BR112014024074B1 - medical device with a surface comprising gallium oxide - Google Patents

Abstract

Abstract "Medical device with a surface including gallium oxide" The present invention relates to a medical device intended for contact with living tissue and comprising a substrate with a surface, wherein the surface comprises a layer including gallium oxide. . A layer including gallium oxide has been shown to inhibit biofilm formation on the surface of the medical device, which may reduce the risk of infection, for example around a dental implant. A method for producing the medical device comprises: a) providing a substrate with a surface; and applying a gallium compound on said surface to form a layer, preferably employing a thin film deposition technique.

Description

"MEDICAL DEVICE WITH A SURFACE UNDERSTANDING GALLIUM OXIDE" FIELD OF TECHNIQUE

[001] The present invention relates to a medical device with a surface layer including gallium oxide and methods for producing such a device.

BACKGROUND OF THE INVENTION

[002] For any type of medical device intended for contact with living tissue, biocompatibility is a fundamental issue. The risk of a foreign body reaction, clot formation and infection, among many others, need to be addressed and minimized to avoid adverse effects, not only local but also systemic, which can compromise the patient's health and / or lead to failure the device. This is specifically the case for permanent implants.

[003] The healing or regeneration of tissue around an implant is often vital to fix the implant and ensure its long-term functionality. This is especially important for load-bearing implants, such as dental or orthopedic implants.

[004] Dental implant systems are widely used to replace damaged or lost natural teeth. In such implant systems, a dental fixation device (screw), usually made of titanium or an aluminum alloy, is placed in the patient's jaw in order to replace the natural root of the tooth. A pillar-like structure is then attached to the fixation device in order to create a nucleus for the part of the prosthetic tooth that protrudes from the bone tissue, through the soft gingival tissue, towards the patient's mouth. On the abutment, the prosthesis or crown can finally be seated.

[005] For dental fixation devices, a strong connection between bone tissue and the implant is necessary. For implants intended for contact with soft tissues, such as abutments that should be partially located in the soft gingival tissue, compatibility with the soft tissue is also vital for the full functionality of the implant. Typically, after implantation of a dental implant system, a abutment is partially or completely surrounded by the gingival tissue. It is desirable that the gingival tissue heals quickly and firmly around the implant, not only for medical reasons, but also for aesthetic reasons. A tight seal between the oral mucosa and the dental implant serves as a barrier against the microbial environment in the oral cavity and is fundamental to the success of the implant. This is especially important for patients with poor oral hygiene and / or inadequate bone or mucosal quality. Poor healing or weak connection between the soft tissue and the implant increases the risk of infection and peri-implantitis, which can ultimately lead to bone resorption and failure of the implant.

[006] There are several strategies to increase the chances of successful implantation of a medical device, for example, to increase the rate of formation of new tissue and / or to increase the rate of tissue binding to the implant surface, in situations where want the union of the tissue-implant, or reduce the risk of infections. The formation of new tissue can be increased, for example, by various changes on the surface and / or by the deposition of bioactive agents on the surface.

[007] The risk of infection related to dental implants is currently addressed primarily by preventive measures, such as maintaining good oral hygiene. Once a biofilm is formed on the surface of a dental implant, it is difficult to remove by applying antibacterial agents. In the case of infection in the bone or soft tissue that involves a dental implant (peri-implantitis), mechanical debridement is the basic element, sometimes combined with antibiotics, antiseptics and / or ultrasonic or laser treatment.

SUMMARY OF THE INVENTION

[008] The present invention aims to overcome this problem and provide a medical device, such as an implant with a surface that reduces the risk of infection when the medical device comes into contact with living tissue.

[009] According to a first aspect of the invention, this and other objectives are achieved by a medical device intended for contact with living tissue, which comprises a substrate with a surface layer including gallium oxide, especially Ga2O3. The layer comprised may have an atomic concentration (% at, atomic percentage) of gallium of at least 5% at. In embodiments of the invention, the concentration of gallium in said layer is at least 10% at, more preferably at least 15% at and even more preferably at least 20% at. The layer can have a gallium content of up to 40% at.

[010] The surface of a medical device with a layer incorporating gallium oxide has been shown to be effective against various strains of bacteria and has been shown to inhibit biofilm formation in vitro. The medical device according to the invention can also be effective against other microbes, such as fungi.

[011] In embodiments of the invention, said living tissue is soft tissue. Alternatively, said living tissue can be cartilage or bone tissue.

[012] Gallium oxide is generally well tolerated by living tissue in a mammal and can be deposited on a surface using a thin-film deposition technique. Gallium oxide is useful in the present invention, specifically for dental implant applications, as it can provide an aesthetically desirable surface layer, especially with regard to color. Gallium oxide, such as Ga2O3, can be deposited using thin-film deposition techniques, including atomic layer deposition.

[013] In embodiments of the invention, the layer including a gallium compound further comprises a gallium salt. For example, a gallium salt can be deposited on a first layer including a first gallium compound, for example, gallium oxide. A deposit of gallium salt can increase the release of gallium from the surface very early after contact with living tissue, thereby temporarily reinforcing an antibacterial or antimicrobial effect of the layer.

[014] In general, the layer including the gallium compound can have a thickness in the range of 10 nm to 1.5 pm, preferably from 10 nm to 1 pm, such as from 10 nm to 100 nm. A layer of at least 10 nm may be sufficient to provide a desirable antibacterial effect, while layers up to 1 pm thick may be desirable for aesthetic reasons, having a suitable color for, for example, dental implants.

[015] In embodiments of the invention, gallium oxide can be crystalline. In other embodiments, gallium oxide can be amorphous.

[016] Typically, in embodiments of the invention, the layer including gallium oxide can be a homogeneous layer. The layer can also be a non-porous layer. A non-porous layer is typically less susceptible to bacterial growth and biofilm formation when compared to a porous layer.

[017] The substrate on which the layer is provided including at least one gallium compound may comprise a metallic material, preferably titanium or titanium alloy. Alternatively, the substrate can comprise a ceramic material. In other embodiments, the substrate may comprise a polymeric material or a composite material.

[018] The medical device of the invention is typically an implant intended for long-term contact or implantation in living tissue. In one embodiment, the medical device is an implant intended for implantation at least partially in soft tissue. For example, the medical device can be a dental implant, specifically a dental abutment. In another embodiment, the medical device may be a hearing device anchored to the bone. In still other embodiments of the invention, the medical device may be intended for short-term or prolonged contact with living tissue, typically soft tissue. For example, the medical device may be a catheter adapted for insertion into a body cavity, such as a blood vessel, digestive tract or urinary system.

[019] In another aspect, the invention provides a method for producing a medical device as described herein, comprising: a) providing a substrate having a surface; and b) applying gallium oxide to said surface to form a layer.

[020] Ga2O3 can be applied using a thin-film deposition technique, for example, atomic layer deposition.

[021] A medical device as described above can be used to prevent the formation of biofilm and / or bacterial infection in surrounding tissue, especially soft tissue. Specifically, the medical device of the invention can be used to prevent bacterial infection in gingival tissue and / or peri-implantitis.

[022] It is noted that the invention relates to all possible combinations of characteristics recited in the claims.

DESCRIPTION OF THE DRAWINGS

[023] Figure 1 is a side view of a medical device according to an embodiment of the invention, in which the medical device is a dental abutment.

[024] Figure 2 illustrates a cross-sectional part of a medical device according to the modalities of the invention, showing a substrate material and a layer including gallium oxide.

DETAILED DESCRIPTION OF THE INVENTION

[025] It has been discovered that a medical device with a surface layer including a gallium oxide, notably Ga2O3, provides very advantageous effects in terms of reduced risk of infection, better tissue healing and / or aesthetic performance. It has been shown that a titanium body having a surface incorporating gallium (Ga) in the form of a gallium oxide coating (Ga2Ü3) can prevent the growth of bacteria on and around the surface, and thus can be useful in preventing harmful infections around, for example, a dental abutment implanted in the gums.

[026] According to the present invention, a tissue contact surface is a surface of a medical device that includes gallium oxide in the form of Ga2Ü3. For example, gallium oxide can be applied to a medical device as a surface layer.

[027] Gallium has been used in medicine since at least the 1940s, primarily as a radioactive agent for medical imaging. The antibacterial properties of gallium have been investigated in several studies. In Kaneko et al. (2007), it was established that gallium nitrate (Ga (NO3) 3) inhibits the growth of Pseudomonas aeruginosa from batch cultures. Olakanmi et al (2010) found that Ga (NO3) 3 inhibited the growth of Francisella novicida. Gallium interferes with iron metabolism. It can be assumed that gallium is also effective against other microbes, for example, fungi such as yeasts or molds.

[028] Directive 2007/47 / EC defines a medical device as: "any instrument, apparatus, equipment, software, material or other article, whether used alone or in combination, including software intended by its manufacturer to be used specifically for purposes diagnostic and / or therapeutic and that is necessary for the proper application of the medical device, intended by the manufacturer to be used in humans. ”In the context of the present invention, only medical devices intended for contact with living tissue are considered, that is, any instrument, apparatus, equipment, material or other article of a physical nature that are intended to be applied, inserted, implanted or otherwise brought into contact with the body, a part of the body or an organ. , part of the body or organ can be that of a human or animal, typically mammal. Preferably, however, the medical device is intended for and to humans The medical devices included in the definition above are, for example, implants, catheters, shunts, tubes, stents, intrauterine devices and prostheses.

[029] Specifically, the medical device may be a medical device intended for implantation into living tissue or for insertion into an individual's body or body part, including insertion into a body cavity.

[030] The present medical device can be used for short-term, prolonged or long-term contact with living tissue. “Short term”, in this specification, means a duration of less than 24 hours, according to the definitions found in the ISO 10993-1 standard for the biological evaluation of medical devices. In addition, "extended", according to the same standard, refers to a duration of 24 hours to up to 30 days. Thus, according to the same rule, "long term" means a duration of more than 30 days. Thus, in some embodiments, the medical device of the invention may be a permanent implant, intended to remain for months, years or even a lifetime in an individual's body.

[031] In this specification, the term “implant” includes, in its scope, any device, of which at least part is intended for implantation into the body of a vertebrate animal, especially a mammal, such as a human. Implants can be used to replace anatomical parts and / or restore any function of the body. In general, an implant consists of one or several parts of the implant. For example, a dental implant typically comprises a dental fixation device attached to secondary parts of the implant, such as an abutment and / or a restorative tooth. However, any device, such as a fixation device, intended for implantation, can be designated separately as an implant, even if other parts are to be connected to it.

[032] "Biocompatible", in this specification, means a material that, when in contact with living tissue, does not elicit, because it is of this type, an adverse biological response (for example, inflammation or other immunological reactions) of that tissue.

[033] “Soft tissue”, in this specification, means any type of tissue, especially types of mammalian tissue, other than bone or cartilage. Examples of soft tissue for which the medical device is suitable include, but are not limited to, connective tissue, fibrous tissue, epithelial tissue, vascular tissue, muscle tissue, mucosa, gums and skin.

[034] In this specification, “homogeneous layer” refers to a layer having a chemical composition that is uniform in all directions (three dimensions).

[035] Figures 1 and 2 illustrate an embodiment according to the present invention, in which the medical device is a dental abutment. The dental abutment 100 comprises a body formed of substrate material 102 covered with a layer 101 including gallium oxide. Layer 101 forms the surface of the abutment, intended to meet and contact the gingival tissue after implantation.

[036] The medical device of the invention can be made of any suitable biocompatible material, for example, materials used for implantable devices. Typically, the medical device comprises a substrate with a surface that includes a gallium compound. The substrate can, for example, be made of a biocompatible metal or metal alloy, including one or more materials selected from the group consisting of titanium, zirconium, hafnium, vanadium, niobium, tantalum, cobalt and iridium, in addition to their alloys. Alternatively, the substrate of the medical device can be made of biocompatible ceramics, such as zirconia, titania, metallic ceramics with shape memory and their combinations. In embodiments in which the medical device is used as or integrates a dental abutment, the substrate is preferably made of a metallic material.

[037] In contact with oxygen, the metals titanium, zirconium, hafnium, tantalum, niobium and their alloys react instantly and form an inert oxide. Thus, the article surfaces of these materials are virtually always covered with a thin layer of oxide. The native oxide layer of a titanium substrate consists mainly of titanium (IV) dioxide (T1O2) with minimal amounts of TÍ2O3, TiO and TÍ3O4.

[038] Therefore, in modalities in which the medical device comprises one or more of titanium, zirconium, hafnium, tantalum, niobium or an alloy of any of these, the medical device typically has a native surface layer of metal oxide. Such a native metal oxide layer can, in turn, be covered by a thin film including Ga2O3.

[039] In other embodiments of the present invention, the medical device, especially the substrate, can be made of a biocompatible polymer, typically selected from the group consisting of polyether ether ketone (PEEK), polymethylmethyl crylate (PMMA), polylactic acid (PLLA) and polyglycolic acid (PGA) and any combinations and copolymers thereof.

[040] In embodiments of the invention, the medical device is intended for short-term, prolonged or long-term contact with living tissue. For example, the medical device of the invention may be an implant, typically intended to replace or restore, temporarily or permanently, a function or structure of the body.

[041] Typically, at least part of the surface of the medical device is intended for contact with soft tissue, and at least part of this surface of contact with soft tissue has a layer including Ga2O3. For example, the medical device can be an implant intended for primary contact or exclusively with soft tissue, for example, a dental abutment. Alternatively, the medical device may be an implant to be inserted partially into the bone and partially into the soft tissue. Examples of such implants include one-piece dental implants and bone-anchored hearing devices (also called bone-anchored hearing aids). When only part of the implant is intended for contact with soft tissue, it is preferred that the layer including the gallium oxide is arranged on at least a part of a contact surface with the soft tissue.

[042] The medical device may also be suitable for contact with cartilage.

[043] In other modalities, the medical device can be used for contact with bone tissue, for example, the jaw, femur or skull of a mammal, especially a human. Examples of such medical devices include dental fixation devices and orthopedic implants.

[044] According to the present invention, the surface layer includes gallium oxide (Ga2O3). Gallium oxide can be present in amorphous or crystalline form. Crystalline forms of gallium oxide include a-Ga2O3, p-Ga2O3, y-Ga2O3, δ-Ga2O3 and e-Ga2O3. In addition, a surface layer of gallium oxide can be at least partially hydroxylated to form hydroxy-oxide.

[045] Without intending to be bound by any specific theory, it is believed that, when in contact with living tissue and / or body fluids, a layer of gallium oxide exhibits slow, sustained release of gallium ions. Such release may be slower and more sustained when compared to the release of gallium ions by a precipitated gallium salt and may therefore provide a long-term effect with respect to biofilm formation. In addition, a deposited surface layer using a thin film deposition method, as employed in embodiments of the invention, can adhere firmly to the underlying substrate and thus can avoid problems related to exfoliation and flaking of the surface layer. Exfoliation and peeling can give rise to the adverse inflammatory response of the surrounding tissue and, in addition, can weaken the biofilm prevention effect of the superficial layer.

[046] Depending on the intended use of the medical device, different release properties may be desirable. For example, a higher gallium release rate may be more favorable for short-term use, that is, for a medical device intended for short-term contact with living tissue, when compared to a device intended for prolonged contact or long term. The rate of release can be affected by several factors, for example, the crystallinity of gallium oxide. Optionally, in embodiments of the invention, the medical device can additionally comprise a gallium salt selected from the group consisting of gallium acetate, gallium carbonate, gallium chloride, gallium citrate, gallium fluoride, gallium format, iodide gallium, gallium lactate, gallium maltolate, gallium nitrate, gallium oxalate, gallium phosphate and gallium sulphate. Such a gallium salt can be provided as a deposit, for example, precipitated on the layer including the gallium compound.

[047] As mentioned above, gallium oxide is typically contained in an applied surface layer. In embodiments of the invention, gallium oxide can make up most of said layer. The atomic concentration (% at) of the elements that together make up the gallium oxide constitutes at least 50% at of the layer, preferably at least 70% at and more preferably at least 80% at of the elements of the layer. The atomic concentration of gallium in the layer can be in the range of 5% up to 40% at, for example, at least 10% at, at least 15% at, at least 20% at, at least 30% at or at least 35 % at and up to 40% at.

[048] The use of a layer including gallium oxide (Ga2O3) results in the maximum gallium content in the 40% at layer and the maximum oxygen content in the 60% at layer. However, impurities and contamination, for example, by carbon, can be present in up to 20% at.

[049] The atomic concentration can be measured, for example, to a depth of 40 nm or less, and preferably no more than the thickness of the layer. The atomic concentration can be measured by means of X-ray fo-toelectronic spectroscopy (XPS).

[050] As mentioned above, when in contact with living tissue, some gallium may be released from the surface of the medical device over time. Therefore, after implantation, the gallium content and possibly also other materials present on the surface of the medical device can change over time.

[051] Furthermore, the layer including gallium oxide may contain impurities or contamination, for example, by carbon, typically in an amount of 20% at or less and preferably 15% at or less or 10% at or less. Such contamination may arise, for example, from the packaging. It can be noted that the wet packaging, in which the surface can be protected by water, ethanol or the like, reduces the amount of carbon contamination, when compared to the dry packaging in which the surface is exposed to the air that normally contains volatile hydrocarbons. Contamination can also appear on the surface of the substrate before the layer including gallium oxide is applied. The level of contamination, typically represented by the atomic carbon concentration, can be reduced by cleaning the surface before applying gallium oxide and, optionally, after applying gallium oxide and / or avoiding subsequently contaminating the surface before measuring the concentration atomic structure of elements on the surface.

[052] The maximum atomic concentration of the elements of gallium oxide in the layer can be easily determined from the stoichiometry of the composition.

[053] Table 1 summarizes the possible atomic concentration ranges for a layer including gallium oxide.

Table 1. Exemplary atomic concentrations of the elements of gallium oxide [054] In some embodiments, the surface layer consists essentially of gallium oxide. According to the precedent, “essentially consists of”, in this specification, it means that the layer contains little or no other material (contaminants, etc.) except gallium oxide, only, for example, up to 10% at, preferably up to 5% at, more preferably up to 2% at and even more preferably up to 1% at other material.

[055] In general, the layer including gallium oxide is free of carrier material, such as polymers, solvents, etc.

[056] The layer including gallium oxide can have a thickness in the range of 1 nm to 1.5 pm. A layer at least 1 nm thick can provide sufficient antimicrobial effect. Increasing the thickness of the layer may result in a whiter color, which may be desirable for dental applications. However, a layer also approximately 10 nm thick may be more aesthetically advantageous than current commercial dental abutments. For example, a 40 nm gallium oxide layer has a deep bronze color that would be less visible through a patient's gums than today's titanium gray-metal abutments.

[057] When looking primarily for an antimicrobial effect, the layer containing the gallium oxide can have a thickness of 10 to 100 nm or, optionally, up to 300 nm. On the other hand, when the aesthetic aspect of, for example, a dental abutment is of high importance, a layer thickness in the range of 0.5 to 1.5 pm, for example, 0.7 to 1.5 pm or 0.7 to 1 pm may be preferred. However, thinner layers can also provide an acceptable colored appearance and that at least can be more advantageous than prior art dental abutments.

[058] The layer including gallium oxide can be a dense layer, that is, a non-porous layer.

[059] In embodiments of the invention, the surface of the medical device may comprise a single layer. Alternatively, in other embodiments, the medical device may comprise multiple layers, at least one of which includes gallium oxide.

[060] In embodiments of the invention, a gallium salt, optionally forming an additional layer, can be provided on at least a portion of a layer deposited as a thin film including a gallium compound. For example, a solution of at least one gallium salt can be applied over a thin film deposited layer of the gallium compound and allowed to evaporate. Such modalities can provide a high initial gallium release when in contact with living tissue, which can be advantageous in many situations, not only prolonged but also long-term contact with tissue.

[061] In embodiments of the invention, the substrate may have a rough surface on which a layer including gallium acid is disposed. Since the layer including gallium oxide may be thin, for example, 100 nm or less, there may be good conformability in the stepped covering, meaning that the layer including gallium oxide follows the roughness of the underlying surface and substantially preserves it, without making it smoother. However, in embodiments in which it is relatively thick, the layer including gallium oxide can reduce the roughness of the underlying substrate surface.

[062] The roughness of the substrate surface and, therefore, optionally also the surface of the medical device formed by the layer including gallium oxide, can have a surface roughness Ra on average of at least 0.05 gm, typically at least 0.1 gm, for example, at least 0.2 gm. Considering that surfaces with a surface roughness (Ra) averaging at least 0.2 gm are considered more susceptible to biofilm formation, a layer including gallium oxide, as described here, can be especially advantageous for medical devices with surface roughness at least 0.2 gm, and can be increasingly useful to prevent biofilm formation in medical devices with even higher surface roughness. As an example, a dental abutment comprising a titanium substrate can have a surface roughness of approximately 0.2-0.3 gm. A superficial layer of gallium oxide with a thickness of approximately 40 nm can substantially preserve this surface roughness (which may be desirable, for example, to facilitate the firm anchoring of the implant in the surrounding tissue), but which can, however, prevent formation of biofilm on the implant surface and, consequently, reduce the risk of infection and peri-implantitis.

[063] The layer including gallium oxide can be formed by applying gallium oxide on the surface of a medical device to form a surface layer. Gallium oxide can be applied using known deposition techniques, especially thin film deposition techniques. Suitable techniques may include physical deposition, chemical deposition and physical-chemical deposition. An example of such techniques is the deposition of atomic layer (ALD) that can be used to provide, for example, a layer of gallium oxide on a substrate surface (Nieminen et al, 1996; Shan et al, 2005).

[064] The ALD technique and others of thin film deposition are associated with several advantages for the deposition of the gallium compound (s), such as controlled thickness, controlled composition, high purity, conformability in the step covering, good uniformity (resulting in a homogeneous layer) and good adhesion of the layer.

Examples Example 1. Production [065] Commercially pure titanium (cp) discs (grade 4) were manufactured and cleaned before depositing a 40 nm thick layer of amorphous Ga2O3 by atomic layer deposition (Picosun, Finland) , with precursors of GaCl3 and H2O, respectively. The specimens were then packed in plastic containers and sterilized with electron beam irradiation.

Example 2. Surface characterization [066] For all surface characterization experiments, eight specimens each of commercially pure titanium (cp), cp titanium coated with Ga2O3, produced as described above and cp titanium coated with commercially available TiN were prepared as described in Example 1 (clean, coating using ALD in the case of specimens covered with Ga2O3, packaged and sterilized). Specimens coated with TiN were included for comparison, since a TiN coating is known to provide a weakly anti-bacterial effect.

[067] It was found that the surface morphology and roughness did not change due to ALD coating, but there was a slight increase in hydrophobic properties. a) Surface chemistry [068] Surface morphology and surface chemistry were analyzed with environmental scanning electron microscopy (XL30 ESEM, Philips, Netherlands) / energy dispersive spectroscopy (Genesis System, EDAX Inc., USA) a an acceleration voltage to 10-30 kV. The elements detected on the surface of the specimens coated with Ga2O3 were oxygen (O), gallium (Ga) and titanium (Ti). Ga concentrations varied between 4 and 9% atomic (% at), as measured with acceleration voltages at 30 kV and 10 kV, respectively. The analytical depth estimated for this technique is approximately 1 pm, that is, much deeper than the layer thickness. Differences in terms of surface morphology could not be detected between controls of commercially pure titanium and titanium coated with Ga2Ü3.

[069] Additionally, surface chemistry was analyzed with X-ray photoelectronic spectroscopy (XPS, Physical Electronics, USA), which is a more sensitive technique for surfaces than energy dispersive spectroscopy. As a source of X-rays, monochromatic AlKa was used. The beam was focused to 100 gm. The detected elements were oxygen (O), gallium (Ga) and carbon (C). Gallium concentrations varied between 34 and 37% at. Oxygen concentrations varied between 47 and 50% at. The analytical depth estimated for this technique is approximately 5-10 nm. The results are summarized in Table 2.

_________Table 2. Atomic concentration of elements detected using XPS b) Surface morphology [070] Surface roughness was measured with surface profilometry (Ho-mmel T1000 wave, Hommelwerke GmbH, Germany). A vertical measuring range of 320 gm and an evaluation length of 4.8 mm were used. Two specimens of each type were included in the analysis, and three measurements per specimen were performed. The surface roughness Ra was calculated after using a filtration process, cutting at 0.800 mm. The results are shown in Table 3. _________Table 3. Surface roughness (Ra) ± standard deviations (SD) ________ c) Wettability [071] In order to investigate wettability, the contact angle was measured using an angle measurement system (Drop Shape Analysis System DSA 100, Kruss GmbH, Germany). The measurements were performed with deionized water. The results indicate that all specimens were hydrophobic (> 90 °), see Table 4.

Table 4. Angles of contact °) ± standard deviations (SD) Example 3. Antimicrobial effect of surfaces covered with gallium oxide [072] It was found that a titanium body with a surface comprising gallium (Ga) in the form of Gallium oxide is able to prevent the growth of Pseudomonas aeruginosa and Staphylococcus aureus on and around a surface and thus can be useful in preventing the harmful occurrence of infection around, for example, a dental abutment implanted in the gums. a) Inhibition of bacterial growth in plaque due to streak depletion [073] In a first experiment, commercially pure titanium discs (0 6.25 mm), with or without coating with gallium oxide, were placed on agar plates containing colonies homogeneously distributed from Pseudomonas aeruginosa. After incubation for 24 hours at 37 ° C, there was a zone free of visible colonies 4 mm wide, around the discs with gallium oxide that were surrounded by bacterial colonies. b) Inhibition of bacterial growth using the film contact method [074] In a second experiment, a film contact method (Ya-suyuki et al, 2010) was employed. Plates sown by depletion in streaks of Pseudomonas aeruginosa (PA01) or methicillin-resistant Staphylococcus aureus (MRSA) were prepared, and 1 colony was inoculated in 5 mL of triptych soy broth (TSB) inside culture tubes and grown under stirring for 18 hours. Cell density was measured on a spectrophotometer at OD 600 nm and cells were counted using a cell counting chamber. The cell culture was adjusted with sterile TSB to 1-5 X 10 6 cells / ml. Specimens of commercially pure titanium (cp) discs (0 6.25 mm), cp titanium discs with gallium oxide coating or cp titanium discs with a commercially available titanium nitride (TiN) coating were prepared aseptically and placed respectively in a well of a 12-well plate. A transparent plastic film was perforated and sterilized using 70% ethanol and UV irradiation on both sides. A 15 µl drop of bacteria in TSB was applied to each specimen. A thin plastic film per specimen was placed over the bacteria in the specimens so that the bacterial solution spread evenly over the specimen's surface, ensuring good contact. After incubation for 24 hours at 30 ± 1 ° C, the film of each specimen was removed aseptically and washed by piping 1 ml of PBS on the surface into a 2 ml Eppendorf tube, separated by specimen. The specimens were transferred to the same Eppendorf tubes as those used to wash the film. First, the surface of each specimen was washed by pipetting exactly the same PBS with which the film had previously been washed. Then, the specimens were subjected to sonication for 1 minute and vortexed vigorously for 1 minute in the same tube that had been previously used when the film was washed. Serial dilutions and plate counts were performed. The plates were incubated for 24 hours, and the number of colonies was counted and recorded. The antibacterial activity of titanium coated with gallium oxide was determined and found to be 92% reduction against PA01 and 71% reduction against MRSA, when compared to titanium, see Tables 5 and 6.

Table 5. Viability counts (cfu / mL) ± standard deviations (SD) after incubation for 24 hours of test specimens against Pseudomonas Aeruginosa (PA01) Table 6. Viability counts (cfu / mL) ± standard deviations (SD) after 24-hour incubation of test specimens against methicillin-resistant Staphylococcus aureus (MRSA) __________________________________________________ c) In situ effect on biofilm [075] In a third experiment, the antibacterial activity of titanium discs, with or without a gallium oxide coating, was evaluated in situ using the Live / Dead® BacLight ™ dye (Life Technologies Ltd, UK). Plates sown by depletion in streaks of Pseudomonas aeruginosa (PA01) were prepared and 1 colony was inoculated in 5 ml of 5 ml TSB into culture tubes and cultivated under shaking conditions for 18 hours. Cell density was measured on a spectrophotometer at OD 600 nm and adjusted with sterile TSB to 1 x 106 cells / mL. Aliquots of 400 gL of bacteria were removed for slides of 8 compartments. The biofilm was allowed to form for 24 hours at 35 ± 2 ° C. Specimens of commercially pure titanium (cp) discs (0 6.25 mm), cp titanium discs with gallium oxide coating or cp titanium discs with a titanium nitride (TiN) coating were aseptically prepared and applied about the biofilm. Antibacterial activity was analyzed in situ using the Liv / Dead® dye.

[076] In situ analyzes indicated that both coatings with titanium nitride and gallium oxide are endowed with anti-biofilm activity, when compared with uncoated titanium in terms of viability. In the 24-hour analysis, it was seen that the typical biofilm mushroom structure had disappeared for titanium nitride and gallium oxide. It was also found that more dead cells were seen in gallium oxide than in titanium nitride.

[077] The person skilled in the art realizes that the present invention is in no way limited to the preferred embodiments described above. On the contrary, many modifications and variations are possible within the scope of the appended claims.

[078] Additionally, variations to the revealed modalities can be understood and made by the technician in the subject when practicing the claimed invention, from a study of the drawings, the specification and the attached claims. In the claims, the word "comprises" does not exclude other elements or steps, and the indefinite article "one" or "one" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

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Claims (18)

1. Medical device intended for contact with living tissue CHARACTERIZED by the fact that it is selected from the group consisting of a dental implant, a hearing device anchored in the bone and an orthopedic implant, and comprises a substrate having an antimicrobial surface layer comprising Ga2O3, in whereas said layer is non-porous and has a thickness in the range of 10 nm to 1.5pm, where said layer has a gallium content of at least 10% at, and where said layer is free of carrier material, such as polymers and solvents. 2. Medical device according to claim 1, CHARACTERIZED by the fact that said living tissue is soft tissue. 3. Medical device according to claim 1 or 2, CHARACTERIZED by the fact that said layer has a thickness in the range of 10 nm to 1 pm. Medical device according to any one of claims 1 to 3, CHARACTERIZED by the fact that said layer has a gallium content of at least 20% at. Medical device according to any one of claims 1 to 4, CHARACTERIZED by the fact that said layer has a gallium content of up to 40% at. Medical device according to any one of claims 1 to 5, CHARACTERIZED by the fact that said layer is a homogeneous layer. Medical device according to any one of claims 1 to 6, CHARACTERIZED by the fact that said substrate comprises a metallic material, preferably titanium or titanium alloy. Medical device according to any one of claims 1 to 6, CHARACTERIZED by the fact that said substrate comprises a ceramic material. Medical device according to any of claims 1 to 6, CHARACTERIZED by the fact that said substrate comprises a polymeric material. Medical device according to any one of claims 1 to 6, CHARACTERIZED by the fact that said substrate comprises a composite material. 11. Medical device according to any one of claims 1 to 10, CHARACTERIZED by the fact that it is an implant intended for contact with living tissue for a duration of more than 30 days. 12. Medical device according to any one of claims 1 to 10, CHARACTERIZED by the fact that it is intended for contact with living tissue for a duration of 24 hours up to 30 days. 13. Medical device according to any one of claims 1 to 10, CHARACTERIZED by the fact that it is intended for contact with living tissue for a duration of less than 24 hours. 14. Medical device according to any of claims 1 to 13, CHARACTERIZED by the fact that said implant is a dental implant. 15. Medical device according to claim 14, CHARACTERIZED by the fact that said dental implant is a dental abutment. 16. Medical device according to any one of claims 1 to 11, CHARACTERIZED by the fact that said implant is a hearing device anchored in the bone. 17. Medical device according to any one of claims 1 to 11, CHARACTERIZED by the fact that said implant is an orthopedic implant. 18. Method for producing a medical device, as defined in any of claims 1 to 17, CHARACTERIZED by the fact that it comprises: a) providing a substrate having a surface; and b) apply Ga2O3 to said surface to form an antimicrobial surface layer having a thickness in the range of 10 nm to 1.5 gm, in which said layer is non-porous, is free of carrier material, such as polymers and solvents and has a gallium content of at least 10%, preferably using a thin film deposition technique.