WO2024240434A1

WO2024240434A1 - Scaffold multi-coating

Info

Publication number: WO2024240434A1
Application number: PCT/EP2024/061160
Authority: WO
Inventors: Dana DOHR; Heinz Müller; Dalibor Bajer; Stefan OSCHATZ; Michael Teske; Niels Grabow; Sabine Illner
Original assignee: Cortronik GmbH
Priority date: 2023-05-22
Filing date: 2024-04-24
Publication date: 2024-11-28

Abstract

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

Description

Scaffold multi-coating

The invention relates to an implant and to a method for producing such an implant.

The development of biodegradable metal- and/or polymer-based frameworks, which are often referred to as scaffolds, represents an important step in the further development of implant technology with regard to the reduction of late effects that generally occur with the use of permanent implants. Nevertheless, the degradation of resorbable implants such as frameworks in the form of vascular frameworks or vascular scaffolds is too rapid and uncontrolled, meaning that their vascular-supporting properties may be lost too early.

Biodegradable implants, in particular frameworks/scaffolds, have increasingly become the focus of scientific attention in recent years. Relevant developments have been made in the field of cardiovascular diseases, for example. One of the most important cardiovascular diseases is atherosclerosis of the coronary vessels. This is characterised by a narrowing of the lumen of the mostly large, outer coronary vessels (coronary sclerosis) [1] and extends to chronic total occlusion. Cardiac ischaemia, which may lead to myocardial infarction, is the result. Depending on the number and size of the affected vessels, percutaneous transluminal coronary angioplasty (PTCA) is performed in addition to drug therapy, depending on the patient's symptoms, according to current guidelines. This may involve either dilating the stenosis using a balloon catheter or implanting a vascular support, a so-called coronary stent [2], In the course of coronary stent implantation, a tubular or lattice-like metal framework (vascular support) is inserted into the stenotic vessel, placed against the vessel wall and usually remains there permanently, as the materials used are usually biostable (e.g. CoCr and NiTi alloys). Bioresorbable vascular supports (scaffolds) have been developed to reduce the long-term consequences that may result from a permanent implant. These scaffolds consist, for example, of bioresorbable metals [3] or polymers, which are usually coated with a biodegradable, active-substance-carrying polymer. The late effects of a permanent implant may be minimised with degradable scaffolds, but their biocorrosion or resorption is often too rapid and uncontrolled, meaning that the supportive properties of the scaffolds may be lost too early. This is just one example of the use of degradable implants and the associated challenges.

Over time, many different polymer classes have become established in biomaterial and implant technology. Biostable, hydrophobic polymers are used in a wide range of clinical applications: thermoplastic polyurethanes (TPU), for example, are used in synthetic heart valves and catheter tubes due to their haemocompatibility 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 the class of bioresorbable polymers, such as polylactides, in particular poly-L-lactic acid (PLLA) [7], Poly-L-lactic acid is suitable as an active substance depot, but is degraded more quickly by the degradation of biocorrosive metal -based implants [7], The literature describes that the biostable, hydrophobic fluoropolymers such as polyvinylidene fluoride may be used as corrosion protection for metal implants [8,9] or are already used as an active-substance-releasing layer on permanent, commercially available stent systems.

The strategies of vascular scaffolds available to date are aimed at adapting the metal alloy components, which leads to slower degradation of the scaffold. In addition, efforts are being made to reduce the strut thickness, which, against the background of haemodynamics, leads to a lower risk of thrombosis. An adjustment of the alloy components with simultaneous reduction of the strut thickness may only be realised inadequately due to the mechanical properties of the underlying metals. The use of a biostable barrier layer would enable a delay in degradation with a simultaneous reduction in the strut thickness of the vascular scaffold.

Based on this, the invention addresses the problem of extending the service life of a degradable implant. In particular, it should be possible to simultaneously release an active substance by means of the implant. This problem is solved by an implant having the features of claim 1 and by a method having the features of claim 14.

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

According to claim 1, an implant is disclosed, comprising: a metal, biodegradable main body with a surface, a barrier layer applied to the surface of the main body and comprising a polymer, wherein the barrier layer, in particular the polymer, is configured to delay biodegradation of the main body.

According to a preferred embodiment, the barrier layer consists of the polymer.

Furthermore, according to a preferred embodiment of the invention, it is provided that the polymer is a biostable polymer. For the purposes of the present invention, biostable is intended to mean robust against hydrolytic and/or oxidative degradation or physical degradation processes in the physiological environment of the human organism.

The barrier layer is therefore preferably configured to assume a barrier function between the main body and the surrounding medium in the implantation area or a further layer arranged on the barrier layer, in the long term or permanently, wherein the further layer (in particular top layer) may carry a pharmacologically active substance and may be configured, for example, as a bioresorbable polymer layer. The barrier layer preferably protects the additional layer and delays the biodegradation of the main body and thus a premature loss of function of the implant.

A thin film coating of a preferably biostable polymer according to the invention serves to protect the main body, in particular of a vascular support or a scaffold, from biocorrosion or bioresorption and thus to enable a time-delayed, controlled degradation. The aim is to harmonise the degradation time with the required support time. A multi-coating may be produced in the same way as drug-coated stent systems, so-called drug eluting stents (DES), by combining the thin film coating described above with a coating containing the active substance. However, it may also function purely as a passivation layer in the event that a drug is applied to the surface without a polymer.

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

The present invention makes it possible to delay the degradation of vascular supports or scaffolds, for example, in such a way that a sufficiently long supporting effect is achieved in the stenotic vessel. A biostable polymer is preferably used for this purpose, which serves as a barrier layer between the vascular support and the intracorporeal media. The barrier layer makes it possible to delay the diffusion of the ambient medium to the surface of the main body of the vascular support, to mitigate the removal of corrosion products from the implant and thus to influence the speed of the corrosion reaction. This has the advantage of slowing down the biodegradation and corrosion of vascular supports.

Delayed and controllable implant degradation may help to maintain the desired mechanical properties of a degradable implant, in particular a vascular support, for longer and thus prevent restenosis of the affected vessel, among other things. A further advantage of metalbased vascular supports is the formation of passivating metal oxide/hydroxide films (corrosion products), which have low reactivity with the surrounding environment, thus reducing the risk of negative systemic reactions to temporarily formed intermediates.

In addition, according to one embodiment, the thin-film coating made of the preferably biostable polymer acts as a barrier between the vascular support or main body and an active substance depot made of a polyester, in particular poly-L-lactic acid (PLLA), for example to slow down the demonstrably accelerated degradation of the PLLA [7], Furthermore, according to a preferred embodiment of the barrier layer, the surface of the main body is only partially covered and/or porous. Porosities with a pore size greater than 0.3 nm are preferred. Furthermore, it is preferred that the pore sizes are in the range of 0.3 to 500 nm.

A further possibility of controlled degradation is therefore that one part of the implant is provided with a biostable layer and another part is not; in this case, the uncoated part of the implant or main body will degrade comparatively quickly, while the coated part retains its structural integrity over a comparatively much longer period of time. This may be useful, for example, if a gradual loss of mechanical stability of the degradable implant is desired.

According to a preferred embodiment, the main body has segments, preferably ring-shaped segments, which are connected to each other via longitudinal connectors.

According to a preferred embodiment, at least one of the longitudinal connectors, preferably all of the longitudinal connectors, is not covered with the barrier layer. In other words, the barrier layer is interrupted at the longitudinal connectors. As a result, these areas degrade more quickly and the main body preferably loses its longitudinal integrity relatively early, immediately after the healing phase, and then no longer exerts any bending stresses on the vessel, while the radial support effect of the individual segments is maintained for much longer and the vessel lumen is thus supported for much longer.

According to a further preferred embodiment, it is provided that the barrier layer comprises a layer of a first polymer and an overlying layer of a second polymer, wherein the layer of the first polymer is interrupted on at least one longitudinal connector, preferably on all longitudinal connectors, while the layer of the second polymer is also applied to the longitudinal connectors. The first polymer may be a thermoplastic polyurethane, in particular 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 polyhydroxy butyrate (PHB) such as P(4HB). Altematively - or in addition - the layer thickness and porosity of the above-mentioned barrier layers may also preferably be adjusted by a corresponding manufacturing process and thus the degradation period of the implant may be controlled in a targeted way. In particular, according to a preferred embodiment of the invention, it is intended to produce a defined porosity of the barrier layer so that the entry of the physiological medium or the removal of reaction products may be controlled and thus the degradation kinetics may be influenced accordingly.

Furthermore, according to a preferred embodiment of the invention, it is provided that 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 from 2 weeks to years, preferably in the range from 1 month to 1 year, further preferably in the range of 2 - 9 months, wherein the barrier layer and/or the polymer shields an area of the surface of the main body covered by the barrier layer and/or the polymer from external influences before the end of the service life and largely or completely counteracts the biodegradation of the main body, and wherein accelerated biodegradation of the main body is possible after the end of the service life or the biodegradation is counteracted to a lesser extent.

In particular, it should be noted here that, according to a preferred embodiment of the invention, it is provided that the barrier layer and/or the polymer of the barrier layer in the implanted state of the implant has a service life which is adapted to the implant, the implant function and the implantation site, wherein the barrier layer and/or the polymer shields an area of the surface of the main body covered by the barrier layer and/or the polymer from external influences before the end of the service life and counteracts the biodegradation of the main body, and enables the biodegradation of the main body after the end of the service life.

According to a particularly preferred embodiment of the invention, the implant is configured as a vascular support (so-called scaffold). In further preferred embodiments, the implant is formed as one of the following structures: a clip, a graft, a mesh, a lattice, a plate, a prosthesis, a screw, a catheter, a staple, a framework structure.

According to a further embodiment, the implant is configured for implantation at one of the following implantation sites: uterus, bile duct, heart, lung, pancreas, gastrointestinal tract, urethra, eye, a vessel, all access routes to the aforementioned implantation sites.

According to a preferred embodiment, the polymer of the barrier layer is preferably selected from the class of thermoplastic polyurethanes (TPU) including polycarbonate urethanes (PCU), in particular modified PCU. For the purposes of the present invention, modified PCUs are copolymers in which cleavable crosslinkers or degradable components are incorporated. Suitable crosslinkers or degradable components that may be incorporated are, for example, PCU-co-polyethylene glycols, polyurethane-co-silicones; fluoropolymers such as polyvinylidene fluoride, including copolymers such as, among others poly(vinylidene fluoride-co-hexafluoropropylene) and fluorosilicones; polysulfones; thermoplastic elastomers and copolyesters such as polyether esters, polyether block amides; polycarbonates; polyacrylates such as polybutyl methacrylate, polyethyl methacrylate or polybutylene terephthalates.

Advantageously, it was found that such modified PCUs have a reduced degradation time.

According to a particularly preferred embodiment, the polymer of the barrier layer is a polycarbonate urethane. In a particular embodiment, the polymer of the barrier layer is PCU- co-polyethylene glycol, in the polymerisation of which degradable reactive monomers such as special amino acids, peptides or amines have been added to the polyols. In such a composition, the PCU-co-polyethylene glycols are slightly degradable but retain strong biostability.

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

It has been shown with surprising advantage that a coating made of the thermoplastic polycarbonate urethane, which belongs to the polyurethanes, shows a similar and enormously improved protective function as compared to the polyvinylidene fluorides in degradation tests of a metal degradable implant framework.

According to a further preferred embodiment of the invention, the implant is provided with a top layer applied to the barrier layer.

Furthermore, according to a preferred embodiment of the invention, it is provided that the top layer carries a pharmacologically active substance and is configured to release the active substance to a human or animal body in the implanted state of the implant.

According to a preferred embodiment, the top layer comprises the pharmacologically active substance in a proportion in the range of 10-20 wt.%.

According to a further preferred embodiment of the invention, it is provided that the top layer comprises or consists of a substance, wherein the substance is selected from the group consisting of: polyester, poly-L-lactic acid.

In a preferred alternative embodiment of the invention, it is provided that the top layer is polymer-free. This means in particular that a medicament or a pharmacologically active substance is applied directly and polymer-free to the barrier layer. This type of coating is suitable for highly lipophilic substances, for example. In this case, the barrier layer may reduce or prevent undesirable interactions of the degradation reaction of the metal-based main body of the implant with the drug or the drug elution.

Furthermore, according to a preferred embodiment of the invention, it is provided that a layer thickness of the barrier layer and the top layer taken together is less than or equal to 10 pm, or wherein a layer thickness of the barrier layer - considered individually - is less than or equal to 10 pm.

This ensures in particular that the mechanical properties of the implant or the vascular support, in particular with regard to guidability, recoil and dilatation and crimping capacity, are not negatively influenced and that the dimensions of the struts of the vascular support ("strut thickness") remain within a range in which no negative effects on the clinical results need to be feared.

According to a particularly preferred embodiment of the invention, it is provided that the main body comprises a metal alloy or consists of the metal alloy, wherein the main component of the metal alloy is preferably magnesium. The preferred magnesium alloys are particularly preferably 3 types of alloys; these are alloys from the group of Mg- Al alloys, Mg-Zn-Ca alloys or alloys containing Y and rare earths.

In the case of Mg- Al alloys, the alloy preferably contains between 5 and 10 wt.% Al and < 1 wt.% other alloying elements.

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

Another preferred alloy is an alloy containing > 90 wt.% Mg, 0.01 - 5.5 wt.% Y, 1.5 - 5.5 wt.% rare earths and < 1 wt.% other elements. Rare earths are defined here as elements with atomic numbers 57 - 71. Magnesium alloys with the following compositions are preferred for the present invention:

Instead of the metal main body, the main body may also be made of at least one polymer.

A further aspect of the present invention relates to a method for producing an implant according to any one of the preceding claims, wherein the method comprises at least the steps of: providing the main body, and applying a polymer solution, in which the polymer is dissolved, to the surface of the main body to form the barrier layer.

Preferably, the polymer is selected from the group comprising or consisting of: polyurethanes, in particular polyurethane co-silicones and polycarbonate urethanes (PCU); fluoropolymers, in particular fluorosilicones; polyesters, in particular polycarbonates, polybutyl methacrylate and polybutylene terephthalate (PBT), polysulfones; polyether block amides.

According to a preferred embodiment of the method, it is provided that the polymer is dissolved in a solvent selected from the group consisting of: chloroform (CHCh), dichloromethane (DCM), tetrachloromethane (CCh), hexafluoroisopropanol (HFIP), acetone, trifluoroethanol (TFE), dimethyl-formamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), isopropanol, hexane, heptane, ethyl acetate, methyl ethyl ketone.

According to a further preferred embodiment of the method, the solvent with the polymer dissolved therein is added to a gas stream and transported to the surface of the main body by means of the gas stream so that the solvent impinges on the surface. Such a method is also known as an airbrush method. According to a preferred alternative embodiment of the method, the solvent with the polymer dissolved therein is applied to the surface of the main body by electrospraying. According to a further preferred embodiment of the method, the polymer is applied to the surface of the main body by means of ultrasonic vapour deposition.

Said top layer (see above) may then be applied to the barrier layer, which may carry the pharmacologically active substance. As explained above, the top layer may comprise a polymer. Alternatively, the top layer may be polymer-free and may in particular be formed by or may comprise said active substance itself.

With regard to the method according to the invention, reference is also made to the implant according to the invention. In particular, the method may be configured such that the features of the implant described above are provided.

In the following, exemplary embodiments of the invention as well as further features and advantages of the invention will be explained with reference to the figures, in which: Fig. 1 shows a schematic representation of an embodiment of an implant according to the invention, which may in particular be a vascular support for cardiovascular intervention (A), as a sectional view (B, right) in comparison with a conventional polymer monocoating as an active substance carrier without a barrier effect (B, left) and (C) as a sectional view showing the coating, having a barrier layer on a main body and a top layer with an incorporated pharmacologically active substance,

Fig. 2 shows an overview of examples of possible coating systems of an implant according to the invention (I.), wherein the respective implant is first coated with a barrier layer (II.) of a polymer A and then with an active substance layer (III.) of polymer B, wherein a wide variety of coating techniques may be used,

Fig. 3 shows SEM images of a scaffold multi-coating in the form of a dual coating after microsection preparation. (A) Strut of a coated scaffold in cross-section, (B) close-up of a coated scaffold in cross-section with individual gold sputtering of each coating for improved detection of the coating edges in SEM images and (C) close-up of a coated scaffold in cross-section without individual gold sputtering. PVDF stands for PVDF-HFP, and

Fig. 4 shows the time to the first fracture or fragment formation or collapse of the main body of the implant in hours for various implants A, B, C, D, E, F.

Fig. 1 shows an embodiment of an implant according to the invention, here exemplified by a vascular support (also referred to as a vascular scaffold), which has a biodegradable main body 2 consisting of interconnected struts, which is preferably made of a magnesium alloy as described herein.

The implant 1 has at least one barrier layer 3 applied to the surface 2a of the main body 2 and a top layer 4 arranged thereon. The top layer 4 may comprise a polymer and optionally a pharmacologically active substance 5, which may be incorporated into the top layer or the polymer of the top layer. In a further embodiment, the top layer 4 may be, for example, a polymer-free active substance layer.

According to a preferred embodiment, the barrier layer 3 is a biostable barrier layer 3 which rests on the main body 2 of the implant 1 (in particular vascular scaffold), wherein an active substance-carrying top layer 4, preferably consisting of poly-L-lactic acid, is provided which rests on the barrier layer 3. The invention makes it possible to temporarily delay the degradation of a biodegradable main body 2, wherein the degradation period may be controlled via the layer thickness, the manufacturing process and the type of composition of the biostable barrier layer. Possible coatings are summarised in principle to give an overview in Fig. 2.

According to a further preferred embodiment of the invention, the implant 1 has a biostable barrier layer 3 and optionally a drug layer applied thereto, which is preferably polymer-free. In particular, the pharmacologically active substance may therefore be applied directly to the barrier layer 3.

The biostable barrier layer 3 allows a slow diffusion here of the physiological medium of the body into which the implant 1 is implanted, so that a very slow resorption or degradation of the metal main body 2 may take place. After complete transformation of the metal main body 2, the layer 5 of the biostable polymer remains as a biostable, mesh-like membrane without mechanical stability in the tissue at the implantation site.

The special feature of the invention in both basic embodiments of the invention is preferably the use of a biostable, hydrophobic polymer as a component of a barrier layer, which protects the implant or the main body in view of its resistance, in particular oxidation resistance, to intracorporeal media and thus delays the degradation of the main body. Due to the low layer thickness, the biostable polymer forms a thin skin after degradation of the main body, which is expected to have a defined service life and no harmful effects for the patient.

Specification of polymers and monomers In the context of the present invention, all homopolymers, blend polymers and copolymers of the following classes may be used as biostable polymers of the barrier layer 5:

• polyurethanes, e.g. pellethanes, polycarbonate urethanes, polyurethane co-silicones

• fluoropolymers, e.g. polyvinylene fluoride-co-hexafluoropropylene, fluorosilicones

• polyesters, e.g. thermoplastic copolyester elastomers (TPC-ET)

• polysulfones

• polyether block amides, e.g. Pebax

• polycarbonates (PC)

• polybutyl methacrylate (PBMA)

• polybutylene terephthalate (PBT)

Preferred polymers are polycarbonate urethane or fluoropolymer. It has been shown to be advantageous that particularly long service lives may be achieved when using the preferred polymers.

Specification of the pharmaceutical

The selection of the pharmacologically active substance in the active-substance-carrying top layer as well as its concentration and release kinetics is based on already established local DDS systems in which a drug or an active substance is incorporated into the polymer in the broadest sense or anchored to the surface and includes, among other things, active substances or drugs with an antiproliferative effect, active substances or drugs with an antiinflammatory effect, active substances or drugs with an anti- thrombotic effect, in particular paclitaxel, antiproliferative agents such as limus derivatives, in particular sirolimus, everolimus, zotarolimus, biolimus, tacrolimus and derivatives thereof, mycophenolic acid, angiopeptin, enoxaprine, hirudin, acetylsalicylic acid, dexamethasone, rifampicin, minocycline, budesonide, desonide, corticosterone, cortisone, hydrocortisone, prednisolone, heparin, heparin derivatives, urokinase, PPACK.

Specification of the implant selection

In principle, degradable implants may be used in the sense of the present invention. These may be used in the vascular field, but also in the orthopaedic field. According to a preferred embodiment, the implant is a vascular support, wherein the main body provides a corresponding scaffold structure. However, the invention may in principle be applied to implants in which the control of biodegradation or protection from intracorporeal media is advantageous, namely preferably:

- metal, biodegradable materials as implant, e.g. as bone screws, Kirschner wires, vascular scaffolds, preferably made of Mg alloys, and

- polymer-based, bioresorbable implants or vascular scaffolds.

- Scaffolds for use in hollow organs or tubular cavities of the human or animal body, such as the intestine, bile duct, trachea or oesophagus, pancreas, ureter or urethra or sinuses, wherein the scaffold performs a supporting function and/or is used for the application of a drug.

Fig. 2 gives examples of possible preferred implants 1, in particular vascular supports (scaffolds), grafts, meshes, lattices, plates, prostheses, screws, catheters, clips.

Specification of the coating technology

An adaptation of the coating structure and the associated control of the degradation of a degradable implant may be achieved by using different coating techniques:

According to one embodiment, a polymer layer generated by electrospraying enables the generation of a defined surface structure and thus offers the possibility of degradation control via a three-dimensional system.

According to an alternative embodiment, a uniform, micrometre-thick polymer layer/barrier layer 3 is produced by spraying on the polymer (spray coating), the layer thickness of said layer enabling the degradation to be controlled.

According to a further preferred embodiment, the barrier layer 3 is applied by means of ultrasonic atomisation or vapour deposition, which has the advantage of forming very small droplets of the coating medium, making it possible to produce coatings with a very small layer thickness and to wet surfaces with a complex structure. This coating method is also suitable for aqueous solutions. Specific examples of the invention are described below.

Exemplary embodiment 1

With the aim of delaying the biodegradation of a degradable vascular scaffold 1, a biostable, biocompatible polymer, for example PVDF-HFP, is applied to a metal main body 2 made of a high-purity magnesium alloy comprising 6.5 wt.% Al and no other alloying elements. Depending on the thickness of the applied coating, either a completely or partially opaque, porous coating may be produced. In this example, the polymer coating has a layer thickness of 5 ± 3 pm and is applied to the entire surface 2a of the main body 2 of the vascular scaffold 1 using an airbrush method. For this purpose, the PVDF-HFP is dissolved in a solvent (mixture), e.g. acetone, in a proportion of 0.2 -1.0 % by mass. After the spraying process, the carrier materials are incubated under vacuum at approx. 80°C for 10-15 hours in order to completely eliminate the solvent. The main body surface 2a now has a hydrophobic, continuous coating that prevents the main body 2 from coming into contact with intracorporeal media (see e.g. Fig. 3). Following the introduction of an active substance depot to prevent restenosis due to the anti-proliferative effects of the drug, an active- substance-carrying coating of PLLA is applied to the implant 1 with barrier layer 3. The components are dissolved in chloroform and sprayed over the PVDF-HFP protective layer using the spraying method. The construct is incubated again at approx. 80°C for 10-15 hours. This is followed by a defined ETO sterilisation of the implant 1. As part of a coronary stent implantation, the multi-coated vascular scaffold 1 is placed in the stenotic vessel using the standard surgical technique. After expansion of the scaffold 1, it remains in the vessel, embedded in the vascular endothelium. While the radial force of the precursor models decreases rapidly due to the 60-day degradation, the PVDF-HFP coating protects the metal scaffold 1 from corrosive media and thus ensures that the radial force is maintained for longer. After a defined dwell time, both the scaffold 1 and the active-substance-carrying biodegradable top coating 4 (PLLA) are degraded.

Fig. 3 shows an SEM image of a multi-coating of a main body 2 of a scaffold in the form of a dual coating after microsection preparation. (A) Strut of a coated main body 2 in crosssection, (B) close-up of a coated main body 2 in cross-section with individual gold sputtering of each coating for improved detection of the coating edges in SEM images and (C) closeup of a coated main body 2 in cross-section without individual gold sputtering. PVDF stands for PVDF-HFP.

Exemplary embodiment 2:

A biodegradable main body 2 of a vascular scaffold 1, produced from a high-purity magnesium alloy having the following composition: Mg - approx. 4 wt.% Y - approx. 2 wt.% Nd - approx. 0.5 wt.% Gd - approx. 0.5 wt.% Dy - approx. 0.5 wt.% Zr and < 1% other elements, is provided with a biostable PCU coating, wherein a top layer 4 of paclitaxel is applied to the PCU layer. The polycarbonate urethane (PCU) is ADIAMat S from ADIAM Life Science AG, Germany.

Exemplary embodiment 3 :

A biodegradable main body 2 of a vascular scaffold, made of a high-purity magnesium alloy comprising 2.0 wt.% Zn and 0.4% Ca, consisting of ring-shaped segments which are connected by means of longitudinal connectors. The main 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 degrade more quickly and the main body loses its longitudinal integrity relatively early, immediately after the healing phase, and then no longer exerts any bending stresses on the vessel, while the radial support effect of the individual segments is maintained for much longer and the vessel lumen is thus supported for much longer.

Exemplary embodiment 4:

In this example, a biodegradable main body of a vascular clip made of a magnesium alloy is used to temporarily close a blood vessel. The clip is attached to the vessel to be closed using a clip applicator. The main body of the clip is provided with a polyurethane barrier layer to which a layer of a PLLA-PCL blend is applied, from which an anti-inflammatory active substance is eluted.

Exemplary embodiment 5: In this exemplary embodiment, a biodegradable main body 2 of a scaffold 1 is made of a magnesium alloy for use in the bile duct. The biodegradable scaffold 1 may be used to reconstruct the lumen of the bile duct if, for example, it is compressed by a tumour in the surrounding tissue and the bile may no longer flow out. Due to the low pH value of the bile, it is particularly important to protect the magnesium matrix 2 from degrading too quickly. For this purpose, a thin layer of PCU or PVDF-HFP of approx. 1 - 4 pm is applied to the main body 2 of the scaffold 1 as a barrier layer 3 using a spraying method. In a second step, a top layer 4 of a second polymer (e.g. a PLLA, a PCL or blends or copolymers thereof or a PLGA) may then be applied to the barrier layer 3, wherein a cytostatic active substance which may slow down the proliferation of a tumour is eluted from the top layer 4. Such a scaffold 1 may also be used for malignant stenoses in the urinary tract after adjustment of the diameter.

Exemplary embodiment 6:

In this exemplary embodiment, a biodegradable main body of a scaffold made of a magnesium alloy is used in blood vessels or other hollow organs, in which two polymers with different degrees of influence on the degradation slowdown of the magnesium alloy, which are applied to the main body of the scaffold in a specific geometry, are used to specifically control the support properties of the design over time. For example, a PCU coating leads to a very strong extension of the support duration, while a PLLA, PCL or PHB coating, for example, leads to a significantly lower extension of the support duration.

If the initially applied PCU coating is now deliberately interrupted, e.g. on the longitudinal connectors of the design, the degradation process takes hold there after the overlying PLLA, PCL or P4HB coating has largely degraded and the longitudinal connector is destroyed, while the rest of the main body is still largely protected by the PCU coating. In this case, the radial support effect is still maintained, while the degradation-related destruction of the longitudinal connector means that the transmission of forces in the longitudinal direction of the scaffold is no longer possible. This may be necessary, for example, if no longitudinal forces are to be transmitted in the vessel or hollow organ in which the scaffold was implanted. At the same time, such a principle promotes faster degradation or resorption of the scaffold main body compared to a continuous coating. The applied top layer 4, which may be a PLLA, PCL or P4HB coating, for example, may additionally elute a pharmacologically active substance as described above, e.g. an active substance/drug of the limus group in the case of a vascular scaffold.

Fig. 4 shows, for different coating systems A, B, C, D, E, F, the time in hours until the first fracture or the first fragment formation or collapse of the main body of the implant and illustrates the advantageous technical effects achieved by the invention.

The coating systems tested are the following systems:

A: Reference system I with commercial PLLA-SIR coating (poly-L-lactic acid with sirolimus as pharmacologically active substance) on a body made of a magnesium alloy with an Al content of between 6.0 and 7.0 wt.%.

B: Reference system II with a main body made of a magnesium alloy with an Al content of between 6.0 and 7.0 wt.% and a PLLA-SIR coating applied to it.

C: Mixed system with a main body made of a magnesium alloy with an Al content of between 6.0 and 7.0 wt.% and a coating, applied thereto, comprising poly-L-lactic acid (PLLA), PCL and sirolimus (SIR).

D: Test system I with a main body made of a magnesium alloy with an Al content of between 6.0 and 7.0 wt.% and barrier layer applied thereto (PVDF-HFP) and a top layer applied to the barrier layer, comprising poly-L-lactic acid (PLLA) with sirolimus (SIR) as pharmacologically active substance.

E: Test system II with a main body made of a magnesium alloy with an Al content of between 6.0 and 7.0 wt.% and barrier layer applied thereto (PCU) and a top layer applied to the barrier layer, comprising poly-L-lactic acid (PLLA) with sirolimus (SIR) as pharmacologically active substance

F: Reference system II with magnesium alloy as the main body and, applied thereto, a coating of PLLA and rapamycin (sirolimus). The implants/coating systems D and E clearly showed a favourably increased time until the first fracture/fragment formation/collapse. None of the implants D (test system I) showed any damage, and therefore the test was terminated after 650 hours.

The test results thus illustrate the effectiveness of biostable barrier layers on main bodies of Mg-alloy scaffolds. In particular, it was surprisingly shown that controlling the degradation of a bioresorbable scaffold is only possible with very special polymers. Polycarbonate urethanes (e.g. ADIAMat S) and fluoropolymers (PVDF, PVDF-HFP) are particularly suitable for this purpose.

Which implants and combination coatings are particularly promising naturally also depends on the corresponding body medium or implantation site (pH value). Other possible applications within the scope of the present invention are not only scaffolds with Mg main bodies, but also bioresorbable bone screws/fibres, wires for fixing fractures (cribbing wires, Kirschner wires), screws for fixing ligaments, e.g. in cruciate ligament operations, made of magnesium alloys, as well as implantable Mg-based hernia meshes (e.g. for hernias in the abdominal cavity) and all conceivable implants that are only intended to be resorbed after months/years and not after just a few weeks.

The introduction of a biostable polymer as a barrier layer under an active-substance-carrying, bioresorbable top layer or as a barrier layer with an optional polymer-free active substance layer, in particular for vascular supports (scaffolds), makes it possible to protect the implant from corrosive media over a longer period of time. The scaffold or implant degradation may be controlled in a targeted manner via the layer thickness and composition of the barrier layer, wherein the porosity is determined by the manufacturing technique used. Compared to the prior art, this offers the advantage of being able to maintain the radial force of a metal vascular scaffold for longer.

In addition, the biostable polymer extends the degradation time of an active- sub stance- carrying top layer of, e.g., poly-L-lactic acid, as this acts as a barrier between the PLLA and the main body of the vascular scaffold, which contains magnesium for example, thus ensuring defined pharmacokinetics.

The biostable polymer of the barrier layer has only inadequate performance as a permanent stent graft in terms of deployment force, deployment pressure, radial force, strut thickness, recoil and flexibility, but has increased resistance to pH stresses or oxidation. For this reason, its use as a coating on preferably metal vascular scaffolds/implants, which should be protected from intracorporeal media, is particularly advantageous and useful. The barrier layer is present here in particular as a thin-film coating, the thickness of which is preferably minimal in relation to the strut thickness of the main body of the scaffold. The barrier layer remaining after degradation of the main body does not cause any mechanical irritation due to its flexibility. In the case of degradable scaffold structures, it remains as a biostable, meshlike membrane in the tissue of the vessel/implantation site.

To summarise, the advantages of using the biostable barrier layer with a polymer-based or polymer-free active substance layer on metal implants or scaffolds lie in the following

1. in the protection of the biodegradable implant from intracorporeal media,

2. in the reduction of the release of possible allergens or metal ions and thus avoidance of associated harmful systemic effects, and

3. in the protective effect of the barrier layer for the active-substance-carrying top layer, in particular against disruptive influences of the degradation products of the implant (e.g. to maintain set or established release profiles of the implant).

Bibliography

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Claims

1. An implant (1) comprising: a metal, biodegradable main body (2) with a surface (2a), a barrier layer (3) arranged on the surface (2a) of the main body (2) and comprising a polymer, wherein the barrier layer (3) is configured to delay biodegradation of the main body (2), and wherein the polymer is selected from the group consisting of: polyurethanes, in particular polyurethane-co-silicones and polycarbonate urethanes (PCU); fluoropolymers, in particular fluorosilicones; polyesters, in particular polycarbonates, polybutyl methacrylate and polybutylene terephthalate (PBT), polysulfones; polyether block amides.

2. The implant according to claim 1, wherein the barrier layer (3) only partially covers the surface (2a) of the main body (2) and/or is porous with a pore size 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 in the range from 2 weeks to years, wherein the barrier layer (3) and/or the polymer shields an area of the surface (2a) of the main body (2) covered by the barrier layer (3) and/or the polymer from external influences before the end of the service life and prevents biodegradation of the main body.

5. The implant according to any one of the preceding claims, wherein the polycarbonate urethane is in the form of a chemically modified copolymer into which cleavable crosslinkers or degradable components are incorporated.

6. The implant according to claim 5, wherein the crosslinkers or degradable components are selected from the group consisting of PCU-co-poly ethylene glycols, polyurethane- co-silicones; fluoropolymers such as polyvinylidene fluoride, including copolymers such as, inter alia, poly(vinylidene fluoride-co-hexafluoropropylene) and fluorosilicones; polysulfones; thermoplastic elastomers and copolyesters such as polyether esters, polyether block amides; polycarbonates; polyacrylates such as polybutyl methacrylate, polyethyl methacrylate or polybutylene terephthalates.

7. The implant according to any one of preceding claims 1 to 6, wherein the polymer is PCU-co-polyethylene glycol, in the polymerisation of which degradable reactive monomers have been added to the polyols.

8. The implant according to aby one of the preceding claims, wherein the implant (1) has a top layer (4) applied to the barrier layer (3).

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

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

11. The implant according to any one of the preceding claims, wherein a layer thickness of the barrier layer (3) and the top layer (4) taken together is less than or equal to 10 pm, or wherein a layer thickness of the barrier layer (3) is less than or equal to 10 pm.

12. The implant according to any one of the preceding claims, wherein the main body (2) comprises or consists of a metal alloy, wherein the main component of the metal alloy is magnesium.

13. A method for producing an implant according to any one of the preceding claims, comprising the steps of: providing the main body (2), applying a polymer solution, in which the polymer is dissolved, to the surface (2a) of the main body (2) to form the barrier layer (3), wherein the polymer is selected from the group comprising or consisting of: polyurethanes, in particular polyurethane-co-silicones and polycarbonate urethanes (PCU); fluoropolymers, in particular fluorosilicones; polyesters, in particular polycarbonates, polybutyl methacrylate and polybutylene terephthalate (PBT), polysulfones; polyether block amides.

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

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