simulated Body Fluid, SBF), resulting in the nucleation of calcium phosphates as a function of the interaction between Ca ions and existing phosphates in SBF and the carboxylic/carboxylate group, free on the surface of modified alumina. Calcium phosphate nuclei give rise to crystals from this material, which grow adhered to the surface of the material, covering it with a calcium phosphate layer. The formation of the calcium phosphate coating adhered to the surface of alumina changes its behavior from bioinert into biocompatible, resulting in the integration and optimum fixation of implants and prostheses built with this modified material to the host tissue.

Since the composition of SBF is similar to the composition of fluids present in the human body, the formation of the phosphate calcium coating also occurs spontaneously when implants having surfaces formed by all phases of alumina, sapphire, boehmite,

aluminum oxidehydroxydes, and metallic aluminum modified by the reaction with dicarboxylic acids are implanted, without the need of a previous treatment with SBF. This spontaneous formation of calcium phosphates on the surface in the organism indicates that the modified bioinert material becomes biocompatible solely with the modification of the surface by dicarboxylic acids.

The subject invention refers to a biocompatible material which, when in contact with body fluid or simulated body fluid, promotes the growth of calcium phosphate crystals on its surface.

The invention described herein seeks to combine the advantages of the mechanical properties of the implants formed by all , phases of alumina, sapphire, boehmite, aluminum oxidehydroxides, and metallic aluminum with the biointeraction of ceramics constituted of calcium phosphates. This invention refers to the formation of a calcium phosphate coating adhered onto the surface of this materials, without the need of a thermal treatment typical of coating processes commonly used for metal implants, thus keeping the properties of calcium phosphates deposited on the surface of prostheses and implants. In a similar way, the method proposed by this invention does not suffer from the disadvantages caused by the complex shapes of prostheses and implants and which are associated with conventional methods.

Another aspect of the invention is that the surface modification, as proposed, results, after implantation, in the spontaneous formation of a calcium phosphate coating on the surface, once prostheses and implants are implanted in the organism.

The surface modification proposed by the invention results in a full bioactivity change of the formed surfaces through all phases of alumina, sapphire, boehmite, aluminum oxidehydroxydes, and metallic aluminum, changing them from bioinert to biocompatible, inducing bone formation between the implant and the host bone, without formation of fibrous tissue, as is typical for alumina implants without surface modification.

This invention refers to the formation of carboxylate-alumoxanes from the reaction of dicarboxylic acids and Al-OH groups present in the surface of the material to be used, modifying the surface of the formed solids through all phases of alumina, sapphire, boehmite, aluminum oxyhydroxides, as well as metallic aluminum. The formation of carboxylate-alumoxanes on the surface of bioinert materials as described in this invention modifies the bioinert behavior of the surface of the material, rendering it biocompatible. This modification enables the formation of calcium phosphate upon the same, which heavily changes the biocompatibility of these materials.

The present invention describes the employment of dicarboxylic acids, such as oxalic acid, propanedioic acid, butanedioic

acid, and the like, as a reagent for the formation of carboxylate- alumoxanes on surfaces formed by all phases of alumina, sapphire, boehmite, and other aluminum and metallic aluminum oxidehydroxides with the purpose of modifying them and making them biocompatible.

Dicarboxylic acid forms the compound alumoxane, by the reaction of one of the carboxylic groups with the Al-OH groups present on the surface of the material. This reaction chemically bonds the chain of dicarboxylic acid to the surface of the material. The other carboxylic group remains free and, if ionized in the form of carboxylate, will form chelates having calcium ions present in the body fluid or in solutions which simulate the body fluid. The interaction of the carboxylate group which remains free and directed outwards the surface of alumina with calcium ions leads to the precipitation and adhesion of calcium phosphate crystals to this surface. This interaction which results in the formation of calcium phosphate crystals adhered to the modified surface may occur either in vivo by means of the contact with body fluids or in vitro by means of the contact with solutions that simulate body fluids. In the case of in vitro formation, it represents a surface treatment which performs the same functions as the procedures used for the coating of prostheses and implants with calcium phosphates.

The formation of calcium phosphates may occur in a spontaneous way when implants, prostheses, and other types of

materials having this modified surface are put in contact with body fluids, when implanted in humans and animals, and also in a induced way when implants, prosthesis, and other types of materials having this modified surface are put in contact with solutions which simulate body fluids containing, in its composition, calcium ions and phosphate ions.

Alumina and sapphire are bioceramics with excellent mechanical properties and widely used in medical practice as orthopedic and odontological prostheses. However, its use as a bioceramic becomes restricted due to its bio-inertia. Thus, the surface modification of all phases of alumina, sapphire, boehmite, and aluminum oxyhydroxides, as well as metallic aluminum, from bioinert into biocompatible widely extends the use of these materials as biomaterials, especially in improving and extending its use as orthopedic and dental prosthesis.

Although there are documents making reference to compounds called alumoxanes or even AIxOx compounds in the fields of catalysis, polymers, and biomaterials, as is the case of documents such as US6207130, WO0009578, and US6322890, the invention described herein differs by the fact that it provides a process for modifying the surface of materials together with the controlled growth of calcium phosphate crystals and the change of the bioinert nature of surfaces formed by all phases of alumina, sapphire, boehmite, aluminum oxidehydroxydes, and metallic aluminum, into

biocompatible.

Thus, the invention described herein represents a simple, fast, and low-cost process which enables the coating of materials used for implants comprised of aluminum oxidehydroxydes and even metallic aluminum.

Although there are techniques used in surface coating, such as plasma spray, deep coating, and ion implantation, none of them has been used so far for coating alumina surfaces with calcium phosphates. Therefore, the related invention is not an improvement over any process, but a development of an easy, simple, and low-cost procedure for coating an alumina surface by chemically reacting said surface with a dicarboxylic acid in order to allow the coating thereof with calcium phosphate thanks to this modification.

Thus, the present invention reveals itself as an advantageous solution which aims exactly to ensure the modification of the surface by means of a chemical reaction, without the possibility of lixiviating the modifier group nor changing the mechanical properties of the substrate, is a simple and cheap procedure, involves reagents which can be easily found in a laboratory, and does not require any advanced apparatus therefor.

The invention described herein combines the advantages of the mechanical properties of the implants formed by all phases of alumina, sapphire, boehmite, and other aluminum

oxidehydroxydes, as well as metallic aluminum, with the biointeraction of ceramics constituted of calcium phosphates.

The invention provides a method of coating with calcium phosphate when the surface is put in contact with solutions which simulate body fluids (simulated body fluid SBF) which is adhered onto the surface, without it being necessary a thermal treatment typical of processes for coating with calcium phosphates, thus preserving integrally the biocompatible material properties for deposits obtained by this method. Similarly, the method proposed by this invention does not suffer from the disadvantages caused by the complex shapes of prostheses and implants and associated with for conventional methods.

Another aspect of the invention is that the surface modification, as proposed, after the prosthesis or implant implantation (in vivo formation), will also result in the spontaneous formation of a calcium phosphate coating on the surface, without the need of a previous in vitro treatment.

The change of surfaces formed by all phases of alumina, sapphire, boehmite, and other aluminum oxidehydroxydes, as well as metallic aluminum, from bioinert into biocompatible nature, occurs in the reaction of these surfaces with dicarboxylic acids.

This reaction is carried out by hot immersing the body whose surface is to be modified in solutions of dicarboxylic acid in an organic solvent (ethanol, xylol, or any other solvent in which

dissolution of dicarboxylic acid occurs). The extent of surface modification is a function of the treatment time, the concentration of dicarboxylic acid in the solution, and the properties of dicarboxylic acid. After this hot treatment, the object, implant, or prosthesis may be immersed in a simulated body fluid solution or another solution containing calcium and phosphate ions for the formation of a coating of calcium phosphate crystals. However, if the objected is implanted without this previous treatment in solutions containing phosphate and calcium ions the contact body fluids does not result in the spontaneous formation of the coating with calcium phosphates.

The surface modification and alumoxane formation reaction was reported about 20 years ago and is used exclusively for the surface modification of boehmite powders (hydroxilated alumina). Resulting powders and many of its uses have been patented during this time. The patented uses involve the use as a catalyst for various polymerization reactions, as a charge for polymers, as well as a charge for biocompatible polymers. However, the modification with dicarboxylic acids and change of the material from bioinert into biocompatible as proposed by this invention has not been reported.

In addition to improving the biocompatibility of already existing prostheses, the invention enables the development of other types of prostheses composed of materials having surfaces similar to those formed by all phases of alumina, sapphire, boehmite, and other aluminum oxidehydroxydes, which could not be

accomplished precisely because of the lack of biocompatibility from these materials.

The subject invention also refers to the use of the biocompatible material described herein in orthopedic and odontological implants and/or prostheses.

Some exemplary preferred embodiments of the subject invention are described in the following. The embodiments described herein should be construed as one possible way of carrying out the present invention and are not to limit the scope of protection thereof.

Ex. 1 - Obtainment of biocompatible material from γ-alumina

Alumina used in this example is a γ-alumina synthesized via sol-gel pathway. This kind of alumina is an aluminum oxide having a face centered cubic system. More precisely, it has the structure of a spinel. Spinels are oxides whose cations are surrounded by oxygens in tetrahedral and octahedral arrangements. However, when synthesizing this kind of alumina through a pathway other than that, the result can be a mixture of this material with other kinds of phases (such as δ and θ ). Moreover, this special synthesis pathway allows, by means of the slow hydrolysis of urea, the pH of the solution to increase gradually, enabling a greater control of particle size. This pathway is made by adding urea in a solution practically saturated with aluminum nitrate until a molar ratio Al ³⁺ /urea of 1/13 is achieved.

The solution is filtered, after being left to rest for one hour, at room temperature. Next, the solution is heated at 9O ⁰ C until it changes into a gel and then the sample is calcined at 300 ⁰ C for half an hour. This alumina was used largely due to the high amount of OH groups on its surface which allows the same to react with dicarboxylic acids.

With alumina prepared, wafers from this material were made by using a press having a pressure of 8000 psi. Next, wafers were placed in a solution of 0.02 M of oxalic acid in ethanol during 8 hours at 7O ⁰ C in a thermostated bath. Thereafter, temperature of reaction medium was reduced to 25 ⁰ C and the system was kept this way during 24 hours. Finally, wafers were washed with distilled water and the material was ready for undergoing biocompatibility tests by immersing it in a simulated body fluid at 37°C during six hours.

Ex. 2 - Obtainment of biocompatible material from commercial alumina

The same procedure of example 1 may be carried out with aluminum oxides which originally did not have OH groups, as long as more steps are added to the procedure to allow OH groups to be formed on their surfaces. For commercial alumina, the procedure for this formation consisted, after preparing the wafers, in immersing the same in aqueous solution of NaOH IM during 5 seconds and then immersing them in a beaker with distilled water. It should be pointed out that time must be followed precisely in this procedure, since it was repeated with 10 seconds of immersion in NaOH solution and,

according to the micrographs obtained, formed crystals already began losing their structure. The rest of the procedure was identical to that described in example 1.

The chemical reaction involving the alumina surface with oxalic acid is shown in Figure 1.

Ex. 3 - Obtainment of biocompatible material from α-alumina

The surface modification of α-alumina requires a larger procedure, since this is the most inert form of alumina. All other forms are converted into α when subjected to high temperatures. Monocrystalline α -alumina is known as sapphire and the procedure was also carried out therewith. Pieces of this synterized material were also used. In order to modify the surface of α-alumina, whose system is hexagonal trigonal, treatment with NaOH was firstly carried out, but due to the lack of reactivity of the material, fused NaOH was used during two hours. Thereafter, samples were washed and coated with γ- alumina, by dipping the samples in aluminum gel and calcining them at 400 ⁰ C during two hours. This gel dipping and calcining procedure was repeated five times for each sample. In order to ensure the activation of the surface, immersion of the NaOH aqueous solution was also performed, in the same way as commercial alumina wafers. The rest of the procedure was the same as described in Example 1 , except for the immersion time in SBF, which was of 24h.

What must be preserved in the experiment in order to the obtainment of the invention to be successful are the concentrations of NaOH and oxalic acid solutions (this concentration is recommendable as these acids may act as peptizing agents instead of reacting with the surface of alumina), as well as the immersion time of the material into the latter for activating the surface. As a result of SBF simulating the conditions of the organism, the temperature of 37 ⁰ C during the immersion of the materials should be kept, but the time may vary. With respect to the synthesis temperature of the alumoxane, it is limited to the boiling point of the applied solvent, in this case 79 ⁰ C for ethanol. However, variations may occur with respect to the type of solvent and also regarding the dicarboxylic acid used, thus, the temperature at which the system is kept during the synthesis of the alumoxane can also be changed.

Results:

After the procedure, samples were analyzed by scanning electron microscopy, wherein it can be seen in figures 2B (γ- alumina) and 3B (commercial alumina) that there is a growth of calcium phosphate crystals on the surface of modified aluminas, but there are no crystals on the surfaces without modification shown in figures 2A (γ-alumina) and 3A (commercial alumina), suggesting that the reaction with oxalic acid is essential for this to occur. However, for α -alumina samples, micrographs had not shown crystal formation as in figures 2B and 3B, but the ultimate analysis by electron dispersive

spectroscopy had shown the presence of calcium phosphate on the surface of the samples.

Determination of the elemental composition of modified surfaces was also performed after the procedure by means of electron dispersive spectroscopy (EDS), which are shown in figures 4 (γ-alumina) and figure 5 (commercial alumina). With results shown in figures 4 and 5, it can be noted that the crystals formed on the surfaces are really of calcium phosphate.