Scaffold Multi-coating

Abstract

The present invention relates to an implant (1) comprising a biodegradable metal body (2) having a surface (2a), and a barrier layer (3) containing a polymer disposed on the surface (2a) of the body (2), wherein the barrier layer (3) is configured to delay the biodegradation of the body (2). The present invention also relates to a method for producing the implant according to the present invention.

Description

Technical Field

[0001] The present invention relates to an implant and a method for generating such an implant.

Background Art

[0002] The development of biodegradable metal and / or polymer-based frameworks, often referred to as scaffolds, represents an important step in the further development of implant technology related to reducing the late effects that often occur with the use of permanent implants. Nevertheless, the degradation of absorbable implants, such as frameworks in the form of vascular frameworks or vascular scaffolds, is too rapid and uncontrolled, i.e., their vascular support properties may be lost too early.

[0003] Biodegradable implants, particularly frameworks / scaffolds, have attracted increasing scientific attention in recent years. For example, relevant developments have been made in the field of cardiovascular disease. One of the most important cardiovascular diseases is coronary artery atherosclerosis. This is characterized by narrowing of the lumen of the large outer coronary vessels (coronary artery sclerosis)[1], which can progress to chronic total occlusion. The result is cardiac ischemia, which can lead to myocardial infarction. Depending on the number and size of affected vessels, percutaneous transcatheter coronary angioplasty (PTCA) is performed in addition to drug therapy, according to current guidelines and the patient's symptoms. This may involve either dilating the narrowed area using a balloon catheter or placing a vascular support, so-called coronary stent[2]. During coronary stent placement, a tubular or grid-like metal framework (vascular support) is inserted into the narrowed vessel and positioned against the vessel wall, but the material used is usually biostable (e.g., CoCr and NiTi alloys) and therefore usually remains there permanently. Bioresorbable vascular scaffolds have been developed to mitigate the long-term effects that can arise from permanent implants. These scaffolds consist of, for example, bioresorbable metals[3] or polymers coated with polymers that typically carry biodegradable active materials. While the delayed effects of permanent implants can be minimized with biodegradable scaffolds, their biodegradation or absorption is often too rapid and uncontrolled, meaning that the scaffold's support properties may be lost too quickly. This is just one example of the challenges associated with the use of biodegradable implants.

[0004] Over time, many different classes of polymers have been established in biomaterials and implant technology. Biostable hydrophobic polymers are used in a wide range of clinical applications: for example, thermoplastic polyurethane (TPU) is used in synthetic heart valves and catheter tubing due to their hemocompatibility and high flexibility [4,5]. Other relevant polymer-based biomaterials are thermoplastic fluoropolymers such as polyvinylidene fluoride (PVDF) or poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) [6], and classes of bioabsorbable polymers such as polylactides, particularly poly-L-lactic acid (PLLA) [7]. Poly-L-lactic acid is suitable as an active substance depot but degrades more rapidly by the degradation of biocorrosive metal-based implants [7]. The literature describes how biostable hydrophobic fluoropolymers such as polyvinylidene fluoride may be used as corrosion protection for metal implants [8,9], or are already used as active substance release layers on permanent commercial stent systems.

[0005] Strategies for vascular scaffolds available to date have aimed to adapt the metal alloy components, which results in slower scaffold degradation. Furthermore, efforts have been made to reduce strut thickness, which, in light of the hemodynamic background technology, reduces the risk of thrombosis. Adjusting the alloy components while simultaneously reducing strut thickness is only partially achievable due to the mechanical properties of the underlying metal. The use of a biostable barrier layer would allow for delayed degradation while simultaneously reducing the strut thickness of the vascular scaffold. [Overview of the project]

[0006] Based on this, the present invention addresses the problem of extending the service life of biodegradable implants. In particular, the implant should be capable of simultaneously releasing active substances.

[0007] This problem is solved by an implant having the features of claim 1 and a method having the features of claim 14.

[0008] Advantageous embodiments of these aspects of the present invention are presented in the corresponding dependent claims and are described below.

[0009] According to claim 1, - A biodegradable metal body with a surface, - Applied to the surface of the main body, comprising a barrier layer containing a polymer, An implant is disclosed in which a barrier layer, particularly a polymer, is configured to delay the biodegradation of the main body.

[0010] According to a preferred embodiment, the barrier layer is made of a polymer.

[0011] Furthermore, according to preferred embodiments of the present invention, the polymer is provided to be a biostable polymer. For the purposes of the present invention, biostable means robust against hydrolysis and / or oxidative degradation or physical degradation processes in the physiological environment of the human body.

[0012] Therefore, the barrier layer is preferably configured to function as a barrier between the main body and the surrounding medium within the implantation area or any further layers placed on the barrier layer, for a long period or permanently, and the further layers (especially the uppermost layer) may carry a pharmacologically active substance and may be configured, for example, as a bioabsorbable polymer layer. The barrier layer preferably protects the additional layers, delays the biodegradation of the main body, and therefore delays the premature loss of function of the implant.

[0013] The thin film coating of preferably biostable polymers according to the present invention serves to protect the main body, particularly the vascular support or scaffold, from biocorrosion or bioabsorption, and thus enable time-delayed, controlled degradation. The objective is to harmonize the degradation time with the required support time. Multi-coatings can be produced in the same manner as drug-coated stent systems, so-called drug-eluting stents (DES), by combining the thin film coating described above with a coating containing an active substance. However, if the drug is applied to a polymer-free surface, it can also function purely as a passivation layer.

[0014] Furthermore, the protective effect of the barrier layer prevents the degradation and corrosion products of the implant from adversely affecting the layer carrying the active substance. In one embodiment, the multi-coating consists of at least two layers: namely, a preferably biostable barrier layer that directly covers the main body (e.g., a vascular support or scaffold), and a biodegradable top layer carrying the active substance, preferably based on a polyester derivative. In an alternative embodiment, as described, a simple, preferably biostable barrier layer is present on the implant surface, to which the active substance may be applied directly.

[0015] The present invention makes it possible to delay the degradation of a vascular support or scaffold so that, for example, a sufficiently long support effect is achieved in a narrowed blood vessel. A biostable polymer is preferably used for this purpose, which acts as a barrier layer between the vascular support and the internal medium. The barrier layer delays the diffusion of the surrounding medium onto the surface of the vascular support body, mitigates the removal of corrosion products from the implant, and thus influences the rate of the corrosion reaction. This has the advantage of slowing the biodegradation and corrosion of the vascular support.

[0016] Delayed, controllable implant degradation can help maintain the desired mechanical properties of biodegradable implants, particularly vascular supports, for longer periods, and thus, above all, help prevent restenosis of affected vessels. A further advantage of metal-based vascular supports is the formation of a passivated metal oxide / hydroxide film (corrosion product) with low reactivity to the surrounding environment, thus reducing the risk of negative systemic reactions to the transiently formed intermediates.

[0017] Furthermore, according to one embodiment, a thin film coating, preferably made of a biostable polymer, acts as a barrier between the vascular support or body and an active substance depot made of polyester, particularly poly-L-lactic acid (PLLA), thereby slowing, for example, the clearly accelerated degradation of PLLA [7].

[0018] Furthermore, according to a preferred embodiment of the barrier layer, the surface of the main body is partially covered and / or porous. Porosity with a pore diameter greater than 0.3 nm is preferred. Moreover, the pore diameter is preferably in the range of 0.3 to 500 nm.

[0019] Therefore, a further possibility for controlled degradation is that a biostable layer is provided on part of the implant, while another part is not. In this case, the uncoated portion of the implant or body degrades relatively rapidly, while the coated portion maintains its structural integrity for a considerably longer period. This may be useful, for example, when the gradual loss of mechanical stability of a degradable implant is desired.

[0020] According to a preferred embodiment, the body has segments, preferably ring-shaped segments, connected to one another via longitudinal connectors.

[0021] According to a preferred embodiment, at least one, preferably all, of the longitudinal connectors is not covered by the barrier layer. In other words, the barrier layer is interrupted at the longitudinal connectors. As a result, these areas decompose more rapidly, and the body loses its longitudinal integrity relatively quickly, preferably immediately after the healing phase, and therefore no longer imparts any bending stress to the blood vessel, but the radial support effect of the individual segments is maintained for a much longer period, and thus the vascular lumen is supported for a much longer period.

[0022] In a more preferred embodiment, the barrier layer comprises a first polymer layer and a second polymer layer on top of it, wherein the first polymer layer is interrupted over at least one longitudinal connector, preferably all longitudinal connectors, and the second polymer layer is also applied to the longitudinal connectors. The first polymer may be a thermoplastic polyurethane, particularly a polycarbonate urethane such as ADIAMat S, or a polyester ether urethane such as Elast-Eon. The second polymer may be polylactic acid (PLA) such as PLLA, polycaprolactone (PCL), or polyhydroxybutyrate (PHB) such as P(4HB).

[0023] Alternatively or additionally, the thickness and porosity of the barrier layer described above may also be adjusted, preferably by the corresponding manufacturing process, so that the degradation period of the implant can be controlled in a targeted manner. In particular, according to a preferred embodiment of the present invention, it is intended to generate a specified porosity of the barrier layer so that the entry of physiological media or the removal of reaction products can be controlled, and so that the reaction kinetics of degradation can be affected accordingly.

[0024] Furthermore, according to a preferred embodiment of the present invention, the barrier layer and / or the polymer of the barrier layer in the implanted state of the implant has a service life in the range of 2 weeks to several years, preferably in the range of 1 month to 1 year, more preferably in the range of 2 to 9 months. The barrier layer and / or the polymer shields the surface area of the body covered by the barrier layer and / or the polymer from external influences before the end of the service life, suppressing almost or completely the biodegradation of the body. After the end of the service life or after the degree of biodegradation suppression becomes less, accelerated biodegradation of the body is provided to be possible.

[0025] In particular, according to a preferred embodiment of the present invention, the barrier layer and / or the polymer of the barrier layer in the implanted state of the implant has a service life adapted to the implant, implant function and implantation site. The barrier layer and / or the polymer shields the surface area of the body covered by the barrier layer and / or the polymer from external influences before the end of the service life, suppressing the biodegradation of the body. It should be noted here that after the end of the service life, biodegradation of the body is made possible.

[0026] According to a particularly preferred embodiment of the present invention, the implant is configured as a vascular support (so-called scaffold).

[0027] In a more preferred embodiment, the implant is formed as one of the following structures: clip, graft, mesh, lattice, plate, prosthesis, screw, catheter, staple, framework structure.

[0028] According to a further embodiment, the implant is configured to be implanted in one of the following implantation sites: uterus, bile duct, heart, lung, pancreas, gastrointestinal tract, urethra, eye, blood vessel, all access routes to the above-mentioned implantation sites.

[0029] According to a preferred embodiment, the polymer of the barrier layer is preferably selected from the class of thermoplastic polyurethanes (TPU) including polycarbonate urethane (PCU), especially modified PCU. For the purposes of the present invention, the modified PCU is a copolymer incorporated with a cleavable cross-linking agent or a degradable component. Suitable cross-linking agents or degradable components that can be incorporated are, for example, PCU-co-polyethylene glycol, polyurethane-co-silicone; fluoropolymers including polyvinylidene fluoride and fluorosilicone, such as copolymers including poly(vinylidene fluoride-co-hexafluoropropylene); polysulfone; thermoplastic elastomers and copolyesters such as polyether ester, polyether block amide; polycarbonate; polyacrylates such as polybutyl methacrylate, polyethyl methacrylate, or polybutylene terephthalate.

[0030] Advantageously, it has been found that such modified PCU has a shortened degradation time.

[0031] According to a particularly preferred embodiment, the polymer of the barrier layer is polycarbonate urethane. In a specific embodiment, the polymer of the barrier layer is PCU-co-polyethylene glycol, and in its polymerization, a degradable reactive monomer such as a special amino acid, peptide or amine is added to the polyol. In such a composition, PCU-co-polyethylene glycol is slightly degradable but retains strong biostability.

[0032] According to a particularly preferred alternative embodiment, the polymer of the barrier layer is a fluoropolymer, especially polyvinylidene fluoride (PVDF, Cas number: 24937-79-9) or poly-(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP, Cas number: 9011-17-0).

[0033] A remarkable advantage is that coatings made of thermoplastic polycarbonate urethane, which belongs to the polyurethane family, were shown to exhibit similarly significantly improved protective functions compared to polyvinylidene fluoride in degradation tests of metal-degradable implant frameworks.

[0034] According to a more preferred embodiment of the present invention, the implant is provided with an uppermost layer applied to the barrier layer.

[0035] Furthermore, according to a preferred embodiment of the present invention, the uppermost layer is provided to carry a pharmacologically active substance and to be configured to release the active substance into the body of a human or animal while the implant is in place.

[0036] According to a preferred embodiment, the top layer contains a pharmacologically active substance in a proportion ranging from 10 to 20% by weight.

[0037] According to a more preferred embodiment of the present invention, the top layer is provided to contain or consist of a substance selected from the group consisting of polyester and poly-L-lactic acid.

[0038] In a preferred alternative embodiment of the present invention, the top layer is provided to be polymer-free. This specifically means that the drug or pharmacologically active substance is applied directly to the barrier layer and is polymer-free. This type of coating is suitable, for example, for highly lipophilic substances. In this case, the barrier layer can reduce or prevent undesirable interactions between the decomposition reaction of the metal-based body of the implant and the drug or drug elution.

[0039] Furthermore, according to a preferred embodiment of the present invention, the combined thickness of the barrier layer and the uppermost layer is 10 μm or less, or the thickness of the individually considered barrier layer is 10 μm or less.

[0040] This ensures that the mechanical properties of the implant or vascular support are not adversely affected, particularly with respect to inductance, rebound and expansion, and crimping ability, and that the dimensions of the struts of the vascular support ("strut thickness") remain within a range where there is no need to worry about adverse effects on clinical outcomes.

[0041] In a particularly preferred embodiment of the present invention, the body contains or is made of a metal alloy, and the main component of the metal alloy is preferably magnesium. The preferred magnesium alloy is particularly preferably three types of alloys. These are alloys from the group consisting of Mg-Al alloys, Mg-Zn-Ca alloys, or alloys containing Y and rare earth elements.

[0042] In the case of Mg-Al alloys, the alloy preferably contains 5 to 10% by weight of Al and <1% by weight of other alloying elements.

[0043] In the case of Mg-Zn-Ca alloys, the alloy preferably contains <1% by weight of Ca and <2% by weight of Zn, as well as <1% by weight of other alloying elements.

[0044] Another preferred alloy is one containing >90 wt% Mg, 0.01 to 5.5 wt% Y, 1.5 to 5.5 wt% rare earth elements, and <1 wt% other elements. Rare earth elements are defined here as elements with atomic numbers 57 to 71. Magnesium alloys having the following compositions are preferred for the present invention: Instead of a metal body, the body may be made of at least one polymer.

[0045] A further aspect of the present invention is a method for producing an implant according to any one of the prior claims, - Steps to provide the main body, and The present invention relates to a method comprising at least the step of applying a polymer solution, obtained by dissolving a polymer, to the surface of a body to form a barrier layer.

[0046] Preferably, the polymer is selected from the group comprising or consisting of polyurethanes, particularly polyurethane-co-silicone and polycarbonate urethane (PCU); fluoropolymers, particularly fluorosilicone; polyesters, particularly polycarbonate, polybutyl methacrylate and polybutylene terephthalate (PBT), polysulfone; and polyether block amides.

[0047] A preferred embodiment of this method provides that the polymer is dissolved in a solvent selected from the group consisting of chloroform (CHCl3), dichloromethane (DCM), tetrachloromethane (CCl4), hexafluoroisopropanol (HFIP), acetone, trifluoroethanol (TFE), dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), isopropanol, hexane, heptane, ethyl acetate, and methyl ethyl ketone.

[0048] According to a more preferred embodiment of this method, the solvent in which the polymer is dissolved is added to a gas stream and transported by the gas stream to the surface of the body so that the solvent collides with the surface. Such a method is also known as the airbrush method. According to a preferred alternative embodiment of this method, the solvent in which the polymer is dissolved is applied to the surface of the body by electrospray. According to a more preferred embodiment of this method, the polymer is applied to the surface of the body by ultrasonic deposition.

[0049] Next, the top layer (see above) can be applied as a barrier layer capable of supporting a pharmacologically active substance. As described above, the top layer may contain a polymer. Alternatively, the top layer may be polymer-free, and in particular, may be formed by or contain the active substance itself.

[0050] With regard to the method according to the present invention, the implant according to the present invention is also referred to. In particular, the method may be configured to provide the features of the implant described above.

[0051] Hereinafter, exemplary embodiments of the present invention, as well as further features and advantages of the present invention, will be described with reference to the drawings. [Brief explanation of the drawing]

[0052] [Figure 1] Figure 1 shows a schematic diagram (A) of an embodiment of an implant according to the present invention, which can be a vascular support in particular for cardiovascular intervention, as a cross-sectional view (B, right) compared with a conventional polymer single coating as an active substance carrier that does not have a barrier effect (B, left), and (C) a cross-sectional view showing a coating having a barrier layer on the main body and an uppermost layer into which a pharmacologically active substance is incorporated. [Figure 2] Figure 2 is a schematic diagram illustrating an example of a possible coating system for an implant (I.) according to the present invention, in which each implant is first coated with a barrier layer (II.) of polymer A, and then with an active material layer (III.) of polymer B, and a wide variety of coating techniques can be used. [Figure 3] Figure 3 shows SEM images of multi-coated scaffolds in the form of double coating after microsection preparation. (A) Cross-sectional view of the struts of the coated scaffold, (B) Enlarged cross-sectional view of the coated scaffold with individual gold sputtering applied to each coating to improve detection of the coating edges in the SEM image, and (C) Enlarged cross-sectional view of the coated scaffold without individual gold sputtering. PVDF stands for PVDF-HFP. [Figure 4] Figure 4 shows the time (in hours) until the first fracture, fragmentation, or collapse of the implant body for various implants A, B, C, D, E, and F. [Modes for carrying out the invention]

[0053] Figure 1 shows an embodiment of the implant according to the present invention, which has a biodegradable body 2 comprising interconnected struts, preferably made of a magnesium alloy as illustrated herein, and illustrated here by a vascular support (also called a vascular scaffold).

[0054] The implant 1 has at least one barrier layer 3 applied to the surface 2a of the main body 2, and an uppermost layer 4 disposed thereon. The uppermost layer 4 may include a polymer and, optionally, a pharmacologically active substance 5 that can be incorporated into the uppermost layer or the polymer of the uppermost layer. In a further embodiment, the uppermost layer 4 may be, for example, a polymer-free active substance layer.

[0055] In a preferred embodiment, the barrier layer 3 is a biostable barrier layer 3 placed on the body 2 of the implant 1 (particularly a vascular scaffold), and an uppermost layer 4 is provided on the barrier layer 3, supporting an active substance, preferably poly-L-lactic acid. The present invention makes it possible to temporarily slow the degradation of the biodegradable body 2, and the degradation period can be controlled by the thickness of the biostable barrier layer, the manufacturing process, and the type of composition. A possible coating in principle is summarized in Figure 2.

[0056] According to a more preferred embodiment of the present invention, the implant 1 comprises a biostable barrier layer 3 and a drug layer applied thereto, optionally, preferably polymer-free. Therefore, the pharmacologically active substance may be applied directly to the barrier layer 3.

[0057] The biostable barrier layer 3 here allows for the slow diffusion of the physiological medium of the body in which the implant 1 is placed, resulting in the very slow absorption or degradation of the metal body 2. After the metal body 2 is completely deformed, the biostable polymer layer 5 remains in the tissue of the implantation site as a biostable mesh-like membrane with no mechanical stability.

[0058] A special feature of the present invention in both basic embodiments is preferably the use of a biostable hydrophobic polymer as a component of the barrier layer, which protects the implant or body with respect to its resistance to internal media, particularly oxidation resistance, and thus delays the degradation of the body. Due to its thin layer thickness, the biostable polymer forms a thin skin after the degradation of the body, which is expected to have a specified service life and not have any harmful effects on the patient.

[0059] Specifications of polymers and monomers In the context of the present invention, all homopolymers, blended polymers, and copolymers of the following classes may be used as biostable polymers for the barrier layer 5. • Polyurethane, e.g., pelletane, polycarbonate urethane, polyurethane co-silicone • Fluoropolymers, e.g., polyvinylene fluoride-co-hexafluoropropylene, fluorosilicones • Polyester, for example, thermoplastic copolyester elastomer (TPC-ET) • Polysulfone • Polyether block amides, e.g., Pebax • Polycarbonate (PC) • Polybutyl methacrylate (PBMA) • Polybutylene terephthalate (PBT)

[0060] Preferred polymers are polycarbonate urethane or fluoropolymers. It has been shown that using preferred polymers is advantageous, particularly in that a long service life can be achieved.

[0061] Pharmaceutical specifications The selection of pharmacologically active substances in the uppermost layer carrying the active substance, as well as their concentration and release kinetics, are based on established local DDS systems in which the drug or active substance is incorporated into the polymer or immobilized on the surface in the broadest sense, and include, in particular, antiproliferative agents such as paclitaxel, limus derivatives, especially sirolimus, everolimus, zotarolimus, biolimus, tacrolimus and their derivatives, mycophenolic acid, angiopeptin, enoxaprine, hirudin, acetylsalicylic acid, dexamethasone, rifampicin, minocycline, budesonide, desonide, corticosterone, cortisone, hydrocortisone, prednisolone, heparin, heparin derivatives, urokinase, and PPACK.

[0062] Implant selection specifications In principle, biodegradable implants can be used in the sense of the present invention. These can be used not only in the vascular field but also in the orthopedic field. According to a preferred embodiment, the implant is a vascular support, and the body provides a corresponding scaffold structure. However, the present invention, in principle, favors implants where control of biodegradation or protection from internal media is advantageous, i.e., preferably, - Preferably made of Mg alloy, a biodegradable metal material for implants, such as bone screws, Kirschner wires, and vascular scaffolds, and - Polymer-based bioabsorbable implants or vascular scaffolds, -Scaffolds for use in hollow organs or tubular cavities of the human or animal body, such as the intestines, bile ducts, trachea or esophagus, pancreas, ureters or urethra, or paranasal sinuses, wherein the scaffolds perform a support function and / or are used for the application of drugs. It can be applied to this.

[0063] Figure 2 shows examples of possible and preferred implants 1, particularly vascular supports (scaffolds), grafts, meshes, grids, plates, prostheses, screws, catheters, and clips.

[0064] Specifications of coating technology The compatibility of the coating structure and the associated control of the disintegration of disassemblable implants can be achieved by using the following different coating technologies.

[0065] According to one embodiment, the polymer layer produced by electrospray enables the creation of a predetermined surface structure and thus provides the possibility of decomposition control by a three-dimensional system.

[0066] According to an alternative embodiment, a uniform micrometer-thick polymer layer / barrier layer 3 is generated by spraying it onto the polymer (spray coating), and the thickness of the layer allows for control over degradation.

[0067] In a more preferred embodiment, the barrier layer 3 is applied by ultrasonic atomization or vapor deposition, which has the advantage of forming very small droplets of the coating medium, producing a coating with a very thin layer thickness that allows wetting of surfaces with complex structures. This coating method is also suitable for aqueous solutions.

[0068] Specific examples of the present invention are described below.

[0069] Exemplary Embodiment 1 To delay the biodegradation of the biodegradable vascular scaffold 1, a biocompatible polymer with biostability, such as PVDF-HFP, is applied to a metal body 2 made of a high-purity magnesium alloy containing 6.5 wt% Al and free of other alloying elements. Depending on the thickness of the applied coating, a completely or partially opaque porous coating can be produced. In this example, the polymer coating has a layer thickness of 5 ± 3 μm and is applied to the entire surface 2a of the body 2 of the vascular scaffold 1 using an airbrush method. For this purpose, PVDF-HFP is dissolved in a solvent (mixture), such as acetone, at a ratio of 0.2 to 1.0 mass%. After the spraying process, the carrier material is incubated under vacuum at approximately 80°C for 10 to 15 hours to completely remove the solvent. Here, the body surface 2a has a continuous hydrophobic coating that prevents the body 2 from coming into contact with the internal media (see, for example, Figure 3). After the introduction of an active substance depot to prevent restenosis by the antiproliferative effect of the drug, a coating carrying the active substance of PLLA is applied to the implant 1 having a barrier layer 3. The components are dissolved in chloroform and sprayed onto the PVDF-HFP protective layer using a spray method. The construct is incubated again at approximately 80°C for 10-15 hours. This is followed by the prescribed ETO sterilization of implant 1. As part of coronary stent placement, the multi-coated vascular scaffold 1 is placed into the stenotic vessel using standard surgical techniques. After expansion of scaffold 1, it remains in the vessel and is embedded in the vascular endothelium. The radial force of the prototype model rapidly decreases due to degradation over 60 days, but the PVDF-HFP coating protects the metal scaffold 1 from corrosive media, thus ensuring that the radial force is maintained for a longer period. After a prescribed residence time, both scaffold 1 and the biodegradable topcoat 4 (PLLA) carrying the active material degrade.

[0070] Figure 3 shows SEM images of the multi-coated scaffold body 2 in the form of double coating after the preparation of microscopic microsections. (A) Cross-sectional view of the struts of the coated body 2, (B) Enlarged cross-sectional view of the coated body 2 with individual gold sputtering applied to each coating to improve detection of the coating edges in the SEM image, and (C) Enlarged cross-sectional view of the coated body 2 without individual gold sputtering. PVDF stands for PVDF-HFP.

[0071] Exemplary Embodiment 2: The biodegradable body 2 of the vascular scaffold 1, made from a high-purity magnesium alloy with the following composition: Mg-approximately 4 wt% Y-approximately 2 wt% Nd-approximately 0.5 wt% Gd-approximately 0.5 wt% Dy-approximately 0.5 wt% Zr, and <1% of other elements, is coated with a biostable PCU coating, and the top layer 4 of paclitaxel is applied to the PCU layer. The polycarbonate urethane (PCU) is ADIAMat S from ADIAM Life Science AG in Germany.

[0072] Exemplary Embodiment 3: A biodegradable vascular scaffold body 2 is made of a high-purity magnesium alloy containing 2.0 wt% Zn and 0.4% Ca, consisting of ring-shaped segments connected by longitudinal connectors. Body 2 is coated with a biostable barrier layer 3 made of PVDF-HFP. The biostable barrier layer 3 made of PVDF-HFP is interrupted at the longitudinal connectors. As a result, these areas decompose more rapidly, and the body loses its longitudinal integrity relatively quickly immediately after the healing phase, thus no longer exerting any bending stress on the blood vessel, but the radial support effect of the individual segments is maintained for a much longer period, and therefore the vascular lumen is supported for a much longer period.

[0073] Exemplary Embodiment 4: In this example, a biodegradable vascular clip made of magnesium alloy is used to temporarily close a blood vessel. The clip is attached to the blood vessel to be closed using a clip applicator. The clip body has a polyurethane barrier layer, to which a layer of PLLA-PCL blend, which elutes anti-inflammatory active substances, is applied.

[0074] Exemplary Embodiment 5: In this exemplary embodiment, the biodegradable body 2 of the scaffold 1 is made of a magnesium alloy used for bile ducts. The biodegradable scaffold 1 may be used to reconstruct the lumen of a bile duct, for example, when it may be compressed by a tumor in the surrounding tissue and bile may no longer be able to flow out. Due to the low pH value of bile, it is particularly important to protect the magnesium matrix 2 from degrading too rapidly. For this purpose, a thin layer of PCU or PVDF-HFP of about 1-4 μm is applied to the body 2 of the scaffold 1 as a barrier layer 3 using a spray method. In a second step, an upper layer 4 of a second polymer (e.g., PLLA, PCL, or a blend or copolymer thereof, or PLGA) may then be applied to the barrier layer 3, and a cell division inhibitory substance that can slow tumor growth is eluted from the upper layer 4. Such a scaffold 1 can also be used for malignant strictures of the urinary tract after adjustment of its diameter.

[0075] Exemplary Embodiment 6: In this exemplary embodiment, a biodegradable body of a scaffold made of magnesium alloy is used for blood vessels or other hollow organs, and two polymers having different degrees of influence on the decomposition slowing of the magnesium alloy are applied to the body of the scaffold in a specific geometric shape to specifically control the support properties of the design over time. For example, a PCU coating results in a very large extension of support duration, while, for example, a PLLA, PCL, or PHB coating results in a significantly shorter extension of support duration.

[0076] If the initially applied PCU coating is intentionally interrupted, for example, on the longitudinal connector of the design, the PLLA, PCL, or P4HB coating on top will almost completely decompose, and the decomposition process will begin after the longitudinal connector is destroyed, while the rest of the body will still be largely protected by the PCU coating. In this case, the radial support effect is still maintained, but the destruction associated with the decomposition of the longitudinal connector means that longitudinal force transmission of the scaffold is no longer possible. This may be necessary, for example, when longitudinal force is not transmitted within the blood vessel or hollow organ into which the scaffold is implanted. At the same time, such a principle promotes a more rapid decomposition or absorption of the scaffold body compared to continuous coating.

[0077] For example, the applied top layer 4, which may be a PLLA, PCL, or P4HB coating, can further elute the pharmacologically active substances described above, such as the limus group active substances / drugs in the case of a vascular scaffold.

[0078] Figure 4 shows the time (in hours) to the first fracture, first fragmentation, or collapse of the implant body for different coating systems A, B, C, D, E, and F, illustrating the advantageous technical effects achieved by the present invention.

[0079] The coating systems tested are as follows: A: A reference system using a commercially available PLLA-SIR coating (poly-L-lactic acid containing sirolimus as a pharmacologically active substance) on a body made of a magnesium alloy containing 6.0-7.0% by weight of Al. B: Reference system II, consisting of a body made of a magnesium alloy containing 6.0-7.0% by weight of Al, and a PLLA-SIR coating applied thereto. A mixing system comprising a body made of a magnesium alloy containing 6.0-7.0% by weight of Al, and a coating applied thereto containing poly-L-lactic acid (PLLA), PCL, and sirolimus (SIR). Test system I, comprising a main body made of a magnesium alloy containing 6.0-7.0% by weight of Al, a barrier layer (PVDF-HFP) applied thereto, and an uppermost layer applied to the barrier layer containing poly-L-lactic acid (PLLA) with sirolimus (SIR) as a pharmacologically active substance. Test system II, comprising a main body made of a magnesium alloy containing 6.0-7.0% by weight of Al, a barrier layer (PCU) applied thereto, and an uppermost layer applied to the barrier layer containing poly-L-lactic acid (PLLA) with sirolimus (SIR) as a pharmacologically active substance. F: Reference system II using a magnesium alloy as the main body and coatings of PLLA and rapamycin (sirolimus) applied thereto.

[0080] Implant / coating systems D and E clearly showed a preferredly increased time until the first fracture / fragmentation / collapse. Since neither implant D (test system I) showed damage, the test was terminated after 650 hours.

[0081] Therefore, the test results demonstrate the effectiveness of the biostable barrier layer on the Mg alloy scaffold body. In particular, and surprisingly, it was shown that controlling the degradation of the bioabsorbable scaffold is only possible with very specific polymers. Polycarbonate urethane (e.g., ADIAMat S) and fluoropolymers (PVDF, PVDF-HFP) are particularly suitable for this purpose.

[0082] Which implant and combination of coatings is particularly promising naturally depends on the corresponding bodily medium or implantation site (pH value). Other possible applications within the scope of the present invention include not only scaffolds with a Mg body, but also bioabsorbable bone screws / fibers, wires for fixing fractures (Crawing wires, Kirschner wires), screws made of magnesium alloy for fixing ligaments, for example in cruciate ligament surgery, as well as implantable Mg-based hernia meshes (for example in the case of intra-abdominal hernias), and all conceivable implants intended to be absorbed only after months / years rather than just weeks.

[0083] By introducing biostable polymers, particularly as a barrier layer beneath a bioabsorbable top layer carrying active materials for vascular scaffolds, or as a barrier layer with an optional polymer-free active material layer, it becomes possible to protect implants from corrosive media for longer periods. Degradation of the scaffold or implant can be controlled in a targeted manner by the thickness and composition of the barrier layer, and the porosity is determined by the manufacturing technique used. Compared to conventional techniques, this offers the advantage of being able to maintain the radial force of the metal vascular scaffold for a longer period.

[0084] Furthermore, the biostable polymer acts as a barrier between PLLA and the main body of the vascular scaffold, for example, magnesium, thereby extending the degradation time of the top layer supporting the active substance, such as poly-L-lactic acid, and thus ensuring the specified pharmacokinetics.

[0085] The biostable polymer of the barrier layer has only insufficient performance as a permanent stent graft in terms of deployment force, deployment pressure, radial force, strut thickness, rebound, and flexibility, but it has increased resistance to pH stress or oxidation. For this reason, its use as a coating on vascular scaffolds / implants, preferably metal ones, that should be protected from internal media, is particularly advantageous and useful. The barrier layer exists here in particular as a thin film coating, and its thickness is preferably minimal relative to the strut thickness of the scaffold body. The barrier layer remaining after the decomposition of the body does not cause mechanical irritation due to its flexibility. In the case of a decomposable scaffold structure, it remains in the tissue of the vascular / implantation site as a biostable mesh-like membrane.

[0086] In summary, the advantages of using a biostable barrier layer along with a polymer-based or polymer-free active material layer on a metal implant or scaffold are as follows: 1. Protection of biodegradable implants from internal media, 2. Reduction of the release of potential allergens or metal ions, and thus avoidance of associated adverse systemic effects, and 3. Protective effect of the barrier layer on the top layer carrying the active substance against the destructive effects of implant degradation products (e.g., to maintain the implant's setting or established release profile).

[0087] References

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Claims

1. An implant (1), An implant (1) comprising a biodegradable metal body (2) having a surface (2a), and a barrier layer (3) disposed on the surface (2a) of the body (2) and containing a polymer, wherein the barrier layer (3) is configured to delay the biodegradation of the body (2), and the polymer is selected from the group consisting of polyurethane, particularly polyurethane-co-silicone and polycarbonate urethane (PCU); fluoropolymer, particularly fluorosilicone; polyester, particularly polycarbonate, polybutyl methacrylate and polybutylene terephthalate (PBT), polysulfone; and polyether block amide.

2. The implant according to claim 1, wherein the barrier layer (3) partially covers the surface (2a) of the main body (2) and / or is porous having a pore diameter greater than 0.3 nm.

3. The implant according to claim 1 or 2, wherein the polymer is a biostable polymer.

4. The implant according to claim 1 or 2, wherein the barrier layer (3) and / or the polymer in the implanted state of the implant (1) has a service life ranging from two weeks to several years, and before the end of the service life, the barrier layer (3) and / or the polymer shields the area of ​​the surface (2a) of the main body (2) covered with the barrier layer (3) and / or the polymer from external influences and prevents biodegradation of the main body.

5. The implant according to any one of claims 1 to 4, wherein the polycarbonate urethane is in the form of a chemically modified copolymer incorporating a cleavable crosslinking agent or a biodegradable component.

6. The implant according to claim 5, wherein the crosslinking agent or biodegradable component is selected from the group consisting of PCU-co-polyethylene glycol, polyurethane-co-silicone; fluoropolymers such as polyvinylidene fluoride and fluorosilicone, particularly including copolymers such as poly(vinylidene fluoride-co-hexafluoropropylene); polysulfone; thermoplastic elastomers and copolyesters such as polyether esters and polyether block amides; polycarbonate; polyacrylates such as polybutyl methacrylate and polyethyl methacrylate; or polybutylene terephthalate.

7. The implant according to any one of claims 1 to 6, wherein the polymer is PCU-co-polyethylene glycol, and in its polymerization, a degradable reactive monomer is added to the polyol.

8. The implant according to any one of claims 1 to 7, wherein the implant (1) has an uppermost layer (4) applied to the barrier layer (3).

9. The implant according to claim 8, wherein the uppermost layer (4) carries a pharmacologically active substance (5) and is configured to release the active substance into the body of a human or animal while the implant is in place.

10. The implant according to claim 8 or 9, wherein the uppermost layer (4) contains or consists of a substance, the substance being selected from the group consisting of polyester and poly-L-lactic acid, or the uppermost layer is polymer-free.

11. The implant according to any one of claims 1 to 10, wherein the combined thickness of the barrier layer (3) and the uppermost layer (4) is 10 μm or less, or the thickness of the barrier layer (3) is 10 μm or less.

12. The implant according to any one of claims 1 to 11, wherein the main body (2) contains or is made of a metal alloy, and the main component of the metal alloy is magnesium.

13. A method for producing an implant according to any one of claims 1 to 12, - The step of providing the main body (2), A method comprising the steps of: applying a polymer solution obtained by dissolving a polymer to the surface (2a) of the main body (2) to form a barrier layer (3), wherein the polymer is selected from the group including or comprising polyurethane, particularly polyurethane-co-silicone and polycarbonate urethane (PCU); fluoropolymer, particularly fluorosilicone; polyester, particularly polycarbonate, polybutyl methacrylate and polybutylene terephthalate (PBT), polysulfone; and polyether block amide.

14. The polymer is chloroform (CHCl ３ ), dichloromethane (DCM), tetrachloromethane (CCl ４ The method according to claim 13, wherein the solvent is selected from the group consisting of ), hexafluoroisopropanol (HFIP), acetone, trifluoroethanol (TFE), dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), isopropanol, hexane, heptane, ethyl acetate, and methyl ethyl ketone.

15. The method according to claim 13 or 14, wherein the uppermost layer (4) is applied to the barrier layer (3).

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