Method for producing an implant comprising a coating with silver particles and implant with silver containing coating

Abstract

The disclosure relates to a method for producing an implant comprising a coating with silver, comprising the steps: - providing a metal substrate, - applying several layers with silver particles with a silver concentration of 2 to 20 µg / cm2 in total by plasma electrolytic oxidation in an electrolytic bath, wherein the layers with silver particles are applied in one single electrolytic bath.

Description

[0001] Method for producing an implant comprising a coating with silver particles and Implant with silver containing coating

[0002] Description

[0003] Field of the Invention

[0004] The invention relates to a method for producing an implant which is coated with a silver particle containing surface . In further, the invention relates to an implant which comprises silver particles containing coating .

[0005] Background of the Invention

[0006] Implants with an antimicrobial coating which comprises silver particles are known .

[0007] 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 .

[0008] 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 .

[0009] 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 edgy three- dimensional surfaces , e . g . threads for introducing bone screws .

[0010] In further, the anti-microbial ef fect occurs in the tissue immediately adj acent to the surface of the implant . Due to the toxicity of silver, the silver content of the coating should be kept as low as possible .

[0011] The release of silver should be restricted with respect to the necessary time period after implantation and with respect to the concentration of released silver after the implantation .

[0012] In particular, a fast release of silver immediately after implantation is desired in order to achieve a suf ficient antimicrobial ef ficacy . Then, the formation of a possibly harmful concentration in the surrounding tissue shall be avoided .

[0013] Obj ect of the invention

[0014] 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 sophisticated properties with respect to silver release in a time window after implantation .

[0015] Summary of the Invention

[0016] The obj ect of the invention is achieved by a method for manufacturing an implant and by an implant according to the subj ect matter of the independent claims .

[0017] Preferred embodiments and refinements of the invention are subj ect of the dependent claims , the description, and the drawings .

[0018] The invention relates to a method for producing an implant , which comprises a coating with silver . The method comprises the steps :

[0019] - providing a metal substrate ;

[0020] - applying an adhesion promoter layer by anodi zing the metal substrate ;

[0021] - applying at least several layers with silver particles with a silver concentration of 2 to 20 pg / cm2in total by plasma electrolytic oxidation in an electrolytic bath, wherein the layers with silver particles are applied in one single electrolytic bath .

[0022] According to an embodiment of the invention, the several layers with silver particles have a silver content of 5 to 14 , preferably 7 to 10 pg / cm2.

[0023] Surprisingly, the inventors found out , that the concentration of silver increase from layer to layer towards the outer surface of the implant .

[0024] Surprisingly this also applies for a multi-layer system, in particular for an implant comprising 3 to 20 layers with silver particles , preferably 4 to 8 layers .

[0025] Without being bound on this theory, the inventors suspect that the content of oxides which are formed from the substrate material during the plasma electrolytic process decreases from layer to layer . Therefore , a high ef ficacy can be achieved by using such a multi-layer system, in particular by applying more than three layers .

[0026] 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 .

[0027] According to a refinement of the invention, there is, before applying the layers with silver particles, an adhesion promoter layer applied onto the metal substrate by anodizing the metal substrate.

[0028] Such 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. Furthermore, it was observed that the anodized layer also improves 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.

[0029] Preferably, the step of anodizing the metal substrate and the step of applying at least one layer with silver particles are performed in the same electrolytic bath.

[0030] Preferably, the anodized layer is applied with a thickness of less than 0.5 pm, in particular with a thickness between 0.05 pm to 0.5 pm.

[0031] The layers comprising silver particles are thicker as the anodized adhesion promoter layer.

[0032] Preferably, the at least one silver layer / s is / are applied with a thickness between 3 and 10 pm in total.

[0033] The implant can be embodied as a bone plate or a screw.

[0034] According to an embodiment of the invention, a titanium or a titanium alloy is provided as the metal 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 / cm2from the silver content of the topside.

[0035] 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 / cm2from the silver content of the screw head.

[0036] The anodized layer does not comprise a major silver content. In particular, the anodized layer is applied with a silver content of less than 0.5 pg / cm2, in particular of 0.05 pg / cm2to 0.2 pg / cm2.

[0037] Preferably, the entire coating is applied with a content of 0.2 - 2 wt.-% Ag, preferably 0.5 - 1.5 wt.-%.

[0038] The step of anodizing the metal substrate can be performed by applying a first voltage, and wherein the step of applying the layer with silver particles is performed with a second voltage which is higher than the first voltage.

[0039] The invention further relates to an implant being produced with a method as describes before.

[0040] In further, the invention relates to an implant, wherein the implant comprises a metal substrate with a coating, wherein the coating comprises a multitude of layers with silver particles , and wherein the concentration of silver increases from layer to layer towards the outer surface of the implant .

[0041] Preferably, the implant comprises several layers with silver particles , in particular 3 to 20 layers , preferably 4 to 8 layers .

[0042] Preferably, the silver concentration increases from layer to layer towards the surface , in particular by 1 - 50 % , preferably 2 - 10 % .

[0043] The implant may comprise an adhesion promoter layer between the metal substrate and the multitude of layers with silver particles .

[0044] The adhesion promoter layer may be embodied as an anodi zed layer .

[0045] Preferably, the anodi zed layer has a silver content of less than 0 . 5 pg / cm2.

[0046] Brief Description of the Drawings

[0047] The invention shall be described in more detail with reference to the drawings .

[0048] Fig . 1 is a flow chart , showing the steps of performing a method of producing an implant according to an embodiment of the invention .

[0049] 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.

[0050] Fig. 4a and Fig. 4b show exemplary embodiments of an implant.

[0051] Detailed Description of the Drawings

[0052] Fig. 1 is a flowchart of producing an implant according to an embodiment of the invention.

[0053] An electrolytic bath containing dispersed nano-sized silver particles is provided.

[0054] The substrate is immersed into the bath.

[0055] By applying a first voltage, an oxide layer is applied onto the substrate, which serves as an adhesion promoter layer for the following layers with silver particles.

[0056] Then, the voltage is increased. The second higher voltage results in the formation of a plasma adjacent to the surface of the substrate.

[0057] Thus, a multitude of layers is applied by temporary switching on the second voltage. In particular, four to eight layers may be applied.

[0058] As a result, a substrate is provided with a homogeneous coating which comprises silver particles in a concentration which increases from layer to layer towards the surface.

[0059] 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.

[0060] 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, efficacy 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.

[0061] In detail, the antimicrobial efficacy can be tested as follows :

[0062] First, the silver content of the sample in the layer system has to be determined.

[0063] Characteristic X-radiation of the elements (EDX) can be used to analyze the elemental composition, in particular the silver content .

[0064] 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:

[0065] The samples are cleaned with an acid solution. Then, measurements can be done using optical emission spectrometry (ICP-OES) according to 0NORM EN ISO 11885 (01.11.2009) using a validated method. The results are obtained in pg Ag absolute (per sample piece) .

[0066] 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 .

[0067] 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.

[0068] 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) .

[0069] The following criteria can be fulfilled:

[0070] 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.

[0071] 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 .

[0072] 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 / cm2or more show an efficacy > 3 log scales. The sample with 10 pg / cm2is still highly active > 4 log scales.

[0073] According to the invention, implants with an increase antimicrobial efficacy can be provided.

[0074] Fig. 4a is an explanatory illustration of an implant designed as a bone plate 10. Such a bone plate 10 has at least two, preferably a plurality of holes Ila - lln which can be used for inserting bone screws.

[0075] The hole Ila is designed as a so-called compression hole. This compression hole Ila serves in interaction with the bone screw (shown in Fig. 4b) to move the fragments of the bone towards each other.

[0076] The holes Ila - lln have inner surfaces which are at least partially rounded. According to the invention, the silver coating with an increased homogeneity also extends through these interior surfaces.

[0077] Fig. 4b shows an implant which is designed as a bone screw 20.

[0078] The bone screw 20 consists of a shaft 21 with a head. The shaft 21 has a thread for insertion into the bone. The base of the thread is also provided with a homogeneous silver coating. Further, the bone screw 20 comprises a screw head 22 . The screw head 22 may comprise a head thread to provide angularly stable fixation in the respective hole .

[0079] According to the invention, implants with an increased antimicrobial ef ficacy can be provided .

Claims

Claims :

1. Method for producing an implant comprising a coating with silver, comprising the steps:- providing a metal substrate;- applying several layers with silver particles with a silver concentration of 2 to 20 pg / cm2in total by plasma electrolytic oxidation in an electrolytic bath, wherein the layers with silver particles are applied in one single electrolytic bath.

2. The method according to the preceding claim, wherein 3 to 20 layers with silver particles, preferably 4 to 8 layers, are applied.

3. The method according to the preceding claims, wherein, before applying the layers with silver particles, an adhesion promoter layer is applied onto the metal substrate by anodizing the metal substrate.

4. The method according to any of the preceding claims, wherein the step of anodizing the metal substrate and the step of applying at least one layer with silver particles are performed in the same electrolytic bath.

5. The method according to any of the preceding claims, wherein the anodized layer is applied with a thickness of less than 0.5 pm, with a thickness between 0.05 pm to 0.5 pm.

6. The method according to any of the preceding claims, wherein the at least one silver layer / s is / are applied with a thickness between 3 and 10 pm in total.

7. The method according to any of the preceding claims, wherein a bone plate or a screw is provided as the metal substrate .

8. The method according to any of the preceding claims, wherein a titanium or a titanium alloy is provided as the metal substrate.

9. The method according to any of the preceding claims, wherein an implant, in particular embodied as a bone plate, is provided, which comprises a substantially even topside and at least one hole or thread with a rounded interior surface, wherein the rounded interior surface and the even topside are coated, and wherein the silver content on the rounded interior surface differs less than 2.5 pg / cm2from the silver content of the top side.

10. The method according to any of the preceding claims, wherein the several layers with silver particles with a silver content of 5 to 14, preferably 7 to 10 pg / cm2in total are applied.

11. The method according to any of the preceding claims, wherein the anodized layer is applied with a silver content of less than 0.5 pg / cm2, in particular from 0.05 pg / cm2to 0.2 pg / cm2.

12. The method according to any of the preceding claims, wherein the coating is applied with a content of 0.2 - 2 wt.-% Ag, preferably 0.5 - 1.5 wt.-%.

13. The method according to any of the preceding claims wherein the step of anodizing the metal substrate is performed by applying a first voltage, and wherein the step of applying the layer with silver particles isperformed with a second voltage which is higher than the first voltage.

14. Implant being produced with a method according to any of the preceding claims.

15. Implant, in particular produced with a method according to any of the preceding claims, wherein the implant comprises a metal substrate with a coating, wherein the coating comprises a multitude of layers with silver particles, wherein the concentration of silver increases from layer to layer towards the outer surface of the implant.

16. 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.

17. 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 %.

18. Implant according to any of the preceding claims, wherein the implant comprises an adhesion promoter layer between the metal substrate and the multitude of layers with silver particles.

19. Implant according to the preceding claim, wherein the adhesion promoter layer is embodied as an anodized layer.

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

21. Implant according to any one of the preceding claims, wherein the implant has at least a log 3, preferably a log 4 reduction against Staphylococcus aureus DSM799 / ATCC 6538 with a concentration of 106 CFU / ml after pre-incubation in artificial wound fluid with 5% bovine serum albumin (BSA) , 142 mM NaCl, 2.5 mM CaC12 for 3, more particularly 7 days at 37 °C.

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