DE102005018644A1 - Implant for treatment of defects in long bone, comprises layers of flat, bioresorbable material, adapted to the shape of the defect, having porosity that allows entry of cells and blood vessels - Google Patents

Abstract

Implant (A) for treatment of long bone defects comprises at least two layers of a flat structure, made of bioresorbable material, adapted to the geometry of the defect, where the layers comprise stacks, rolls, coils and/or folds of the flat structures, and the structures and/or layers together have cavities on the outside that permit inward migration of cells and inward growth of blood vessels. Independent claims are also included for: (1) flat structures, as described, that include cavities forming an interconnected porosity; and (2) preparing (A).

Description

The The invention relates to an implant, for certain fabrics for the treatment of tubular bone defects, in particular segmental long bone defects and a method of making the implant.

Of the Loss of a segment of bone mass must be in the long bones be treated that over a compartmentalization promoted the bone regeneration and at the same time an ingrowth of non-specific connective tissue in the defect as possible is prevented. Next is to maintain the mechanical Function requires a fixation. This can be both inside the body as well as outside to come to rest.

The Separation between the said defect space and the surrounding tissue can be done by a partially permeable resorbable polymer membrane (Gerber A, Gogolewski S, Injury 33 (2002), S-B43-57). By the Application of periostal flaps can achieve the same goal. In both cases is the new bone formation by autologous cancellous bone, which in the introduced compartment is supported. there However, one is limited to small defect areas, since endogenous Material for defect filling only limited available is. Especially after tumor resections, these methods are therefore suboptimal. For the mechanical stabilization of the defect becomes an intramedullary nail into the medullary spaces used and fixed.

A another possibility To get the new bone tissue to make room, is the use of partially porous Hollow cylinders made of resorbable polymers. Soaked in a suspension of bone marrow aspirate, Blood and other body fluids These are coaxially positioned around the central intramedullary nail. This was by Davydov, Belykh, Shaposhnikov et. al. proposed (WO 90/11726). The low porosity in conjunction with the dimensions of the implant leads to a Obstruction of mass transport. This is accompanied by the problem of Supply of living material inside the implant. Of the high volume fraction of polymer can during its degradation to a strong acidification of surrounding tissue, thereby suppressing osteogenesis or can be prevented.

But also polymeric materials that are not subject to absorption, are used as a temporary placeholder such as e.g. PMMA (Romana MC, Masquelet AC; Plast. Reconstr. Surg. 85 (1990), 587-592). In spite of their good biocompatibility and mechanical properties that may correspond to the use outweighs while the disadvantage of missing tissue functions.

Out EP 12 52 905 A2 are resorbable, textile patch implants of poly (3-hydroxybutyric acid) -Flächengebilden known. Such patch implants are used essentially for closing tissue defects. These implants must have no porosity. This would prevent compartmentalization. A combination with foils is used to reduce the Durchlässigleit. Furthermore, a targeted adaptation and preparation is necessary. A sufficient cytocompatibility is z. B. achieved only by plasma treatments (Schmack G et al, BIOmaterialien 3 (1) 2002, 21-25). To create a biocompatible surface area, further measures are therefore essential.

EP 0 744 762 B1 describes embroidered surgical textile implants in combination with a base fabric. Characteristics are defined by a special fiber combination and a special folding, winding or loading with growth factors. Biomimetic modeling of the niche or even in vitro tissue engineering are not considered.

task The invention is an implant as well as specific fabrics for the treatment of tubular bone defects to accomplish. In this case, the implant and the tissue formation and the Promote ingrowth of bone, connective and supply tissues and Taxes.

According to the invention Task thereby solved an implant, the at least two layers of fabrics contains bioabsorbable materials, wherein the fabrics and the layers of the sheets to the geometry of the long bone defect are adapted and the layers of stacks and / or rolls and / or Winding and / or folding of the fabrics exist. there assign the fabrics and / or layers with each other and externally connected cavities and an interconnected porosity on, which allow the migration of cells and ingrowth of blood vessels.

In According to an advantageous embodiment of the invention, the implant from at least two layers of partially or wholly with an artificial extracellular matrix coated fabrics.

The fabrics intended for the implants according to the invention consist of bioresorbable materials, are adapted to the geometry of the long bone defect and follow suit Inside and outside cavities and an interconnected porosity, which allows the ingress of cells and blood vessel ingrowth.

The for the Determine implants according to the invention sheet have a thickness of 0.05 - 5 mm in the unloaded condition. The fabrics have one Porosity, which accounts for at least 60% of the total volume. This porosity is interconnected and thereby makes the pore volume in the interior of the surface of the sheet from accessible. At least 50% of the porosity is contained in pores that have a smallest diameter of more than 40 μm to have. This volume is called main porosity. Lying several pores in the main porosity to each other, the diameter of the connection opening is not less than 40 μm.

The Structure of the fabrics according to the invention allows it to always be stacked or rolled so that the contact surfaces at least 60% agreement the two structures is present. That means that at least 60% of the open area also on openings of the adjacent area comes to rest.

The for the Determine implants according to the invention sheet are preferably adapted to their physicochemical surface properties modified before implantation. Preference is given to a hydrophilic surface produced by wet chemical processes. In the event that the fabric is made of polyesters, a hydrophilic surface is preferred by treatment with acids, Bases or enzymes, e.g. Esterases generated. This will be the Wettability of the fabrics, especially those with small seam spacing and / or short stitch lengths or - in the case of Vlies - tight Structure-wide, with aqueous media for further Process steps improved. This is also true in the case of the following Coating with components of the extracellular matrix beneficial.

The for the Determine implants according to the invention sheet are preferably on a part of their surface or completely with an artificial one extracellular Matrix coated, which colonization with a specific Cell type promotes and / or the proliferation of progenitor cells and their differentiation allowed.

among them For example, different proportions of the coating on the surface of the fabric (full Coating or partial coating), differences in composition the artificial one extracellular Matrix, in the substructuring of the extracellular matrix and / or in place the coating with the artificial extracellular matrix on the sheet to understand.

The Coating of the fabric takes place disorderly or ordered, for example by means of spatially resolved microdosing. The aim of this approach is to allow 3 dimensional spatially resolved processes the adhesion, Migration, proliferation and differentiation of different cell types targeted control (cell guidance).

Preferably becomes the artificial one extracellular Matrix by directional or non-directional freeze-drying processes or by partially mixing the solution with aqueous gels of carbohydrates or glycosaminoglycans. In both cases will allows that the inner surfaces of the fabric (Mesh, pores) remain accessible. This is advantageous to allow ingrowth of the cell material.

The Composition of the artificial extracellular Matrix is dependent from the desired Tissue function (e.g., blood vessel formation, cartilage, Bone).

In a preferred embodiment, the artificial extracellular matrix contains structural proteins, preferably xenogenic collagens of all types, or polypeptides derived therefrom, which are applied to the sheet with a surface density of 10 to 100 μg / mm ² . These structural proteins favor the tissue-specific adhesion and proliferation of human cells ex vivo and in particular allow, favor or induce the differentiation of human mesenchymal stem cells (hMSC) or other osteoprogenitor cells.

In a particularly preferred embodiment are collagen type I or polypeptides derived therefrom Main component of the artificial extracellular Matrix. Such an artificial one extracellular Matrix promotes in particular the formation of bone tissue.

For the treatment of cartilage defects is preferred collagen II main component of artificial extracellular Matrix.

In contrast, vascularization requires a vascular-analogous artificial extracellular matrix. In particular, structural proteins of the vessel lining are used as part of the artificial extracellular matrix, preferably fibrinogen. This artificial extracellular matrix, which is used for blood vessel formation, promotes in particular the colonization with human dermal mi endothelial progenitor cells and / or proliferation of human mesenchymal stem cells and their differentiation along a vascular endothelial cell line.

The artificial extracellular Matrix is preferably further used to further there Substances of the natural extracellular Immobilize matrix. By adsorption or installation optional followed by covalent crosslinking, e.g. glycosaminoglycans (Chondroitin sulfate, heparan sulfate), glycoproteins, proteoglycans or structural proteins mentioned above. This extra Optionally, components serve for improved differentiation of the applied cell material. By interacting with certain Supplements of cell culture or native serum components such as e.g. Cytokines or hormones unfold the artificial extracellular matrix here a co-stimulatory effect, in a more complete or accelerated differentiation results. This procedure open e.g. the possibility, within several surface elements to generate different differentiation states of the cell material.

The sheets are preferably stacked or wound into a three-dimensional structure. The assignment of the layers and, if appropriate, their stabilization can be achieved by fixing to an intramedullary nail, another fixator ( 8th ), such as resorbable screws and by sewing.

When Starting material for serve the fabrics preferably textile fabrics bioabsorbable materials, such as poly (3-hydroxybutyrate) (P3HB) or poly-L-lactic acid (50mol%) - glycolic acid (mol50%) (PLGA).

she can by embroidering with resorbable multi- or monofilament threads removable carrier fleece, preferably from water-soluble, non-toxic polyvinyl alcohol (PVA). Likewise, others can textile processes are used to the precursors of the fabrics to create. In this case, advantageously several materials are combined. That way you can location-dependent different material properties are set. So will for example, a local control of the degradation rate reached. By using two materials with different degradation characteristics in a plane it is possible to obtain a compartmentalization in the edge area and still in the Interior in a thoughtful way due to faster bioresorption space to create for native de novo tissue.

It can also felt-like non-woven fabrics or porous sheets, which are about process steps like for example foaming, Pressing of granules or fibers followed by leaching of a soluble Second phase to be generated.

Of the Structure of the three-dimensional implant of several layers of two-dimensional fabrics advantageously allows easy patient-specific adaptation to the present defect size the combination of a suitable number of layers of the used At given thickness of the fabrics.

According to the invention is a Implant for the treatment of tubular bone defects from at least two layers of fabrics made of bioabsorbable materials and with inward and outward reaching cavities and an interconnected porosity, wherein the geometry of the long bone defect determined and transferred into two-dimensional structural patterns for the fabrics becomes, whereby the fabrics based on this structural data and before implantation according to the defect geometry merged and implanted in the defect space.

The Geometry of each sheet is preferably determined from three-dimensional data from computed tomography. In the process, patient data of the defect volume are obtained by using common methods for producing sectional representations from computer tomography data transferred into two-dimensional structure pattern.

The Defect geometry is translated into two-dimensional structural patterns for the sheets. In the simplest case, it can be based on simple pre-assembled standard geometries (Discs, ellipses, ...) used become. If 3D data is available, the shaping can take place via a CAD interface and the structuring of the fabrics by For example, cutting processes or textile processes take place. So can in addition to a specific geometry, also gradients in the material surface density are generated, which have congruence with the tissue. Or the material composition is spatially resolved varies, for example, different degradation times adjoin adjacent areas.

The fabric so produced can be physicochemical surface modified become. Preferably, the surface is hydrophilized. This step serves for improved biofunctionalization and optimization the surface for the direct cell and tissue contact. The physicochemical modification can be spatially resolved or over the entire surface done by acids, Bases or suitable enzymes are applied.

Now may be the application of an artificial extracellular matrix consequences. It is used for cell guidance (control of adhesion, proliferation, differentiation, ...) and can consist of any number of components. The concentration and the composition of the matrix can be a function of the place be.

The functionalized fabrics are colonized with cells that are ideally patient-like and facilitate the restoration of tissue function in defect or secure. The cell colonization of the surfaces takes place from suspension and leads to a homogeneous cell covering on the two surfaces of the Sheet. In vitro can these fabrics be cultivated very well. The accessibility of the cells with nutrients and Supplements are excellent as there are no paths in volume Need to become (Flow instead of diffusion). So, depending on the situation, first of all Proliferation rate can be improved and a subsequent dose of corresponding active ingredients to a - at least onset - differentiation to lead.

In front The implants become the tissues according to the above determined defect geometry merged. It is created by stacks or roles one spatially structured volume. By the procedure become the local characteristics of the carrier material (Sheet), the local matrix composition (functionalization) and the local Presence of certain cell types (colonization) controllable.

With a fixation, this construct is implanted in the defect space.

alternative The shaping can also be done by cutting or punching Areas of felt-like non-woven fabrics or porous panels corresponding thickness by laser, water jet or punching respectively.

In both cases can be a defined spatially resolved Gradient of material surface density be set, for example in the case of textile fabrics by radially extending seam lines at an angular distance of 10 ° and parallel to the outer contour guided seams, the a linear porosity gradient from 90% (outdoor) to 65% (indoor) produce. This approach aims three aspects: to achieve a compartmentalization, the mechanical Set properties of the fabrics spatially resolved and to control the ingrowth of cells in a targeted manner (cell guidance).

By the stacking of several layers of individual different coated fabric fabric In the implant advantageously functionally different areas produced, depending on the composition of the artificial extracellular matrix or different depending on the pre-colonization with different cell types Exercise tissue functions, e.g. the formation of bone tissue, cartilaginous tissue or sprouting of blood vessels.

In an operation, the defect space is filled with the implant, wherein the differently coated and possibly populated with cells sheet preferably alternately stacked so that congruence with the surrounding Fabric exists.

The implant according to the invention allows so for example, filling of segmental defects in long bones with a stack of coated fabrics that come with a central intramedullary nail to be stabilized as a fixator.

In As a result of the implantation resulting holes can also by introducing a stack of coated fabrics are supplied. In the epiphysis of the long bone In this case, a stack can be introduced which is in the uppermost layer with cartilage-type connective tissue components such as collagen II and hyaluronic acid functionalized.

Especially It is advantageous to coat the fabrics coated with the extracellular matrix in the cell culture medium prior to assembly of the implant with defective and defective environment-typical cells to contact, as the on the fabrics adherent Cells by the loose arrangement of the fabrics in the medium better through nutrients and Supplements are achievable than with conventional methods. This allows an increased Proliferation yield in combination with a following accelerated Differentiation of progenitor cells. In a particularly preferred embodiment invention, the cells used come from the patient himself. At the same time result from this advantageous procedure in Volume homogeneous with similar or different cell types populated three-dimensional implants.

Based of the following embodiments the invention closer explained. In the drawings show

1 : a schematic representation of the production of an implant according to the invention from several layers of differently coated fabrics,

2 : a first textile fabric,

3 : a second textile fabric,

4 a third textile fabric,

5 a fourth textile fabric,

6 : a pile fixed with threads,

7 a staple fixed and reinforced with an intramedullary nail,

8th : a band of fabrics to form a stack,

9 a wrap of two fabrics,

10 : a sheet of a nonwoven,

11 : a sheet of a porous plate.

In the attached Drawings use the following reference numerals:

1

sheet

2

thread

3

Mark Nagel

4

contoured tape

5

hole

6

spatially resolved functionalized areas

7

stack

8th

fixator

embodiments

1 shows a schematic representation, is explained by means of which, as from several layers of textile fabrics 1 an implant according to the invention for the treatment of a long bone defect is constructed.

2 shows a textile fabric 1 which is circular with a diameter of twenty mm, has a central concentric circular opening of four mm diameter, the stitch length and the seam spacing being 0.6 mm. In addition, the textile fabric contains 1 four radially arranged, equally distributed slots with a width of one mm.

3 shows a second textile fabric 1 with interconnected hollow volume (mesh spaces). The structure has orthogonal and circumferential seam lines. The contour shape can be freely generated according to the determined defect geometry and is preferably derived from patient-specific data.

4 shows a third textile fabric 1 similar to that 3 , which is additionally provided with a central opening of 4 mm diameter and has a different material surface density. The seam lines run parallel to the outer contour and radially at an angular distance of 10 ° and produce a linear porosity gradient of 90% (outdoor area) to 65% (indoor area).

5 shows the fabric 1 out 4 , but spatially resolved coated with an artificial extracellular matrix. The gray value of the area shows the area concentration, where black represents the maximum area concentration and white represents the minimum area concentration.

6 shows three stacked sheets 1 according to 3 their position to each other by thread-like fasteners 2 is fixed, which is approximately perpendicular through the fabric 1 run.

7 shows three stacked sheets 1 which are in position to each other on an intramedullary nail 3 are attached. The three fabrics are spatially differently coated ( 1a and 1b ).

8th shows a contoured band 4 made of a fleece, which is a librello made of coherent, centrally perforated ronde-shaped fabrics 1 equivalent. The diameter of all ronde-shaped surface elements 1 is 35 mm, the overlapping area has a maximum extension of 5 mm. The holes 5 have a diameter of 5 mm. This band 4 is coated in accordance with Embodiment 2 with a matrix of collagen I and chondroitin-4-sulfate. At a defined position becomes an additional spatially resolved coating with heparan sulfate 6 introduced analogously to Example 1, which leads to a congruent volume of this functionalization during folding.

By folding the contoured band 4 a pile is created 7 from fabrics 1 , This is in each kink another Ronde-shaped sheet 1 which is also functionalized with heparan sulfate in a spatially resolved manner 6 is. However, this functionalization extends to the edge of the construct, thus establishing contact of this volume with the outer interface of the implant. The contoured band 4 and the Ronde-shaped fabrics 1 have spatially resolved functionalized areas 6 and holes 5 that at the stack 7 to be congruent with each other.

The colonization and preculture takes place according to Embodiment 1 is fixed centrally with an intramedullary nail.

9 shows two superimposed sheets 1α and 1β having a fixator 8th to be wound in the defect space.

There are by embroidering with parameters of embodiment 1 rectangular sheets 1 generated (30 mm × 200 mm). The first fabric 1α becomes with matrix 1 coated from embodiment 2. The second fabric 1β receives a functionalization with heparan sulfate analog embodiment 1 , The two fabrics 1α and 1β are superimposed to a fixator 8th wrapped and attached to the fixator with suitable suture material. The colonization and preculture is carried out according to Embodiment 1.

10 shows a sheet 1 , which was obtained by a cutting process from a nonwoven fabric.

11 shows a fabric punched out of an interconnected porous flat semi-finished product 1 ,

Embodiment 1

Treatment of a long bone defect of 3 cm in length To treat a long bone defect of 3 cm in length, initially two different textile fabrics are used 1 (Scaffolds) from 12 filamentary threads of poly (3-hydroxybutyrate) (P3HB) embroidered on a backing fleece made of polyvinyl alcohol with lockstitch.

A first textile fabric is used after appropriate preparation for colonization with osteoblasts, which build on this a bone tissue (see 1 below). A second textile fabric is used after appropriate preparation for colonization with endothelial cells, which build on this vascular tissue (see 1 above).

The first fabric (type 1) is circular, 20 mm in diameter, and has a central concentric circular opening of 4 mm in diameter, stitch length and seam spacing are 0.6 mm. The second textile fabric (type 2) additionally contains 4 radially arranged, uniformly distributed slots with a width of 1 mm (see 2 ).

The finished embroidered fabrics 1 are dissolved by rinsing with 60 ° C warm water in which dissolves the polyvinyl alcohol, from the carrier fleece. Any existing residues of silicone-containing lubricants are in a high-purity heptane bath at room temperature from the textile fabrics 1 away. By a subsequent immersion of the textile fabrics 1 in methanolic (50% v / v) sodium hydroxide solution (1.5 mol / l) for a period of 30 min, the surface of the textile fabrics 1 hydrophilized.

For coating the first textile fabric 1 (Type 1 ), a tropocollagen I solution (10 mg / ml in 10 mmol / l acetic acid) containing chondroitin 4-sulfate (2 mg / ml) is prepared. The pH is adjusted to 7.4 by appropriate buffers. A collagen mass equivalent of 30 μg / mm ² is applied to the fabrics and incubated for 12 hours to form a pattern at 37 ° C. Freezing at -20 ° C, followed by freeze-drying, crosslinking with EDC (N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide) (CAS 25952-53-8, 20 mg / ml, pH 5.5) and final rinsing with saline and distilled water ensure substructuring. The textile fabrics thus produced 1 are sterilized with ethylene oxide.

The coating of the second textile fabric 1 (Type 2) is done accordingly, but chondroitin-4-sulfate was replaced with 0.5 mg / ml heparan sulfate.

The sterilized textile fabrics be stirred out Suspension with amplified human mesenchymal stem cells (hMSC) populated. The average number of cells is 2.5 105 per textile fabric.

Cultivation for the textile fabrics 1 Type 1 is perfusion culture. The medium used is DMEM (Dulbecco's minimum essential medium), with the addition of 10% autologous serum, dexamethasone (10 nmol / l), b-GP (beta-glycerophosphate) (10 mmol / l), ascorbate (50 μg / ml) ,

Cultivation for the textile fabrics 1 Type 2 is also in perfusion culture. The medium used is DMEM, with the addition of 10% autologous serum. The flow rates are chosen so that constant pH values and nutrient concentrations are established.

After 15 to 20 days of culture, the cell-populated textile fabrics become 1 taken sterile and at the implantation site on the intramedullary nail 3 plugged. The recommended sequence is formed by stacking 3 series from 9 textile fabrics 1 Type 1 and Type 2 textile fabric. By this stacking, a tissue replacement according to the principle of tissue engineering (TE 1 ), which fills the bone defect during implantation.

Embodiment 2

For the treatment of 3 cm Defect length:

All fabrics 1 are made of 12 filamentary threads of P3HB embroidered on a fleece made of polyvinyl alcohol (lockstitch). The carrier is triggered with warm water (T = 60 ° C) in large excess. Silicone-containing lubricants are removed from the constructs in a high-purity heptane bath at room temperature. The immersion in methanolic (50% v / v) sodium hydroxide solution (1.5 M) for a period of 30 minutes is used for superficial hydrophilization. After coating the fabrics 1 (see below), the sterilization is carried out with ethylene oxide. The sterilized fabrics 1 are colonized from stirred suspension with amplified expanded hMSC. The mean cell number is 2.5 10 ⁵ per sheet 1 ,

P3HB-sheet Type 1:

Analogous to the comments on 4 ,

Matrix for P3HB sheets Type 1:

A tropocollagen I solution (10 mg ml ^-1 in 10 mM acetic acid) containing chondroitin 4-sulfate (2 mg ml ^-1 ) is prepared. The pH is adjusted to 7.4 by a buffer. The application is carried out spatially resolved from a microdosing system in such a way that the collagen surface concentration corresponding to the porosity gradient decreases from the outside inwards ( 5 ). Along the circumference, a strip of fibronectin gel (10 mg / ml) is dosed over a width of 3 mm in order to increase cell adhesion there. Structure formation lasts 12 h at 37 ° C.

P3HB-sheet Type 2:

• like type 1, but in addition with 4 radially arranged, evenly distributed slots with a Width of 1 mm;

Matrix Type 2:

• however, chondroitin 4-sulfate was replaced with 0.5 mg ml ^-1 heparan sulfate. The application of the fibronectin is carried out analogously to the collagen coating.

The cultivation for the type 1 fabrics takes place in perfusion culture. The medium used is DMEM supplemented with 10% autologous serum, dexamethasone (10 nM), b-GP (10 mM), ascorbate (50 μg ml ^-1 ).

The Cultivation for the fabric Type 2 is also in perfusion culture. As a medium comes DMEM, with the addition of 10% autologous serum. The flow rates are to be chosen so that Constant pH values and nutrient concentrations to adjust.

After 15 to 20 days culture time, the cell-matrix constructs are removed sterile and placed on the intramedullary nail at the implantation site 3 stuck ( 7 ).

Embodiment 3

Treatment of 1 cm drill defect at the epiphysis:

Starting material for the production of the fabrics 1 is a needled felt fleece made of a multifilament poly-L-lactic acid (50mol%) - glycolic acid (mol50%) (PLGA) thread. By means of stamping form sheets 1 cut out, which correspond as a stack of the generated bore hole geometry. Hydrophilization and sterilization take place.

The shape of the PLGA sheet 1 are the bore diameter adapted blanks (s. 11 ).

Matrix Type 1:

A sterile tropocollagen II solution (10 mg ml ^-1 in 10 mM acetic acid) containing hyaluronic acid (2 mg ml ^-1 ) is prepared. The pH is adjusted to 7.4 by a buffer. In this case, a physiological osmolarity is achieved.

Matrix Type 2:

A tropocollagen I solution (10 mg ml ^-1 in 10 mM acetic acid) containing chondroitin 4-sulfate (2 mg ml ^-1 ) is prepared.

in the In the case of matrix 1, the gel with patient's own is prior to fibrillogenesis Cartilage cells (chondrocytes) mixed and on the fabrics precultivated in chondrogenic differentiating medium. This can before or during of the procedure.

Cultivation for the surface elements 1 Type 2 is performed in perfusion culture with osteogenic additives prior to surgery. After 15-20 days of culture, the cell-matrix constructs are removed under sterile conditions.

Thus, the inner defect space with multiple layers of bone-specific surface elements 1 Type 2 are filled. The conclusion is formed by two layers of surface elements 1 of type 1. The outer, slightly enlarged position is sutured to the fixation on the periosteum.

Claims (29)

Implant for the treatment of long bone defects, characterized in that the implant contains at least two layers of fabrics of bioresorbable materials, that the fabrics and the layers of the fabrics are adapted to the geometry of the long bone defect, that the layers of stacks and / or rollers and / or Winding and / or folding of the sheets exist and that the sheets and / or layers have mutually and externally connected cavities, which allow the migration of cells and ingrowth of blood vessels. Implant according to claim 1, characterized in that that the layers and / or fabrics partially or entirely with an artificial one extracellular Matrix are coated. Implant according to claim 2 or 3, characterized that parts of a sheet or at least two sheets are coated differently. Implant according to claim 2 or 3, characterized that one of the extracellular Matrices colonization with osteoprogenitor cells or osteoblasts promotes. Implant according to one of claims 2 to 4, characterized that one of the extracellular Matrices colonization with chondroprogenitor cells or chondrocytes promotes. Implant according to one of claims 2 to 5, characterized that one of the extracellular Matrices colonization with endothelial progenitor cells or endothelial cells promotes. Implant according to one of claims 2 to 6, characterized that the surface the fabric is hydrophilized. Implant according to one of claims 2 to 7, characterized that at least one sheet coated with collagen I. Implant according to one of claims 2 to 8, characterized that at least one sheet coated with collagen II. Implant according to one of claims 2 to 9, characterized that at least one sheet coated with heparan sulfate. Implant according to claim 1, characterized in that that parts of a sheet or at least two sheets spatially resolved are structured. Implant according to claim 1, characterized that parts of a sheet or at least two sheets a different material surface densities exhibit. Implant according to claim 1, characterized in that that at least two sheets different outer contours exhibit. Implant according to claim 2, characterized in that the coating is structured so as to be spatially resolved on at least one fabric is. Implant according to claim 14, characterized in that that the coating is structured by freeze drying. Implant according to claim 1, characterized in that that at least a part of the superimposed sheets are fixed in position to each other. Implant according to claim 16, characterized in that that the fabrics arranged around an intramedullary nail or by means of a resorbable Fixateurs are fixed. Implant according to claim 16, characterized in that that provided for fixing the layers of the fabric thread-like fastening elements are that run approximately vertically through the fabric. Implant according to claim 1, characterized in that that at least one sheet a textile fabric is. Implant according to claim 1, characterized in that that the textile fabric made of bioresorbable polyhydroxyalkanoate, preferably made of poly (3-hydroxybutyric acid) is. sheet for a Implant for the treatment of tubular bone defects, characterized in that the sheet of bioresorbable Materials consists of that the fabric the geometry of the long bone defect is adjusted and that the sheet inside and outside reaching cavities and an interconnected porosity that is immigrant of cells as well as ingrowth of blood vessels allowed. sheet according to claim 21, characterized in that at least parts of the fabric spatially resolved are structured and / or a different material surface density and / or have a different material composition. sheet according to claim 21 or 22, characterized in that the surface of the sheet is hydrophilized. sheet according to one of claims 21 to 23, characterized in that the sheet partially or entirely with an artificial extracellular matrix is coated. sheet according to one of claims 21 to 24, characterized in that the sheet or parts thereof are coated differently. sheet according to claim 25, characterized in that one of the extracellular matrices promotes colonization with osteoprogenitor cells or osteoblasts. sheet according to one of claims 24 to 26, characterized in that one of the extracellular matrices promotes colonization with chondroprogenitor cells or chondrocytes. Process for producing an implant for Treatment of long bone defects from at least two layers of fabrics made of bioabsorbable materials and with inward and outward reaching cavities and an interconnected porosity, being the geometry of the long bone defect and transferred into two-dimensional structural patterns for the sheets becomes, the fabrics be made on the basis of this structural data and before implantation merged according to the defect geometry and implanted in the defect space. Method according to Claim 28, characterized that the fabrics surface modified and with an artificial one extracellular matrix be coated.