Implantable medical device with a zirconium dioxide layer and its manufacturing method

Description

[0001] The present invention relates to an implantable medical device comprising a layer made of or comprising zirconia, and a method of preparing it.

[0002] The art documents are illustrated by documents EP 1 527 790 A1 and WO 2018 / 190674 A1.

[0003] Dental implants are artificial roots that are embedded in the bone, and are intended to create an anchor capable of receiving a removable or fixed dental prosthesis.

[0004] Implant-supported dentures are more comfortable and discreet than removable dentures. They also preserve the jawbone and keep existing teeth healthy. Installing a bridge, on the other hand, requires trimming the adjacent teeth to provide support, thus removing some of the enamel. Another disadvantage of a bridge is that the bone around the missing tooth will gradually resorb. Finally, compared to a removable denture, implants offer greater comfort, better functionality, stability, normal chewing, and a sense of belonging.

[0005] The history of dental implants truly began in the 1950s, when Swedish Professor Per Ingvar Brånemark, considered the father of modern implantology, discovered the exceptional affinity of titanium for living bone. Titanium then became the first known material that was completely biocompatible. Professor Brånemark thus decided to use titanium to treat edentulous patients, developing at the time a titanium screw that is fixed in the jaw to serve as a support for a dental prosthesis.

[0006] Upon contact with titanium, the bone will heal and fuse: this is the phenomenon of osseointegration, which takes 2 to 6 months depending on the clinical case. The dental implant becomes functional. It is used either as a support for a fixed prosthesis (bridge or crown) or to stabilize a removable prosthesis.

[0007] Before the use of titanium became widespread, dental implants could not be integrated into the jawbone, as is possible today.

[0008] However, like all metals, titanium is not unalterable in the presence of a biological environment such as saliva, and the products resulting from its electrochemical corrosion can prove toxic, and give rise to immediate or delayed allergic reactions which could explain the successive failures of dental implants which occur in certain patients. Indeed, potential hypersensitivity to titanium implants is currently a recognized fact. It is observed that a significant part of the population is sensitive to the presence of metal in the mouth. This sensitivity results in various symptoms, such as headaches, skin irritation, altered taste, joint problems or even chronic fatigue.Many implant-related health problems have been attributed to oxidation and / or corrosion events that occur due to the biological environment, material fatigue, mechanical stress, electrogalvanism, exposure to the aggressive oral environment, locally elevated fluoride concentrations, as is the case with the application of fluoride gels, material wear, or a combination of all these factors.

[0009] More recently, zirconia implants have appeared. The electrochemical problem caused by titanium does not exist with zirconium oxide ceramic implants. Zirconia is an inert bioceramic that has excellent biomechanical properties, transmits less heat than titanium, does not induce any galvanic reaction, and unlike titanium, is not susceptible to corrosion in the oral environment. In the absence of free electrons, zirconium oxide ceramics are electrical insulators and therefore completely metal-free. Zirconia, not being a thermal conductor, means that implants can be ground in the mouth without the risk of causing bone necrosis. Its white color favors aesthetic restorations. Zirconium oxide ceramic is thus extremely biocompatible and apparently has no impact on the immune system.In addition, with zirconia, bacterial plaque is not deposited and this promotes the hygiene and durability of the implant-supported restoration.

[0010] However, titanium remains superior to zirconia from a mechanical point of view; it is a ductile material with a toughness six times greater. Its ultimate strength is significantly higher than zirconia. In addition, the price of zirconia implants currently remains higher than that of conventional titanium implants.

[0011] The invention therefore aims to provide implantable medical devices, in particular dental implants, having excellent bio- and immunocompatibility while retaining very good osteointegration and advantageous mechanical properties.

[0012] Another aim of the invention is to provide a method for preparing such implantable medical devices which is easy to implement, without significant modifications compared to the methods for obtaining commercial implants.

[0013] Yet another object of the invention is to provide a method for preparing such implantable medical devices, which does not alter the target roughness of commercial implants.

[0014] Thus, according to a first aspect, the invention relates to an implantable medical device comprising on all or part of its surface a layer made of or comprising zirconia, said layer having a thickness between approximately 50 and approximately 2000 nm.

[0015] Surprisingly, the layer consisting of or comprising zirconia of the implantable medical devices of the invention, with its specific thickness, does not modify or almost does not modify the roughness of said devices. This layer also has excellent adhesion to the surface of the devices and gives said devices the advantageous properties of zirconia, for example its desirable visual appearance.

[0016] According to a particular embodiment, the zirconia is not in the presence of, or in the form of, an alloy comprising, in addition to zirconia, aluminum, titanium and / or carbon, the zirconia in particular not being in the form of a zirconia-aluminum alloy, for example an ATZ, zirconia-titanium or zirconia-carbon alloy.

[0017] According to a particular embodiment, said layer has a thickness of between approximately 100 or 200 and approximately 2000 nm, in particular between approximately 500 or 600 and approximately 800 nm.

[0018] According to a particular embodiment, the invention relates to a device as defined above, comprising a layer made of or comprising zirconia, said layer having on a part of the surface of said device a thickness of between approximately 50 and approximately 2000 nm, in particular between approximately 50 and approximately 1200 nm, and on another part of the surface of said device a thickness of between approximately 50 and approximately 2000 nm, in particular between approximately 800 and approximately 2000 nm.

[0019] According to a particular embodiment, the zirconia is yttria-containing zirconia.

[0020] According to a particular embodiment, the zirconia is partially or totally in its quadratic, cubic or monoclinic phase, in particular monoclinic.

[0021] According to a particular embodiment, the layer comprises, in addition to zirconia, at least one element or compound comprising an element chosen from Mg, Ca, Ag, and Zn, in particular in metallic or oxide form.

[0022] The at least one element or compound comprising an element chosen from Mg, Ca, Ag, and Zn may be within the layer comprising zirconia, and / or at the surface of the layer comprising zirconia. In the latter case, the layer according to the invention consists of a first sub-layer comprising zirconia and a second sub-layer of said at least one element or compound comprising an element chosen from Mg, Ca, Ag, and Zn, in particular on all or part of the sub-layer comprising zirconia.

[0023] According to a particular embodiment, the element chosen from Mg, Ca, Ag, and Zn, is at least partially on the surface of the layer, in particular over 1 to 100%, for example over 10 to 30%, of said surface.

[0024] According to a particular embodiment, the invention relates to a device as defined above, which, in particular on its surface, excluding said layer, is devoid of zirconia or a compound comprising it.

[0025] According to a particular embodiment, the invention relates to a device as defined previously, which, in particular its surface, is made of or comprises titanium or aluminum.

[0026] According to a particular embodiment, the titanium is grade 4 titanium, or in the form of an alloy, in particular grade 5 titanium or a titanium-niobium alloy.

[0027] According to a particular embodiment, the titanium or the alloy containing it has been machined, in particular cold drawn, molded, sintered, printed by additive manufacturing.

[0028] According to a particular embodiment, said layer has a roughness Ra of from 0 to 4.0 µm, for example from 0.01 or 0.02 to 4.0 µm, in particular from 0.6 to 2.0 µm, in particular from 1.0 to 1.5 µm.

[0029] The device as mentioned above may be any implantable medical device well known to those skilled in the art.

[0030] According to a particular embodiment, said device is an implant, in particular a dental implant, or a prosthesis, in particular a hip prosthesis, more particularly a cup, a shoulder prosthesis, or a knee prosthesis.

[0031] According to a particular embodiment, said device is a dental implant comprising a bone contact zone, all or part of the surface of which is covered with said layer with a first thickness of between approximately 50 and approximately 2000 nm, in particular between approximately 50 and approximately 1200 nm, and a gingival contact zone, all or part of the surface of which is covered with said layer with a second thickness of between approximately 50 and approximately 2000 nm, in particular between approximately 800 and approximately 2000 nm.

[0032] According to another aspect, the invention also relates to a method for preparing an implantable medical device comprising on all or part of its surface a layer made of or comprising zirconia, said layer having a thickness of between approximately 50 and approximately 2000 nm, said method comprising a step of depositing, on all or part of the surface of an implantable medical device, a layer made of or comprising zirconia, said layer having a thickness of between approximately 50 and approximately 2000 nm, said deposition being carried out by physical vapor deposition (PVD) or by dynamic projection by cold gas (cold spray).

[0033] The deposition can be carried out by any physical vapor deposition or cold gas dynamic projection technique, well known to those skilled in the art.

[0034] Any particular embodiment described above in relation to the device of the invention also applies here, alone or in combination.

[0035] According to a particular embodiment, the physical vapor deposition is carried out by magnetron cathode sputtering.

[0036] According to a particular embodiment, said implantable medical device is rotating, or not, around at least one axis of rotation during all or part of the deposition.

[0037] According to a particular embodiment, the deposition is carried out by physical vapor deposition (PVD), in particular by magnetron sputtering, and is carried out in the presence of a zirconium or yttria-containing zirconium target.

[0038] According to a particular embodiment, the deposition is carried out in the presence of a zirconium target and a target of at least one element or a compound comprising at least one element chosen from Mg, Ca, Ag, and Zn.

[0039] According to another particular embodiment, the deposition is carried out in the presence of a zirconium target, and by bringing the device into contact with at least one element or a compound comprising at least one element chosen from Mg, Ca, Ag, and Zn, by electrophoresis or by plasma jet.

[0040] According to a more particular embodiment, said at least one element or at least one compound comprising at least one element chosen from Mg, Ca, Ag, and Zn is introduced, in particular in the form of nanoparticles, into the plasma jet formed during the deposition of zirconia.

[0041] According to another more particular embodiment, said at least one element or compound comprising at least one element chosen from Mg, Ca, Ag, and Zn is deposited concomitantly with the zirconia.

[0042] According to yet another more particular embodiment, said at least one element or compound comprising at least one element chosen from Mg, Ca, Ag, and Zn is deposited after the zirconia has been deposited.

[0043] According to a particular embodiment, the variation between the roughness Ra of the initial device and the roughness Ra of the device obtained at the end of the method is less than or equal to approximately 25%, for example less than or equal to approximately 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1%.

[0044] According to another particular embodiment, the variation between the roughness Ra of the initial device and the roughness Ra of the device obtained at the end of the method is less than or equal to approximately 1%, for example less than or equal to approximately 0.9; 0.8; 0.7; 0.6; 0.5; 0.4; 0.3; 0.2; or 0.1%.

[0045] According to a particular embodiment, the deposition step is preceded by a stripping step, in particular plasma stripping, of the device.

[0046] This step can, if necessary, increase the adhesion of the layer made up of or comprising zirconia. The implantable medical device can be obtained by any technique well known to those skilled in the art.

[0047] For example, the implantable medical device, in particular a dental implant, can be obtained by machining, in particular cold drawing, molding, sintering, printing by additive manufacturing, or any other ad hoc technique well known to those skilled in the art.

[0048] According to another aspect, the invention relates to an implantable medical device capable of being obtained according to the method as defined above. Definitions

[0049] As used herein, the value ranges of "xy" or "from x to y" or "between x and y" include the bounds x and y as well as the integers between these bounds. For example, "1-5", or "from 1 to 5" or "between 1 and 5" denote the integers 1, 2, 3, 4 and 5. Preferred embodiments include each individual integer in the value range, as well as any subcombination of these integers. For example, preferred values ​​for "1-5" may include the integers 1, 2, 3, 4, 5, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, etc.

[0050] As used herein, the term "about" particularly refers to a range of values ​​within ± 10% of a specific value. For example, the term "about 100" includes values ​​of 100 ± 10%, i.e., values ​​from 90 to 110.

[0051] By "zirconia" is meant in particular zirconium dioxide, also known as zirconium(IV) oxide, or a compound of formula ZrO 2 .

[0052] By "roughness R a" is meant in particular the average distance between the mean line and the peaks and troughs of a given surface. It therefore includes, for a given surface, the average deviation, or arithmetic mean of the distances between successive peaks and troughs. For example, the roughness evaluation length may be 1.25 mm (corresponding in particular to a cut-off wavelength of the high-pass filter of the measuring device of 0.25 mm), in particular for a roughness R a such that 0.02 < Ra ≤ 0.1; 4.00 mm (corresponding in particular to a cut-off wavelength of the high-pass filter of the measuring device of 0.80 mm), in particular for a roughness R a such that 0.1 < Ra ≤ 2; or 12.50 mm (corresponding in particular to a cut-off wavelength of the high-pass filter of the measuring device of 2.50 mm), in particular for a roughness R a such that 2 < Ra ≤ 10.

[0053] "Ra" thus corresponds in particular to the difference between this average distance and the "central line". More specifically, the roughness Ra is measured according to the ISO 4287 standard, for example on a Dektak Stylus ® profilometer (Bruker). EXAMPLES Example 1: preparation of an implantable medical device according to the invention

[0054] A commercially available implantable medical device, for example a dental implant, is prepared according to the following steps: cleaning with alcohol (pure ethanol); bathing in an ultrasonic bath with water, for example distilled water; drying by blowing with clean air; installation of the device in the PVD machine; if necessary, cleaning the device by blowing with clean air; vacuuming the PVD machine; if necessary, plasma etching of the device.

[0055] Once the device is prepared as indicated above, the layer consisting of or comprising zirconia is deposited on said device as follows: cleaning of the PVD machine (in particular sandblasting of the substrate holder, suppressor screens, etc.); installation of the zirconium target, possibly yttria-treated; installation of the device on the rotating substrate holder; vacuuming of the machine (for example 2 to 5.10 -6 < mbar); introduction of the plasma gas (for example 30 sccm of argon); introduction of the reactive gas (for example 6 sccm of oxygen); adjustment of the pressure inside the deposition chamber using the rolling valve (for example to 0.75Pa); starting of the pulsed DC generator (Power = 0.5A - Frequency = 100Khz - Dead time = 2µs for example); if necessary: ​​initiation of the plasma using an RF generator; deposition time to be adapted depending in particular on the thickness of the desired deposition layer (for 100 nm, 1 hour of deposition may be necessary, for example on a non-industrial machine.For 800 nm, approximately 8 hours of deposition may be necessary); end of deposition (by stopping the generator and the gas flow in particular); stopping the turbo molecular pump and the primary pump; purging the production chamber; recovery of the device according to the invention, preferably with gloves.

[0056] The parameters indicated above are given as an example and can be easily adapted by those skilled in the art, depending on the PVD machine used.

[0057] In particular, devices of the invention were obtained according to the present example, with a zirconia thickness of 100 nm or 800 nm, from commercial dental implants: Name of the device of the invention Reference of the commercial implant used Zirconia layer thickness A100 Naturall+ from ETK ® company 100 nm A800 Naturall+ from ETK ® company 800 nm B100 Natea+ from ETK ® company 100 nm B800 Natea+ from ETK ® company 800 nm

[0058] Each of the four implants above was completely coated with zirconium oxide using magnetron sputtering. The target was pure zirconium in metallic form. The gas present was oxygen, and the substrate was the implant to be sputtered.

[0059] Thus, by ion bombardment on the zirconium target, a metallic zirconium vapor is formed which is oxidized by the oxygen present during its journey to the implant. The zirconium oxide then attaches to the implant. Example 2: tear tests carried out on the devices of the invention

[0060] Two devices of the invention obtained according to Example 1, one with a zirconia thickness of 100 nm, the other with a zirconia thickness of 800 nm, were scratched in a checkerboard pattern using a diamond comb. The scratches are spaced approximately 750 µm apart.

[0061] A piece of tape is stuck onto the formed checkerboard and then torn off.

[0062] The checkerboard is then observed under an optical microscope.

[0063] When the checkerboard observed under the microscope is intact, the test is passed. When the layer is peeled off, torn off in at least one place on the checkerboard, the test is not passed.

[0064] For both devices of the invention, the zirconia layer is perfectly adherent after the test. No delamination is visible. The test is therefore successful and the adhesion of the layer is highly satisfactory for the devices of the invention. Example 3: Roughness measurements on the devices of the invention Materials and methods

[0065] Cross-sections of the devices of the invention, for example of the apical part of a dental implant according to the invention, were made using a micro-cutting machine. Samples of each device 4 to 6 mm thick were thus obtained. Each of them was analyzed using a profilometer and a scanning electron microscope (SEM). This allows, if necessary, to maintain the integrity of the devices studied.

[0066] The profilometer (or roughness meter) measures deviations from 500 Å to 1 mm of a surface. It consists of a diamond stylus that is placed and moved over the sample with a constant force. This physical data is converted into electrical information on a computer. The topography, surface waviness, and roughness of the sample are obtained.

[0067] Each measurement is performed on three different areas of each device sample. These measurements are 200 µm. In order to obtain a representative value of the surface roughness, the average of the three values ​​obtained was calculated.

[0068] The measurement is carried out on a Dektak Stylus ®< profilometer (Bruker) according to the ISO 4287 standard.

[0069] The scanning electron microscope (SEM) allows for atomic composition measurements of devices from samples. Composition measurements are made by energy dispersive X-ray spectroscopy (EDS) by X-ray emission. The impact of the electron beam on the sample produces X-rays characteristic of the elements present in the sample. An instantaneous qualitative composition measurement spectrum of the sample is obtained, along with three-dimensional image acquisition. Results

[0070] The roughness of the devices A, B, C and D of the invention, mentioned in Example 1, was measured as indicated above.

[0071] A reference implant (outside the invention), a commercial implant without a zirconia layer, was also considered.

[0072] The results obtained, corresponding to the average of three measurements, as indicated above, show that the variation between the roughness Ra of the initial device and the roughness Ra of the device obtained at the end of the process is less than or equal to approximately 25%, in particular less than or equal to approximately 20%, in particular less than or equal to approximately 7%.

Claims

1. An implantable medical device comprising on all or part of its surface a layer comprising zirconia, said layer having a thickness of between about 50 and 2000 nm, wherein the layer comprises, in addition to zirconia, at least one element or compound comprising an element selected from Mg, Ca, Ag, and Zn, in particular in metallic or oxide form, located at least partially on the surface of the layer.

2. The device according to claim 1: - wherein said layer has a thickness between about 100 or 200 and about 2000 nm, in particular between about 500 or 600 and about 800 nm; or - comprising a layer comprising zirconia, said layer having on a part of the surface of said device a thickness between about 50 and about 2000 nm, in particular between about 50 and about 1200 nm, and on another part of the surface of said device a thickness between about 50 and about 2000 nm, in particular between about 800 and about 2000 nm.

3. The device according to any one of the preceding claims, wherein the zirconia is yttriated zirconia, and / or partially or totally in its quadratic, cubic or monoclinic, in particular monoclinic, phase.

4. The device according to any one of the preceding claims, wherein said at least one element or compound comprising an element selected from Mg, Ca, Ag, and Zn, is located at least partially on the surface of the layer, over 10 to 30% of said surface.

5. The device according to any one of the preceding claims, which, in particular its surface, consists of or comprises titanium or aluminium, the titanium being in particular grade 4 titanium, or in the form of an alloy, in particular grade 5 titanium or a titanium-niobium alloy.

6. The device according to any one of the preceding claims, wherein said layer has a roughness Ra of between 0 and 4.0 µm, notably from 0.6 to 2.0 µm, in particular from 1.0 to 1.5 µm.

7. The device according to any one of the preceding claims, which is an implant, in particular a dental implant, or a prosthesis, in particular a hip prosthesis, more particularly a cup, a shoulder prosthesis, or a knee prosthesis.

8. A method of preparing an implantable medical device according to any one of claims 1 to 7, comprising a step of depositing, on all or part of the surface of an implantable medical device, a layer comprising zirconia, said layer having a thickness of between about 50 and about 2000 nm, said deposition being performed by physical vapor deposition (PVD); in the presence of a zirconium target and a target of at least one element or compound comprising at least one element selected from Mg, Ca, Ag, and Zn ; or in the presence of a zirconium target, and by contacting the device with at least one element or compound comprising at least one element selected from Mg, Ca, Ag and Zn, by electrophoresis or by plasma jet, said at least one element or at least one compound comprising at least one element selected from Mg, Ca, Ag and Zn being introduced, in particular in the form of nanoparticles, into the plasma jet formed during zirconia deposition.

9. The method according to claim 8, wherein the physical vapor deposition is performed by magnetron sputtering.

10. The method according to any one of claims 8 to 9, wherein said implantable medical device is rotated, or not, about at least one axis of rotation during all or part of the deposition.

11. The method according to any one of claims 8 to 10, wherein said at least one element or a compound comprising at least one element selected from Mg, Ca, Ag, and Zn is deposited: - concomitantly with zirconia; or - after the zirconia has been deposited.

12. The method according to any one of claims 8 to 11, wherein the variation between the roughness Ra of the initial device and the roughness Ra of the device obtained at the end of the method is less than or equal to approximately 25%.