Medical device, in particular a stent

Abstract

The invention relates to a medical device, in particular a stent, having a self-expandable mesh structure, which is at least partially tubular and is able to widen automatically from a compressed cross-sectional diameter to an expanded cross-sectional diameter, wherein the mesh structure has at least one mesh structure element (10) which is encased, in particular in its entirety, by a nanostructure coating formed of fibrin nanofibres (11, 12), wherein the nanostructure coating has a first layer (L1), which forms an in particular felt-like or fleece-like matrix of crosslinked fibrin fibres (11), wherein some fibrin fibres (12) protrude freely above the first layer (L1), and a second layer (L2) of an in particular nap-like single-fibre structure, and wherein the nanostructure coating additionally contains a growth factor or a peptide having the functional structure of a growth factor, which growth factor or peptide is integrated in the first layer (L1) and / or the second layer (L2).

Description

[0001] Medical device, in particular stent

[0002] Description

[0003] The invention relates to a medical device, in particular a stent, according to the preamble of patent claim 1. Such a medical device is known, for example, from DE 10 2018 110 591 A1.

[0004] The aforementioned DE 10 2018 110 591 A1 describes, in particular, a stent with a biological coating that promotes endothelialization, i.e., the attachment of endothelial cells to the stent. The base of the stent is a self-expanding mesh structure that is at least partially tubular and can be automatically expanded from a compressed cross-sectional diameter to an expanded cross-sectional diameter.

[0005] The mesh structure comprises at least one mesh element coated with a nanostructure coating. This nanostructure coating is formed from fibrin nanofibers.

[0006] To form the biological coating in the known stent, fibrinogen is first introduced and then converted to fibrin by the addition of thrombin. The fibrin forms threads that extend outward from the surface of the mesh structure. This creates a loose fibrin network into which heparin can be incorporated.

[0007] Although the previously known medical device shows good results in endothelialization, further improvement is desirable. Therefore, the object of the present invention is to provide a medical device that achieves a further improvement in endothelialization.

[0008] According to the invention, this object is achieved by the further development according to patent claim 1. Accordingly, the invention is based on the idea of ​​specifying a medical device, in particular a stent, with a self-expanding mesh structure that is at least partially tubular and can be automatically expanded from a compressed cross-sectional diameter to an expanded cross-sectional diameter. The mesh structure has at least one mesh structure element that is, in particular completely, encased in a nanostructure coating made of fibrin nanofibers. According to the invention, the nanostructure coating has a first layer that forms a matrix, in particular a felt-like or fleece-like matrix, of interconnected fibrin fibers, with some fibrin fibers protruding freely beyond the first layer and forming a second layer made of a single-fiber structure, in particular a pile-like structure.In addition, the nanostructure coating additionally contains a growth factor or a peptide with the functional structure of a growth factor, which is integrated into the first layer and / or the second layer. "Integrated" here refers to the fact that the growth factor or a peptide with the functional structure of a growth factor is present in the first layer and / or the second layer in bound or unbound form.

[0009] The invention differs from the previously known prior art in that the nanostructure coating is essentially formed in two layers and additionally contains a growth factor or a peptide with the functional structure of a growth factor. A first layer, which preferably lies directly on the surface of the mesh element, comprises a matrix of cross-linked fibrin fibers. This matrix is ​​particularly dense. In this respect, the matrix can also be described as felt-like or nonwoven. The fibrin fibers of the first layer are, in particular, cross-linked or matted with one another. A particularly dense fibrin structure is formed thereon.

[0010] However, some of the fibrin fibers protrude beyond the first layer and form a single-fiber structure. The protruding fibrin fibers are preferably uncrosslinked in the second layer and, rather, protrude beyond the first layer as individual fibers. These individual fibers, or individual fiber portions, essentially form a pile-like structure. Thus, the second layer contains a particularly loose fibrin fiber structure. Essentially, the nanostructure coating is comparable to a velour carpet, in which the textile fibers in a first layer are crosslinked or matted with one another, and in an overlying layer, individual textile fibers protrude freely, thus forming the pile of the velour.

[0011] The growth factor integrated into the nanostructure coating, or the peptide with the functional structure of a growth factor, further improves the cell viability of the medical device, resulting in better and faster endothelialization.

[0012] In the context of the present invention, the "peptide with the functional structure of a growth factor" refers to a peptide that, like a growth factor, is capable of binding to a specific receptor in the cell membrane of another cell, which, in its biological function, is designed and intended to bind to growth factors. Compared to the growth factor, it is therefore a shortened protein fragment or a peptide that has the same amino acid sequence as the corresponding portion of the growth factor and can bind to corresponding receptors, or a peptide that has been synthetically produced by combinatorial methods for binding to corresponding receptors.

[0013] It has been shown that this special structure of the nanostructure coating provides an overall increased surface area for endothelial cell adhesion. This significantly improves endothelialization. The first layer, which is more highly cross-linked than known from the prior art, can essentially exhibit sponge-like properties, allowing a greater amount of heparin to be absorbed into the first layer. The heparin improves the antithrombogenicity of the nanostructure coating. This does not preclude the heparin from also binding to the second layer. Rather, the heparin can bond with the nanostructure coating across the entire layer thickness.

[0014] The growth factor can, in principle, be any known growth factor, with growth factors selected from the group comprising vascular endothelial growth factors (VEGF), fibroblast growth factors (FGF), epidermal growth factors, platelet-derived growth factors, neurotrophins, and insulin-like growth factors being particularly suitable. In one embodiment, the peptide having the functional structure of a growth factor is derived from such a growth factor, i.e., it has a structure that is at least 95%, and preferably at least 97%, identical to a partial structure of the growth factor, and with deviations in identity being formed by conservative substitutions.In this context, "identity" refers to sequence identity, and the term "conservative substitution" refers to the replacement of one amino acid in the sequence by another amino acid whose properties are similar in terms of electrical charge, functional groups contained, hydrophobicity, and size.

[0015] Particularly preferred growth factors in the context of the invention described here are vascular endothelial growth factors and fibroblast growth factors, and particularly preferred peptides are peptides having the functional structure of such a growth factor.

[0016] To provide improved endothelialization, it is advantageous if the growth factor or the peptide with the functional structure of a growth factor is covalently bound to components of the nanostructured coating. This binding is conveniently achieved via binding to the fibrin nanofibers of the nanostructured coating. The covalent binding can be achieved through any chemical reaction compatible with the conditions during the manufacturing of the medical device. The binding can occur directly to the fibrinogen before it is used to form the fibrin nanothreads, or the growth factor or the peptide with the functional structure of the growth factor can be incorporated into the nanostructured coating after its production.

[0017] In this case, but also in the case of covalent bonding to fibrinogen, the growth factor or peptide can be conveniently bound to components of the nanostructure coating via an amino group, click chemistry, or a thiol group. The bond is particularly preferably the reaction product of a primary amine with a dialdehyde or epoxide, the reaction product of a CC triple bond with an azide group (commonly known as "click chemistry"), or the reaction product of a thiol group with an alkene or epoxide group. These reactions have the advantage that they generally proceed selectively, and the desired bond can also be formed under aqueous conditions. For the reactions mentioned, it is not crucial which of the functional groups is bound to the growth factor or peptide with the functional structure of the growth factor, i.e., this or the peptide can, for example,a CC triple bond or an azide group and in the respective cases one component of the nanostructure coating has the respective complementary group (i.e. an azide group or a CC triple bond).

[0018] In a preferred embodiment of the medical device according to the invention, the nanostructure coating has a protein quantity of at least 2 pg / cm 2 , especially more than 2 pg / cm 2 , especially more than 3 pg / cm 2Experimentally, it has been shown that such a protein quantity results in a sufficiently dense yet thin nanostructure coating. A thin nanostructure coating is advantageous for keeping the overall thickness of the mesh element within a range, allowing the entire medical device to be easily compressed to the smallest possible cross-sectional diameter. This is the prerequisite for the medical device to be guided to the treatment site via small catheters. This allows even small blood vessels, particularly in the cerebral region, to be treated.

[0019] In addition, a thin nanostructure coating ensures that the overall wall thickness of the device remains small, thus not significantly impairing blood flow through a blood vessel. This prevents vascular constriction (stenosis) caused by the device.

[0020] It is particularly advantageous if the first layer has a first amount of protein and the second layer a second amount of protein, wherein the first amount of protein is greater than the second amount of protein. Specifically, it has been shown that a ratio between the first amount of protein and the second amount of protein of at least 2, in particular at least 3, in particular at least 4, is advantageous. This ensures that, on the one hand, the first layer is sufficiently dense to form a sponge-like structure for the incorporation of heparin or other substances, and on the other hand, the second layer has a sufficiently loose structure to ensure improved adhesion of endothelial cells. Heparin can also bind covalently to the second layer and prevent blood clotting there due to its anti-thrombogenic properties.However, it is expected that a larger amount of heparin will accumulate in the first layer due to its sponge-like structure, which will then be gradually released to the second layer. In this respect, the first layer can also serve as a drug reservoir.

[0021] In the medical device according to the invention, in an advantageous embodiment, the first layer can have a height between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. The second layer can have a height between 5 nm and 200 nm, in particular between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm. It is particularly preferred if the total height of the nanostructure coating is at most 300 nm, in particular at most 200 nm, in particular at most 150 nm, in particular at most 120 nm, in particular at most 100 nm, in particular at most 90 nm, in particular at most 80 nm, in particular at most 60 nm.

[0022] The stability of the fibrin nanocoating is advantageously enhanced if the fibrin fibers are formed from cross-linked fibrin molecules. Cross-linking can be achieved by adding a special factor, Factor XHIa, during the manufacturing process. Cross-linking significantly stabilizes the fibrin nanostructure and can improve the previously described benefits with regard to endothelialization. With regard to cross-linking, it is particularly envisaged that the fibrin molecules each have two carboxyl termini (D domains) and one amino terminus (E domain), with the amino terminus of one fibrin molecule being linked to at least one carboxyl terminus of another fibrin molecule, in particular by a covalent bond. The invention is explained in more detail below using an exemplary embodiment with reference to the attached schematic drawings.

[0023] Fig. 1 is a schematic cross-sectional view through a mesh structure element with a nanostructure coating of a medical device according to the invention according to a preferred embodiment;

[0024] Fig. 2 is a plan view of a nanostructure coating of a network structure element of a medical device according to the invention in a scanning electron microscope image; and

[0025] Fig. 3 is a schematic representation of the cross-linking of fibrin molecules to form a stabilized fibrin fiber.

[0026] Fig. 4 the comparison of cell viability on a glass surface, a glass surface modified with fibrin and heparin (Fb + H), a glass surface modified with fibrin, heparin and factor XIII and a glass surface modified with fibrin, heparin, factor XIII, FGF and VEGF

[0027] Fig. 1 shows a schematic representation of a mesh structural element 10 of a medical device, in particular a stent. Generally, the medical device comprises a plurality of mesh structural elements 10 that form a mesh structure. The mesh structural elements 10 may be formed by wires that are interwoven to form a mesh structure. Alternatively, the mesh structural elements 10 may also form webs of a one-piece mesh structure. This is the case, for example, with stents that are cut in one piece from a tube. Such stents are often referred to as laser-cut stents.

[0028] The schematic representation according to Fig. 1 essentially shows a cross-section through the network structure element 10, wherein for reasons of clarity the nanostructure coating is only shown on one surface. However, the nanostructure coating extends over the entire outer surface of the network structure element 10, i.e. the network structure element 10 can be completely coated by the nanostructure coating. In particular, it is provided that the nanostructure coating extends only over the outer circumferential surface of the individual network structure elements 10. Cells or meshes of a network structure, i.e. openings that are delimited by the individual network structure elements 10, are preferably not covered by the nanostructure coating. However, it is advantageous if all network structure elements 10 of the network structure are completely coated with the nanostructure coating.

[0029] The nanostructure coating has a first layer LI, which lies directly on the surface of the mesh element 10. The first layer LI is formed by fibrin fibers 11, which form a densely networked matrix. The fibrin fibers 11 thus interlock and are highly compacted, essentially forming a nonwoven-like first layer LI.

[0030] The schematic representation according to Fig. 1 shows that individual fibrin fibers 12 protrude above the first layer LI. These protruding fibrin fibers 12 form a second layer L2 of the nanostructure coating above the first layer LI. The second layer L2 is formed by a single-fiber structure, i.e., the fibrin fibers 12 are present as free fibers, in particular with largely free ends. The second layer L2 thus essentially forms a pile of protruding fibrin fibers 12.

[0031] The illustration in Fig. 1 can be compared to a velour carpet, in which the mesh structure element 10 forms the base. Textile fibers are arranged on the base, with the textile fibers being cross-linked in a first layer directly on the base to form a nonwoven. Individual fibers of the nonwoven protrude beyond the first layer and form a pile of individual fibers. A similar structure is created here with the nanostructure coating.

[0032] In Figure 1, growth factor proteins 13, represented by •, are covalently bound to fibrin threads located in the first and second layers.

[0033] The structure of the nanostructure coating is visible in the scanning electron microscope image shown in Fig. 2. The image shows fibrin fibers 11, 12 arranged on a mesh structural element 10. The fibrin fibers 11, 12 have different thicknesses in the image. This different thickness is primarily due to the perspective. This means that the thicker fibrin fibers 12 are arranged closer to the microscope lens than the thinner fibrin fibers 11. In other words, the thicker fibrin fibers 12 shown in the scanning electron microscope image protrude further beyond the outer surface of the mesh structural element 10 than the thinner fibrin fibers 11.

[0034] Fig. 2 clearly shows that the fibrin fibers 11 arranged closer to the mesh element 10 exhibit strong cross-linking and thus form the fleece-like first layer L1 of the nanostructure coating. Individual, thicker fibrin fibers 12 protrude further, thus being at a greater distance from the mesh element 10. These individual fibrin fibers 12 are present as individual fibers and form the pile-like second layer L2 of the nanostructure coating. Fig. 2 clearly shows that the second layer L2 has a significantly lower fibrin fiber density than the first layer L1.

[0035] The individual fibrin fibers 11, 12 are formed from fibrin molecules 20, which bond together upon addition of thrombin, so that the fibrin fibers 11,

[0036] 12. In a very simplified representation, as shown in Fig. 3, each fibrin molecule 20 has a central amino terminus, also referred to as the E domain 21. Individual monomers extend from the E domain 21, forming a so-called coiled-coil structure 24. On the outside of the molecule are carboxy termini, referred to as the D domain 22.

[0037] By adding thrombin, fibrin peptides are cleaved, whereby the released fibrin monomers are linked by polymer bonds 23. By further adding a fibrin-stabilizing factor (factor XHIa), cross-linking bonds 13 are formed. The cross-linking bonds

[0038] 13 are formed between the E domain 21 and at least one D domain 22 of another fibrin molecule 20. In particular, adjacent D domains 22 of two fibrin molecules 20 are connected by the covalent bond 13 to the E domain 21 of a third fibrin molecule 20. The covalent bonds 13 thus form a bridge that stabilizes the weaker polymerization bond 23. Overall, the entire fibrin fiber structure is thus stabilized.

[0039] The nanostructure coating described in connection with the present invention is particularly effective with regard to the attachment of endothelial cells. In experiments, the nanostructure coating was applied to a glass substrate and immersed with the glass substrate in an endothelial cell solution. It was shown that the nanostructure coating is designed in such a way that at least 60,000, in particular between 60,000 and 90,000, endothelial cells per square centimeter attach to the nanostructure coating. This represents a significant increase in the number of endothelial cells per square centimeter compared to previous biological coatings.

[0040] Not only is the number of endothelial cells per square centimeter increased with the nanostructured coating of the invention, but it has also been shown that cell viability is significantly increased after three days compared to previous biological coatings. Thus, after three days, more endothelial cells survive on the nanostructured coating of the medical device according to the invention than on other previously known biological coatings. Specifically, cell viability was experimentally determined using a CCK-8 assay on a stent with the nanostructured coating described here after three days, resulting in an absorption value of significantly more than 0.2 at a wavelength of 450 nm.

[0041] In Figure 4, the cell viability of human umbilical vein endothelial cells (HUVEC) was investigated on a glass surface without a coating and on glass surfaces modified with various coatings. Coating with fibrin and heparin showed significantly improved viability; cross-linking of the fibrin with fibrin-stabilizing factor (factor XIII) does not significantly affect viability, but prevents easy detachment of the fibrin film from the surface. By contrast, the addition of FGF and VEGF according to the invention significantly increased cell viability. Based on this result, significantly improved endothelialization can be expected for such a surface modification.

[0042] 10 network structure element

[0043] 11 Fibrin fiber of the fiber matrix

[0044] 12 Fibrin fiber of the single fiber structure 13 Growth factor

[0045] 14 covalent bond

[0046] 20 fibrin molecules

[0047] 21 E-Domain

[0048] 22 D domain 23 Polymer binding

[0049] 24 Coiled-coil structure

[0050] LI first layer

[0051] L2 second layer

Claims

Claims 1. A medical device, in particular a stent, comprising a self-expanding mesh structure which is at least partially tubular and can be automatically expanded from a compressed cross-sectional diameter to an expanded cross-sectional diameter, wherein the mesh structure comprises at least one mesh structure element (10) which is, in particular completely, coated by a nanostructure coating formed from fibrin nanofibers (11, 12), characterized in that the nanostructure coating comprises a first layer (LI) which forms a matrix, in particular a felt-like or fleece-like matrix, of interlinked fibrin fibers (11), wherein some fibrin fibers (12) protrude freely beyond the first layer (LI) and form a second layer (L2) of a single-fiber structure, in particular a pile-like structure, and wherein the nanostructure coating additionally contains a growth factor or a peptide with the functional structure of a growth factor,which is integrated into the first layer (LI) and / or the second layer (L2).

2. Medical device according to claim 1, characterized in that the growth factor or the peptide having the functional structure of a growth factor is covalently bound to components of the nanostructure coating, in particular to fibrin nanofibers of the nanostructure coating.

3. Medical device according to claim 2, characterized in that the attachment of the growth factor or the peptide with the functional structure of a growth factor to components of the nanostructure coating takes place via an amino group, click chemistry or a thiol group, wherein the attachment is preferably the reaction product of the reaction of a primary amine with a dialdehyde or epoxide, the reaction product of a CC triple bond with an azide group, or the reaction product of a thiol group with an alkene or epoxide group.

4. Medical device according to one of the preceding claims, characterized in that the growth factor is selected from the group comprising vascular endothelial growth factors, fibroblast growth factors, epidermal growth factors, platelet-derived growth factors, neurotrophins and insulin-like growth factors and the peptide having the functional structure of a growth factor is derived from such a growth factor.

5. Medical device according to one of the preceding claims, characterized in that the nanostructure coating contains a protein quantity of at least 2 pg / cm 2 , especially more than 2 pg / cm 2 , especially more than 3 pg / cm 2 , has.

6. Medical device according to one of the preceding claims, characterized in that the first layer (LI) has a first amount of protein and the second layer (L2) has a second amount of protein, wherein a ratio between the first amount of protein and the second amount of protein is at least 2, in particular at least 3, in particular at least 4.

7. Medical device according to one of the preceding claims, characterized in that the second layer (L2) has a greater height than the first layer (LI).

8. Medical device according to one of the preceding claims, characterized in that the first layer (L1) has a height between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm, and the second layer (L2) has a height between 5 nm and 200 nm, in particular between 5 nm and 100 nm, in particular between 5 nm and 50 nm, in particular between 5 nm and 30 nm, in particular between 10 nm and 40 nm, in particular between 20 nm and 30 nm.

9. Medical device according to one of the preceding claims, characterized in that the fibrin fibers (11) are formed from cross-linked fibrin molecules (20).

10. Medical device according to claim 9, characterized in that the fibrin molecules (20) each have two carboxyl termini (D-domains (22)) and one amino terminus (E-domain (21)), wherein the amino terminus of one fibrin molecule (20) is connected to at least one carboxyl terminus of another fibrin molecule (20), in particular by a covalent bond (13).

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