Method for manufacturing an implant with a silver particle-containing coating and implant with silver particle-containing coating

Abstract

The disclosure relates to a method for manufacturing an implant with a silver-containing coating, comprising the following steps: - Providing a metal substrate, - Application of several layers containing silver particles with a total silver concentration of 2 to 20 µg / cm² 2 by plasma electrolytic oxidation in an electrolysis bath, wherein the silver particle-containing layers are applied in a single electrolysis bath.

Description

Field of invention

[0001] The invention relates to a method for manufacturing an implant coated with a silver particle-containing surface. The invention further relates to an implant comprising a silver particle-containing coating. Background of the invention

[0002] Implants with an antimicrobial coating that includes silver particles are known.

[0003] Document WO 2010 / 139451 A2 discloses a method for manufacturing such an implant using a plasma electrolytic oxidation process. The implant is immersed in an electrolyte containing colloidally dispersed silver particles. Using the plasma electrolytic oxidation process, these particles can be embedded in a layer that also consists of oxides of the substrate material.

[0004] Document WO 2017 / 050610 A1 reveals that it is surprisingly possible to apply multiple layers on top of each other using a plasma electrolytic oxidation process.

[0005] However, it is difficult to provide a plasma electrolytic oxidation process that ensures a homogeneous coating, especially a homogeneous distribution of the silver particles. This is particularly true for curved and angular three-dimensional surfaces, such as threads for inserting bone screws.

[0006] Furthermore, the antimicrobial effect occurs in the tissue immediately adjacent to the implant surface. Due to the toxicity of silver, the silver content of the coating should be kept as low as possible.

[0007] The release of silver should be limited with regard to both the required timeframe after implantation and the concentration of silver released after implantation. In particular, rapid release of silver immediately after implantation is desirable to achieve sufficient antimicrobial efficacy. Subsequently, the formation of a potentially harmful concentration in the surrounding tissue should be avoided. Object of the invention

[0008] Against this background, one object of the invention is to provide an implant and a method for manufacturing such an implant with a coating which has mature properties with regard to silver release in a time window after implantation. Summary of the invention

[0009] The object of the invention is achieved by a method for manufacturing an implant and by an implant according to the subject matter of the independent claims.

[0010] Preferred embodiments and further developments of the invention are the subject of the dependent claims, the description and the drawings.

[0011] The invention relates to a method for manufacturing an implant comprising a silver-containing coating.

[0012] The process includes the following steps: - Providing a metal substrate, - Applying an adhesion promoter layer by anodizing the metal substrate, - Application of at least several layers containing silver particles with a total silver concentration of 2 to 20 µg / cm² 2by plasma electrolytic oxidation in an electrolysis bath, wherein the silver particle-containing layers are applied in a single electrolysis bath.

[0013] According to one embodiment of the invention, the multiple silver particle-containing layers have a silver content of 5 to 14 µg / cm². 2 on, preferably from 7 to 10 µg / cm² 2 .

[0014] The inventors surprisingly discovered that the silver concentration increases from layer to layer towards the outside of the implant.

[0015] Surprisingly, this also applies to a multi-layer system, in particular to an implant comprising 3 to 20 silver particle-containing layers, preferably 4 to 8 layers.

[0016] Without committing to this theory, the inventors hypothesize that the oxide content formed from the substrate material during the plasma electrolytic process decreases from layer to layer. Therefore, high efficiency can be achieved by using such a multilayer system, particularly by applying more than three layers.

[0017] The silver concentration can increase from layer to layer towards the surface, in particular by 1 - 50%, preferably by 2 - 10%.

[0018] The silver distribution can be investigated by creating a SIMS depth profile.

[0019] According to a further development of the invention, an adhesion promoter layer is applied to the metal substrate before the application of the silver particle-containing layers, namely by anodizing the metal substrate.

[0020] Such a thin oxide layer applied by anodizing improves the adhesion of a layer applied to the anodized layer. This helps to avoid cracks and larger uncoated areas. Furthermore, it has been observed that the anodized layer also improves the homogeneity of the silver layer. Uniform distribution can also be achieved in curved and rounded areas, particularly on the inside of holes and on the base of a thread.

[0021] Preferably, the step of anodizing the metal substrate and the step of applying at least one layer containing silver particles are carried out in the same electrolysis bath.

[0022] Preferably, the anodized layer is applied in a thickness of less than 0.5 µm, in particular in a thickness between 0.05 µm and 0.5 µm.

[0023] The silver particle-containing layers are thicker than the anodized adhesion promoter layer.

[0024] Preferably, the at least one silver layer(s) are applied with a total thickness between 3 and 10 µm.

[0025] The implant can be in the form of a bone plate or a screw.

[0026] According to one embodiment of the invention, titanium or a titanium alloy is provided as the metal substrate.

[0027] The implant, in the form of a bone plate, has a substantially flat top surface and at least one hole with a rounded inner surface or with a thread, wherein the coating also covers the at least one hole as well as the top surface, and wherein the silver content in the hole is less than 2.5 µg / cm². 2 differs from the silver content of the top side.

[0028] According to another embodiment, the screw-shaped implant 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 is less than 2.5 µg / cm². 2 differs from the silver content of the screw head.

[0029] The anodized layer contains no significant amount of silver. In particular, the anodized layer has a silver content of less than 0.5 µg / cm². 2 , especially of 0.05 µg / cm² 2 up to 0.2 µg / cm³ 2 , upset.

[0030] Preferably, the entire coating is applied with an Ag content of 0.2 - 2 wt.%, preferably 0.5 - 1.5 wt.%.

[0031] The step of anodizing the metal substrate can be carried out by applying a first voltage, with the step of applying the silver particle-containing layer being carried out with a second voltage that is greater than the first voltage.

[0032] The invention further relates to an implant that is manufactured using a method as described above.

[0033] The invention further relates to an implant, wherein the implant comprises a metal substrate with a coating, wherein the coating comprises a plurality of silver particle-containing layers, and wherein the silver concentration increases from layer to layer towards the outside of the implant.

[0034] Preferably, the implant comprises several layers containing silver particles, in particular 3 to 20 layers, preferably 4 to 8 layers.

[0035] Preferably, the silver concentration increases from layer to layer towards the surface, in particular by 1 - 50%, more preferably by 2 - 10%.

[0036] The implant can include an adhesion promoter layer between the metal substrate and the majority of silver particle-containing layers.

[0037] The adhesion promoter layer can be designed as an anodized layer.

[0038] Preferably, the anodized layer has a silver content of less than 0.5 µg / cm². 2 on. Brief description of the drawings

[0039] The invention is described in more detail below with reference to the drawings. Fig. Figure 1 shows a flowchart illustrating the steps involved in carrying out a method for manufacturing an implant according to an embodiment of the invention. Fig. Figure 2 shows a schematic representation of the coating. With reference to Fig. Section 3 explains in more detail the antimicrobial effectiveness of coated implants. Fig. 4a and Fig. Figure 4b shows exemplary embodiments of an implant. Detailed description of the drawings

[0040] Fig. Figure 1 shows a flowchart for the manufacture of an implant according to an embodiment of the invention.

[0041] An electrolysis bath containing dispersed nanoscale silver particles is provided.

[0042] The substrate is immersed in the bath.

[0043] By applying an initial voltage, an oxide layer is applied to the substrate, which serves as an adhesion promoter layer for the subsequent silver particle-containing layers.

[0044] The voltage is then increased. The second, higher voltage leads to the formation of a plasma adjacent to the substrate surface.

[0045] Briefly applying the second voltage allows for the application of multiple layers. In particular, four to eight layers can be applied.

[0046] The result is a substrate with a homogeneous coating containing silver particles with a concentration that increases from layer to layer towards the surface.

[0047] Fig. Figure 2 schematically represents the surface area of ​​the implant 10 / 20. A bonding agent layer 1 is applied as the first layer. Preferably, this bonding agent layer 1 is applied in the same electrolysis bath in which the silver particle-containing layers 2a - 2n are also applied.

[0048] According to one embodiment of the invention, the antimicrobial efficacy of the implant is so high that, after pre-incubation in artificial wound fluid with 5% bovine serum albumin (BSA), 142 mM NaCl and 2.5 mM CaCl2 for 3, in particular 7 days at 37 °C, the implant exhibits an efficacy of at least 3 log, preferably 4 log, against Staphylococcus aureus DSM 799 / ATCC 6538 with a concentration of 10 6 KFU / ml is shown.

[0049] Specifically, the antimicrobial efficacy can be tested as follows: First, the silver content of the sample must be determined in the layered system.

[0050] The characteristic X-ray radiation of the elements (EDX) can be used to analyze the elemental composition, especially the silver content.

[0051] Furthermore, inductively coupled plasma optical emission spectrometry (ICP-OES) can be used to determine the overall silver content of the layers. Specifically, this can be carried out as follows: The samples are cleaned with an acid solution. Measurements can then be carried out using inductively coupled plasma optical emission spectrometry (ICP-OES) according to ÖNORM EN ISO 11885 (01.11.2009) using a validated method. The results are obtained in µg Ag absolute (per sample).

[0052] Based on the surface area, the concentration of silver can be expressed in µg Ag / cm². 2 will be calculated.

[0053] The antibacterial efficacy of silver-coated samples can be determined using a proliferation test. Staphylococcus aureus DSM 799 / ATCC 6538 was used as the microbial test strain. To simulate implantation conditions, the 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 CaCl2) in a volume sufficient for complete submersion.

[0054] After the pre-incubation period, the samples are washed. To test the antimicrobial efficacy, the bacterial solution is added to each sample and incubated at 37 °C for 1 hour to allow the bacterial cells to adhere to the sample surface.

[0055] The samples are then incubated for 18 hours at 37 °C. After taking the test samples, efficacy is determined by measuring bacterial (daughter cell) growth every 30 minutes over a period of 48 hours using optical density (OD). In the proliferation test, materials are considered antimicrobial if the release of daughter cells is inhibited by ≥ 99.9% (3 log steps).

[0056] The following criteria can be met: A 4-log reduction in bacterial colonization after 3 days of wound fluid exposure and a 3-log reduction in bacterial colonization after 7 days of wound fluid exposure.

[0057] Fig. Figure 3 shows the antimicrobial efficacy in proliferation tests on samples, represented as the net time to OD increase, in hours, for the silver concentration series of samples against Staphylococcus aureus. The solid line corresponds to an antimicrobial activity of 3 log units, the dashed line to 4 log units.

[0058] To verify the dose-dependent antimicrobial efficacy, three different concentrations were used for this study.

[0059] The results show that the antimicrobial efficacy decreases dose-dependently over time with incubation in artificial wound fluid. After pre-incubation periods of 1 day and 3 days, efficacy of > 4 log units was observed at all concentrations. After 14 days of pre-incubation, the samples with 5 µg / cm² showed 2 or more, an efficacy of > 3 log levels. The sample with 10 µg / cm² 2was still highly effective with > 4 log levels.

[0060] The invention makes it possible to provide implants with increased antimicrobial efficacy.

[0061] Fig. Figure 4a represents, for illustrative purposes, an implant designed as a bone plate 10. Such a bone plate 10 has at least two, preferably a plurality of, holes 11a-11n which can be used for inserting bone screws.

[0062] Hole 11a is designed as a so-called compression bore. This compression bore 11a interacts with the bone screw (in Fig. (shown in 4b) to move the bone fragments towards each other.

[0063] Holes 11a - 11n have inner surfaces that are at least partially rounded. According to the invention, the silver coating extends with increased homogeneity over these inner surfaces as well.

[0064] Fig.Figure 4b shows an implant designed as a bone screw 20.

[0065] 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 also has a homogeneous silver coating.

[0066] Furthermore, the bone screw 20 includes a screw head 22. The screw head 22 may have a head thread to enable angularly stable fixation in the respective hole.

[0067] According to the invention, implants with increased antimicrobial efficacy can be provided. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] WO 2010 / 139451 A2

[0003] WO 2017 / 050610 A1

[0004] Cited non-patent literature

[0000] EN ISO 11885 (01.11.2009

[0051]

Claims

[1] Method for manufacturing an implant with a silver-containing coating, comprising the following steps: - Providing a metal substrate; - Application of several layers containing silver particles with a total silver concentration of 2 to 20 µg / cm² 2 by plasma electrolytic oxidation in an electrolysis bath, wherein the silver particle-containing layers are applied in a single electrolysis bath. [2] Method according to the preceding claim, wherein 3 to 20 layers containing silver particles are applied, preferably 4 to 8 layers. [3] Method according to the preceding claims, wherein an adhesion promoter layer is applied to the metal substrate prior to the application of the silver particle-containing layers by anodizing the metal substrate. [4] 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 containing silver particles are carried out in the same electrolysis bath. [5] Method according to any of the preceding claims, wherein the anodized layer is applied in a thickness of less than 0.5 µm, with a thickness between 0.05 µm and 0.5 µm. [6] Method according to any of the preceding claims, wherein the at least one silver layer(s) with a total thickness between 3 and 10 µm is / are applied. [7] Method according to any of the preceding claims, wherein a bone plate or a screw is provided as the metal substrate. [8] Method according to any of the preceding claims, wherein titanium or a titanium alloy is provided as the metal substrate. [9] A method according to any of the preceding claims, wherein an implant is provided, in particular in the form of a bone plate, having a substantially flat top surface and at least one hole or thread with a rounded inner surface, wherein the rounded inner surface and the flat top surface are coated and wherein the silver content on the rounded inner surface is less than 2.5 µg / cm² 2 differs from the silver content of the top side. [10] Method according to one of the preceding claims, wherein the multiple silver particle-containing layers have a total silver content of 5 to 14 µg / cm² 2 , preferably 7 to 10 µg / cm² 2 , are applied. [11] Method according to any of the preceding claims, wherein the anodized layer has a silver content of less than 0.5 µg / cm² 2 , especially of 0.05 µg / cm² 2 up to 0.2 µg / cm³ 2 , is applied. [12] Method according to one of the preceding claims, wherein the coating is applied with an Ag content of 0.2 - 2 wt.%, preferably 0.5 - 1.5 wt.%. [13] Method according to any of the preceding claims, wherein the step of anodizing the metal substrate is carried out by applying a first voltage, and wherein the step of applying the silver particle-containing layer is carried out with a second voltage which is greater than the first voltage. [14] Implant manufactured according to a method according to any of the preceding claims. [15] Implant, in particular manufactured according to a method according to one of the preceding claims, wherein the implant comprises a metal substrate with a coating, the coating comprises a plurality of layers containing silver particles, the silver concentration increases from layer to layer towards the outside of the implant. [16] Implant according to the preceding claim, wherein the implant comprises several layers containing 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 by 2 - 10%. [18] Implant according to one of the preceding claims, wherein the implant comprises an adhesion promoter layer between the metal substrate and the plurality of silver particle-containing layers. [19] Implant according to the preceding claim, wherein the adhesion promoter layer is designed as an anodized layer. [20] Implant according to any of the preceding claims, wherein the anodized layer has a silver content of less than 0.5 µg / cm² 2 exhibits. [21] Implant according to any of the preceding claims, wherein the implant reduces the concentration of Staphylococcus aureus DSM 799 / ATCC 6538 at a concentration of 10 by at least 3 log, preferably 4 log. 6 CFU / ml, after pre-incubation in artificial wound fluid with 5% bovine serum albumin (BSA), 142 mM NaCl, 2.5 mM CaCl2 for 3, especially 7 days at 37 °C.

Images