Biodegradable implant comprising a coated magnesium alloy product

Abstract

The invention relates to a biodegradable implant comprising a surface-coated magnesium alloy product, wherein the coating layer contains oxides and / or phosphates of rare earth elements, Mg, Ca, Zn, Zr, Mn, or Ag, and wherein the coating is preferably produced by plasma electrolytic oxidation (PEO). The invention further comprises a method for producing the coated magnesium alloy product of the implant.

Description

Scope of the invention:

[0001] The invention relates to a biodegradable implant comprising a surface-coated magnesium alloy product. The invention further includes a method for producing the magnesium alloy product. Background of the invention:

[0002] Magnesium (Mg) is the fourth most abundant cation in the human body, with an estimated value of 1 mol of magnesium in the body of an average 70 kg adult, with approximately half of the total physiological magnesium stored in bone tissue. The presence of magnesium in the skeletal system has a positive effect on bone strength and bone growth. Magnesium alloys have a specific density (1.74–2 g / cm³). 3 ) and a Young's modulus (41-45 GPa), which is similar to that of human bone (1.8 - 2.1 g / cm²). 3 , 3 - 20 GPa) comes closest.

[0003] Therefore, magnesium alloys are particularly superior to other metal or polymer implants in terms of physical and mechanical properties for orthopedic and bone repair or replacement applications, as the difference in Young's modulus between the implant and natural bone can lead to stress-shielding effects. This, in turn, results in a stress concentration at the bone-implant interface, thereby reducing the stimulation of new bone growth and decreasing implant stability.

[0004] Another major advantage of using magnesium and its alloys as implant materials, for example in the manufacture of surgical implants, is their ability to biodegrade in situ. This means that the implant does not remain in the body. Further surgery to remove the implant is unnecessary, and the risks associated with prolonged implant incorporation, such as poor patient compliance, allergies, inflammation, microgliding, particle abrasion, infections, osteoarthritis, or osteopenia due to stress shielding, are significantly reduced or eliminated.

[0005] The in vivo degradation (also known as biodegradation) of magnesium and its alloys is associated with the production of hydrogen, which can subsequently form gas bubbles in tissue. While not limited to a specific theory, it is believed that this problem is caused in vivo by a rapid initial degradation process of the magnesium implant. The degradation rate of the magnesium alloy appears to be too fast, particularly evident immediately after implantation. This leads to the formation of gas bubbles or pockets that could damage surrounding tissue. This is a major drawback of magnesium and hinders the widespread use of magnesium-based implants.

[0006] Although magnesium and its alloys have been investigated as implants for almost two centuries, commercially available implants containing magnesium and its alloys that exhibit favorable degradation behavior are still not available. The advantages and obvious benefits of biodegradable metal implants are driving research into improved magnesium alloy materials and the development of implantation devices derived from them.

[0007] However, the design of optimized tissue implants is hampered by the fact that Mg is a special lightweight metal that requires specific knowledge, careful professional handling, and experience-based design to be a successful biomaterial.

[0008] In summary, a ready-to-use implant should meet several complex requirements. First, it should provide sufficient support at the time of implantation, but ideally be biodegradable so that the deteriorating implant structures are replaced by the body's own regenerating tissue / bone structures. Second, the materials and the structures built from them should provide a good substrate for the colonization, proliferation, and / or differentiation of biological cells. Third, the materials should be non-toxic and non-immunogenic. Fourth, the implant should be usable in various pathological situations to enable the regeneration of different tissues. State-of-the-art implants only partially meet these needs and exhibit disadvantages in one or more of these requirements.

[0009] Gnedenkov et al. (Protection of Metals and Physical Chemistry of Surfaces, 2013, 49,7, p. 874-879) describe a method for coating a magnesium alloy and teaches a coating that contains two substances, namely magnesium oxide and the complex calcium phosphate compound hydroxyapatite.

[0010] German patent DE 10 2016 007 176 A1 relates to a resorbable implant of high purity and discloses a marginal zone comprising a calcium phosphate layer and an oxide layer, thus disclosing only two coating substances. DE 10 2016 007 176 A1 does not disclose the type of oxide.

[0011] EP 2 545 945 A2 relates to an implant, a component set, and a method for manufacturing the same, and teaches for the coated implant a marginal zone comprising a calcium phosphate layer and an oxide layer, thus teaching only two coating substances. The type of oxide is also not disclosed.

[0012] Therefore, there remains a need for an improved magnesium-based implant. The aim of the present invention is to provide a biodegradable magnesium-based implant that overcomes at least one of the aforementioned disadvantages.

[0013] This problem is solved by providing a biodegradable implant according to claim 1. Specific embodiments are the subject of further independent claims. Summary of the invention:

[0014] In one aspect, the present invention presents a biodegradable implant comprising a magnesium alloy product coated on its surface with a coating comprising at least three of the following substances • a metal oxide of a metal selected from rare elements, Ca, Zn, Zr, Mn or Ag and / or • a metal phosphate of a metal selected from rare elements, Ca, Zn, Zr, Mn or Ag, wherein the magnesium alloy is selected from the group consisting of an Mg-Y-RE alloy containing rare elements (RE), or an Mg-Ca-Zn or Mg-Zn-Ca alloy, with or without the addition of Zr, with Ca and Zn contents each below 1 wt.%.

[0015] The implant of the presented invention has several advantages over other implant products from the prior art.

[0016] The coating of the invention represents, in addition to the well-known variation of the magnesium alloy composition, a further dimension of magnesium product modification.

[0017] It thus adds another variable to the production of magnesium alloy implants and can be combined with established Mg alloys.

[0018] The coated magnesium alloys are both non-toxic and non-immunogenic and therefore have a sufficient safety profile.

[0019] In particular, the magnesium alloy does not require the use of aluminum, which is one of the most common alloying components in magnesium alloys (see, for example, AZ31 / AZ91). Aluminum is a neurotoxic metal and possibly the most aggravating and preventable factor associated with Alzheimer's disease.

[0020] Due to their mixed metal phosphate / oxide coating, their in vivo degradation rate, which is in the clinically relevant range, is, for example, fast enough on the one hand to be replaced by regenerating tissue / regenerating bone and, on the other hand, not too fast to cause hydrogen gases or pockets.

[0021] Furthermore, the coated magnesium alloy of the invention exhibited a degradation rate with a lower standard deviation, thus offering better predictability. This enables shorter development cycles and reduces the need for animal model testing.

[0022] Furthermore, the surface coating increases the surface hardness of the material and enables its use for implant structures that must withstand significant mechanical loads, such as screws, plates, wedges, pins, anchors or nails.

[0023] During degradation, Mg reacts with water to form the strong base magnesium hydroxide. The inventors were also able to demonstrate that the coated magnesium alloy products of this invention exhibit only a moderate increase in pH value during in vivo degradation, which remained well within the physiological range of 7 to 8.

[0024] Another advantage of magnesium as an implant material is the fact that magnesium is a natural component of the body and also fulfills many important functions. Biodegradation leads to the formation of Mg. 2+ -cations that are beneficial for various cell types, but especially nerve cells.

[0025] As the inventors discovered, the coated Mg alloy can be produced by plasma electrolytic oxidation (PEO), which is a process that can also be carried out on an industrial scale.

[0026] Furthermore, the PEO coating process enables the coating of sensitive structures with complex internal geometry.

[0027] Since the implant product of this invention can be based on known magnesium alloys, it can be manufactured easily and cost-effectively. Detailed description of the invention:

[0028] According to the invention, the coating comprises at least three of the two listed classes of substances, selected from a first class of phosphates and a second class of oxides. Accordingly, the coating comprises three, four, five, six, seven, eight, nine, ten, or even more of the listed substances.

[0029] In one embodiment of the invention, the metal oxide or the metal phosphate forms a crystalline domain within the coating. In a preferred embodiment, the coating is a layer with a crystal content of more than 10%, preferably with a crystal content of more than 20%, particularly preferably with a crystal content of more than 30%, and especially with a crystal content of more than 50%.

[0030] In an alternative embodiment of the invention, the metal oxide or the metal phosphate forms an amorphous domain within the coating layer. In a preferred embodiment, the coating layer corresponds to an amorphous layer. Here, the term "amorphous layer" is defined as a layer with a crystal content of less than 5%, preferably with a crystal content of less than 2%, particularly preferably with a crystal content of less than 1%, and especially with a crystal content of less than 0.5%.

[0031] In one embodiment, the coating layer has a thickness between 2 and 50 µm, preferably 5 to 35 µm, particularly preferably between 8 and 24 µm and particularly between 12 and 18 µm.

[0032] In a further embodiment, the coating layer contains metal fluorides, the concentration of which increases from the upper surface of the coating to the lower alloy product-oriented surface of the coating, preferably forming a distinct metal fluoride-enriched zone on the underside of the coating layer.

[0033] In a preferred embodiment, the coating layer has two fluoride-enriched zones located on the lower surface and the upper surface of the oxide sublayer. The oxide sublayer forms the lower layer of the coating, which is on the alloy surface.

[0034] The top surface of the coating has a mean Vickers hardness of 150 to 800, preferably 200 to 600 and particularly preferably 250 to 400, as measured according to DIN EN ISO 6507-1 / 4:2018.

[0035] The coating comprises at least two sublayers, a lower barrier layer located in the direction of the alloy product, and a porous upper layer.

[0036] In a preferred embodiment, the rare earth elements are selected as the metal component of the oxides / phosphates of the coated layer from the list consisting of yttrium (Y), scandium (Sc), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb) and lutetium (Lu), including any combination thereof, as a component of the oxides / phosphates of the coating.

[0037] In a preferred embodiment of the invention, the coating is produced by plasma electrolytic oxidation (PEO).

[0038] In another embodiment, the coating of the magnesium alloy product is a porous layer, preferably having a porosity of 2 to 50%, more preferably 3 to 25%, and particularly preferably 4 to 12%. The pores allow body fluid to reach the magnesium alloy as the internal product material, which then begins to degrade, forming magnesium hydroxide and hydrogen. Furthermore, the pores allow adjacent tissue to grow into the pores, thus improving the encapsulation of the implant.

[0039] In one embodiment, the coating is provided with a channel network that imparts porosity to the layer. Preferably, the channel network is designed with openings facing the surface of the coating layer, the respective surface cross-sectional diameters of which are smaller than the respective channel depth. The channels of the channel network can extend in the direction of the coating depth or in a radial direction. The channel branches or sections can be straight and / or curved.

[0040] In a preferred embodiment, the channel network comprises interconnected channel branches which, viewed in cross-section, extend over at least most of the layer.

[0041] In a preferred embodiment, the channels of the network are mainly interconnected.

[0042] In a complementary embodiment, the channels of the network are mainly not connected to each other.

[0043] The canal network generally provides a good substrate for the ingrowth of cells and tissues. This ingrowth could be further enhanced by pre-filling the canal network with bioactive compounds such as substances that initiate or stimulate bone growth.

[0044] In an alternative embodiment, the coating does not have a channel network.

[0045] Preferably, the pores on the upper surface of the coating have an average pore size between 0.1 µm. 2 up to 10 µm 2 , preferably of 2 µm 2 up to 8 µm 2 and especially preferably of 4 µm 2 up to 6 µm 2 .

[0046] In one embodiment, the magnesium alloy of the product is an Mg-Y-RE-Zr alloy, and preferably an Mg-Y-Nd-Zr alloy, also known as WE43 alloy. In particular, the rare earth elements (RE) Dy, Y, Nd, and Gd exhibit low toxicity and are advantageous for improving the mechanical and corrosion properties. Due to its excellent properties, such as relatively slow degradation in aqueous solutions and good electrochemical properties combined with outstanding mechanical properties, WE43 alloy is the preferred magnesium alloy.

[0047] In one embodiment, the magnesium alloy is an Mg-Y-Nd alloy with or without the addition of Zr. In a preferred embodiment, the magnesium alloy has a yttrium content between 3 and 5 wt.% and an Nd content between 2 and 4 wt.%.

[0048] In another embodiment, the Mg alloy contains calcium and zinc, preferably Mg-Ca-Zn or Mg-Zn-Ca with or without the addition of Zr, particularly preferably with Ca and Zn contents each below 1 wt.%.

[0049] In another embodiment, the coating layer of the surface-coated magnesium alloy product comprises a coating consisting essentially of the elements magnesium, oxygen and phosphorus, relating to a mixed Mg oxide / Mg phosphate layer.

[0050] In one embodiment, the coated magnesium alloy product of the invention has a hydrogen gas evolution rate of less than 1.0 ml / cm². 2 , preferably less than 0.6 ml / cm² 2 , preferably less than 0.2 ml / cm² 2 and even more preferably less than 0.1 ml / cm² 2, measured by continuous volumetric measurement of the generated hydrogen gas after 100-hour incubation in Minimum Essential Medium (MEM) at 37°C under non-turbulent stirring. Due to this reduction in hydrogen production compared to prior art magnesium implants, the implant according to the invention has improved tissue compatibility and safety, since the formation of gas bubbles or pockets is greatly reduced.

[0051] In a second aspect, the invention relates to a method for producing a coating layer on the surface of the magnesium alloy product according to the invention by plasma electrolytic oxidation (PEO).

[0052] Plasma electrolytic oxidation (PEO), also known as micro arc oxidation (MAO), is a promising new method capable of producing a stable and adherent oxide layer on metals such as magnesium. This process is based on the anodic oxidation of the metal when connected to a high-voltage source immersed in a suitable electrolyte.

[0053] Plasma electrolytic oxidation (PEO) is a technique used to produce a hard, wear- and corrosion-resistant coating on valve metals such as aluminum, titanium, magnesium, and their alloys. The PEO process evolved from conventional anodizing, although it utilizes a higher voltage and a suitable electrolyte. The defining characteristic of PEO processes is the generation of small, short-lived microdischarges (plasma channels) on a treated metal surface, which transform the metal surface into a hard, oxide-containing layer. The PEO process is carried out in environmentally friendly electrolytes that do not contain chromates. Additionally, high throwing power (the ability to deposit a coating uniformly on an irregularly shaped metal) is another advantage of the process.

[0054] During PEO, various processes occur, such as the formation of an oxide layer, dielectric breakdown, gas evolution, and metal dissolution. The coating formation depends on the type of power supply, the solution used, and the substrate.

[0055] In a preferred embodiment, the method for producing a coating on the surface of a magnesium alloy product comprises the following steps: (i) Providing an aqueous electrolyte solution containing an inorganic phosphate, (ii) Exposing a magnesium alloy product to the aqueous electrolyte solution, such that the surface of the magnesium alloy product to be treated is immersed in the electrolyte solution, (iii) Applying a voltage difference between the magnesium alloy product and a second electrode located in the aqueous electrolyte system to generate plasma electrolytic oxidation on the immersed surface of the magnesium alloy product, so that the immersed surface is converted into a mixed oxide / phosphate film.

[0056] In a preferred embodiment, the electrolyte solution to be used in the PEO process (also called "PEO electrolyte solution") contains an inorganic phosphate, preferably selected from the list consisting of phosphoric acid, Na3PO4, Na4P2O7, Na5P3O 10 , Na6P6O 18 , Na2HPO4, NaH2PO4, and K2P2O7.

[0057] The inorganic phosphate is preferably contained in the aqueous electrolyte solution at a concentration between 1 and 250 g / L, preferably between 10 and 100 g / L and even more preferably between 45 and 65 g / L.

[0058] The aqueous PEO electrolyte solution contains, in addition to an inorganic phosphate, one or more alkaline compounds, which are preferably selected from the list consisting of potassium hydroxide, lithium hydroxide, sodium hydroxide and ammonium hydroxide.

[0059] The alkaline compound is preferably contained in the aqueous electrolyte solution at a concentration between 1 and 250 g / L, preferably between 10 and 100 g / L and even more preferably between 35 and 75 g / L.

[0060] The aqueous PEO electrolyte solution further comprises one or more additives selected from hydrogen fluoride, urotropin and boric acid.

[0061] The additive is preferably contained in the aqueous electrolyte solution at a concentration between 1 and 400 g / L, preferably between 25 and 350 g / L and even more preferably between 30 and 80 g / L.

[0062] In a preferred embodiment, the voltage applied in the PEO process results in an alternating current, preferably with a sinusoidal waveform.

[0063] In a preferred embodiment, the voltage applied in the PEO process results in a pulsed alternating current, which is also referred to as bipolar pulsed.

[0064] In another preferred embodiment, the voltage applied in the PEO process results in a constant current.

[0065] In another preferred embodiment, the voltage applied in the PEO process leads to an anodically pulsed current, which is also referred to as unipolar pulsed.

[0066] In a more preferred embodiment, the pulsed currents are rectangular.

[0067] In an alternative embodiment, the pulsed currents are sinusoidal or sawtooth-shaped.

[0068] In particular, a rectangular pulse shape is used for the PEO coating process, whereby the PEO coating process is carried out with a constant current.

[0069] Plasma electrolytic oxidation (PEO), also known as micro arc oxidation (MAO), is a promising new method capable of producing a stable and adherent oxide layer on metals such as magnesium. This process is based on the anodic oxidation of the metal when connected to a high-voltage source immersed in a suitable electrolyte. The specific electrolyte solution influences the stability of the passive layer, the size and distribution of sparks, and the phases formed.

[0070] Plasma electrolytic oxidation (PEO) is a technique used to produce a hard, wear- and corrosion-resistant coating on valve metals such as aluminum, titanium, magnesium, and their alloys. The PEO process evolved from conventional anodizing, although it uses a higher voltage. The characteristic feature of PEO processes is the generation of small, short-lived micro-discharges (plasma channels) on a treated metal surface, which transform the metal surface into a hard oxide layer. The PEO process is carried out in environmentally friendly electrolytes that do not contain chromates. Additionally, high throwing power (the ability to deposit a coating uniformly on an irregularly shaped metal) is another advantage of the process.

[0071] During PEO, various processes occur, such as oxide layer formation, dielectric breakdown, gas evolution, and metal dissolution. Coating formation depends on the power supply, the solution used, and the substrate. Treatment parameters, such as current or voltage and process duration, influence coating formation and thus the coating properties. The complexity of the process and the number of factors influencing coating formation make process optimization challenging. EXAMPLES

[0072] For the preparation of test samples, an extruded WE43 magnesium alloy bar with a diameter of 20.6 mm was cut into 1.5 mm thick wafers. After treatment with an acidic activation solution (see below), the wafers were installed in an electrolytic PEO system immersed in various electrolyte solutions and subjected to the PEO protocol.

[0073] The composition of WE43 is as follows: • 3.7% - 4.3% Yttrium • 2.3% - 3.5% rare earth elements • 0.1% - 0.6% Zirconia • Residual magnesium

[0074] The following electrolyte solutions were used in the PEO process for comparison: electrolyte composition E1 Magnesium reference (WE 43) E2 Silicate and KOH E3 Silicate and KOH and borate E4 Silicate and KOH and titanate E5 Silicate and KOH and borate and titanate E6 Phosphate and KOH E7 Phosphate and ammonium hydroxide E8 Phosphate and KOH and aluminate E9 Phosphate, ammonium hydroxide, and urea E10 Phosphate and ammonium hydroxide and EDTA E11 Phosphate and ammonium hydroxide and fluoride and urotropin E12 Phosphate and ammonium hydroxide and borate and fluoride and urotropin

[0075] The conditions for the PEO treatment were individually adapted for each test sample to produce a layer thickness of 10 ± 3.5 µm.

[0076] The following PEO parameters were applied: Activation of the test patterns Incubate for 20 seconds in an activation solution containing 2 g of oxalic acid dihydrate in 100 ml of distilled water, followed by incubation for 10 minutes in distilled water. Energy source Munk PSP product family (Munk GmbH, Hamm, Germany) regulation Constant current mode Pulse shape Unipolar, rectangular frequency 1,000 Hz Current density 1.6 - 4.9 A / dm 2 (final) tension 400 - 500 V Coating duration 15 - 45 min Electrolyte temperature 12 - 21 °C Stirring speed 250 rpm

[0077] The PEO was performed in an apparatus, as schematically shown in Fig. The test samples coated with electrolyte solutions E1 to E12 (E1 being the uncoated negative control) were designated S1 to S12 and subjected to further analysis. Analysis of PEO-coated WE43 test samples S1 to S121. Morphological analysis

[0078] To investigate the morphology of the different coatings, the test specimens were analyzed using scanning electron microscopy (SEM). The top surface of the coated specimens was analyzed in plan view or in a cross-sectional view after sectioning. Exemplary images of the SEM analysis are shown in Fig. shown. 2. EDS spectra

[0079] The chemical composition of the coating layer was analyzed using energy-dispersive X-ray spectroscopy (EDS). The EDS spectrum for probe S6 is shown in Fig. (shown at bottom right). In a more detailed EDS analysis, a cross-section of the PEO-coated magnesium alloy ZX00 was analyzed for its elemental composition using EDS. The results are shown in Fig. in the form of so-called live maps and in the Fig. The phase spectrum was represented as element superpositions. For five different phases, the phase spectrum was collected and analyzed using the software TEAM™ version V4.4.1 (AMETEK GmbH, Weiterstadt, Germany).

[0080] The eZAF Smart Quant method was used, which is an algorithm for quantifying an extended tilt range of up to 70 degrees for flat and polished probes. It includes corrections for atomic number (Z), absorption (A), and fluorescence (F).

[0081] The element distribution for these five phases is in the Fig. The EDS peaks are X-rays emitted when electrons return to the K-electron shell and are therefore indicated with a "K" in the illustrations.

[0082] Finally, a point analysis was performed using the cross-section of the two PEO-coated alloys ZX00 and WE43 to select two points: EDS point 1 within the coating and EDS point 2 within the Mg alloy product. The elemental distributions for these two points were determined using eZAF Smart Quant. The elemental distribution for the PEO-coated alloys ZX00 and WE43 is shown in Fig. depicted.

[0083] In particular, the presence of carbon is an artifact due to probe preparation, as the probe is embedded in an epoxy resin and the freshly prepared surface becomes contaminated with carbon-containing compounds. 3. X-ray crystallography

[0084] The chemical composition of the PEO-coated Mg alloy was analyzed by X-ray crystallography using the XRD ID 3003 TT diffractometer system (GE Sensing & Inspection Technologies GmbH, Hürth, Germany). The Bragg-Brentano geometry (symmetrical) was used with Cu-K alpha Radiation and a 1D detector with a 0.03°2theta step size were used. In a separate analysis, the following parameters were used: grazing incidence (omega angles of 1, 3, 5, and 7°) with Cu-K alpha - Radiation from secondary long Soller collimator and scintillation detector with 0.05 °2theta step size and 5 measurement times.

[0085] As in the Fig. As shown, the peaks derived from a Mg alloy with its hexagonal P36mmc structure dominate the spectrum. However, in the region between 39 and 45 2Theta, several peaks showed the presence of Mg4Zn7 (monoclinic MgZn crystal of space group C2 / m), and a peak at 42.9 2Theta, representing MgO periclase (hexoctahedral crystal of space group Fm-3m), is evident.

[0086] As in a separate analysis in the Fig. The broad peak in the range between 20 and 35 2Theta shows that the coating consists of amorphous material. 4. Analysis of pore size and porosity

[0087] The SEM images of the surface of test samples S2 to S12 were analyzed morphometrically by converting the image to 8-bit format using the software ImageJ (Wayne Rasband, USA) and then binaryizing it. After manually assigning a threshold for pore identification, the pore size (i.e., the pore size in µm) was determined. 2 (specified pore area) and the porosity in % are determined. The results are in Fig. shown. 5. Hardness analysis

[0088] The hardness of test samples S1 to S12 was determined by Vickers microhardness testing with n = 5 using the Fischerscope H100C (Helmut Fischer GmbH, Sindelfingen, Germany) in the cross-section of the test sample. The Vickers hardness for S1 to S12 is shown in Fig.The data is shown. It is evident that the coating leads to an increased hardness of the Mg alloy products. Among the phosphate-based electrolytes, the order of hardness is as follows: S7 > S6 > S9 ~ S10 ~ S11 > S12. 6. Analysis of degradability

[0089] The degradability of test sample S11 compared to an uncoated WE43-Mg alloy product was determined by volumetric analysis of the hydrogen gas generated during degradation. A test apparatus according to Hofstetter et al. (“Assessing the degradation performance of ultrahigh-purity magnesium in vitro and in vivo”, Corrosion Science, 2015 (91): 29-36) was used. The test samples were incubated for 100 hours in Minimum Essential Medium (MEM) at 37 °C with non-turbulent stirring, and the hydrogen gas evolution rate was measured by intermittent 12-hour interval measurements of the generated hydrogen gas. The degradation rates are shown in Fig.The uncoated sample showed a steady increase to up to 1.2 ml / cm² after 100 hours. 2 Hydrogen shows that the PEO-coated sample S11 leads to a hydrogen quantity of approximately 0.1 ml cm⁻¹. 2 . 7. Biocompatibility analysis

[0090] For the in vitro toxicity analysis of the coated test samples, an in vitro test scheme conforming to DIN EN ISO 10993 was applied. This test scheme includes indirect tests by analyzing extracts as well as a direct test. The tests were performed using the mouse fibroblast cell line L929. 7.1 Testing of the extracts

[0091] The indirect examination was carried out as follows: • Sterilization of the test samples by immersion in isopropanol for 5 minutes and drying in a sterile fume hood. • Production of aqueous extracts by incubating test samples S1 to S12 (n = 2) for 72 hours with 3 ml of MEM cell culture medium under cell culture conditions (37 °C, 5 % CO2, 95 % humidity) • Centrifuge the extracts at 14,000 rpm for 10 minutes to remove particles. • Plating of 100 µl CCL1 cells (1 × 10 5 cells / ml) in a 96-well plate and subsequent 24-hour incubation under cell culture conditions • Addition of 100 µl of extract (n = 4 for each test sample) per well • Incubation for another 24 hours • Analysis of cells using the BrdU, LDH and XTT tests

[0092] The results are in Fig.It is evident that in the LDH test, samples S6 to S12 are similar in their effect to the negative control (NK) and thus show no obvious sign of toxicity. This correlates with the results of the TTX and BrdU tests, which show that samples S6 to S12 do not impair cell viability compared to the negative control (NK). 7.2 Testing with direct contact

[0093] The direct inspection was carried out as follows: 1 ml of the CCL1 cell suspension (2.4 × 10 5The test sample (cells / ml) was plated onto a 24-well plate and incubated for 24 hours under cell culture conditions. The cells were then analyzed using vital staining by adding 2.5 mg fluorescein diacetate (FDA) and 3 µg propidium iodide (PI) and incubating for 3 minutes at room temperature. Five different positions of the test specimen from each sample were analyzed using fluorescence microscopy.

[0094] A RM polyurethane plate containing 1% zinc diethyldithiocarbamate (ZDEC) (Hatano Research Institute, Food and Drug Safety Center, Kanagawa, Japan) served as a positive control. Negative controls were performed using an HDPE plastic film or a Grade 4 pure titanium body (Eutitan, Eukamed eK, Essen, Germany). Images were analyzed using a multifactorial subjective assessment performed by three independent observers. The three effects—PI-positive cells, rounded cells, and cell count reduction—were quantified in four steps, as shown in the following table: effect Occurrence (compared to negative control) significance 0 1 2 3 Reduction of cell count no effect slight reduction Medium reduction significant reduction Cell growth Rounded cells no effect small number increased number high number Cell morphology PI-positive cells no effect small number increased number high number Cell damage

[0095] The cumulative rating ranges from 0 for excellent biocompatibility to 9 for high cytotoxic potential. The mean ratings are in Fig. shown. The coated samples S10 and S11 showed the best results. Brief description of the drawings

[0096] These and other aspects of the invention will become apparent from the embodiments described below and will be explained with reference to them.

[0097] The invention will now be described by way of example with reference to embodiments and the accompanying drawings.

[0098] In the drawings: Fig. shows a schematic drawing of a cell for PEO anodizing. Fig. shows the results of the digital analysis of the coated test specimens S1 to S12 with regard to porosity (in %) and pore size (pore area in µm). 2 Figure B shows the SEM images that depict the surface morphology of the test sample S6 along with the EDS spectrum. Fig. shows the results for the LDH, XTT and BrdU tests of extracts from test specimens S1 to S12. Fig.shows the cumulative results of the in vitro toxicity test of samples S1 to S12, including a negative control (NK) and a positive control (PK) after direct plating of CCL1 cells onto the coated test samples S1 to S12. Fig. The image shows the cross-section of the PEO-coated ZX00 Mg alloy in the SEM image (right) and, using a color-coded image, the distribution of the different coating phases as a so-called live map (left). The figure key for the color-coded phases with their elemental composition is shown below. Fig. Figure 6 shows the cross-section of the PEO-coated ZX00 Mg alloy with color-coded element overlays for all elements in the upper left, with the element color assignment shown in the upper right. The following section shows the representation of the separate elements for fluorine, magnesium, aluminum, and phosphorus. Fig.Figure 7 shows the cross-section of the PEO-coated ZX00 Mg alloy with color-coded separate representation of the elements for calcium, iron, nickel, zinc and zirconium. Fig. shows the results of the EDS analysis with eZAF Smart Quant for four different phases of the PEO-coated Mg alloy ZX00. Fig. This shows the results of the EDS analysis with eZAF Smart Quant for two different phases of the PEO-coated Mg alloy ZX00. Below is an example EDS spectrum (here for the PK / MgK / CK phase). Fig. Figure 10 shows the cross-section of the PEO-coated ZX00 Mg alloy with selection of two different EDS points, for which the elemental composition determined by eZAF Smart Quant is shown below. Fig.shows the cross-section of the PEO-coated WE43 Mg alloy with selection of two different EDS points, for which the elemental composition determined by eZAF Smart Quant is shown below. Fig. The results of the X-ray crystallographic analysis for a PEO-coated Mg alloy with two different impulse representations are shown. Fig. The results of the X-ray crystallographic analysis for a PEO-coated Mg alloy WE43 and ZX00 are shown at different angles. Fig. The degradability of test sample S11 was demonstrated in comparison to an uncoated WE43 Mg alloy product, as evidenced by volumetric analysis of the hydrogen gas produced during degradation. The degradation rate is shown as the amount of hydrogen gas produced over the incubation period.

[0099] In the illustrations, identical numbers consistently refer to the same objects. Objects in the illustrations are not necessarily drawn to scale. Detailed description of the embodiments

[0100] The various embodiments of the invention will now be described with reference to the illustrations.

[0101] Fig. Figure 1 shows a schematic diagram of the PEO cell for coating Mg alloy products. Electrolyte circulation helps to remove gas bubbles from the surface of the Mg alloy product, which could impair the growth of a homogeneous layer. By injecting fine air bubbles (i), the laminar boundary layer is continuously removed, thus achieving enhanced exchange with the electrolyte. Definitions

[0102] The term “biodegradable”, as used in connection with the present invention, refers to a device that is degradable under physiological conditions.

[0103] The term “biodegradation”, as used here for the breakdown of the implant in the recipient's organism, is synonymous with the terms “degradation”, “absorption”, “resorption”, “corrosion” and “biocorrosion”.

[0104] The term "plasma anodizing," as used here, is synonymous with the following terms: "Anodic oxidation under spark discharge (ANOF)," "Micro arc oxidation (MAO)," "Anodic spark deposition (ASD)," "Microplasma oxidation (MPO)," "Plasma chemical oxidation (PCO)," and "Micro arc discharge oxidation (MDO)."

[0105] Within the scope of this application, the term "coating" also includes the transformation of surface material and surface modification.

[0106] The terms "spark discharge" and "plasma discharge" used here are synonymous.

[0107] The term “oxide”, as used in the context of the present invention, also includes oxide hydrates.

[0108] The term "phosphate" used here refers to phosphates, diphosphates and polyphosphates.

[0109] As used here, a "metal phosphate" is a chemical compound of a metal and at least one phosphate group that is a chemical derivative of a phosphoric acid. A phosphoric acid is hereby defined as a proton-donating phosphorus-oxygen compound and includes all types of H₂O. x P y O z -compounds such as orthophosphoric acid, metaphosphoric acid, polyphosphoric acid, phosphonic acid and phosphorous acid.

[0110] Within the scope of the present invention, a "metal oxide" is a chemical compound containing at least one oxygen atom and a metal cation as a further element. Examples are MgO, ZnO, CaO, ZrO2, or ZnO.

[0111] As used in connection with the invention, the term ‘biocompatible’ refers to a device that is substantially non-toxic in an in vivo environment and is not substantially rejected by the physiological system of a recipient. List of reference symbols a power source b Electrolyte solution c Counter electrode d Mg alloy test piece e Gas intake f encapsulation g heat exchanger h electrolyte circulation i Air supply j Filter

Claims

[1] Biodegradable implant comprising a magnesium alloy product coated on its surface with a coating layer of at least three substances which are a. a metal oxide of a metal selected from rare earth elements, Mg, Ca, Zn, Zr, Mn or Ag; and / or b. a metal phosphate of a metal selected from rare earth elements, Mg, Ca, Zn, Zr, Mn or Ag, wherein the magnesium alloy is selected from the group consisting of an Mg-Y-RE alloy containing rare elements (RE), or an Mg-Ca-Zn or Mg-Zn-Ca alloy, with or without the addition of Zr, with Ca and Zn contents each below 1 wt.%. [2] Biodegradable implant according to claim 1, wherein the coated magnesium alloy product has one or more of the following properties: a. the metal oxide or metal phosphate forms a crystalline domain within the coating layer; b. the metal oxide or metal phosphate forms an amorphous domain within the coating layer; c. the coating layer has a thickness between 2 and 50 µm, preferably between 5 and 35 µm, particularly preferably between 8 and 24 µm and especially between 12 and 18 µm; d. the coating layer comprises metal fluorides, the concentration of which increases from the upper surface of the coating layer down to the lower, alloy product-oriented surface of the coating layer, preferably forming a pronounced metal fluoride-enriched zone at the lower surface of the coating layer; e. the upper surface of the coating layer has a mean Vickers hardness of 150 to 800, preferably of 200 to 600 and more preferably of 250 to 400, measured according to DIN EN ISO 6507-1 / 4: 2018; f. the coating layer comprises at least two sublayers, which are a lower alloy product-oriented barrier layer and a porous top layer; g. the rare earth elements are selected from the list consisting of Y, Sc, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu; h. the coating layer is produced by plasma electrolytic oxidation (PEO). [3] Biodegradable implant according to claim 1 or 2, wherein the coating layer is a porous layer which preferably has a porosity of 2 to 50%, more preferably between 3 to 25%, and particularly preferably between 4 to 12%. [4] Biodegradable implant according to claim 3, wherein the pores on the upper surface of the coating layer have a mean pore size of between 0.1 and 10, preferably 2 and 8, particularly preferably 4 and 6 µm 2 has. [5] Biodegradable implant according to any of the preceding claims, wherein the Mg-Y-RE alloy is an Mg-Y-Nd with or without the addition of Zr, preferably with a Y content between 3 and 5 wt.% and an Nd content between 2 and 4 wt.% . [6] Biodegradable implant according to any of the preceding claims, wherein the coated magnesium alloy product, after incubation for 100 hours in Minimum Essential Medium (MEM) at 37 °C under non-turbulent stirring, exhibits a hydrogen gas evolution rate of less than 1.0 ml / cm² 2 , preferably of less than 0.6 ml / cm² 2 , preferably less than 0.2 ml / cm² 2 , and even more preferably less than 0.1 ml / cm² 2 , measured by continuous volume measurement of the generated hydrogen gas. [7] Method for producing a coating layer on the surface of a magnesium alloy product according to claims 1 to 6, comprising the following steps: (i) Providing an aqueous electrolyte solution containing an inorganic phosphate, (ii) Exposing a magnesium alloy product to the aqueous electrolyte solution, such that the surface of the magnesium alloy product to be treated is immersed in the electrolyte solution, (iii) Applying a voltage difference between the magnesium alloy product and a second electrode positioned in the aqueous electrolyte system to generate plasma electrolytic oxidation on the immersed surface of the magnesium alloy product, (iv) so that the immersed surface is transformed into a mixed oxide / phosphate film. [8] Method for treating a surface of a magnesium alloy product according to claim 7, wherein the aqueous electrolyte solution has one or more of the following properties: a. The aqueous electrolyte solution comprises an inorganic phosphate, preferably selected from the list consisting of phosphoric acid, Na3PO4, Na4P2O7, Na5P3O 10 , Na6P6O 18 , Na2HPO4, NaH2PO4, and K2P2O7; b. The aqueous electrolyte solution contains an inorganic phosphate at a concentration between 1 and 250 g / L; c. The aqueous electrolyte solution comprises, in addition to the inorganic phosphate, one or more alkaline compounds, preferably selected from the list consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide; d. The aqueous electrolyte solution further comprises one or more additives selected from hydrogen fluoride, urotropin and boric acid. [9] Method for treating a surface of a magnesium alloy product according to one of claims 7 or 8, wherein the voltage applied in step (iii) is unipolar pulsed with a pulse frequency which is preferably between 1 and 2,000 Hz, more preferably between 5 and 500 Hz and further preferably between 8 and 150 Hz.

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