WO2024260651A1

WO2024260651A1 - Implant comprising a coating with silver particles and method for producing an implant

Info

Publication number: WO2024260651A1
Application number: PCT/EP2024/063648
Authority: WO
Inventors: Amir Eliezer; Michel LAFUENTE
Original assignee: Aap Implantate AG
Current assignee: Aap Implantate AG
Priority date: 2023-06-21
Filing date: 2024-05-17
Publication date: 2024-12-26
Anticipated expiration: 2025-12-21

Abstract

The disclosure relates to an implant with a metal substrate comprising a coating with silver, wherein the coating comprises at least one layer with silver particles with a silver content of 2 to 20 µg/cm² in total. The implant comprises an adhesion promoter layer between the metal substrate and the at least one silver layer. The adhesion promoter layer is embodied as an anodized layer.

Description

Implant comprising a coating with silver particles and method for producing an implant

Description

Field of the Invention

The invention relates to an implant which comprises silver particles containing coating . In further, the invention relates to a method for producing an implant which is coated with a silver particle containing surface .

Background of the Invention

Implants with an antimicrobial coating which comprises silver particles .

Document WO 2010/ 139451 A2 discloses a method for producing such an implant by using a plasma electrolytic oxidation process . The implant is immersed into an electrolyte which comprises colloidal dispersed silver particles . By using a plasma electrolytic oxidation process , it is possible to embed these particles in a layer which is also formed by oxides of the substrate material .

Document WO 2017 / 050610 Al discloses that it is surprisingly possible to apply several layers upon each other by using a plasma electrolytic oxidation process .

However, it is di f ficult to provide a plasma electrolytic oxidation process which provides homogenous coating, in particular homogenous distribution of the silver particles . This applies in particular to curved and edged three- dimensional surfaces , e . g . threads for inserting bone screws . A non-uni form distribution may result in the risk of inflammations in areas with a small silver concentration .

The anti-microbial ef fect occurs in the tissue immediately adj acent to the surface of the implant . Due to the toxicity of silver, it is also not possible to increase the silver concentration to the point where also the areas with a small silver concentration have suf ficient anti-microbial properties .

Obj ect of the invention

Given this background, it is an obj ect of the invention to provide an implant and a method for producing such an implant with a coating having an increased homogeneity .

Summary of the Invention

The obj ect of the invention is achieved by an implant and by a method for producing an implant according to subj ect matter of the independent claims .

Preferred embodiments and refinements of the invention are subj ect of the dependent claims , the description, and the drawings .

The invention relates to an implant with a metal substrate comprising a coating with silver, wherein the coating comprises at least one layer with silver particles with a silver content of 2 to 20 pg/ cm² in total .

The total concentration of silver can be determined by using SEM-EDX or XPS analysis . In further, optical emission spectrometry (ICP-OES) can be used to determine (ICP-OES) , according to ONORM EN ISO 11885 (01.11.2009) .

According to the invention, the implant comprises an adhesion promoter layer between the metal substrate and the, at least one, silver layer.

The adhesion promoter layer is embodied as an anodized layer.

The inventors found out that a thin oxide layer which is applied by anodization increases the binding of a layer which is applied onto the anodized layer. Cracks and larger uncoated areas can be avoided. It was also observed that the anodized layer also increases the homogeneity of the silver layer. A uniform distribution can be achieved also in curved and rounded areas, in particular on interior surfaces of holes and on the base area of a thread.

According to an embodiment of the invention, the implant comprises several layers with silver particles, in particular 3 to 20 layers, preferably 4 to 8 layers.

It had been found out that such a layer system also increases the homogeneity of the entire coating.

Such a multi-layer system also increases the silver contained from layer to layer even if all layers are applied in the same electrolytic bath. Without being bound on this theory, the inventors suspect that the concentration of oxides which are formed from the substrate material during the plasma electrolytic process decreases from layer to layer. Therefore, a high efficacy can be achieved by using such a multi-layer system, in particular by applying more than three layers. The silver concentration can increase from layer to layer towards the surface, in particular by 1 - 50 %, preferably 2 - 10 %.

The silver distribution can be examined by making a sims-depth profile .

According to an embodiment, the anodized adhesion promoter layer has a silver content of less than 0.5 pg/cm².

Preferably, the anodized layer has a thickness of less than 0.5 pm, in particular between 0.05 pm to 0.5 pm.

The at least one layer with silver particles is preferably applied by plasma electrolytic deposition.

The silver layers preferably have a thickness between 1 and 50 pm, in particular preferred between 3 and 10 pm, in total.

According to an embodiment, the metal substrate is a titanium or a titanium alloy substrate.

The implant embodied as a bone plate comprises a substantially even topside and at least one hole with a rounded interior surface or threads, wherein the coating also covers the at least one hole and the topside, and wherein the silver content on the hole differs less than 2.5 pg/cm² from the silver content of the topside.

According to a further embodiment, the implant embodied as a screw comprises a screw head and a threaded shaft, wherein the coating also covers the threaded shaft and the screw head, and wherein the silver content of the threaded shaft differs less than 2.5 pg/cm² from the silver content of the screw head. According to a further embodiment of the invention, the several layers with silver particles have a silver content of 5 to 14, preferably 7 to 10 pg/ cm² in total.

Preferably, the anodized first layer has a silver content of less than 0.5 pg/cm², in particular of 0.05 pg/cm² to 0.2 pg/ cm².

According to an embodiment, the coating comprises 0.2 - 2 wt . - % Ag, preferably 0.5 - 1.5 wt.-% in total.

The coating may comprise:

30 - 70 wt.-% Ti, preferably 40 - 60 wt.-%,

20 - 60 wt.-% 0, preferably 30 - 50 wt.-%,

2 - 8 % P, preferably 4 - 6 % less than 5 wt.-% Al, preferably 1 - 3 wt.-% and/ or less than 3 wt.-% V, preferably 1 - 2 wt.-%.

The plasma electrolytic applied multi-layer system seems to serve as a protective coating and the amount of alloying elements of the substrate in the surface is reduced. The concentration of alloying elements, such as aluminum and vanadium, in the substrate material can be increased without having the risk that harmful concentrations of these elements in the surrounding tissue occur. Hence, the mechanically stability of the implant can be increased.

According to an embodiment of the invention, the substrate comprises vanadium, and wherein the concentration of vanadium in the coating is less than 50 % of the concentration in the substrate .

According to a further embodiment of the invention the substrate comprises aluminum, and wherein the concentration of aluminum in the coating is less than 50 % of the concentration in the substrate .

By using the adhesion promoter layer, it is possible to provide a uni form surface .

In particular the surface of the coating is spotless . According to the invention, spotless may be defined as the coating having not more than 3 spots with a diameter between 1 and 3 mm .

The invention furthermore relates to a method for producing an implant with a silver containing coating .

In particular, an implant as described above is produced .

The method comprises the steps :

- providing a metal substrate

- applying an adhesion promoter layer by anodi zing the substrate

- applying at least one layer with silver particles by using a plasma deposition method .

Preferably, a multitude of layers with silver particles are deposited upon each other .

It had been found out that with the claimed range of silver particles in the coating, a very high ef ficacy can be achieved and simultaneously the formation of a harmful concentration of silver in the tissue can be avoided .

Brief Description of the Drawings

The invention shall be described in more detail with reference to the drawings . Fig. la and Fig. lb show exemplary embodiments of an implant.

Fig. 2 is a schematic illustration of the coating.

With reference to Fig. 3, the antimicrobial efficiency of coated implants shall be explained in more detail.

Detailed Description of the Drawings

Fig. la is an explanatory embodiment of an implant which is embodied as a bone plate 10. Such a bone plate 10 comprises at least two, preferably a multitude of holes Ila - lln, which can be used to introduce bone screws.

Hole Ila is embodied as a so-called compression hole. This compression hole Ila serves in interaction with the bone screw (shown in Fig. lb) to move the fragments of the bone towards each other.

The holes Ila - lln comprise interior surfaces which are at least partially rounded. According to the invention, the silver coating with an increased homogeneity also extends through these interior surfaces.

Fig. lb shows an implant which is embodied as a bone screw 20.

Fig. 2 is a schematic illustration of the surface area of the implant 10/20. As a first layer, an adhesion promoter layer 1 is applied. Preferably this adhesion promoter layer 1 is applied in the same electrolytic bath in which also the layers with silver particles 2a - 2n are applied. For applying the adhesion promoter layer 1, a voltage is applied, which is so low that the formation of plasma is avoided. A conventional anodization process results in a thin oxide layer 1 on the surface.

Then, the voltage is increased and a multitude of layers which comprise silver particles 2a - 2n are applied. Since the amount of oxides which are formed by oxidizing the substrate material decreases from layer to layer, the silver content increases from layer to layer. This results in an increased anti-microbial efficiency.

The bone screw 20 comprises a shank 21. The shank 21 comprises a thread for introducing into the bone. Also, the tooth base of the thread comprises a homogenous silver coating.

In further, the bone screw 20 comprises a screw head 22. The screw head 22 may comprise a head thread to engage an anglestable fixation in the respective hole.

According to an embodiment of the invention, the antimicrobial efficacy of the implant is high enough so that the implant has at least a log 3, preferably a log 4, efficiency against Staphylococcus aureus DSM 799/ATCC 6538 with a concentration of 106 CFU/ml after preincubation in artificial wound fluid with 5% Bovine Serum Albumin (BSA) , 142 mM NaCl, 2.5 mM CaC12 for 3, in particular 7 days at 37 °C.

In detail, the antimicrobial efficiency can be tested as follows :

First, the silver content of the sample in the layer system has to be determined. Characteristic X-radiation of the elements (EDX) can be used to analyze the elemental composition, in particular the silver content .

In further, optical emission spectrometry (ICP-OES) can be used to determine the total silver content of the layers. In detail, this can be performed as follows:

The samples are cleaned with an acid solution. Then, measurements can be done using optical emission spectrometry (ICP-OES) according to ONORM EN ISO 11885 (01.11.2009) using a validated method. The results are obtained in pg Ag absolute (per sample piece) .

On basis of the surface area, the concentration of silver in pg Ag/cm²can be calculated.

The determination of the antibacterial effectiveness of silver coated samples can be tested with a proliferation assay. Staphylococcus aureus DSM 799 / ATCC 6538 was used as microbial test strain. To simulate implantation conditions, test samples are incubated for the respective period (3 days or 7 days) in artificial wound fluid (5% BSA, 142 mM NaCl, 2.5 mM CaC12) in a volume to allow complete immersion of the test s amp 1 e .

After preincubation period samples are washed. For antimicrobial efficacy testing, the bacteria solution is added to each sample and incubated at 37°C for Ih to allow bacterial cells to adhere to the sample surface.

Afterward the samples are incubated at 37°C for 18h. After removal of the test samples the Efficacy was defined once the bacterial growth (of the daughter cells) was recorded every 30 minutes for a period of 48h by optical density (OD) measurements. Materials are considered as antimicrobial in the proliferation assay, if the release of daughter cells is inhibited by > 99.9% (3 log scales) .

The following criteria can be fulfilled:

A 4-log reduction in bacterial colonization after 3 days wound fluid exposure and a 3-log reduction in bacterial colonization after 7 day wound fluid exposure.

Fig. 3 shows a proliferation assay based antimicrobial efficacy as net OD Onset hours of the silver concentration series on samples against Staphylococcus aureus. The solid line indicates an antimicrobial activity of 3 log scales, the dotted line 4 log scales.

To verify the dose-dependent antimicrobial efficacy, three different concentrations have been used for this investigation .

The results show that the incubation in artificial wound fluid decreases the antimicrobial efficacy over time in a dose dependent manner. After Id and 3d preincubation period, all concentrations showed efficacy > 4 log scales. After 14d of preincubation, the samples with 5 pg/cm² or more show an efficacy > 3 log scales. The sample with 10 pg/cm² is still highly active > 4 log scales.

According to the invention, implants with an increased antimicrobial efficiency can be provided.

Claims

Claims :

1. Implant with a metal substrate comprising a coating with silver, wherein the coating comprises at least one layer with silver particles with a silver content of 2 to 20 pg/ cm² in total, characterized in that the implant comprises an adhesion promoter layer between the metal substrate and the at least one layer with silver particles, and wherein the adhesion promoter layer is embodied as an anodized layer.

2. Implant according to the preceding claim, wherein the implant comprises several layers with silver particles, in particular 3 to 20 layers, preferably 4 to 8 layers.

3. Implant according to the preceding claim, wherein the silver concentration increases from layer to layer towards the surface, in particular by 1 - 50 %, preferably 2 - 10 %.

4. Implant according to any of the preceding claims, wherein the anodized layer has a silver content of less than 0.5 pg/ cm².

5. Implant according to any of the preceding claims, wherein the at least one layer with silver particles is applied by plasma electrolytic deposition.

6. Implant according to any of the preceding claims, wherein the anodized layer has a thickness of less than 0.5 pm, in particular between 0.05 pm to 0.5 pm.

7. Implant according to any of the preceding claims, wherein the at least one silver layer/s has/have a thickness between 1 and 50 pm, preferably 3 and 10 pm, in total.2

8. Implant according to any of the preceding claims, wherein the implant is embodied as a bone plate or as a screw.

9. Implant according to any of the preceding claims, wherein the metal substrate is a titanium or a titanium alloy substrate .

10. Implant according to any of the preceding claims, wherein the implant, in particular embodied as a bone plate, comprises a substantially even topside and at least one hole or thread with a rounded interior surface, wherein the coating also covers the rounded interior surface, and wherein the silver content on the rounded interior surface differs less than 2.5 pg/cm² from the silver content of the top side.

11. Implant according to any of the preceding claims, wherein the several layers with silver particles have a silver content of 5 to 14, preferably 7 to 10 pg/cm² in total.

12. Implant according to any of the preceding claims, wherein the anodized first layer has a silver content of less of less than 0.5 pg/cm², in particular of 0.05 pg/cm² to 0.2 pg/cm².

13. Implant according to any of the preceding claims, wherein the coating comprises 0.2 - 2 wt.-% Ag, preferably 0.5 - 1.5 wt . .

14. Implant according to any of the preceding claims, wherein the coating comprises 30 - 70 wt.-% Ti, preferably 40 - 60 wt.-%,

20 - 60 wt.-% 0, preferably 30 - 50 wt.-%,

15. Implant according to any of the preceding claims, wherein the substrate comprises vanadium, and wherein the concentration of vanadium in the coating is less than

50 % of the concentration in the substrate.

16. Implant according to any of the preceding claims, wherein the substrate comprises aluminum, and wherein the concentration of aluminum in the coating is less than

50 % of the concentration in the substrate.

17. Implant according to any of the preceding claims, wherein the surface of the coating is spotless, in particular wherein the coating has not more than 3 spots with a diameter between 1 and 3 mm.

18. Implant according to any of the preceding claims wherein the implant has at least a log 3, preferably a log 4, efficiency against Staphylococcus aureus DSM 799/ATCC 6538 with a concentration of 106 CFU/ml after preincubation in artificial wound fluid with 5% Bovine Serum Albumin (BSA) , 142 mM NaCl, 2.5 mM CaC12 for 3, in particular 7 days at 37 °C.

19. Method for producing an implant, in particular an implant according to any or the preceding claims, comprising the steps :

- providing a metal substrate

- applying an adhesion promoter layer by anodizing the substrate

20 . The method according to the preceding claim, wherein a multitude of layers with silver particles are deposited upon each other .