Implant for treating a defect of the dura mater, in particular for replacement and / or closure of the dura mater

Abstract

The invention relates to an implant (1) for treating a defect, in particular for replacement and / or closure, of the dura mater. The implant (1) comprises a layer (2) with recombinant collagen and a fiber layer (3).

Description

[0001] P 62314 WO 19 December 2025

[0002] - 1 - CG / CG

[0003] Implant for treating a defect of the dura mater, in particular for replacing and / or closing the dura mater

[0004] SCOPE OF APPLICATION AND STATE OF THE ART

[0005] The invention relates to an implant for treating a defect of the dura mater, in particular for replacing and / or closing the dura mater.

[0006] It is known to use the patient's own tissue to treat defects of the dura mater. If the defect cannot be closed directly with a suture, or if it is not medically advantageous for the patient to use their own tissue for closure, implants made of decellularized animal tissue or synthetic polymers are used.

[0007] Implants made from decellularized tissue of animal origin, such as bovine, porcine, equine, or marine tissue, often exhibit very good biocompatibility. However, they carry the risk of transmitting pathogens and of causing inconsistencies due to the animal and / or tissue origin. Furthermore, such implants require increasing regulatory effort and are also increasingly subject to ethical concerns.

[0008] Implants made of synthetic polymers, such as polylactic acid, polyurethane, polyethylene terephthalate, or similar materials, are often characterized by very good mechanical properties and adjustable degradation rates. However, they generally lack biological markers for rapid and effective cell adhesion, migration, and proliferation.

[0009] TASK AND SOLUTION

[0010] The object of the invention is to provide an implant that is suitable for treating a defect of the dura mater, in particular for replacing and / or closing the dura mater, and in particular avoids the disadvantages mentioned in the introduction in connection with known implants.

[0011] This problem is solved by an implant with the features according to independent claim 1. Preferred embodiments of the implant are defined in the dependent claims. The wording of all claims is hereby incorporated by express reference into the present description.

[0012] The invention relates to an implant for treating a defect, in particular for replacing and / or closing, of the dura mater, preferably the cranial dura mater.

[0013] The implant consists of: a layer of recombinant collagen and a fibrous layer.

[0014] For the purposes of this invention, the term "dura mater" refers to the outermost meningeal membrane (pachymeninx) that surrounds the central nervous system. It borders the adjacent bones of the skull and / or spinal column. Based on its location within the skull or spinal canal, it is classified as either the cranial dura mater or the spinal dura mater. Both structures merge at the foramen magnum.

[0015] For the purposes of the present invention, the term "dura mater cranialis" refers to the part of the dura mater (pachymeninx) that surrounds the brain within the cranial cavity. It belongs to the meninges and extends caudally as the dura mater spinalis of the spinal cord.

[0016] The cranial dura mater is located within the skull cavity. It consists of an outer layer, the stratum fibrosum or stratum periosteale, and an inner layer, the stratum neurotheliale or stratum meningeale, which lies towards the arachnoid.

[0017] The stratum fibrosum consists of dense connective tissue with numerous collagenous and elastic fibers. Functionally, it forms the periosteum of the cranial cavity, which is firmly fused to the skull bone in large areas. At the foramina and sutures, it transitions continuously into the pericranium on the outer surface of the skull. At the orbital fissures, the dura mater transitions into the periosteum of the orbital cavity (periorbita).

[0018] The inward-facing stratum neurotheliale is a multilayered structure of epithelium-like meningeal cells (dura neurothelium). The sealed, narrow intercellular space between the innermost layer of the dura neurothelium and the outer arachnoid cell layer forms a diffusion barrier between cerebrospinal fluid and the blood vessel system of the dura (part of the blood-cerebrospinal fluid barrier). The dura neurothelium terminates at the points where cranial nerves exit the dura mater.

[0019] For the purposes of this invention, the term "dura mater spinalis" refers to the part of the dura mater (pachymeninx) that surrounds the spinal cord. The dura mater spinalis is also a meninge. It forms the continuation of the dura mater cranialis behind the foramen magnum.

[0020] The spinal dura mater envelops the spinal cord in the vertebral canal in the form of an elongated dural sac. Similar to the dura mater in the skull, the spinal dura consists of a fibrous layer and a neurothelial layer; however, the fibrous layer is not directly connected to the bone, as there is a separate periosteum. This allows the dural sac to be surrounded by an epidural space containing loose connective tissue with numerous fat cells and a venous plexus (internal vertebral venous plexus).

[0021] For the purposes of the present invention, the term "layer containing recombinant collagen" shall be understood to mean a layer which contains or consists of recombinant collagen.

[0022] For the purposes of the present invention, the term "fiber layer" shall be understood to mean a layer that has fibers or consists of fibers. Preferred embodiments of the fibers are described in more detail below.

[0023] For the purposes of the present invention, the term “recombinant collagen” shall be understood to mean collagen, in particular biotechnologically produced collagen, which has been produced with the aid of a genetically modified organism, in particular a genetically modified single-cell or multi-cell organism, or with transiently transfected cell cultures.

[0024] Furthermore, the term "recombinant collagen" within the meaning of the present invention can mean a recombinant collagen protein, i.e., a complete recombinant collagen protein, in particular recombinant tropocollagen, and / or parts, i.e., fragments, in particular one or more polypeptides, in particular one or more polypeptide fragments, of recombinant collagen. In particular, the collagen within the meaning of the present invention can be collagen protein and / or hydrolyzed collagen.

[0025] The layer of recombinant collagen advantageously gives the implant according to the invention excellent biocompatibility. Furthermore, the layer of recombinant collagen promotes cell ingrowth into the implant. It is also advantageous that recombinant collagen, including its properties, can be produced reproducibly. This, in turn, has a beneficial effect on any additives to the layer of recombinant collagen and thus to the implant itself. Overall, the implant according to the invention therefore avoids the disadvantages of collagen-containing implants of natural origin known from the prior art, such as the transmission of pathogens, inconsistencies caused by animal and / or tissue origin, etc.

[0026] The fibrous layer advantageously allows the implant to be sutured, i.e., fixed with sutures. Furthermore, the fibrous layer of the implant can advantageously create a seal against the cerebrospinal fluid.

[0027] In one embodiment of the invention, the layer containing recombinant collagen is designed in a sponge-like shape.

[0028] In a further embodiment of the invention, the layer containing recombinant collagen is present in freeze-dried, i.e., lyophilized, form. Freeze-drying or lyophilization advantageously produces the sponge-like structure of the layer containing recombinant collagen mentioned in the previous paragraph.

[0029] Preferably, the layer containing recombinant collagen is in freeze-dried form and has a sponge-like shape.

[0030] The two aforementioned embodiments of the invention have the particular advantage that the implant can be fixed to the dura mater to be treated without additional aids, such as sutures or adhesives.

[0031] Alternatively, the layer with recombinant collagen can be designed in a nonwoven form, especially as a spray or spunbond nonwoven.

[0032] Preferably, the implant is in vivo degradable (degradable in vivo) or in vivo resorbable.

[0033] The term “in vivo degradable” (or “in vivo biodegradable”) refers, within the meaning of the present invention, to a material that is metabolized in a human or animal body, particularly under the influence of enzymes. The degradation of the implant can proceed completely to mineralization, i.e., the release of chemical elements and their incorporation into inorganic compounds such as carbon dioxide, oxygen, and / or ammonia, or it can remain at the stage of biodegradable intermediate or transformation products.

[0034] For the purposes of the present invention, the term "animal body" shall be understood to mean the body of a non-human mammal, such as a horse, a cow, a goat, a sheep, a pig or a rodent.

[0035] For the purposes of the present invention, the term “in vivo resorbable” refers to a material which is absorbed in a human or animal body by living cells or living tissue, such as kidneys.

[0036] Preferably, the implant is degradable in vivo within a period of 3 months to 1.5 years, particularly 3 months to 1 year or 6 months to 1.5 years. This allows the implant to replace the function of the dura mater until regeneration of the native dura mater is complete.

[0037] The in vivo degradability of the implant can advantageously be specifically controlled by selecting the materials used for its manufacture and / or processing. In vivo degradability of the implant is important not only to restore the initial state of the treated dura mater tissue without the permanent presence of a foreign body in the human or animal body, but also to prevent long-term side effects and, in particular, to make an implant available for all patient groups, including children.

[0038] In a further embodiment of the invention, the layer containing recombinant collagen is designed to be open-pored. An open-pore design advantageously allows the migration of fibroblasts, which are important for the regeneration of the dura mater.

[0039] Preferably, the layer containing recombinant collagen has pores with a mean diameter of 20 pm to 400 pm or 60 pm to 400 pm, in particular 30 pm to 400 pm or 90 pm to 400 pm, preferably 90 pm to 300 pm. The mean pore diameter can be determined, in particular, by scanning electron microscopy. The aforementioned mean pore diameters have the advantage that they not only promote the migration of fibroblasts into the layer containing recombinant collagen and thus the implant, but also encourage vascularization of the native dura mater tissue to be regenerated. Furthermore, the layer containing recombinant collagen can have an interconnectivity, in particular determined by scanning electron microscopy, of 60% to 99%, in particular 90% to 98%, preferably 95% to 98%.

[0040] For the purposes of the present invention, the term “interconnectivity” means a proportion of pores that are interconnected (so-called interconnecting pores) relative to the total number of pores in a layer.

[0041] Furthermore, the layer with recombinant collagen can have a porosity, i.e. a void volume caused by pores, in particular determined by scanning electron microscopy, of 30% to 98%, in particular 40% to 98%, in particular 45% to 80%, preferably 62% to 76%.

[0042] Furthermore, the layer with recombinant collagen can have a layer thickness of 0.2 mm to 4.7 mm, in particular 0.2 mm to 3.3 mm, preferably 0.33 mm to 0.70 mm.

[0043] Furthermore, the layer with recombinant collagen can have a basis weight of 0.002 g / cm². 2 up to 0.030 g / cm³ 2 , in particular 0.005 g / cm² 2 up to 0.028 g / cm³ 2 , preferably 0.005 g / cm³ 2 down to 0.018 g / cm³2 exhibit.

[0044] Furthermore, the layer with recombinant collagen can have a density of 0.005 g / cm³. 3 up to 2 g / cm² 3 , in particular 0.02 g / cm³ 3 up to 2 g / cm² 3 , preferably 0.2 g / cm³ 3 up to 0.9 g / cm³ 3 exhibit.

[0045] Furthermore, the layer with recombinant collagen can exhibit an elongation at break, in particular determined by means of a uniaxial tensile test, of 6.4% to 135%, in particular 14.4% to 66.9%, preferably 14.4% to 41%.

[0046] Furthermore, the layer with recombinant collagen can have a tensile strength, in particular determined by means of a uniaxial tensile test, of 0.05 MPa to 30 MPa, in particular 6.4 MPa to 20 MPa, preferably 7.2 MPa to 8.8 MPa.

[0047] Furthermore, the layer with recombinant collagen can have a tensile strength, in particular determined by means of a uniaxial tensile test, of 1 N to 70 N, in particular 7 N to 70 N, preferably 20 N to 70 N.

[0048] In a further embodiment of the invention, the recombinant collagen is collagen produced by a prokaryotic expression system, in particular by bacteria, preferably Escherichia coli, or by a eukaryotic expression system, in particular by transgenic plants, mammalian cells, insect cells, and / or yeast cells. The transgenic plants may preferably be tobacco plants. The mammalian cells may be selected, in particular, from the group consisting of CHO cells (Chinese hamster ovary cells), HT-1080 (human fibrosarcoma cells), HEK cells (human embryonic kidney cells, also known as HEK-293), NIH3T3 cells (a fibroblast cell line isolated from a mouse embryo), and combinations of at least two of the aforementioned mammalian cells.Alternatively or in combination, recombinant collagen can be collagen produced from mammary glands of transgenic mice.

[0049] The recombinant collagen is particularly preferably produced by Escherichia coli or a tobacco plant or tobacco plant cells.

[0050] Furthermore, the recombinant collagen is preferably selected from the group consisting of collagen types I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, and combinations of at least two of the aforementioned collagen types. In particular, the recombinant collagen is preferably collagen type I and / or III, or a recombinant collagen with a triple helix structure functionally equivalent to the aforementioned collagen types, but with a shorter chain length.

[0051] In a further embodiment of the invention, the fiber layer comprises microfibers and / or nanofibers, in particular only nanofibers.

[0052] The microfibers can have a mean diameter of 1 pm to 5 pm, especially 2 pm to 5 pm.

[0053] For the purposes of the present invention, the term "nanofibers" shall be understood to mean fibers with a mean diameter, in particular as determined by scanning electron microscopy, of < (read: less than) 1,000 nm. The nanofibers can advantageously stimulate an earlier stage of tissue regeneration. In particular, the presence of nanofibers can positively influence the healing or regeneration of the dura mater via corresponding cell signals.

[0054] Preferably, the fibers, preferably microfibers and / or nanofibers, of the fiber layer have a mean diameter, in particular determined by scanning electron microscopy, of 0.1 nm to 5000 nm, in particular 0.1 nm to 2000 nm, preferably 0.1 nm to 1000 nm.

[0055] In a further embodiment of the invention, the fiber layer is also designed to be open-pored. An open-pored design advantageously allows the migration of fibroblasts, which are important for the regeneration of the dura mater.

[0056] Preferably, the fibrous layer also has pores with a mean diameter of 20 pm to 400 pm or 60 pm to 400 pm, particularly 30 pm to 400 pm or 90 pm to 400 pm, preferably 90 pm to 300 pm. The mean pore diameter can be determined, in particular, by scanning electron microscopy. The aforementioned mean pore diameters have the advantage that they not only promote the migration of fibroblasts into the fibrous layer and thus the implant, but also encourage the vascularization of the native dura mater tissue to be regenerated.

[0057] Furthermore, the fibers, in particular microfibers and / or nanofibers, of the fiber layer can have a cornerless or round, in particular circular, oval or elliptical, cross-section or a polygonal, for example triangular, square, pentagonal, hexagonal, heptagonal, octagonal or nonagonal, cross-section.

[0058] Furthermore, the fiber layer can have an interconnectivity, in particular determined by scanning electron microscopy, of 60% to 99%, in particular 90% to 98%, preferably 95% to 98%.

[0059] Furthermore, the fiber layer can have a porosity, i.e., a void volume caused by pores, in particular determined by scanning electron microscopy, of 30% to 98%, in particular 40% to 98%, in particular 45% to 80%, preferably 62% to 76%.

[0060] Furthermore, the fiber layer can have a thickness of 0.2 mm to 4.7 mm, in particular 0.2 mm to 3.3 mm, preferably 0.33 mm to 0.70 mm. Furthermore, the fiber layer can have a basis weight of 0.002 g / cm². 2 up to 0.030 g / cm³ 2 , in particular 0.005 g / cm² 2 up to 0.028 g / cm³ 2 , preferably 0.005 g / cm³ 2 down to 0.018 g / cm³ 2 exhibit.

[0061] Furthermore, the fiber layer can have a density of 0.005 g / cm³. 3up to 2 g / cm² 3 , in particular 0.02 g / cm³ 3 up to 2 g / cm² 3 , preferably 0.2 g / cm³ 3 up to 0.9 g / cm³ 3 exhibit.

[0062] Furthermore, the fiber layer can have an elongation at break, in particular determined by means of a uniaxial tensile test, of 6.4% to 135%, in particular 14.4% to 66.9%, preferably 14.4% to 41%.

[0063] Furthermore, the fiber layer can have a tensile strength, in particular determined by means of a uniaxial tensile test, of 6.4 MPa to 30 MPa, in particular 6.4 MPa to 20 MPa, preferably 7.2 MPa to 8.8 MPa.

[0064] Furthermore, the fiber layer can have a tensile strength, in particular determined by means of a uniaxial tensile test, of 1 N to 170 N, in particular 7 N to 170 N, preferably 20 N to 170 N.

[0065] In a further embodiment of the invention, the fiber layer is designed in a nonwoven form, i.e., as a nonwoven, in particular as a spray-formed or spunbonded nonwoven. The spunbond can, in particular, be an electrospunbond. This advantageously allows not only the formation of a particularly fine fibrillar and, in particular, porous layer that mimics the extracellular matrix of the native dura mater tissue in its structure and architecture, especially with regard to fiber diameter and / or fiber arrangement and / or pore diameter and / or porosity, which in turn promotes the ingrowth of fibroblasts and the formation of blood vessels. In addition, a nonwoven design of the fiber layer advantageously also provides sufficient mechanical stability with good elasticity and adequate sealing against the cerebrospinal fluid.

[0066] In particular, the fiber layer can be in freeze-dried, i.e., lyophilized, form.

[0067] Preferably, the fiber layer is formed directly on the layer containing recombinant collagen. In particular, the fiber layer can be sprayed, spun, or lyophilized directly onto the layer containing recombinant collagen. This allows for a particularly strong adhesion between the fiber layer and the layer containing recombinant collagen. In a further embodiment of the invention, the implant has an additional layer. This additional layer advantageously further increases the mechanical stability of the implant.

[0068] The additional layer is preferably formed between the layer containing recombinant collagen and the fibrous layer. This additional layer can be formed directly or indirectly between the layer containing recombinant collagen and the fibrous layer. Preferably, the additional layer is formed directly between the layer containing recombinant collagen and the fibrous layer.

[0069] In particular, the next layer can be formed directly on top of the layer with recombinant collagen, and the fiber layer can be formed directly on top of the next layer.

[0070] The next layer is preferably made of textile material. For example, the next layer can be woven, braided, or knitted.

[0071] In a further embodiment of the invention, the additional layer comprises a mesh, in particular a knitted mesh, or the additional layer is in the form of a mesh, in particular a knitted mesh. The mesh can have meshes or pores with a mean diameter, in particular determined by light microscopy with optical measurement, of 0.5 mm to 1 mm, in particular 0.6 mm to 0.9 mm, preferably 0.7 mm to 0.8 mm. Furthermore, the mesh can have a tensile strength, in particular determined by a uniaxial tensile test, of 6.5 kgf / 25 mm to 120 kgf / 25 mm, in particular 10 kgf / 25 mm to 120 kgf / 25 mm, preferably 10.52 kgf / 25 mm to 106 kgf / 25 mm. Furthermore, the mesh can be in vivo degradable or in vivo resorbable. In particular, the mesh can exhibit in vivo degradability or in vivo resorbability of 60 to 90 days.

[0072] Furthermore, the additional layer can be present, in particular, in freeze-dried or lyophilized form. Specifically, the additional layer and the layer containing recombinant collagen can be bonded together by freeze-drying.

[0073] In a further embodiment of the invention, the further layer, in particular the network, comprises polyglycolic acid and / or polyglycolate.

[0074] In a further embodiment of the invention, a cured adhesive layer is formed both between the layer containing recombinant collagen and the further layer, and between the further layer and the fiber layer, particularly directly or indirectly, preferably directly. This embodiment of the invention allows the mechanical stability of the implant to be further increased to a significant advantage, and in particular the risk of cerebrospinal fluid leakage to be further reduced.

[0075] For the purposes of the present invention, the term "cured adhesive layer" means a layer that has a cured adhesive or consists of a cured adhesive. The curing of the adhesive can be based, for example, on polymerization and / or cross-linking.

[0076] The cured adhesive is preferably a cured fabric adhesive, in particular a cured cyanoacrylate adhesive, preferably a cured N-butyl cyanoacrylate adhesive, or a cured fibrin adhesive.

[0077] In a further embodiment of the invention, the fiber layer, in particular the fibers of the fiber layer, comprises a material that is degradable or resorbable in vivo. Preferably, the material that is degradable or resorbable in vivo is a polymer that is degradable or resorbable in vivo. The in vivo degradable or in vivo resorbable material can, in principle, be selected from the group consisting of polyglycolide or polyglycolic acid, polylactide or polylactic acid such as poly-L-lactide or poly-L-lactic acid, polydioxanone, poly-3-hydroxybutyrate or poly-3-hydroxybutyric acid, poly-4-hydroxybutyrate or poly-4-hydroxybutyric acid, polytrimethylene carbonate, poly-e-caprolactone, polyvinyl alcohol, cotton, cellulose, cellulose derivatives, alkylcelluloses, methylcellulose, hydroxyalkylcelluloses, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxyalkylcelluloses, carboxymethylcellulose, starch, amylose, amylopectin, dextran,Dextrin, chitin, chitosan, hyaluronic acid, dextran sulfate, heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, collagen, in particular recombinant collagen, gelatin, elastin, reticulin, fibronectin, laminin, fibrin, fibrinogen, albumin, copolymers thereof, salts thereof, stereoisomers, in particular diastereomers, thereof and combinations, in particular mixtures or blends, of at least two of the aforementioned in vivo degradable or in vivo resorbable materials.

[0078] The following describes particularly preferred embodiments with regard to the in vivo degradable or in vivo resorbable material mentioned in the previous paragraph:

[0079] In a further embodiment of the invention, the fiber layer, and in particular the fibers of the fiber layer, comprises poly-4-hydroxybutyric acid and / or poly-4-hydroxybutyrate. In the case of poly-4-hydroxybutyric acid or poly-4-hydroxybutyrate, it is advantageously a biocompatible material with very good degradation properties. In particular, no acidic degradation products are formed during its degradation.

[0080] In a further embodiment of the invention, the fiber layer, in particular the fibers of the fiber layer, comprises polylactic acid or polylactide. The polylactic acid or polylactide can be poly-D-lactic acid or poly-D-lactide and / or poly-L-lactic acid or poly-L-lactide.

[0081] For the purposes of the present invention, the terms “poly-D-lactic acid” and “poly-D-lactide” shall be understood to mean a polylactic acid and a poly-D-lactide respectively which is produced from D-(+)-lactic acid ((R)-(+)-lactic acid) and which is produced from D-(+)-lactide ((R)-(+)-lactide), respectively.

[0082] For the purposes of the present invention, the terms “poly-L-lactic acid” and “poly-L-lactide” shall be understood to mean a lactic acid and a poly-L-lactide, respectively, which is produced from L-(-)-lactic acid ((S)-(-)-lactic acid) and from L-(-)-lactide ((S)-(-)-lactide), respectively.

[0083] In a further embodiment of the invention, the fibrous layer, and in particular the fibers of the fibrous layer, comprises recombinant collagen. The recombinant collagen can, in particular, be collagen produced by a prokaryotic expression system, especially by bacteria, preferably Escherichia coli, or by a eukaryotic expression system, especially by tobacco plants or tobacco plant cells. Regarding further features and advantages of the recombinant collagen, reference is made to the descriptions already given in connection with the layer containing recombinant collagen, which can also apply analogously to the fibrous layer, and in particular the fibers of the fibrous layer.

[0084] In a further embodiment of the invention, the fibrous layer, in particular the fibers of the fibrous layer, comprises recombinant collagen and at least one synthetic in vivo degradable or synthetic in vivo resorbable polymer, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, polylactide such as poly-L-lactide, and mixtures of at least two of the aforementioned synthetic in vivo degradable or synthetic in vivo resorbable polymers. With regard to the recombinant collagen, reference is made in full to the preceding description. The features and advantages described therein with respect to the recombinant collagen also apply mutatis mutandis to this embodiment of the invention. In a further embodiment of the invention, the fibrous layer comprises fibers with a core-sheath structure.For the purposes of the present invention, the term "fibers with a core-sheath structure" shall be understood to mean fibers with a fiber core and a fiber sheath that at least partially, and in particular only partially or completely, surrounds the fiber core. Preferably, the core of the fibers with a core-sheath structure comprises a synthetic polymer that is degradable or resorbable in vivo, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, polylactide such as poly-L-lactide, and mixtures of at least two of the aforementioned synthetic polymers that are degradable or resorbable in vivo. The sheath of the fibers with a core-sheath structure preferably comprises recombinant collagen. Reference is made to the preceding description with regard to the recombinant collagen.The features and advantages described there in relation to recombinant collagen also apply analogously to this embodiment of the invention.

[0085] In a further embodiment of the invention, the implant comprises the following: a sponge-shaped layer with recombinant collagen, a fibrous layer comprising recombinant collagen and at least one synthetic in vivo degradable or synthetic in vivo resorbable polymer, and a further layer formed between the layer with recombinant collagen and the fibrous layer.

[0086] The sponge-shaped layer containing recombinant collagen can be present, in particular, in freeze-dried form. The further layer is preferably connected to both the layer containing recombinant collagen and the fiber layer via a cured adhesive layer, preferably directly or indirectly, and preferably directly. Regarding further features and advantages of the implant, in particular the layer containing recombinant collagen, the fiber layer, and the further layer, reference is made to the preceding description. The features and advantages described therein with respect to the implant, in particular the layer containing recombinant collagen, the fiber layer, and the further layer, also apply mutatis mutandis to this embodiment of the invention.

[0087] In a further embodiment of the invention, the layer with recombinant collagen, in particular like the fiber layer, is fibrous, in particular nonwoven, in particular as a spray or spun nonwoven, preferably as an electrospun nonwoven.

[0088] In a further embodiment of the invention, the layer with recombinant collagen is coated with an adhesion layer on one side opposite the further layer.

[0089] For the purposes of the present invention, the term "adhesion layer" is understood to mean a layer comprising or consisting of a material that is sticky or adhesive, particularly when in contact with bodily fluids. The adhesion layer may be in freeze-dried form. The sticky or adhesive material is a component of the adhesive layer.The adhesive material may in particular be selected from the group consisting of polyvinyl alcohol, cellulose, cellulose derivatives, alkyl celluloses, methyl cellulose, hydroxyalkyl celluloses, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxyalkyl celluloses, carboxymethyl cellulose, starch, amylose, amylopectin, dextran, dextrin, chitin, chitosan, hyaluronic acid, dextran sulfate, heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, collagen such as in particular recombinant collagen, gelatin, elastin, reticulin, fibronectin, laminin, fibrin, fibrinogen, albumin, copolymers thereof, salts thereof, stereoisomers, in particular diastereomers, thereof and combinations, in particular mixtures or blends, of at least two of the aforementioned adhesive or bonding materials.

[0090] Preferably, the layer containing recombinant collagen is the lowest layer in the implanted state, and the fiber layer is the uppermost layer of the implant in the implanted state.

[0091] Furthermore, the implant, in particular the layer with recombinant collagen and / or the fibrous layer and / or the subsequent layer, or in particular only the layer with recombinant collagen and / or only the fibrous layer and / or only the subsequent layer, may contain additives. The additives may be selected, in particular, from the group consisting of antimicrobial agents, fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), and mixtures of at least two of the aforementioned additives.

[0092] The antimicrobial agent may be, in particular, an antibacterial and / or antiviral agent. The antimicrobial agent may, for example, be selected from the group consisting of gentamicin, vankomycin, silver, copper, zinc, gold, hydroxyapatite, chitosan, and mixtures of at least two of the aforementioned antimicrobial agents. The silver and / or copper and / or zinc and / or gold may be present, in particular, in the form of nanoparticles.

[0093] The fibroblast growth factor may in particular be selected from the group consisting of FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-22, FGF-23 and mixtures of at least two of the aforementioned fibroblast growth factors.

[0094] The vascular endothelial growth factor may in particular be selected from the group consisting of VEGF-A, VEGF-B, VEGF-C, VEGF-D, PIGF (Placental Growth Factor) and mixtures of at least two of the aforementioned vascular endothelial growth factors.

[0095] The nerve growth factor is preferably beta-NGF.

[0096] The insulin-like growth factor may in particular be IGF-1 and / or IGF-2.

[0097] Furthermore, the implant can have a hydrophobic surface, in particular a hydrophobic coating. The hydrophobic surface, in particular the hydrophobic coating, can comprise a hydrophobic material, which is specifically selected from the group consisting of polylactic acid, polylactide, fibroin, polycaprolactone (PCL), zein, and mixtures of at least two of the aforementioned hydrophobic materials. The hydrophobicity of the coating can alternatively or in combination be achieved by structuring the surface of the aforementioned materials or the fiber layer itself with a precisely controlled roughness (similar to the biomimetic principle of the lotus effect). This can advantageously also impart antimicrobial properties to the implant. Furthermore, the implant can be transparent.The transparency of the implant can be specifically adjusted by choosing the materials used for its manufacture and / or their processing techniques.

[0098] Furthermore, the implant can be designed to be MRI-compatible, i.e., compatible with magnetic resonance imaging (MRI). This can be achieved by designing the implant using only non-ferromagnetic materials.

[0099] Furthermore, the implant can have a layer thickness of 0.4 mm to 4.9 mm, in particular 0.4 mm to 3.7 mm, preferably 0.66 mm to 1.4 mm.

[0100] The implant according to the invention is preferably an implant for use in the treatment of a defect, in particular in the replacement and / or closure, of the dura mater, preferably the cranial dura mater.

[0101] Furthermore, the implant can consist in particular of the layer with recombinant collagen and the fiber layer, or of the layer with recombinant collagen, the fiber layer and the further layer.

[0102] Further features and advantages of the invention will become apparent from the claims and from the following description of preferred embodiments with reference to the figure descriptions and the corresponding figures. Features of the invention may be implemented individually or in combination with one another. The embodiments described below serve to further explain the invention without limiting it.

[0103] BRIEF DESCRIPTION OF THE DRAWINGS

[0104] The figures schematically depict the following:

[0105] Fig. 1: an embodiment of an implant according to the present invention,

[0106] Fig. 2: another embodiment of an implant according to the present invention,

[0107] Fig. 3: another embodiment of an implant according to the present invention and Fig. 4: another embodiment of an implant according to the present invention.

[0108] DETAILED CHARACTER DESCRIPTION

[0109] Fig. 1 schematically shows an embodiment of an implant 1 according to the invention. The implant 1 is intended for treating a defect, in particular for replacing and / or closing, the dura mater, preferably the cranial dura mater.

[0110] The implant 1 has a layer 2 with recombinant collagen and a fiber layer 3.

[0111] The recombinant collagen in layer 2 allows implant 1 to advantageously avoid the disadvantages associated with other known implants, such as the transmission of pathogens and inconsistencies originating from animal and / or tissue sources. Furthermore, due to more reproducible manufacturing methods, the recombinant collagen in layer 2 can be better and more reliably formulated with additives, particularly growth factors, preferably fibroblast growth factors, vascular endothelial growth factors, nerve growth factors, epidermal growth factors, insulin-like growth factors, or mixtures thereof. This is especially beneficial for rapid and effective cell adhesion, migration, and proliferation, and thus for the regeneration of native dura mater tissue.

[0112] The fiber layer 3 advantageously ensures a cerebrospinal fluid tightness and, in particular, the sutureability of the implant.

[0113] Layer 2, containing recombinant collagen, is preferably designed to be open-pored.

[0114] Furthermore, layer 2 can be designed to be particularly sponge-like with recombinant collagen.

[0115] Preferably, layer 2 with recombinant collagen has pores with a mean diameter of 20 pm to 400 pm, in particular 30 pm to 400 pm, preferably 90 pm to 300 pm. This advantageously allows both infiltration of layer 2 and thus of the implant 1 with fibroblasts required for the regeneration of dura mater tissue, and in particular vascularization of the dura mater tissue to be regenerated.

[0116] Preferably, layer 2, containing recombinant collagen, is in freeze-dried or lyophilized form. This has the particular advantage that fixation of implant 1 is possible without the use of additional fixatives, such as sutures or adhesives.

[0117] The recombinant collagen of layer 2 is preferably a collagen produced by a prokaryotic expression system, in particular by bacteria, preferably Escherichia coli, or by a eukaryotic expression system, in particular by tobacco plants or tobacco plant cells.

[0118] Preferably, the fiber layer 3 comprises nanofibers 4. A nanofiber-shaped design of layer 3 can advantageously stimulate an earlier stage of tissue regeneration. This can be achieved, in particular, via appropriate cell signals. Overall, this can positively influence the healing and regeneration process of the dura mater being treated.

[0119] The fiber layer 3 is preferably (also) designed to be open-pored. In particular, the fiber layer 3 can have pores with a mean diameter of 20 pm to 400 pm, more particularly 30 pm to 400 pm, preferably 90 pm to 300 pm. The aforementioned pore diameters have the advantage that they allow the migration of fibroblasts important for tissue regeneration as well as the vascularization of dura mater tissue to be regenerated.

[0120] The fiber layer 3 is preferably in the form of a nonwoven fabric. Particularly preferably, the fiber layer 3 is designed as a sprayed nonwoven or spunbond nonwoven, especially an electrospunbond nonwoven. This advantageously allows for the creation of a particularly fine fibrillar and, in particular, porous layer that not only mimics the extracellular matrix of the native dura mater tissue in its structure and architecture, especially with regard to fiber diameter and / or fiber arrangement and / or pore diameter and / or porosity, thereby facilitating the ingrowth of fibroblasts and the formation of blood vessels. In addition, a nonwoven design of the fiber layer 3 advantageously also provides sufficient mechanical stability with good elasticity and adequate sealing against the cerebrospinal fluid.

[0121] Preferably, the fiber layer 3 is formed directly on the layer 2. In particular, the fiber layer 3 can be sprayed or spun directly onto the layer 2. This allows for particularly strong adhesion between layers 2 and 3. Preferably, the fiber layer 3, and especially the fibers 4 of the fiber layer 3, comprises poly-4-hydroxybutyric acid and / or poly-4-hydroxybutyrate. Poly-4-hydroxybutyric acid and poly-4-hydroxybutyrate advantageously exhibit good biocompatibility and very good degradation properties (no acidic degradation products are formed during degradation).

[0122] Fig. 2 shows another embodiment of an implant 1 according to the invention.

[0123] The implant 1 is intended for the treatment of a defect, in particular for the closure and / or replacement, of the dura mater, especially the cranial dura mater.

[0124] The implant 1 has a layer 2 with recombinant collagen and a fiber layer 3.

[0125] Between layer 2 containing recombinant collagen and fibrous layer 3, the implant 1 has a further layer 5. This further layer 5 is preferably formed directly between layer 2 containing recombinant collagen and fibrous layer 3. Alternatively, the further layer 5 may not be formed directly between layer 2 containing recombinant collagen and fibrous layer 3.

[0126] Preferably, the further layer 5 is in the form of a mesh, in particular a knitted mesh. The mesh may preferably comprise polyglycolic acid and / or polyglycolate. The mesh may, in particular, be a mesh for soft tissue reconstruction. Advantageously, the mesh exhibits high tensile strength with, in particular, uniform elongation in the longitudinal and transverse directions of the mesh. Furthermore, the mesh may, in particular, be degradable or resorbable in vivo within a period of 60 to 90 days. A suitable mesh is commercially available from the applicant, for example, under the name Safil® Mesh.

[0127] The additional layer 5 advantageously ensures or further increases the mechanical stability of implant 1. To achieve a good bond with layer 2, the additional layer 5 can be applied to layer 2 in a moist state and then freeze-dried. In other words, both layer 2 with recombinant collagen and the additional layer 3 can be in freeze-dried or lyophilized form.

[0128] Fiber layer 3, in particular fibers 4 of fiber layer 3, may comprise recombinant collagen and / or at least one synthetic in vivo degradable or synthetic in vivo resorbable polymer, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, polylactide such as poly-L-lactide, and mixtures of at least two of the aforementioned synthetic in vivo degradable or synthetic in vivo resorbable polymers. In particular, fiber layer 3, in particular fibers 4 of fiber layer 3, may comprise recombinant collagen and / or polylactic acid or polylactide, in particular poly-L-lactic acid or poly-L-lactide.

[0129] Preferably, the fiber layer 3 is designed as a nonwoven fabric, in particular a spray-on or spunbond nonwoven, preferably an electrospunbond nonwoven.

[0130] Regarding further features and advantages of implant 1, in particular with respect to layer 2 with recombinant collagen and fiber layer 3, reference is made in full to the features and advantages described in connection with the implant shown in Fig. 1. The features and advantages of layer 2 with recombinant collagen and fiber layer 3 described therein apply mutatis mutandis.

[0131] Fig. 3 shows another embodiment of an implant 1 according to the invention.

[0132] The implant 1 is intended for the treatment of a defect, in particular for the closure and / or replacement, of the dura mater, especially the cranial dura mater.

[0133] The implant 1 has a layer 2 with recombinant collagen and a fiber layer 3.

[0134] The fiber layer 3, in particular the fibers 4 of the fiber layer 3, preferably comprise recombinant collagen and / or at least one synthetic in vivo degradable or synthetic in vivo resorbable polymer, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, polylactide such as poly-L-lactide and mixtures of at least two of the aforementioned synthetic in vivo degradable or synthetic in vivo resorbable polymers.

[0135] Between layer 2 with recombinant collagen and the fiber layer 3, the implant 1 has a further layer 5.

[0136] The further layer 5 is connected to both layer 2 with recombinant collagen and fiber layer 3 via a cured adhesive layer 6, preferably directly. This allows for a further increase in the mechanical stability of the implant and, in particular, a further reduction in the risk of cerebrospinal fluid leakage. The cured adhesive can be, in particular, a cured cyanoacrylate adhesive, preferably a cured N-butyl cyanoacrylate adhesive, or a cured fibrin adhesive.

[0137] Regarding further features and advantages of implant 1, in particular with respect to layer 2 with recombinant collagen, fiber layer 3, and the further layer 5, reference is made in full to the features and advantages described in connection with the implants shown in Figures 1 and 2. The features and advantages of layer 2 with recombinant collagen, fiber layer 3, and the further layer 5 described therein apply mutatis mutandis.

[0138] Fig. 4 shows another embodiment of an implant 1 according to the invention.

[0139] The implant 1 is intended for the treatment of a defect, in particular for the closure and / or replacement, of the dura mater, especially the cranial dura mater.

[0140] The implant 1 has a layer 2 with recombinant collagen and a fiber layer 3.

[0141] The fiber layer 3, in particular the fibers 4 of the fiber layer 3, preferably comprise recombinant collagen and / or at least one synthetic in vivo degradable or synthetic in vivo resorbable polymer, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, polylactide such as poly-L-lactide and mixtures of at least two of the aforementioned synthetic in vivo degradable or synthetic in vivo resorbable polymers.

[0142] Layer 2 with recombinant collagen is fibrous, in particular nonwoven, especially as a spray or spun nonwoven, preferably as an electrospun nonwoven, like fiber layer 3.

[0143] Between layer 2 with recombinant collagen and fiber layer 3, the implant 1 has a further layer 5. This further layer 5 can be formed directly or indirectly between layer 2 with recombinant collagen and fiber layer 3.

[0144] Preferably, the further layer 5 is in the form of a mesh, in particular a knitted mesh.

[0145] The network may preferably contain polyglycolic acid and / or polyglycolate. Furthermore, layer 2 is coated with recombinant collagen on one side opposite the further layer 5 with an adhesion layer 7.

[0146] The adhesion layer 7 consists of a material that is sticky or adhesive, particularly upon contact with bodily fluids. The adhesion layer 7 may be present in a freeze-dried form. The sticky or...The adhesive material may in particular be selected from the group consisting of polyvinyl alcohol, cellulose, cellulose derivatives, alkyl celluloses, methyl cellulose, hydroxyalkyl celluloses, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxyalkyl celluloses, carboxymethyl cellulose, starch, amylose, amylopectin, dextran, dextrin, chitin, chitosan, hyaluronic acid, dextran sulfate, heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, collagen such as in particular recombinant collagen, gelatin, elastin, reticulin, fibronectin, laminin, fibrin, fibrinogen, albumin, copolymers thereof, salts thereof, stereoisomers, in particular diastereomers, thereof and combinations, in particular mixtures or blends, of at least two of the aforementioned adhesive or bonding materials.

[0147] Regarding further features and advantages of implant 1, in particular with respect to layer 2 with recombinant collagen, fiber layer 3, and the further layer 5, reference is made in full to the features and advantages described in connection with the implants shown in Figures 1, 2, and 3. The features and advantages of layer 2 with recombinant collagen, fiber layer 3, and the further layer 5 described therein apply mutatis mutandis.

Claims

Patent claims 1. Implant (1) for treating, in particular replacing and / or closing, the dura mater, comprising - a layer (2) with recombinant collagen and - a fibrous layer (3) wherein a further layer (5) is formed between the layer (2) with recombinant collagen and the fibrous layer (3).

2. Implant (1) according to claim 1 , characterized in that the layer (2) is designed in a sponge-like form with recombinant collagen and / or is in freeze-dried form.

3. Implant (1) according to claim 1 or 2, characterized in that the layer (2) with recombinant collagen is designed to be open-pored, preferably having pores with a mean pore diameter of 20 pm to 400 pm, in particular 30 pm to 400 pm, preferably 90 pm to 300 pm.

4. Implant (1) according to one of the preceding claims, characterized in that the recombinant collagen is a collagen produced by a prokaryotic expression system, in particular by Escherichia coli, or by a eukaryotic expression system, in particular by tobacco plant cells.

5. Implant (1) according to one of the preceding claims, characterized in that the fiber layer (3) comprises microfibers and / or nanofibers (4), preferably fibers (4) with a mean diameter of 0.1 nm to 5000 nm, in particular 0.1 nm to 2000 nm, preferably 0.1 nm to 1000 nm.

6. Implant (1) according to one of the preceding claims, characterized in that the fiber layer (3) is designed to be open-pored, preferably having pores with a mean diameter of 20 pm to 400 pm, in particular 30 pm to 400 pm, preferably 90 pm to 300 pm.

7. Implant (1) according to one of the preceding claims, characterized in that the fiber layer (3) is designed in a nonwoven form, in particular as a spray or spunbond nonwoven.

8. Implant (1) according to one of the preceding claims, characterized in that the further layer (5) is in the form of a mesh, in particular a knitted mesh.

9. Implant (1) according to one of the preceding claims, characterized in that the further layer (5), in particular the mesh, comprises polyglycolic acid and / or polyglycolate.

10. Implant (1) according to one of the preceding claims, characterized in that a cured adhesive layer (6) is formed between the layer with recombinant collagen and the further layer (5) and between the further layer (5) and the fiber layer (3), preferably directly.

11. Implant (1) according to one of the preceding claims, characterized in that the fiber layer (3), in particular the fibers (4) of the fiber layer (3), comprises an in vivo degradable or in vivo resorbable material, preferably an in vivo degradable or in vivo resorbable polymer.

12. Implant (1) according to one of the preceding claims, characterized in that the fiber layer (3), in particular the fibers (4) of the fiber layer (3), comprises poly-4-hydroxybutyric acid and / or poly-4-hydroxybutyrate.

13. Implant (1) according to one of claims 1 to 11 , characterized in that the fiber layer (3), in particular the fibers (4) of the fiber layer (3), comprises polylactic acid and / or polylactate, in particular poly-L-lactic acid and / or poly-L-lactate.

14. Implant (1) according to one of claims 1 to 11 , characterized in that the fiber layer (3), in particular the fibers (4) of the fiber layer (3), comprises recombinant collagen.

15. Implant (1) according to one of claims 1 to 11, characterized in that the fiber layer (3), in particular the fibers (4) of the fiber layer (3), comprises recombinant collagen and at least one synthetic in vivo degradable or in vivo resorbable polymer, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, Polylactide such as poly-L-lactide and mixtures of at least two of the aforementioned synthetic in vivo degradable or in vivo resorbable polymers.

16. Implant (1) according to one of claims 1 to 11 or 15, characterized in that the fiber layer (3) comprises fibers (4) with a core-shell structure, wherein the core of the fibers (4) preferably comprises a synthetic in vivo degradable or in vivo resorbable polymer, in particular selected from the group consisting of poly-4-hydroxybutyric acid, poly-4-hydroxybutyrate, polylactic acid such as poly-L-lactic acid, polylactide such as poly-L-lactide and mixtures of at least two of the aforementioned synthetic in vivo degradable or in vivo resorbable polymers, and the shell comprises recombinant collagen.

17. Implant (1) according to one of the preceding claims, characterized in that the implant (1) comprises: a sponge-shaped layer (2) with recombinant collagen, a fiber layer (3) comprising recombinant collagen and at least one synthetic in vivo degradable or in vivo resorbable polymer, and a further layer (5) formed between the layer (2) with recombinant collagen and the fiber layer (3), wherein the further layer (5) is connected to both the layer (2) with recombinant collagen and the fiber layer (3) via a cured adhesive layer (6), preferably directly.

18. Implant (1) according to one of the preceding claims, characterized in that the layer (2) with recombinant collagen is fibrous, in particular nonwoven, in particular as a spray or spunbond nonwoven, like the fiber layer (3).

19. Implant (1) according to claim 18, characterized in that the layer (2) with recombinant collagen is coated with an adhesion layer (7) on one side opposite the further layer (5).

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