A requirement in the use of endosseous implants, for example endosseous dental implants, is to achieve osseo-integration and/or bio-integration of the implant with the bone.

A wide variety of materials have been used for biomedical implants, but only a few fulfill the osseo- integration requirement to a sufficient level.

Titanium and titanium-based alloys are the preferred materials used for such implants. The nature of the native surface oxide of the titanium appears to be the underlying factor for good osseo-integration. The surface oxide appears to promote the deposition of biological molecules and to limit the dissolution of the bulk elements. It is believed that this release determines the biological response to the dental implant.

Although osseo-integrated titanium implants have a long and successful record in treating edentulous patients with normal bone stock, the results obtained from clinical intervention are not as good when bone quantity and quality is inferior. In such cases, achieving an improved level of osseo-integration is an important factor in producing a successful implant.

Additionally, improved osseo-integration may reduce the time required to achieve an adequate load bearing capability which, at present, may be up to 6 months for the upper jaw. The critical role of surface

condition on the clinical performance of titanium based materials has meant that efforts to improve their behaviour have concentrated not only on the alloy composition but also on the use of surface treatments.

Besides endosseous dental implants, a wide range of other biomedical implants have similar requirements for good osseo-integration.

Different surface treatments have been applied to improve the adhesion of cells to biomedical implants, including grit blasting of the surface with particles of an oxide of titanium and applying ceramic coatings.

Application of porous coatings, such as, for example, a 50-100 ism thick hydroxyapatite (HA) type coating by plasma spraying has become widespread since the early 1980s. However, a number of clinical questions regarding their efficacy have been raised, including the mechanical weakness of the coating/substrate interface and the difficulty of producing a uniform layer on complex shaped implants. Another difficulty concerning plasma spraying is that it does not allow the deposition of coatings thinner than about 40 ßm.

The long-term behaviour of these ceramic coatings is jeopardized due to continued (and improperly controlled) dissolution of the coating. The crystallinity of the coating is a major factor in determining dissolution rates with amorphous coatings being more prone to biodegradation than crystalline ones. There is also concern over the possible increase in corrosion rate, both because of increased surface area and crevice corrosion effects. Other ceramic coatings have been produced by other methods including electrochemical treatments, but up till now these have not shown great success. Heat treating in

air has also been reported as a method of achieving a reduction in ion release from a Ti-based alloy into physiological solutions. Several factors might affect ion release from the oxidized surface of the metal, such as increased oxide thickness (typically 2 ~ 4 nm compared with ~ 2.5 nm for the native oxide) and a modified oxide structure.

Accordingly, the present invention provides a process for the production of a biomedical implant having an oxide of titanium on a surface thereof, the process comprising: (a) providing a biomedical implant, at least a surface of which comprises titanium or an alloy thereof ; (b) exposing said surface of the biomedical implant to an oxygen-containing atmosphere having a dew point of < 0°C ; and (c) heating said surface of the biomedical implant in said atmosphere whereby an oxide of titanium is formed on at least said surface.

The dew point of the oxygen-containing atmosphere provides an indication of the humidity of the atmosphere. The atmosphere will generally have a dew point of < 0°C, preferably from-60°C to 0°C, more preferably from-50°C to-5°C, more preferably from - 40°C to-10°C, still more preferably from-30°C to - 15°C.

The process according to the present invention has been found to result in an improvement in the osseo-integration of the biomedical implant compared

with prior art titanium and titanium-based implants.

In particular, the surface morphology of the oxide scale formed in atmospheres having a dew point of from < 0°C appears to be more homogeneous than that formed upon oxidation in a more humid environment, i. e. an environment having a higher dew point. Thus, using an environment having the recited dew point, a less defective and more adherent oxide scale may be formed, which is characterised by a more uniform outer surface.

The dew point of the oxygen-containing atmosphere may be maintained at a substantially constant level during the heating step or, alternatively, may be varied during the heating step. The latter approach may be used to produce variations in the chemistry and/or microstructure of the oxide layer with depth.

Accordingly, it is possible to combine two or more thermal treatments in environments having different levels of humidity in order to obtain a more graded oxide structure.

Heating is typically carried out at a temperature in the range of from 300 to 900°C, more typically from 700 to 900°C, and will generally be performed in a suitable furnace provided with a source, of an oxidising gas and an inlet and outlet. Following the heating step the implant may be allowed to cool (eg furnace cooling) or actively cooled by flowing a cooling fluid over the implant. Additional surface treatment steps may then be carried out. The implant will generally be sterilised prior to use.

The surface of the biomedical implant may maintained at a substantially constant temperature during the heating step. Alternatively, the

temperature may be varied during the heating step.

Again, this latter approach may be used to produce variations in the chemistry and/or microstructure of the oxide layer with depth. Thermal cycling may be carried out during the oxidation treatment in order to improve adherence of the oxide scale. It will be appreciated that non-isothermal treatments or thermal cycling may be carried out while keeping the humidity of the oxidising atmosphere at a substantially constant level. Alternatively, both the temperature and the humidity of the oxidising atmosphere may be varied.

Heating is typically carried out at a heating rate of up to 100°C/min, more typically from 10 to 70°C/min, still more typically from 30 to 50°C/min.

Heating may be continued for any suitable length of time to obtain the desired oxide morphology and/or thickness. For example, heating may typically be carried our for up to 200 hours, or for up to 150 hours, or for up to 100 hours, or for up to 50 hours, or for up to 10 hours, or for up to 1 hour.

The oxidising atmosphere may comprise or consist of oxygen gas and/or a molecular gas or, a vapour that contains oxygen. An example of a suitable atmosphere is air or a gas mixture comprising oxygen and nitrogen. The desired dew point of the atmosphere, which is a measure of its humidity, may be achieved by flowing a proportion or all of one or more of the gases which are comprised in the atmosphere over water. The relative humidity of the atmosphere is preferably less than 10% at 22°C, more preferably less than 5%, still more preferably less than 1%. The water partial pressures is preferably less than 500

Pa, more preferably less than 200 Pa.

The surface of the biomedical implant may comprise commercially pure Ti (cp Ti, Grades 1,2, 3 or 4) ) or the alloy Ti6Al4V. Part or all of the biomedical implant may be formed from titanium or an alloy thereof. As will be appreciated, the process according to the present invention may be performed on part or all of the implant.

The term implant as used herein is meant to encompass all types of biomedical and dental implants, including component parts and portions thereof.

The oxide of titanium formed on the surface of the biomedical implant will typically comprise one or more of Ti02, TiO and Ti203.

The biomedical implant is advantageously an endosseous implant, preferably an endosseous dental implant, including component parts and portions thereof.

It will be appreciated that additional surface modifications to the biomedical implant may be performed before or after the oxidation. treatment.

Examples include mechanical treatments of the surface (eg shot blasting), chemical treatments (eg etching), and physical treatments (eg ion implantation).

The process according to the present invention may, if desired, further comprise a sterilisation step.

The present invention also provides a method of forming an oxide layer on the surface of a biomedical

implant formed from titanium or an alloy thereof, the method comprising: (i) exposing the biomedical implant to an oxygen- containing atmosphere having a dew point of 0°C ; and (ii) heating at least a surface of the biomedical implant in said atmosphere to form an oxide of titanium thereon.

The present invention also provides a method of improving the osseo-integration of a biomedical implant formed from titanium or an alloy thereof, the method comprising: (i) exposing the biomedical implant to an oxygen- containing atmosphere having a dew point of 0°C ; and (ii) heating at least a surface of the biomedical implant in said atmosphere to form an oxide of titanium thereon.

For the avoidance of doubt, all of the features described in relation to the process according to the present invention are equally applicable, either singularly or in combination to the methods described herein.

The present invention also provides a biomedical implant obtainable or whenever produced by a process or method as herein described.

The present invention will now be described further, by way of example, with reference to the

following drawings in which: Figure l (a) is a SEM micrograph showing the surface morphology of titanium exposed at 800°C for 150 hours in dry air (dew point less than-40°C) ; and Figure l (b) is a SEM micrograph showing the surface morphology of titanium exposed at 800°C for 150 hours in humid air (dew point approximately 8° C).

It will be seen that titanium sample shown in the micrograph in Figure l (a), which is in accordance with - the present invention, has a much more homogeneous structure than that shown in Figure l (b), which is not in accordance with the present invention.

In the present invention, a surface modification of a Ti or Ti-based surgical or biomedical implant is effected by a thermal treatment in an oxidising environment such as, for example, air. The humidity of the atmosphere is controlled at a level lower than that present in normal laboratory air. In other words the air is dried. It is believed that the presence of water increases the oxidation rate.

The process and methods according to the present invention provide a number of advantages over the prior art. First, the present invention results in an improvement in the osseo-integration of the biomedical implant. Second, the adherence of the oxide scale to the underlying base material is also improved. Third, by its very nature the present invention enables complex-shaped implants to be substantially uniformly surface-treated. Fourth, it has been found that process and methods according to the present invention also result in a cleaning action, by which contaminants may be removed.