ES2370248B1 - TITANIUM MATERIALS ANODIZED WITH FLUOR. - Google Patents

Abstract

Fluorine anodized titanium materials. # The present invention relates to a material comprising a titanium alloy substrate and on its surface a layer of fluorine doped titanium oxide, its method of obtaining and the use of said material in applications Biomedical

Description

Anodized titanium materials with fluoride.

The present invention relates to a material comprising a titanium alloy substrate and on its surface a layer of fl ow doped titanium oxide, its method of obtaining and the use of said material in biomedical applications.

Prior art

In general, there are different methods of surface modification of titanium and its alloys to achieve antibacterial properties. Most of them focus on taking advantage of the photocatalytic properties of TiO2 to achieve this property.

In this sense, the literature refers to different methods of obtaining this titanium oxide layer: electrochemical methods (anodized), sol-gel, among others.

The majority of the works have focused on the change of structure, from the layer of TiO2 grown, from amorphous to crystalline - anatase type-, since it has been proven that the latter has photocatalytic and biocompatibility properties.

However, most of the works that use the anodizing process for the growth of titanium oxide layers of controlled morphology (porous, nanotubes, barrier) use a subsequent process to achieve this antibacterial property. Fundamentally, these subsequent treatments consist of:

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the impregnation of these anodic layers with antibiotics or other drugs, so that as a result of their release infection is prevented when the device / prosthesis is inserted into the human body.

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The electrodeposition of metal cations, generally Ag +, whose antibacterial properties, are widely known.

Following this same strategy, of surface doping, this functionalization of titanium and its alloys has been addressed through ionic implantation with Ag +, Cu2 + and F− ions. Once again, we seek to incorporate these ions on the surface to ensure that their presence provides the desired property.

Finally, there are other types of work in which the covalent union of an antibiotic, vancomycin, with the surface of titanium alloys, and more specifically with the Ti90Al6V4 alloy, and its impact on bacterial adhesion is studied. The results were satisfactory for S. aureus and S. epidermidis collection strains.

Although the literature is extensive in each of the different methods described above, it is perhaps important to highlight the following two reviews published in the last 5 years, one by Rimondini et al., Journal of Applied Biomaterials and Biomechanics. 2005; vol. 3. No.1: 1-10; and in the article by Zhao et al. from the Journal of Biomedical Materials Research Part B: Applied Biomaterials Biomechanics. 2009; 470-480.

Recently, a work on pure titanium has been published (Puckett et al. Biomaterials 31 (2010) 706-713), in which the anodizing process carried out in fl uoric acid is used to modify the roughness and surface texture. Specifically, nanotextured and nanotube surfaces were obtained. Furthermore, in said article, the radiation with electron beams, "e-beam", is used to generate a surface roughness in the nanometer range.

In this work, although it is done on pure titanium, it is indicated that the viability of these processes for orthopedic applications will be evaluated. And therefore, the influence of the surface roughness obtained by each of the treatment methods, on protein adsorption and bacterial adhesion, is studied.

The authors mention for the first time that the fl ow incorporated during the anodizing process could have an effect on the influence of bacterial adhesion. That is, the authors conclude that the presence of F in the anodic layers increases bacterial adhesion. To corroborate this result, they refer to a series of works related to dental prostheses, in which the fl uor is present in a solution that simulates the environment present in the oral cavity. Therefore, in this case, the fl uor acts as an aggressive ion that attacks titanium, generating microcavities where bacteria can easily anchor. Thus it seems clear that it is the roughness generated by the attack of the fl uor on titanium that favors the anchoring of the bacteria and not, the fl uor itself. In addition, the study uses bacterial strains grown in antibiotic media. Since antibiotics act at various points in the metabolism of the bacteria, their properties could be altered as a result of them, even if the bacteria are resistant in vitro to the concentrations used. Clinical isolates are also not studied, whose characteristics are known to be very different from those of the collection strains, so the results of the study could be questioned if these organisms were used in a culture medium where, in addition, they did not exist antibiotics

Regarding patents, it is interesting to review this 2003 patent: EP 1515759: This patent presents a technique that combines anodizing known as “Spark Anodising” in an alkaline solution with a hydrothermal post treatment to improve the biomimetic capacity of the surface of titanium.

Description of the invention

The present invention provides a material comprising a titanium alloy substrate and on its surface a layer of fluorinated doped titanium oxide, its method of obtaining and the use of said material in biomedical applications.

The antibacterial properties of the surface of the osteoarticular prosthesis materials allow reducing the risk of infection, increasing the possibilities of the prosthesis by minimizing the risk of rejection. This achievement entails great advantages such as reducing the number of interventions, and more importantly, improving the patient's quality of life.

A first aspect of the present invention refers to a material comprising a titanium alloy substrate and on its surface a layer of titanium oxide with a fluorine content of between 4 and 13% atomic, henceforth material of the invention.

In a preferred embodiment, the titanium alloy is selected from: Al, V, Nb, Ta or any combination thereof. The titanium alloy of Ti6Al4V being in a more preferred embodiment.

Preferably the surface titanium oxide layer has an amorphous structure with rutile nanocrystals.

In a second aspect, the present invention refers to a process for obtaining the material of the invention (from now on the process of the invention), which comprises anodizing the titanium alloy substrate in an acid solution containing at least one 0.06% by weight of fl uor.

The present invention consists in the growth of titanium oxide (TiO2) layers on the Ti6Al4V titanium alloy for orthopedic use (although it is applicable to titanium and other alloys), by an anodizing process that allows the incorporation of F in said oxide in contents between 4 and 13% atomic.

In this way, and in a single step, controlling the imposed anodizing conditions (voltage, time, agitation, temperature and medium) it is possible to include the ion with antibacterial properties in the metal surface.

The antibacterial properties, therefore, do not reside in the photocatalytic properties of titanium oxide, but in the fl uor incorporated in said oxide. Therefore, exposure to UV radiation is not necessary to achieve antibacterial functionalization as in the work described in the prior art.

In a preferred embodiment the acid solution containing at least fl uor is H2SO4 or H3PO4 and 0.05 to 0.5% by weight of HF.

Preferably the anodizing is performed in a potentiostat with a constant potential of between 5 and 60 V for 2 to 60 min, and at a temperature of between 10 to 50 ° C.

In a preferred embodiment the anodizing is performed under constant stirring at a speed of between 100 and 800

r.p.m.

The material used as a cathode during the anodizing process must be a chemically stable material in the anodizing solution, capable of supplying the necessary current during the process, preferably this cathode is platinum.

In a preferred embodiment the process of the invention further comprises a pretreatment of surface preparation of the titanium alloy substrate.

In another preferred embodiment the process of the invention further comprises washing and subsequent drying of the anodized material.

In a more preferred embodiment the washing is carried out with distilled water or with a suspension of CaCO3. In a more preferred embodiment where drying is carried out with air at temperatures between 20 and 50 ° C.

Nor is it necessary to carry out post-growth processes of the oxide layer, -impregnation, electrodeposition, hydrothermal treatment, -to carry out the incorporation of the antibacterial agent.

In the developed invention the antibacterial properties do not depend on the morphology of the layer (porous or nano tubular), as it does in the procedures based on impregnation and / or electrodeposition that require a nanotube structure, as support and storage for the antibacterial agent load.

Furthermore, in this invention the antibacterial properties do not depend on the crystalline structure of the oxide, since the antibacterial properties have been achieved with amorphous structure titanium oxides with rutile nanocrystals, unlike the anatase-like crystalline structure that is pursued in the works described in the state of the art, precisely because of their photocatalytic properties and greater bioactivity properties.

However, the morphology of the oxide layer grown through the control of the anodizing process parameters can be controlled by the process of the invention. Depending on the conditions of voltage, time and the medium, porous structures with a pore diameter of 10 nm are achieved; or nanotubes of 100 nm in diameter. Similarly, the thicknesses obtained can vary from 100 nm to 1000 nm.

The invention is carried out by means of a conventional infrastructure, customary in finishing industries, and which does not have a high cost. This constitutes an advantage over the ion implantation procedures known to any person skilled in the art. Ionic implantation is performed under high vacuum conditions and requires sophisticated equipment, which means a higher treatment cost. In addition, this technique is directional, that is, it only treats surfaces that are located directly below the beam, which in principle makes it difficult to treat parts with complex geometries, such as joint prostheses or dental screws. Although today there are orbital supports that rotate the pieces for the uniform treatment of the surface, this entails an additional cost of the already expensive process.

A third aspect of the present invention relates to the use of the material of the invention, for the manufacture of biomedical antibacterial materials. All those metallic materials that require an antiseptic behavior and even in the food sector, such as countertops, cutting utensils and all those applications that require a certain degree of asepsis.

As is known between 20 and 30% of prosthetic replacements are due to a deep infection. Implant contamination in surgery cannot be controlled in the organism if bacterial adhesion occurs followed by biofilm formation and subsequent infection, the treatment of which is often ineffective if the infected prosthesis is not removed.

By "biofilm" is meant in the present invention that organized microbial ecosystem, consisting of at least one microorganism associated with a living or inert surface to which they adhere.

The decrease in the probability of infection during the intervention would therefore lead to a substantial reduction in the number of septic failures, improving the results where the conventional surgical prophylaxis fails, and therefore improving the quality of life of patients receiving a implant.

From the point of view of the surgical technique there are no more possibilities for improvement to avoid these infections. So the only possible way of acting lies in an improvement of the properties of the prosthesis material or its surface. And that is achieved thanks to the use of the material of the invention.

Preferably the material of the invention is used for the manufacture of prostheses. More preferably osteoarticular prostheses, dental implants among others.

In the tests carried out there has been a 40-70% reduction in the adhesion, to the modified material, of two types of bacteria studied in in vitro tests.

Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.

Description of the fi gures

Fig. 1. Shows the scanning electron micrograph of the anodized Ti6Al4V alloy surface 5 minutes in a 1 M H2SO4 solution + 0.06% by weight HF at 20 ° C.

Fig. 2. Shows the photographs taken with a fluorescence microscope (x40), showing the adhesion of the S. epidermidis ATCC 35984 bacteria to the surface of a) Ti6Al4V, b) Ti6Al4V anodized 5 minutes in the solution with HFyc) Ti6Al4V anodized 60 minutes in the solution with HF.

Examples

The invention will now be illustrated by tests carried out by the inventors, which demonstrates the specificity and effectiveness of the material of the invention as a biomedical antibacterial material and its method of production.

Example 1

1.- Prior preparation of the Ti6Al4V alloy surface of ELI grade according to ASTM F136-02.

The samples were cut from a 1.8 cm diameter Ti6Al4V bar. 2 mm thick discs were cut.

The surface to be treated is 2.5 cm2 and they were prepared according to table 1 detailed below:

TABLE 1

2.-After cleaning, the anodizing process was carried out under potentiostatic conditions, imposing a constant potential of 20 V for 5 minutes, in an acid solution of 1 M H2SO4 + 0.06% by weight HF and under constant agitation conditions at a temperature of 20ºC (cte during the whole process). As a cathode, a Pt basket with an area of about 3 cm2 has been used.

3.-Then it was rinsed in abundant distilled water and subsequently dried with cold air for 5 minutes.

Under these conditions, an amorphous TiO2 layer with rutile nanocrystals (TiO2 of tetragonal structure P42), V2O5 and Al2O3, and with F contents of atomic 6% is obtained.

The morphology of the layer grown under these conditions has a duplex structure consisting of a barrier layer, in contact with the substrate, 40 nm thick, and a porous outer layer 60 nm thick. The pore diameter is between 10 and 20 nm, as seen in Figure 1.

Example 2

In the tests carried out for the study of bacterial adherence, S. aureus 15981 and S. epidermidis ATCC 35984 collection strains were used. The strains were studied using the adherence protocol described by Kinnari et al. (J Biomed Mat Res Part A. 2008. 86 (3): 760-8). The experiments were performed in triplicate, obtaining 8 photographs for each material in each experiment. The photographs taken were studied using the ImageJ software. The statistical study was performed using the EPI-INFO software.

The results of these tests have shown a 40-70% reduction in the adhesion, to the modified material, of the two types of bacteria studied in in vitro assays, as can be seen in the photographs of Figure 2. The two species of bacteria used Staphylococcus epidermidis and Staphylococcus aureus, were chosen to be responsible for both 60-80% of infections associated with biomaterials in orthopedic surgery, known producers of biofilms. Subsequently, similar studies were carried out with bacteria isolated from clinical pictures of osteoarticular prosthesis infection, characterized in vitro in terms of their biofilm production mechanisms, using 6 strains of each species in these studies.

In all cases there was a significant reduction in bacterial adhesion with respect to the control material, a greater reduction in the case of S. aureus, regardless of the variability in adhesion presented by clinical isolates, so it could be stated that the Decrease in bacterial adhesion would appear in all cases related to these species.

Claims (18)

one.

Material comprising a titanium alloy substrate and on its surface a layer of titanium oxide with a fluorine content of between 4 and 13% atomic.

2.

Material according to claim 1, wherein the titanium alloy is selected from: Al, V, Nb, Ta or any combination thereof.

3. Material according to any of claims 1 or 2, wherein the titanium alloy is Ti6Al4V.

Four.

Material according to any one of claims 1 to 3, wherein the surface titanium oxide layer has an amorphous structure with rutile nanocrystals.

5.

Material according to any one of claims 1 to 4, wherein the thickness of the fl ow titanium oxide layer has a thickness between 100 nm to 1000 nm.

6.

Method of obtaining the material according to any one of claims 1 to 5, comprising anodizing the titanium alloy substrate in an acid solution containing at least 0.06% by weight of fluorine.

7.

Method according to claim 6, wherein the acid solution containing at least fl uor is H2SO4 or H3PO4 and 0.05 to 0.5% by weight of HF.

8.

Method according to any of claims 6 or 7, wherein the anodizing is performed in a potentiostat with a constant potential of between 5 and 60V for 2-60 min, and at a temperature between 10 to 50 ° C.

9.

Method according to any of claims 6 to 8, wherein the anodizing is performed under constant agitation at a speed of between 100 and 800 rpm.

10.

Method according to any of claims 6 to 9, wherein the material used as a cathode is platinum.

eleven.

Process according to any of claims 6 to 10, which further comprises a pretreatment of surface preparation of the titanium alloy substrate.

12.

Method according to any of claims 6 to 11, further comprising washing and subsequent drying of the anodized material.

13.

Method according to claim 12, wherein the washing is carried out with distilled water or with a suspension of CaCO3.

14.

Process according to claim 12 or 13, wherein the drying is carried out with air at temperatures between 20 and 50 ° C.

fifteen.

Use of the material according to any of claims 1 to 5, for the manufacture of biomedical antibacterial materials.

16.

Use according to claim 15, for the manufacture of prostheses.

17.

Use according to claim 16, for osteoarticular prostheses.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201030720 SPAIN Date of submission of the application: 14.05.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

X

KR 20070011200 A (LEE KWANG MIN et al.) 01/24/2007, summary [online] retrieved from [WPI / Thompson]. 1-17

TO

PUCKETT, S.D. et al “The relationship between the nanostructure of titanium surfaces and bacterial attachment” Biomaterials 30.10.2009, Volume 31 Pages 706.713; Sections 2.1-2.2, 3-5. 1-17

TO

JAKUBOWICZ, J. “Formation of porous TiOx biomaterials in H3PO4 electrolytes” Electrochemistry Communications 26.02.2008, Volume 10 Pages 735-739; sections 2-4. 1-17

TO

XUANYONG LIU et al. “Surface modifications of titanium, titanium alloys, and related materials for biomedical applications” Materials Science and Engineering R 13.01.2005; Volume 47 Pages 49-121; Sections 1.2, 1.2.1, 1.3, 1.3.4 and 3.3, tables 3-5. 1-17

TO

MACAK, J.M. et al. “TiO2 nanotubes: Self-organized electrochemical formation, properties and applications” Current Opinion in Solid State & Materials Science 01.02.2007, Volume 11 Pages 3-18; sections 1.2,1.4,2.2,4.5. 1-17

TO

CIGADA, A. et al. "Increasing of the corrosion resistance of the Ti6Al4V alloy by high thickness anodic oxidation" Journal of Materials Science 1992, Volume 3 Pages 408-412; sections 1,2 and 5. 1-17

TO

BAUER, S. et al. “TiO2 nanotubes: Tailoring the geometry in H4PO4 / HF electrolytes” Electrochemistry Communications 12.07.2006, Volume 8 Pages 1321-1325; sections 1-4. 1-17

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 29.04.2011

Examiner A. Urrecha Espluga Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201030720 CLASSIFICATION OBJECT OF THE APPLICATION A61L27 / 06 (2006.01) A61L27 / 30 (2006.01) A61C8 / 00 (2006.01) C25D9 / 06 (2006.01) Minimum documentation sought (classification system followed by classification symbols) A61L, A61C, C25D Electronic databases consulted during the search (name of the database and, if possible, search terms used) INVENES, EPODOC, WPI, XPESP, NPL, TXTUS. State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201030720 Date of Completion of Written Opinion: 04.29.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 2-5 1.6-17 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-17 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201030720 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

KR 20070011200 A (LEE KWANG MIN et al.) 01/24/2007

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The object of the invention is a material comprising a substrate of a titanium alloy and on its surface a layer of fluorine titanium oxide, its process is obtained and the use of said material for the manufacture of biomedical antibacterial materials. Document D01 discloses a method for anodizing a titanium implant or a titanium alloy. The solution in which it is carried out is 0.1-1.5M H3PO4, H2SO4 and contains 0.5-2.0% fluorine weight. The conditions are room temperature at 100 ° C and 2-50V (summary). Claims 1, 6-17 are novel in the light of what is disclosed in D01 (Art. 6 LP). It is not possible to recognize inventive activity to dependent claims 2-5, relating to the use of a titanium alloy with aluminum and vanadium as a substrate of the biomaterial, specifically Ti6Al4V, since in the absence in description of an advantage or technical effect associated with the The use of said alloy is considered to be well known in the state of the art to use titanium alloys for the fabrication of prostheses or implants, as well as anodizing them in acidic solutions containing HF to obtain a oxide layer of titanium that covers them (documents D02-D7 of the state of the art report) and, therefore, is an arbitrary choice devoid of inventive activity (Art. 8 LP). State of the Art Report Page 4/4