CA2248327A1

CA2248327A1 - Covering membrane, moulded bodies produced therefrom and process for the production thereof

Info

Publication number: CA2248327A1
Application number: CA002248327A
Authority: CA
Inventors: Axel Kirsch; Dietmar Hutmacher
Original assignee: Individual
Current assignee: Individual
Priority date: 1996-03-04
Filing date: 1997-02-04
Publication date: 1997-09-12
Also published as: AU2885097A; WO1997032616A1; EP0885022A1; BR9707903A; DE19654884A1; CN1212632A; JP2000507847A; DE19654884C2

Abstract

The invention relates to a covering membrane for regeneration of tissue and/or bone. Said covering membrane has at least three layers, the two outer layers both consisting of a natural material, and at least one layer arranged therebetween and consisting of at least one synthetic material. The invention also relates to moulded bodies produced from said membrane, uses of the membrane according to the invention, and a process for the production thereof. Said covering membrane and the moulded bodies produced therefrom have an excellent level of biocompatibility, mechanical stability and checkable degradation and resorption kinetics.

Description

COVERING MEMBRANE, MOLDED BODY PRODUCED THEREFROM
AND METHOD FOR THE MANUFACTURE THEREOF

The invention is directed to a covering membrane for tissue regeneration and/or bone regeneration, the employment thereof and molded bodies manufactured therefrom. The invention is also directed to methods for the manufacture of the covering membrane.
In osteosurgery, for example in the reconstruction of bones in plastic surgery or in operations of maxillary surgery, it is standard to fill bone voids in the form of recesses or cavities in the proper body bone 10 tissue with bone-forming material, which is usually composed of a mixture of bone replacement material such as hydroxy lapatite granules and proper body bone particles. In order to assure that the bone-forming material is ossiferously permeated essentially only proceeding from the bone side but is not undesirably permeated by epithelium and sub-epithelial connective tissue, the recess is closed with a coveringmembrane. The bone void can be essentially eliminated, namely, only when a completely ossiferous permeation of the bone-forming material is assured.
The Prior Art, for example, discloses covering membranes of polytetrafluorethylene films that, however, have the disadvantage that they remain in the body after the healing of the bone void and can thereby lead to complications.
The development of bioresorbent polyester films such as disclosed, for example, by WO 92/15340 has created the pre-condition that the previously required covering membrane was no longer present during or after the elimination of the bone void due to ingrown proper body bone tissue.
A great disadvantage of such polyester films, however, is comprised in their great stiffness and brittleness when softeners are not 3 o added. These properties result therein that covering membranes manufactured of such material are diffficult to adapt to the three-dimensionally form bone voids. Up to the time of the resorption, over and above this, there is the latent risk that the extremely thin soft tissue (mucous membrane) Iying above the membrane will be damaged.
Although stiffness and brittleness can be eliminated to the farthest-reaching extent by the addition of softeners, the employment of corresponding softeners is itself not unproblematical in view of the foreign body reactions possibly caused by them, such as, for example, nerve irritations or allergic reactions. A further disadvantage with respect to the employment of softeners is currently to be seen therein that the results of the clinical testing of corresponding substances are only based on a very low number of implemented tests with an equally low number of different softeners.
Another disadvantage of covering membranes composed of lS polyesters is to be seen in their low mechanical loadability. Such membranes are pressed into the bone void even given slight mechanical loads, with the result that only a part of the bone void is filled with bone.
WO 92/10218 discloses a polymer material for covering membranes whose glass transition temperature lies close to the body temperature. As a result thereof, the membrane becomes more flexible in situ and the adaptation of such a covering membrane to a bone void can be easily accomplished. Although the problem of the low flexibility of the polyester material is thus solved, that of inadequate mechanical stability is not.
A further aspect that must be taken into consideration in the design of covering membranes is the biocompatibility of covering membranes, this being expressed in their wettability, the scope to which cells grow in, as well as in the rate of the growth of the cells in the membrane surface.
Given synthetic membranes, attempts are typically undertaken to 3 o compensate the low biocompatibility inherent in the material with a CA 02248327 l998-09-04 corresponding surface fashioning, which is unsatisfactory both in view of the result resulting therefrom as well as of the costs connected therewith.
By contrast to synthetic membranes, covering membranes on the basis of collagen exhibit a clearly improved biocompatibility. Over and 5 above this, a collagen membrane can be stretched by 20 to 50% in the moist condition, this allowing the membrane to be stretched over three-dimensionally complicated bone voids.
However, it is precisely this stretchability that causes such covering membranes to be even less suited for the absorption of mechanical forces 10 than the synthetic membranes. Consequently, a bone void covered with a covering membrane on a collagen basis must be practically completely filled with augmentation material or, respectively, bone replacement material. Particularly given larger bone voids, the employment of augmentation material or, respectively, bone replacement material can be difficult due to the necessity of stable anchoring as well as a permeation of said material by proper body bone material.
As initially mentioned, the intention of employing a covering membrane is to be seen therein that the bone-forming material is ossiferously permeated essentially only proceeding from the bone side.
This assumes that a comparable decomposition kinetic prevails for the entire covering membrane to be decomposed or, on the other hand, that this does not change in an uncontrolled way due to the application of the covering membrane. When, however, a collagen membrane is stretched over a bone void, thinnings of the membrane occur at specific locations, these leading to an accelerated decomposition kinetic and, ultimately, thereto that the bone void is not exclusively ossiferously permeated proceeding from the bone side.
The invention is based on the object of offering a covering membrane that can be biologically decomposed, is highly biocompatible 3 o and exhibits high mechanical loadability, and of offering methods for the manufacture thereof. Further, employments of the covering membrane are to be recited and a molded body is to be disclosed that is especially highly biocompatible and exhibits high mechanical stability, especially given large bone voids.
The object is inventively achieved by a covering membrane for tissue regeneration and/or bone regeneration that comprises at least three layers, whereby the two, respectively outer layers are composed of a natural material and a layer Iying therebetween is composed of at least one synthetic material.
The object is also achieved by a first method for the manufacture of the inventive covering membrane that is characterized by the steps a) introducing a layer composed of a natural material into a mold, b) applying at least one layer of the synthetic material, c) applying a second layer composed of a natural material, d) closing the mold, 15 e) introducing the mold into a pressure vessel and closing the latter, f) admitting CO2 and/or N2 into the pressure vessel, g) setting a pressure p and a temperature T, h) holding the pressure p and the temperature T for a time t, and i) dismantling the pressure p in the interior of the pressure vessel.
An alternative, second method for the manufacture of the covering membrane of the invention proposes that at least one layer of a natural material is extruded onto at least one further layer of the covering membrane that comprises at least the layer of at least one synthetic material Iying between the two outer layers composed of a natural material.
In a further alternative, a third method for manufacturing a covering membrane of the invention provides that at least one layer of a natural material is integrally cast onto at least one further layer of the covering membrane that comprises at least the layer of at least one synthetic 3 o material Iying between the two outer layers composed of a natural material.

CA 02248327 l998-09-04 In a further, fourth alternative, the method for manufacturing a covering membrane of the invention provides that an arrangement of the layers constituting the covering membrane is introduced into a heat compression mold, the heat compression mold is closed, and a temperature T, and a pressure p, is [sic] applied (hot-pressing process).
The inventive employment of the covering membrane of the invention provides that this is employed in vitro and/or in vivo and/or ex vivo.
A further inventive employment is comprised therein that the inventive covering membrane is employed in controlled tissue regeneration and/or controlled bone regeneration.
Finally, the object underlying the invention is achieved in that the inventive molded body is composed of the inventive covering membrane.
It can be provided given the covering membrane of the invention that the synthetic material of the layer Iying between the two respectively outer layers composed of a natural material is biologically degradable.
The invention also proposes that the synthetic material is composed of a thermoplastic.
It can also be provided that the thermoplastic comprises at least one polyester from the family of poly-a-hydroxyl acids such as polytrimethylene carbonate, polydioxanone, polyglycolide, polyactide, poly(L-lactide-co-glycolide) in addition to other copolymers, polyorthoesters and/or polycaprolactone (polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate).
It is provided in one embodiment of the invention that the synthetic material is poly(D,L-lactide).
It can be provided in a further embodiment that the synthetic material is poly(L-lactide-co-D,L-lactide).
The synthetic material preferably exhibits a weight ratio of L-lactide 3 o to D,L-lactide of approximately 40:60, approximately 50:50, approximately 70:30 or approximately 80:20.

CA 02248327 l998-09-04 The invention provides that the layer composed of a synthetic material arranged between the two outer layers composed of a natural material exhibits a cell-occlusive porous structure.
Alternatively, it can be provided that the layer composed of a s synthetic material arranged between the two outer layers composed of a natural material exhibits a cell-occlusive non-porous structure.
It is provided in a preferred embodiment that at least one of the two outer layers composed of a natural material comprises a collagen content.
It is provided in an especially preferred embodiment that at least 10 one of the two outer layers composed of a natural material is composed of collagen.
In another, especially preferred embodiment, the collagen is of type I and/or type IV.
It can thereby be quite especially preferred that both outer layers composed of a natural material are composed of collagen and both layers composed of collagen exhibit a porous structure.
Alternatively, it can be provided that both outer layers composed of a natural material are composed of collagen and one layer composed of collagen exhibits a porous structure and the other layer composed of collagen exhibits a smooth structure.
It can be provided in another alternative that both outer layers composed of a natural material are composed of collagen and both layers composed of collagen exhibit a fiber-like structure.
It can be provided in a further alternative that both outer layers composed of natural material are composed of collagen and one layer composed of collagen exhibits a fiber-like structure and the other layer composed of collagen exhibits a smooth structure.
The invention proposes that the inventive covering membrane comprises a collagen edge.

CA 02248327 l998-09-04 It can be provided in an especially preferred embodiment that the collagen edge comprises a thickness of approximately 5 through approximately 10 mm.
It can be provided that at least one of the layers constituting the covering membrane contains a bone replacement material.
It can thereby be especially preferred that at least one of the outer layers composed of a natural material and/or at least one layer Iying between said outer layers is laced with a bone replacement material.
The invention also proposes that at least one of the layers forming the covering membrane and/or the bone replacement material comprises a content of at least one biologically active agent.
In a preferred embodiment of the invention, at least one of the two outer layers composed of a natural material and/or at least one layer Iying between said outer layers and/or the bone replacement material contains a biologically active agent.
The invention further proposes that the biologically active agent is selected from the group that comprises growth factors, antibiotics, pain-relieving agents, agents that influence the cell division and the vascularization, coagulating and anti-coagulating agents, immune-suppressing and immune-stimulating agents, cytosines, chemical attractants, enzymes and combinations thereof.
It can be provided that, in addition to the layer composed of a synthetic material, at least one further layer of the layers forming the covering membrane comprises a polymer matrix of synthetic material.
Preferably, at least one of the two outer layers composed of a natural material comprises a polymer matrix of synthetic material.
It is especially preferred when the synthetic material is biologically degradable.
It is also preferred when the synthetic material is composed of a 3 o thermoplastic.

The invention proposes that the thermoplastic comprises at least one polyester from the family of poly-a-hydroxyl acids such as polytrimethylene carbonate, polydioxanone, polyglycolide, polyactide, poly(L-lactide-co-glycolide) in addition to other copolymers, polyorthoesters and/or polycaprolactone (polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate).
In a preferred embodiment of the invention, the synthetic material is poly(D,L-lactide).
In a further embodiment of the invention, the synthetic material of the covering membrane is poly(L-lactide-co-D,L-lactide).
The synthetic material preferably comprises a weight ratio of L-lactide to D,L-lactide of approximately 40:60, approximately 50:50, approximately 70:30 or approximately 80:20.
It can also be provided that the polymer matrix is porous.
The invention proposes that the layer containing the polymer matrix composed of synthetic material faces toward the tissue and/or bone to be regenerated.
It can also be provided that the covering membrane is three-dimensionally shaped.
In an especially preferred embodiment, the covering membrane is thermally three-dimensionally shaped.
The first inventive method for the manufacture of the covering membrane of the invention provides that, before and/or after the application, further material that serves for the formation of one or more further layers of the covering membrane is applied tp at least one layer of the synthetic material.
It is also provided that the natural material is collagen.
In an especially preferred embodiment, the collagen is of type I
and/or type IV.
3 o It can be provided that the synthetic is employed as powder and/or granules and/or flakes.

CA 02248327 l998-09-04 The invention proposes that at least the synthetic material comprises a content of at least one biologically active agent.
It is provided in an especially preferred embodiment that the biologically active agent is selected from the group that comprises growth factors, antibiotics, pain-relieving agents, agents that influence the cell division and the vascularization, coagulating and anti-coagulating agents, immune-suppressing and immune-stimulating agents, cytosines, chemical attractants, enzymes and combinations thereof.
The invention proposes that the synthetic materia! is biologically degradable.
The invention further proposes that the synthetic material is composed of a thermoplastic.
It can be provided in a preferred embodiment that the thermoplastic comprises at least one polyester from the family of poly-a-hydroxyl acids such as polytrimethylene carbonate, polydioxanone, polyglycolide, polyactide, poly(L-lactide-co-glycolide) in addition to other copolymers, polyorthoesters and/or polycaprolactone (polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate).
In a preferred embodiment of the invention, the synthetic material iS poly(D,L-lactide).
In a further embodiment of the invention, the synthetic material of the covering membrane is poly(L-lactide-co-D,L-lactide).
The synthetic material preferably comprises a weight ratio of L-lactide to D,L-lactide of approximately 40:60, approximately 50:50, approximately 70:30 or approximately 80:20.
The invention also proposes that the mold is closed pressureless.
The invention proposes that the carbon dioxide and/or nitrogen introduced into the pressure vessel in step f) is introduced in liquid form.
It can also be provided that the carbon dioxide and/or the nitrogen iS converted into a super-critical condition as a result of step g).

The invention proposes that the pressure p amounts to between approximately 2 x 1 o6 and approximately 2 x 1 o8 Pa.
In an especially preferred embodiment, the pressure p amounts to between approximately 5 x 1 o6 Pa and 1.5 x 107 Pa.
The invention further proposes that the temperature T amounts to less than 37~C.
In an embodiment of the invention, the time t amounts to between approximately 10 minutes and approximately 100 minutes.
It is provided in an especially preferred embodiment that the time t amounts to approximately 30 minutes.
The invention also proposes that the pressure p is dismantled with a defined gradient.
In the inventive method for manufacturing the covering membrane of the invention, which is characterized in that further layers can be extruded or cast onto the layer of at least one synthetic material Iying between the two outer layers composed of a natural material, it can be provided that this layer of synthetic material is pre-shaped.
Given the inventive method for manufacturing a covering membrane of the invention that provides that an arrangement of the layers forming the covering membrane is placed into a heat compression mold, the heat compression mold is closed and a temperature T1 and a pressure P1 is applied, the temperature T1 amounts to approximately 100~C or less.
In a preferred embodiment of this method, the invention proposes that the pressure P1 amounts to approximately 1 x 106 through 2 x 106 Pa.
The invention proposes that the inventive molded body formed of the inventive covering membrane is an augmentation molded body for the elimination of bone voids.
- The invention further proposes that the degree of porosity of the two outer layers composed of a natural material differs from that of the covering membrane forming the molded body.

It is provided in a preferred embodiment that the outer layer composed of a natural material and facing toward the bone void in the covering membrane exhibits a higher degree of porosity than the outer layer composed of natural material and facing away from the bone void in the covering membrane.
Over and above this, the invention proposes that the thickness of the outer layer composed of a natural material and facing toward the bone void in the covering membrane differs from the thickness of the outer layer composed of natural material and facing away from the bone void in 10 the covering membrane.
In a preferred embodiment of the invention, the outer layer composed of a natural material and facing toward the bone void in the covering membrane is thicker than the outer layer composed of natural material and facing away from the bone void in the covering membrane.
It is thereby preferably preferred that the outer layer composed of a natural material and facing toward the bone void in the covering membrane is significantly thicker than the outer layer composed of natural material and facing away from the bone void in the covering membrane.
It can be provided, further, that at least the pores of the outer layer composed of a natural material and facing toward the bone void in the covering membrane comprise a volume of approximately 1 through 5 mm3.
The invention further proposes that at least the pores of the outer layer composed of a natural material and facing toward the bone void in the covering membrane comprise a content of autologous bone material.
The invention is based on the surprising perception that the inventive covering membrane for tissue regeneration and/or bone regeneration that comprises at least three layers, whereby the two respectively outer layers are composed of a natural material and at least one layer Iying therebetween is composed of at least one synthetic material, represents a biodegradable or bioresorbable membrane that exhibits and especially good degradation and resorption kinetic and, in addition to its high mechanical stability, excellently assures the barrier function required for the tissue regeneration and/or bone regeneration without a deterioration of the rigidity of the layer assuring the barrier function thereby occurring, and, over and above this, allows an adaptation to the shape prescribed by the geometry of the bone void to be eliminated.
What are [sic] also understood by natural material in this context are derivative forms and mixtures thereof.
The inventive membrane can maintain the barrier function for at least 6 months for small through moderately large bone voids and can then be metabolized by the body or, respectively, organism in a time span of 9 through 12 months without clinical complications. The barrier function amounts to at least 9 months for large-volume bone voids, and the membrane can be metabolized by the body or, respectively, organism in a time span of 15 through 18 months without clinical complications.
As a result of the high biomechanical stability of the inventive covering membrane, no bone replacement material is required for support, as required given mechanically unstable membranes in order to prevent a collapse into the bone void.
As a result thereof that the two respectively outer layers are composed of a natural material, a fast and complication-free integration of the soft tissue into the membrane surface of the covering membrane derives, this being an important biological and clinical prerequisite in order 2 5 to avoid dehiscences of the membrane.
The employment of synthetic material that is biodegradable produces not only the metabolizability of the inventive covering membrane but is also of significance insofar as an independence from the availability of suitable biological material is thus assured, which, over and above this, 3 o can potentially exhibit batch-dependent differences that can then change the properties of the covering membrane in an unpredictable way.

Over and above this, the employment of synthetic material, and specifically of a thermoplastic, offers at particular advantage over, for example, membranes manufactured of collagen since a thinning of the layer(s) relevant for the function of the covering membrane due to the 5 adaptation process given the adaptation of the inventive covering membrane to three-dimensional, architectonically complicated bone voids does not occur, which would then cause an accelerated, uncontrolled degradation kinetic.
Specifically the employment of poly(D,L-lactide) of poly(L-lactide-10 co-D,L-lactide) as synthetic material lends the inventive covering membrane unique degradation and resorption kinetics of a type that is not assured given employment of currently available, biodegradable, natural materials, whereby a weight ratio of L-lactide to D,L-lactide of approximately 40:60, approximately 50:50, approximately 70:30 or approximately 80:20 is especially advantageous in view of the degradation and resorption kinetics.
The layer composed of a synthetic material and arranged between the two outer layers composed of a natural material can exhibit a cell-occlusive porous structure. It is of great significance for bone regeneration that a clear separation between the tissues participating in the tissue and/or bone regeneration is produced. It can thereby be advantageous that the cell-occlusive structure is porous. This is especially called for when, due to the growth characteristics of the cells, for example, a rough surface is required and this, for example, is to serve as attachment point for ingrowing cells. Conversely, it can also be advantageous when the cell-occlusive layer exhibits a non-porous structure, particularly when the layer arranged between the two outer layers composed of a natural material is not occupied by cells but is required as barrier in order, for example, to effect contact inhibition of the 30 cell growth and to thus obtain to a defined tissue structure.

The employment of collagen in the inventive covering membrane involves a number of advantages that can derive both therefrom that at least one of the two outer layers composed of a natural material comprises a collagen content as well as therefrom that at least one of the 5 two outer layers composed of a natural material is composed of collagen.
Particularly speaking in favor of the employment of collagen is the high biocompatibility and fundamentally established biodegradability of this material. Since the stability as well as the barrier function required for a covering membrane is conditioned essentially by the layer of at least 10 one synthetic material Iying between the two outer layers composed of a natural material, the disadvantages with respect to the stability of the material as well as thinning at locations having high tensile stress that accompany collagen can be accepted in view of the excellent biodegradability and lend the inventive covering membrane its unique properties as a whole.
In that at least one of the two outer layers composed of natural material is composed of collagen, the wetting as well as the ingrowth of cells and, finally, the rate of the soft tissue growth into the membrane surface is [sic] improved compared to the conditions given employment of exclusively synthetic polymers or, respectively, covering membranes constructed thereof.
The aforementioned advantages are especially valid when the collagen is of type I and/or IV.
Collagen makes an optimum surface for settlement and ingrowth available to the cells and the tissue. Due to its natural origin, further, collagen makes compounds for biochemical processes and bonds available to the cells. In the case of regeneration of bone voids, for example, the blood coagulum needed at the bone side for successful bone regeneration is thereby bonded and held at the site, i.e. at the bone 3 o void. At the soft tissue side, the collagen enables a fast growth of the CA 02248327 l998-09-04 tissue of the mucous membrane, so that the covering membrane is integrated in the soft tissue in a short time without complications.
The outer layers composed of collagen can either both be porous or, respectively, fibrous or one layer can comprise a porous or, respectively, fibrous and the other a smooth structure. When the side of the covering membrane facing toward the bone void comprises a porous or, respectively, fibrous structure, the surfaces that are especially advantageous in view of the ingrowth behavior derive. Conversely, the smooth structure of the second outer layer assures that the settlement thereof both by desired as well as undesired tissue cells is suppressed to the farthest-reaching extent or, respectively, is controllably retarded.
Further, one thus has the possibility available of influencing the resorption kinetics to a farther-reaching extent, namely not only those of the outer layer(s) composed of natural material but also the intervening layer composed of synthetic material. On the basis of a surface modification, the resorption kinetic of the layer composed of synthetic material, which essentially lends the barrier function, can be influenced to a farther-reaching extent in this way.
Conversely, a fibrous or porous structure of the two outer layers composed of natural material, and specifically of collagen, can assure that the pre-conditions that are required in view of the cell growth and, thus, the complication-free integration of the covering membrane are created for both sides of the membrane. Such a fashioning can be advantageous especially when the bone void to be eliminated is comparatively small and the rate and the extent of the cell growth is [sic] approximately the same at both sides, so that a designational retardation of the cell growth at one side of the membrane, typically that of the soft tissue, by offering a surface less suitable for the cell growth, for example in the form of a smooth surface structure, is not required.
3 o As a result of the polymer matrix reinforcement, a collagen edge of the covering membrane allows the absorption of a certain part of the CA 02248327 l998-09-04 mechanical forces that arise in the adaptation of the covering membrane to the tissue or, respectively, bone void to be eliminated. Over and above this, such a collagen edge, which can amount to approximately 5 through 10 mm, allows the covering membrane to be intimately adapted to the bone. Consequently, the phenomenon of thinning, as observed for collagen membranes, is suppressed.
When at least one of the layers constituting the covering membrane comprises a bone replacement material, it is assured that the regeneration of bones occurs significantly faster, and the corresponding bone replacement materials known in the art serve as point of departure for farther-reaching chondroblastic and osteoblastic activities.
Fundamentally, bone replacement material can be introduced into any arbitrary layer of the covering membrane, whereby it is especially advantageous for obvious reasons to incorporate the bone replacement material into one of the two outer layers composed of natural material, and preferably in that that faces toward the bone void and/or potentially further layers between the outer layer composed of a natural material and facing toward the bone void, on the one hand, and allocated to the layer composed of at least one synthetic material and Iying between the two outer layers composed of a natural material.
In addition to the integration of bone replacement material, the incorporation of at least one biologically active agent offers the possibility of influencing the regeneration process with a multitude of biological processes.
Fundamentally, a corresponding biologically active agent can be added to practically each of the layer [sic] constituting the covering membrane as well as to the elements or structures contained therein, thus, for example, the bone replacement material.
Particularly advantages derive when the layer(s) Iying between the two outer layers composed of a natural material comprises a content of at least one biologically active agent.

CA 02248327 l998-09-04 Growth factors, antibiotics, pain-relieving agents, agents that influence the cell division and the vascularization, coagulating and anti-coagulating agents, immune-suppressing and immune-stimulating agents, cytosines, chemical attractants, enzymes and combinations thereof can 5 thereby serve as biologically active agents.
A person skilled in the art is familiar with the effectiveness and, particularly, with the active mechanisms of said agents. Thus, for example, growth factors can serve to stimulate cells in general and, potentially, specific cell populations to intensified growth in order to fill the 10 existing tissue or bone void as quickly as possible. The employment of antibiotics is particularly indicated when it is a matter of large-area tissue voids or tissue voids that are diffficult to clean or when the milieu into which the covering membrane is introduced exhibits a high germ burden.
Over and above this, agents that influence the cell division and the vascularization allow a rapid regeneration of the tissue or bone void. The addition of coagulating as well as of anti-coagulating agents can be beneficial dependent on the blood supply conditions. The employment of immune-suppressing agents is particularly indicated when a deterioration of the healing process would otherwise occur, for example as a consequence of allergic reactions. Conversely, immune-stimulating agents can be advantageous when it is desirable to generate an intensified immune response in the region of the covering membrane.
Cytocines and chemical attractant can, as a result of the action mechanism [...] the immigration of various cell populations, represent a possibility of controlling or, respectively, forcing the healing process to a farther-reaching extent. The addition of enzymes allows a farther-reaching modification of the regeneration process and can influence both the material of the covering membrane as well as the regenerated or regenerating tissue.
3 o Given said agents, it is also fundamentally possible to realize gradients both within the layers as well as over the layer crossection and/or longitudinal section in order to meet the respective demands of tissue regeneration.
Farther-reaching advantages of the cover membrane, particularly with respect to its stability, derive therefrom that at least one of the two outer layer [sic] composed of natural material comprises a polymer matrix of synthetic material. This polymer matrix can be constructed of synthetic material similar to that contained in the layer of synthetic material Iying between the two outer layers composed of a natural material. The advantages cited there with respect to the degradability and shapability 10 also apply here by analogy.
The porous structure of the polymer matrix enables an ingrowth of cells into the layer(s) of the covering membrane containing the polymer matrix. As a result thereof, the natural material can be resorbed or, respectively, replaced by the ingrowing tissue and, dependent on the 1S selection of the polymer matrix material or, respectively, the dimensioning thereof, its resorption kinetic can be controlled, this resulting therein that the polymer matrix is converted into the regenerating tissue and lends it additional stability until it is likewise ultimately resorbed.
Although it is fundamentally meaningful to integrate said polymer matrix into a plurality of layers of the inventive covering membrane, it is quite particularly advantageous to integrate it in those layers that are located between the tissue and/or bone to be regenerated and the layer Iying between the two outer layers composed of a natural material in order to assure the mechanical stability in specifically this region that is 2S particularly required given large bone voids.
An optimum adaptation to the tissue and/or bone void to be eliminated is assured by the three-dimensional shapability of the covering membrane, particularly in combination with the aforementioned collagen edge. The thermal shapability is essentially influenced by the material 3 o properties of the synthetic material and potentially allows a fine modelling of the covering membrane after it has already been introduced without great mechanical forces having to be thereby exerted, this leading to an especially gentle and dependable application of the covering membrane.
As can already be seen from the above, in vivo employment of the inventive covering membrane is particularly indicated. over and above this, however, there is the possibility of employing such covering membranes in vitro, particularly when it is a matter of producing complex three-dimensional tissue or organ structures that are potentially transplanted.
A fundamental employment is also possible ex vivo, thus, for example, in heart-lung or dialysis apparatus. The tissue or organ parts that are present in the corresponding apparatus and employ the inventive covering membrane as growth and shaping substrate carry out functions that are normally assumed by body-proper structures.
The inventive methods allow the manufacture of the various embodiments of the inventive covering membrane, whereby the advantages inherent in the inventive covering membrane are produced.
in that the temperature in the first inventive method amounts to less than approximately 37~C, the additional of thermally unstable biological agents is unproblematically possible.
The inventive methods allow a defined content of a biologically active agent, individually or in combination, to be realized layer-specifically in the inventive covering membrane and, potentially, to also realize the fashioning of a corresponding gradient.
A molded body can be advantageous manufactured from the inventive covering membrane.
Fundamentally, such molded bodies can be employed for a multitude of applications, thus, for example, for regeneration of tissue and/or bone voids. The advantages of a molded body that serves for the elimination of bone voids shall be discussed below by way of example.
3 o However, it is obvious to a person skilled in the art that corresponding embodiments of the inventive molded body can also be employed for the CA 02248327 l998-09-04 elimination of voids other than a bone void, as described here, and that similar advantageous effects derive therefrom.
In view of the two outer layers composed of a natural material that form the molded body, the inventive molded body exhibits a difference with respect to the degree of porosity, this being comprised therein that the outer layer composed of a natural material typically facing toward the bone void exhibits a higher degree of porosity, this being especially advantageous in view of the ingrowth rate of cell material and the formation of a solid tissue structure. Over and above this, this high 10 porosity allows the bone void to be practically completely filled, and only then does the mass degradation of the layer comprising the synthetic material that lies between the two outer layers composed of a natural material ensue with a controlled kinetic, so that the body metabolizes only as many decomposition products per time unit as the organism can handle with a clinically irrelevant foreign body reaction.
The different thickness of the layer(s) of the covering membrane forming the molded body that faces toward the bone void on the one hand and that of the layer (s) facing away from the bone void is of great advantage, whereby the outer layer composed of a natural material and facing toward the bone void in the covering membrane is typically significantly thicker than the outer layer composed of a natural material facing away from the bone void in the covering membrane. One reason for this is comprised in the filling of the cavity caused by the bone void by the corresponding layers of the covering membrane or, respectively, of the molded body formed therefrom. In addition to an increased mechanical stability produced as a result thereof, a direct interaction of the outer layer of the molded body serving as shaping, supporting and growth substrate with the remaining residual tissue is assured.
A volume of approximately 1 through 5 mm3 of the pores of the outer later composed of a natural material and facing toward the bone void in the covering membrane is especially suited for promoting the ingrowth behavior of cells that eliminate the bone void. This positive effect can be intensified in that a content of autologous bone material is present in the pores, this, without wishing to be subsequently bound thereto, serving as point of departure for especially intensive growth of tissue that eliminates the bone void.
Further features and advantages of the invention derive from the following description, wherein a number of exemplary embodiments are explained in detail with reference to the schematic drawing and manufacturing examples according to the inventive method for o manufacturing the inventive covering membrane are recited.
Thereby shown are:
Figure 1 a schematic illustration of the crossection through an embodiment of the inventive covering membrane;
Figure 2 a schematic illustration of the crossection through a further embodiment of the covering membrane of the invention;
Figure 3 a schematic, perspective illustration of an embodiment of the covering membrane of the invention;
Figure 4 a schematic, perspective illustration of an embodiment of an augmentation molded body of the invention;~0 Figure 5 a schematic illustration of a crossection through the augmentation molded body of the invention shown in Figure 4;
Figure 6 a scanning electron microscope image of the covering membrane of the invention manufactured in Example 1;~5 Figure 7 a further scanning electron microscope image of the covering membrane of the invention manufactured in Example 1;
Figure 8 a scanning electron microscope images of the covering membrane of the invention manufactured in Example 2;

CA 02248327 l998-09-04 Figure 9 a further scanning electron microscope image of the covering membrane of the invention manufactured in Example 2;
Figure 10 a scanning electron microscope image of the covering membrane of the invention manufactured in Example 3; and Figure 11 a further scanning electron microscope image of the covering membrane of the invention manufactured in Example 3.
Figure 1 shows an embodiment of the covering membrane of the invention that is constructed of three layers, whereby the two outer layers 1 and 1' are composed of collagen and exhibit a porous structure. An intervening layer 2 composed of a synthetic material lies between the two outer layers of collagen. The width of the two outer layers composed of natural material is greater than that of the intervening layer 2, this leading thereto that a typically 5 through 10 mm wide collagen edge 3 exists that is especially suited for the adaptation of the covering membrane to the tissue or bone void to be eliminated and, over and above this, absorbing a part of the occurring mechanical load.
The embodiment of the covering membrane of the invention shown in Figure 2 is characterized in that the outer layer 1 composed of collagen exhibits a clearly higher degree of porosity than the outer layer 1' composed of collagen. Over and above this, the highly porous collagen material of layer 1 also comprises bone replacement material 5 that serves as point of departure for especially intensive tissue regeneration activity. The bioresorbent synthetic material of the layer 2 Iying between the two outer layers composed of collagen prevents the cells from growing through beyond the layer 1. Layer 1' comprises a structure that likewise has a cell-occlusive effect.
In a three-dimensional illustration, Figure 3 again illustrates the structuring principle of the covering membrane of the present invention.
Layer 1, composed of collagen in the present case, exhibits a porous CA 02248327 l998-09-04 structure that especially facilitates the ingrowth of cells. The layer 1 is followed by the layer 2 composed of a biodegradable synthetic material that, in conformity with its intended use, is dissolved by the cells growing into the layers 1 and 1' composed of collagen or, respectively, by their biochemical activities. Following as last layer in this embodiment of the covering membrane of the present invention having three layers overall is layer 1' that exhibits a significantly more compact collagen structure that has a cell-occlusive effect. over and above this, layer 1 also comprises a polymer matrix of biodegradable synthetic material that lends the entire covering membrane an enhanced mechanical stability due to its interconnecting effect.
Figure 4 illustrates the basic structure of an augmentation molded body for the elimination of bone voids that is constructed of the covering membrane of the invention. The especially pronounced layer 1 composed of collagen, which exhibits a very high degree of porosity, is followed by a layer 2 composed of the biodegradable synthetic material. The layer 1' of collagen facing away from the bone void exhibits a clearly lower porosity and thickness than the layer 1. As a result of its thickness, layer 1 allows the bone void to be filled and, due to direct contact, assures a rapid ingrowth of cells. Polymer matrix 4, manufactured of biodegradable material, allows a particularly reinforcement of layer 1 and thus substantially increases the mechanical loadability of the augmentation molded body, this yielding a significant advantage particularly given large bone voids to be eliminated.
Figure 5 shows the augmentation molded body of Figure 4 in crossection. The two outer layer 1 and 1' surround the layer 2 composed of biodegradable synthetic.
The inventive covering membrane was manufactured with an inventive method that shall be illustrated on the basis of the examples recited below.

CA 02248327 l998-09-04 EXAM PLES
The following method sequence was realized in all examples recited herein in Table 1:
A first collagen layer was placed into a tool mold and the polymer in granule form was then applied onto the first collagen layer. Subsequently, the second collagen layer was placed onto the synthetic material in granule form, the tool was closed with an extrusion die and introduced as a whole into a high-pressure autoclave.
The high-pressure autoclave was filled with CO2 that was compressed with a reciprocating diaphragm pump. The pressure p and the temperature T in the pressure vessel were set with pressurizing unit and tempering means. A tempering of the autoclave employed was fundamentally possible in limits between -70~C and 400~C. After a gasification time t, the pressure was relieved with an adjustable gradient.
The tool was subsequently removed from the high-pressure autoclave, opened and the three-layer covering membrane of the invention manufactured in this way was removed from the tool.
The test parameters can be taken from Table 1, whereby PDLLA
denotes poly(D,L-lactide) and TCP denotes tri-calcium phosphate.
The collagen layers employed comprised a thickness of 0.2 mm regardless of whether they were rectangular or circular.

Table 1 Example Bottom Middle Top Test pard",eters p[bar] - 9[~C] - dp/dt [bar/s]
collagen PDLLA collagen 120 - 32 - 50 (3 x 3 cm2) (1 5 9) (3 x 3 cm2) 2 collagen PDLLA collagen 120 - 30 - 0.8 (3 x 3 cm2) (1.5 9) (3 x 3 cm2) 3 collagen PDLLA(1.5g) collagen 120 -30- 0.8 (3 x 3 cm2) + 20% TCP (3 x 3 cm2) 4 collagen PDLLA collagen 125 - 30 - 50 (0 10 cm) (1.5 9) (0 10 cm) collagen PDLLA collagen 130 - 37 - 50 (0 10 cm) (1.5 9) (0 10 cm) 6 collagen PDLLA (1.5 9) collagen 130 - 34 - 50 (0 10 cm) + 20% TCP (0 10 cm) All covering membranes manufactured in this way exhibited a high 10 mechanical stability and were thermally shapable.
The images shown as Figures 6 through 11 are scanning electron microscope images of the above examples, whereby Figures 6 and 7 show the result from Example 1, Figures 8 and 9 show the result from Example 2 and Figures 10 and 11 show the result from Example 3. The 15 specimens were broken cold in nitrogen.
It can be seen from Figures 6 through 11 that the bioresorbable polymer layer is compact and the fiber structure of the two collagen layers is undamaged.
Both individually as well as in arbitrary combinations, the features of the invention disclosed in the above specification, in the drawing as well as in the claims can be critical for realizing the various embodiments of the invention.

Claims

New Claims 1-81

1. Covering membrane for tissue regeneration and/or bone regeneration characterized in that the covering membrane comprises at least three layers, whereby the two, respectively outer layers 1, 1' are composed of a natural material and a layer lying therebetween 2 is composed of at least one synthetic material, whereby the layer 2 exhibits a cell-occlusive, porous or cell-occlusive, non-porous structure.

2. Covering membrane according to claim 1, characterized in that the synthetic material is biologically degradable.

3. Covering membrane according to claim 1 or 2, characterized in that the synthetic material is composed of a thermoplastic.

4. Covering membrane according to claim 3, characterized in that the thermoplastic comprises at least one polyester from the family of poly-.alpha.-hydroxyl acids such as polytrimethylene carbonate, polydioxanone, polyglycolide, polyactide, poly(L-lactide-co-glycolide) in addition to other copolymers, polyorthoesters and/or polycaprolactone (polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate).

5. Covering membrane according to one of the claims 1 through 4, characterized in that the synthetic material is poly(D,L-lactide).

6. Covering membrane according to one of the claims 1 through 4, characterized in that the synthetic material is poly(L-lactide-co-D,L-lactide).

7. Covering membrane according to claim 6, characterized in that the synthetic material exhibits a weight ratio of L-lactide to D,L-lactide of approximately 40:60.

8. Covering membrane according to claim 6, characterized in that the synthetic material exhibits a weight ratio of L-lactide to D,L-lactide of approximately 50:50.

9. Covering membrane according to claim 6, characterized in that the synthetic material exhibits a weight ratio of L-lactide to D,L-lactide of approximately 70:30.

10. Covering membrane according to claim 6, characterized in that the synthetic material exhibits a weight ratio of L-lactide to D,L-lactide of approximately 80:20.

11. Covering membrane according to one of the claims 1 through 10, characterized in that at least one of the two outer layers 1, 1' composed of a natural material comprises a collagen content.

12. Covering membrane according to one of the claims 1 through 10, characterized in that at least one of the two outer layers 1, 1' composed of a natural material is composed of collagen.

13. Covering membrane according to claim 11 or 12, characterized in that the collagen is of type I and/or type IV.

14. Covering membrane according to claim 12 or 13, characterized in that both outer layers 1, 1' composed of a natural material are composed of collagen and both layers 1, 1' composed of collagen exhibit a porous structure.

15. Covering membrane according to claim 12 or 13, characterized in that both outer layers 1, 1' composed of a natural material are composed of collagen and one layer composed of collagen exhibits a porous structure and the other layer composed of collagen exhibits a smooth structure.

16. Covering membrane according to claim 12 or 13, characterized in that both outer layers 1, 1' composed of a natural material are composed of collagen and both layers composed of collagen exhibit a fiber-like structure.

17. Covering membrane according to claim 12 or 13, characterized in that both outer layers 1, 1' composed of natural material are composed of collagen and one layer composed of collagen exhibits a fiber-like structure and the other layer composed of collagen exhibits a smooth structure.

18. Covering membrane according to one of the claims 12 through 17, characterized in that the covering membrane comprises a collagen edge.

19. Covering membrane according to claim 18, characterized in that the collagen edge comprises a thickness of approximately 5 through approximately 10 mm.

20. Covering membrane according to one of the claims 1 through 19, characterized in that at least one of the layers constituting the covering membrane contains a bone replacement material.

21. Covering membrane according to claim 20, characterized in that at least one of the outer layers 1, 1' composed of a natural material and/or at least one layer lying between said outer layers 1, 1' is laced with a bone replacement material.

22. Covering membrane according to one of the claims 1 through 21, characterized in that at least one of the layers forming the covering membrane and/or the bone replacement material comprises a content of at least one biologically active agent.

23. Covering membrane according to claim 22, characterized in that at least one of the two outer layers 1, 1' composed of a natural material and/or at least one layer lying between said outer layers and/or the bone replacement material contains a biologically active agent.

24. Covering membrane according to claim 22 or 23, characterized in that the biologically active agent is selected from the group that comprises growth factors, antibiotics, pain-relieving agents, agents that influence the cell division and the vascularization, coagulating and anti-coagulating agents, immune-suppressing and immune-stimulating agents, cytosines, chemical attractants, enzymes and combinations thereof.

25. Covering membrane according to one of the claims 1 through 24, characterized in that, in addition to the layer composed of a synthetic material 2, at least one further layer of the layers forming the covering membrane comprises a polymer matrix of synthetic material.

26. Covering membrane according to claim 25, characterized in that at least one of the two outer layers 1,1' composed of a natural material comprises a polymer matrix of synthetic material.

27. Covering membrane according to claim 25 or 26, characterized in that the synthetic material is biologically degradable.

28. Covering membrane according to claim 27, characterized in that the synthetic material is composed of a thermoplastic.

29. Covering membrane according to claim 28, characterized in that the thermoplastic comprises at least one polyester from the family of poly-.alpha.-hydroxyl acids such as polytrimethylene carbonate, polydioxanone, polyglycolide, polyactide, poly(L-lactide-co-glycolide) in addition to other copolymers, polyorthoesters and/or polycaprolactone (polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate).

30. Covering membrane according to one of the claims 25 through 29, characterized in that the synthetic material is poly(D,L-lactide).

31. Covering membrane according to one of the claims 25 through 29, characterized in that the synthetic material is poly(L-lactide-co-D,L-lactide).

32. Covering membrane according to claim 31, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 40:60.

33. Covering membrane according to claim 31, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 50:50.

34. Covering membrane according to claim 31, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 70:30.

35. Covering membrane according to claim 31, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 80:20.

36. Covering membrane according to one of the claims 25 through 35, characterized in that the polymer matrix is porous.

37. Covering membrane according to one of the claims 25 through 36, characterized in that the layer containing the polymer matrix composed of synthetic material faces toward the tissue and/or bone to be regenerated.

38. Covering membrane according to one of the claims 1 through 37, characterized in that the covering membrane is three-dimensionally shaped.

39. Covering membrane according to claim 38, characterized in that the covering membrane is thermally three-dimensionally shaped.

40. Employment of the covering membrane according to one of the claims 1 through 39 in vitro and/or in vivo and/or ex vivo.

41. Employment of covering membrane according to one of the claims 1 through 40 for the controlled tissue regeneration and/or controlled bone regeneration.

42. Method for the manufacture of a covering membrane according to one of the claims 1 through 39, characterized by the steps a) introducing a layer composed of a natural material into a mold, b) applying at least one layer of the synthetic material, c) applying a second layer composed of a natural material, d) closing the mold, e) introducing the mold into a pressure vessel and closing the latter, f) admitting CO2 and/or N2 into the pressure vessel, g) setting a pressure p and a temperature T, h) holding the pressure p and the temperature T for a time t, and i) dismantling the pressure p in the interior of the pressure vessel.

43. Method according to claim 42, characterized in that, before and/or after the application, further material that serves for the formation of one or more further layer(s) of the covering membrane is applied to at least one layer of the synthetic material.

44. Method according to claim 42 or 43, characterized in that the natural material is collagen.

45. Method according to claim 44, characterized in that the collagen is of type I and/or type IV.

46. Method according to one of the claims 42 through 45, characterized in that the synthetic is employed as powder and/or granules and/or flakes.

47. Method according to one of the claims 42 through 46, characterized in that at least the synthetic material comprises a content of at least one biologically active agent.

48. Method according to claim 47, characterized in that the biologically active agent is selected from the group that comprises growth factors, antibiotics, pain-relieving agents, agents that influence the cell division and the vascularization, coagulating and anti-coagulating agents, immune-suppressing and immune-stimulating agents, cytosines, chemical attractants, enzymes and combinations thereof.

49. Method according to one of the claims 42 through 48, characterized in that the synthetic material is biologically degradable.

50. Method according to one of the claims 42 through 49, characterized in that the synthetic material is composed of a thermoplastic.

51. Method according to claim 50, characterized in that the thermoplastic comprises at least one polyester from the family of poly-.alpha.-hydroxyl acids such as polytrimethylene carbonate, polydioxanone, polyglycolide, polyactide, poly(L-lactide-co-glycolide) in addition to other copolymers, polyorthoesters and/or polycaprolactone (polyhydroxybutyrate and polyhydroxybutyrate-co-hydroxyvalerate).

52. Method according to one of the claims 42 through 51, characterized in that the synthetic material is poly(D,L-lactide).

53. Method according to one of the claims 42 through 51, characterized in that the synthetic material is poly(L-lactide-co-D,L-lactide).

54. Method according to claim 53, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 40:60.

55. Method according to claim 53, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 50:50.

56. Method according to claim 53, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 70:30.

57. Method according to claim 53, characterized in that the synthetic material comprises a weight ratio of L-lactide to D,L-lactide of approximately 80:20.

58. Method according to one of the claims 42 through 57, characterized in that the mold is closed pressureless.

59. Method according to one of the claims 42 through 58, characterized in that the carbon dioxide and/or nitrogen introduced into the pressure vessel in step f) is introduced in liquid form.

60. Method according to one of the claims 42 through 59, characterized in that the carbon dioxide and/or the nitrogen is converted into a super-critical condition as a result of step g).

61. Method according to one of the claims 42 through 60, characterized in that the pressure p amounts to between approximately 2 x 10 6 and approximately 2 x 10 8 Pa.

62. Method according to claim 63, characterized in that the pressure p amounts to between approximately 5 x 10 6 Pa and 1.5 x 10 7 Pa.

63. Method according to one of the claims 42 through 62, characterized in that the temperature T amounts to less than approximately 37°C.

64. Method according to one of the claims 42 through 63, characterized in that the time t amounts to between approximately 10 minutes and approximately 100 minutes.

65. Method according to claim 64, characterized in that the time t amounts to approximately 30 minutes.

66. Method according to one of the claims 42 through 65, characterized in that the pressure p is dismantled with a defined gradient.

67. Method for manufacturing a covering layer according to one of the claims 1 through 39, characterized in that at least one layer of a natural material is extruded onto at least one further layer of the covering membrane that comprises at least the layer 2 of at least one synthetic material lying between the two outer layers 1,1' composed of a natural material.

68. Method for manufacturing a covering layer according to one of the claims 1 through 39, characterized in that at least one layer of a natural material is integrally cast onto at least one further layer of the covering membrane that comprises at least the layer 2 of at least one synthetic material lying between the two outer layers 1,1' composed of a natural material.

69. Method according to claim 67 or 68, characterized in that the layer 2 of synthetic material lying between the two outer layers 1,1' composed of a natural material is pre-shaped before the application of the layers that are composed of natural material.

70. Method for manufacturing a covering membrane according to one of the claims 1 through 39, characterized in that an arrangement of the layers forming the covering membrane is placed into a heat compression mold, the heat compression mold is closed and a temperature T1 and a pressure p1 is applied.

71. Method according to claim 70, characterized in that the temperature T1 amounts to approximately 100°C or less.

72. Method according to claim 70 or 71, characterized in that the pressure p1 amounts to approximately 1 x 10 6 through 2 x 10 6 Pa.

73. Molded body, characterized in that the molded body is composed of a covering membrane according to one of the claims 1 through 41.

74. Molded body according to claim 73, characterized in that the molded body is an augmentation molded body for the elimination of bone voids.

75. Molded body according to claim 73 or 74, characterized in that the degree of porosity of the two outer layers 1,1' composed of a natural material differs from that of the covering membrane forming the molded body.

76. Molded body according to claim 75, characterized in that the outer layer composed of a natural material and facing toward the bone void in the covering membrane exhibits a higher degree of porosity than the outer layer composed of natural material and facing away from the bone void in the covering membrane.

77. Molded body according to one of the claims 73 through 76, characterized in that the thickness of the outer layer composed of a natural material and facing toward the bone void in the covering membrane differs from the thickness of the outer layer composed of natural material and facing away from the bone void in the covering membrane.

78. Molded body according to claim 77, characterized in that the outer layer composed of a natural material and facing toward the bone void in the covering membrane is thicker than the outer layer composed of natural material and facing away from the bone void in the covering membrane.

79. Molded body according to claim 78, characterized in that the outer layer composed of a natural material and facing toward the bone void in the covering membrane is significantly thicker than the outer layer composed of natural material and facing away from the bone void in the covering membrane.

80. Molded body according to one of the claims 73 through 79, characterized in that at least the pores of the outer layer composed of a natural material and facing toward the bone void in the covering membrane comprise a volume of approximately 1 through 5 mm3.

81. Molded body according to one of the claims 73 through 80, characterized in that at least the pores of the outer layer composed of a natural material and facing toward the bone void in the covering membrane comprise a content of autologous bone material.