Membrane for use in directed tissue regeneration

 

(57) Abstract:

The invention relates to a multilayer membrane containing matrix layer consisting predominantly of collagen II and having a loose spongy structure, and at least one barrier layer having a dense, relatively impermeable structure. The membrane is particularly suitable for use in vivo for directed tissue regeneration, in particular for use in the reconstruction of bone or cartilage tissue. The advantage of using membranes is that native cells are not able to penetrate into the layer or grow in a layer having a dense, relatively impermeable structure. 4 C. and 16 h. p. F.-ly.

The technical field

The present invention relates to an implant in the form of a collagen membrane for use in directed tissue regeneration, in particular for use in vivo in the reconstruction of bone or cartilage.

Art

It is well known that tissue regeneration is difficult to reconstruct the cartilage tissue, such as cartilage damage. Cartilage lesions can occur in any joint, although large joints such as the knee and elbow, are Naib is teehankee. Joint damage are the main pathomechanism factor in the development of osteoarthritis. The selection of enzymes leads to an inflammatory process in the synovial membrane, which in turn leads to abrasion of the cartilage and destruction of the surface of the joint. Recent attempts to regenerate in vivo articular cartilage with cartilage defects include implantation of cultured autologous articular chondrocytes (COAG). However, this technique has had limited success.

At present it is generally accepted that the reconstruction of the tissue requires matrix, acting as a channel for cells that grow along the fibers and between the fibers of the matrix. Recently it was proposed to use COAG planted on synthetic and natural absorbable matrices. However, attempts at reconstruction of cartilage tissue using matrices based on polylactic acid, polyglycolic acid and collagen 1 (ossein, the main component of tendons, ligaments and cartilage) or collagen III (hardening component of the walls of hollow organs, including blood vessels, bowel) demanded that the matrices were occupied by chondrocytes in vitro before implantation. This gives an increase in the number of complications, i.e. immunologicals what lentati and cloth compared to the sterile culture of chondrocytes.

International application published under number WO-A-96/25961, offers matrix implant-based collagen II (hendrina, the main component of cartilage), which may be implanted at a site in vivo and which ensure growth of native (natural) chondrocytes on the surface of the matrix, resulting in the regeneration of cartilage. However, the ability of such a matrix to ensure complete regeneration of the cartilage tissue is limited.

There is therefore a need in the matrix of the implant, which would ensure successful ingrowth in his native chondrocytes and thus the regeneration of cartilage tissue after implantation in vivo. At present, the inventors have found that cartilage and, ultimately, new bone tissue can be reconstructed through the use of a matrix of collagen II, which in vivo separated not only from the surrounding connective tissue, but also on the subject of defective bone or cartilage. It is assumed that this can be achieved through the use of the implant in the form of a multilayer membrane, which in itself can prevent unwanted penetration into the matrix surrounding t The invention

In one aspect the invention provides a multi-layer membrane containing matrix layer consisting predominantly of collagen II and having a loose spongy structure, and at least one barrier layer having a dense, relatively impermeable structure.

A particular advantage of using a membrane according to the present invention is that native cells are not able to penetrate into the layer or grow in a layer having a dense, relatively impermeable structure.

Although the authors and do not wish to be bound by theory, it is now considered that the successful regeneration of cartilage requires to prevent a rapid ingrowth in the region of the defect not only native tissue, such as connective tissues, blood vessels, etc., but new bone tissue. This can be achieved using a two-layer membrane according to the present invention, which serves to protect the collagen matrix from ingrowth of native tissue cells with one hand. During surgical implantation of this membrane can be used in combination with tissue graft, such as periosteum graft effectively prevents the ingrowth of nativly is but stitched into place, to permit closure of the defect of bone or cartilage. Then on the location of the defect can be implanted two-layer membrane according to the present invention so that she was in contact with the transplant and could be attached so that the matrix layer was converted to the bone defect. More preferably, the two-layer membrane according to the present invention initially implanted at the defect so that the barrier layer was converted to the defect of bone or cartilage. Then strengthen the periosteum graft so that he was in contact with the matrix layer. The graft can be glued biocompatible adhesive, such as fibrin glue or attach absorbable staples from polylactic acid, or, if necessary, or may be filed so that he subsequently served as an impermeable barrier to growing the adjacent connective tissue.

In an alternative method embodiment of the invention, the membrane itself can effectively prevent the ingrowth of native tissue cells. So, on the other hand, the invention provides a membrane containing at least three layers, in which the matrix layer consisting mainly of the dense, relatively impermeable structure.

Matrix layer can serve as a medium for growing native chondrocytes, thus ensuring the regeneration of cartilage tissue. However, in order to facilitate the regeneration of cartilage tissue, the matrix layer can be impregnated by chondrocytes, either before or after implantation in vivo. Although the matrix layer can be impregnated by chondrocytes immediately prior to implantation, for example, by injection, it is expected that usually the chondrocytes will be entered into the matrix layer by direct injection of a suspension of chondrocytes after implantation. While the chondrocytes present in the core layer of the membrane, is able to carry out the regeneration of cartilage and, ultimately, new bone, while the membrane at the same time prevents the ingrowth of other types of cells from the surrounding tissues.

The chondrocytes for use in the present invention can be obtained from such sources of cells that include allogenic or autologous cells isolated from articular cartilage, periosteum and Nadirashvili, and mesenchymal stem cells from bone marrow (stromal cells). As allogeneic cells have the potential for immune response other articular cartilage. Methods of accumulation of cells are known and include enzymatic cleavage or growth in culture. The selected cells are then propagated in cell culture back before the introduction into the body. Typically, at least 106preferably, at least 107cells should be impregnate in the matrix layer, so as to ensure optimum regeneration of cartilage tissue.

Usually it is desirable that the matrix membrane layer according to the present invention contain glycosaminoglycans (GAGS) such as hyaluronic acid, chondroitin-6-sulfate, keratinolytic, dermatooncology, etc. that serve to create a natural environment in which the chondrocytes can penetrate and multiply. Although you can implement in collagen based glycosaminoglycans from different sources, which do not necessarily have the same composition, molecular weight and physiological properties, as glycosaminoglycans of cartilage, the preferred glycosaminoglycans are glycosaminoglycans extracted from the cartilage. Usually matrix layer preferably contains from 1 to 10 weight percent of glycosaminoglycans, for example 2 to 6 weight percent. Although some glycosaminoglycans may be present in narezushi tissues GAG exist at least partially, as a component of proteoglycans (PG). The use of GAG in the form of GHG undesirable because of potential immunological problems that can be caused by a protein in PG. Therefore, preferably the matrix layer is practically not contain proteoglycans. This can be achieved by making the matrix layer of a mixture of purified, not containing telopeptide collagen II and glycosaminoglycans.

Other additives which may also be present in the core layer include, for example, chondroitin, laminin, fibronectin, calcium alginate or anchorin II, helping the attachment of chondrocytes to collagen II, and growth factors, such as factor induction of cartilage (FIH), insulin-like growth factor (IGF), transforming growth factor (TFG-), present in the form of homodimers or heterodimers, and morphogenetic factors bones (IFC), such as native or recombinant IFC-2, IFC-3 (osteogenic), IFC-4 and IFC-7 (OP-1, osteogenic protein-1). IFC-2 independently affects two methods of bone formation is the direct formation of bone and the formation of cartilage, which is then removed and replaced by bone. The composites of the IFC and collagen, including costituency bone matrix, consists of 90% collagen and 10% Nikolayevich proteins (NCU) to ensure activity IFC or induced IFC/SDB of chondrogenesis. Bone matrix is insoluble collagen basis - and laminin or fibronectin acts as a carrier of IFC. Some growth factors may also be present in an impenetrable layer. However, most of them will be present in the core layer. Typically, the membrane contains from 100 μg to 5 mg of growth factors.

As described above, the membrane includes at least two layers having different patterns. Preferably the barrier layer membrane made mainly of collagen I and III. Alternative it may contain synthetic material, for example synthetic resorbable polymer mesh, which can be covered with a collagen material, such as collagen type I and/or type III collagen.

Examples of suitable synthetic materials include polyesters, homopolymers and copolymers polyglycolic and polylactic (PLA) acids, copolymers of glycolide and lactides, polyarteritis and polycaprolactones. Many examples of these substances are widely available, for example, a company Boehringer Ingelheim in their range of products RESOMER. Preferred TMC polymers in widepotential biodegradiruemym polymer is poly(D,L-lactic acid), in which the ratio of D-lactide and L-lactide is approximately 70:30. The advantage of such synthetic materials is that they can have a high mechanical stability, which allows you to pull the membrane implant on top of the complex, three-dimensional bone defects without breaks. Such materials are also suitable for filing.

The barrier layer mainly consists of long collagen fibers, which are connected so tightly that high-molecular substances cannot penetrate this barrier. Long fiber provides high tensile strength and tear resistance, so that this material is not only good separating membrane, but it can be easy to sew. During surgery it is important that the membrane implants could sew or attach in position, and many of the membrane, proposed earlier, do not possess this property. The membrane according to the present invention sufficiently mechanically stable so that it can be surgically treated before implantation.

The matrix layer is very porous and may have a specific weight to 0.02, which provides very fast ingrowth of cells in this layer. This Scotti. Ideally, the matrix layer should be porous (porous volume fraction and pore size), which allows the adhesion and growth of cells and allows the seeded cells to save chondroitine phenotype, characterized by the synthesis of proteins that are specific for cartilage. The pore size will depend on the process of freeze-drying, used for getting the basics of collagen II, but you can expect that he will be in the range of 10 to 120 μm, for example from 20 to 100 μm. Optionally, the pore size may be equal to about 85 microns. This pore size can be easily obtained by slow freezing at a temperature of from -5oWith -10oC for approximately 24 hours with subsequent freeze-drying or by adding ammonium bicarbonate to the pasta before lyophilization.

Matrix membrane layer preferably provide collagen II is derived from cartilage, preferably hyaline cartilage of pigs.

Although the desired thickness of the matrix layer will depend on the nature of the defect of bone or cartilage that is to be processed, in General it can be expected that it will lie in the range from 2 to 10 mm, for example from 4 to 6 mm. Thickness of the barrier layer is preferably equal to from 0.2 to 2 mm, napery collagen I and III. Because it is derived from a natural source, it is completely absorbed into the body and does not form toxic decomposition products. Such membranes also have a particularly high tensile strength both dry and wet condition and therefore can be optionally made of surgical sutures. Wet material is very elastic, which gives the possibility to draw it on the bone defects of irregular shape.

In addition to collagen, natural animal membranes contain many other biomaterials, which should be removed. Known processing such membranes, enzymes, solvents or other chemicals to the implementation of cleaning and for use of such membranes in medicine. Most of these materials are too thin, and very often they are difficult to use. Collagen fibers lose their native character, and an additional drawback is that the material often has insufficient strength for use as the stitching of the material, it has the property of swelling in water and has no differences between the smooth face and a fibrous back side. It was found that the fibrous form of atsisiusti the most favorable substrate material.

Membrane, providing the barrier layer product according to the present invention, include peritoneal membrane calves or pigs, which retains its natural collagen structure. Peritoneal membrane of young pigs at the age of 6-7 weeks (weighing 60-80 kg) is particularly preferred.

The barrier layer should preferably contain pure, native (not denatured) insoluble collagen and can be manufactured in accordance with the method described in WO-A-95/18638. So natural membrane can first be treated with alkali, for example aqueous NaOH solution at a concentration of 0.2-4 weight. %. This allows the saponification of all fats, and proteins, which are sensitive to alkali. The second step is the processing of the material by the acid, usually an inorganic acid, such as HCl. It removes impurities that are sensitive to acid. The material is then washed until then, until the pH is in the range of 2.5-3.5. After that, the membrane has a smooth, or front, side and loose, more fibrous side. It may be useful to carry out the crosslinking in the membrane by heating to 100-120oC.

Collagen II is used to obtain matricariae layer, containing mainly collagen I and III. It is preferable to remove from the cartilage water by treatment with acetone followed by extraction of fat hydrocarbon solvent, such as n-hexane, although you can use and alkanols, such as ethanol, ethers such as diethyl ether, or chlorinated hydrocarbons such as chloroform, or mixtures thereof. Fat-free material is then treated with alkali, which amylee all residual fats and destroys some of the proteins present. In conclusion, the material is treated with acid, which provides additional degradation of proteins. The material is allowed to swell in water and passed through a colloid mill to obtain a paste.

To obtain a multilayer membrane, a soft paste containing collagen II, applied to the fibrous side of the smooth membrane, obtained for example in accordance with WO-A-95/18638. Normal membrane is placed on a smooth surface face down, so that you can easily apply a paste made of collagen II, for example, by rubbing in the fibrous side of the membrane. Paste this forms a layer of any desired thickness, which tightly adheres to collagen membrane. Educated in such brazilya the desired pore size. If necessary, the part of the matrix layer can be removed, giving the double membrane of uniform thickness. To obtain a three-layer membrane on top of the matrix layer is placed second smooth membrane, and its fibrous side in contact with the matrix layer.

Pasta of collagen II for application to the membrane typically contains 1.0 to 4.0 percent by weight of collagen, preferably 2-3 weight %. For convenience, the pH value of this mixture should be raised to 2.5 to 4.5, preferably to 3.0 to 4.0.

The material of collagen II can be used to form cross-links after the stage of freeze-drying to stabilize the matrix layer. It also improves the mechanical stability of the matrix layer and reduce the rate of resorption in the body. Ideally, the level of cross-linking should be such that the rate of degradation of the matrix corresponded to speed tissue regeneration. Physically cross-linking can be accomplished by heating, but it should be made cautiously, to avoid unwanted loss of rasskazyvaemoe. Preferably heated to temperatures of 100-120oC for a period of from 30 minutes to 5 hours. More preferably the cross-svyazyvanie what length up to 8 hours.

The material of collagen II usually contains glycosaminoglycans. The latter actually react with the collagen II, providing some cross-linking, and give an insoluble product. If necessary, additional cross-linking can be done by heating the material or UV irradiation, as described above. The reaction between glycosaminoglycans and collagen can be done at room temperature at pH in the range of 2.5-3.5. The amount of glycosaminoglycans can vary between 1 and 10 weight percent. The material can be subjected to freezing and freeze-drying immediately after this treatment.

Alternative education pasta can be accomplished by raising the pH of the mass of collagen II. During this procedure, the mass is cooled to about 4oC, and the pH is slowly increased by the addition of cold aqueous solution of NaOH at a temperature of 4oWith up to pH values of 6.5-7.5. Then the mass is maintained at room temperature for 15-25 hours. At this time, the result is a paste, and after the formation of the paste mass can be frozen and subjected to freeze-drying.

Another alternative is to neutralize the weight of collagen II to meant is: fine paste, then you can freeze and subjected to freeze-drying.

Which of the above three methods will be used, depends on the properties of the desired product. The first process gives the most stable product. However, precipitation can lead to the formation of lumps of material, and it has to be done very carefully. The second method gives a soft and homogeneous product, which, however, is more soluble than the product obtained in the first process.

When making pasta, you can optionally enter the desired substances, such as medicines, such as antibacterial, such as taurolidine, or antibiotics such as gentamicin.

After applying the paste to the membrane material is frozen. To obtain reproducible pore size, freezing should be carefully monitored, and it is necessary to precisely adjust the speed and time of freezing, pH and particle size. To get a very small pores, the material can be quickly frozen to a very low temperature.

Then the frozen membrane is subjected to freeze-drying, and then heated to 110-130oC. Thus get some cross St is s, so the thickness of the matrix layer is generally equal to about 2 mm, Then a double membrane is sterilized, for example, gamma radiation or by ethylene oxide. Sterilization of strong radiation, for example radiation From60in doses of 25 kGy can deactivate the IFC. In such circumstances, sterile base can before implantation to impregnate IFC, located in a sterile solution.

The membrane according to the present invention can be used in medicine in the following ways:

As a material for directed tissue regeneration. Matrix layer promotes cell growth. The barrier layer inhibits unwanted growth of cells.

As a material for repair of cartilage defects, that is, lesions that do not affect the subchondral plate, and to restore defects are presented.

The invention also allows the use of multi-layer collagen membrane described above, when directed tissue regeneration. The content of collagen II in the membrane is particularly suitable for the regeneration of cartilage tissue, but also suitable for other types of tissue.

Therefore in another aspect the invention provides a membrane, od CLASS="ptx2">

In addition, the invention provides a method of treating defects of cartilage or bone in the human or animal body, the above method includes the overlay above the diaphragm defect, and above the membrane are oriented in such a way that the barrier layer prevents the ingrowth of unwanted tissue types in the field of regeneration of bone or cartilage.

Description of embodiments of the invention

The following examples are given only as illustrations. In the examples all stages of the process should be carried out under aseptic conditions, for example in "clean rooms".

Example 1.

(A) Peritoneal membranes from young calves were completely released from the meat and fat mechanically washed under running water and treated with 2% NaOH solution for twelve hours. Then the membrane was washed under running water and acidified with 0.5% HCl. After the material zachislila across the thickness (approximately three hours), the material was washed until then, until there was obtained a pH value of 3.5. Then the material was seated 7% salt solution, neutralized with 1% solution of NaHCO3and washed under running water. Then the material dehydratio the optimum animal membrane, containing collagen I and collagen III.

(B) Frozen cartilage from cvitanich pigs were immersed in cold water, thoroughly washed and mechanically cleaned from the remnants of flesh, bones, and solid particles. Then the material for 30 minutes, washed under running water.

Then the material three times crushed in the homogenizer. The size of the visible particles at the end of the grinding was approximately 8 mm

Pieces of cartilage were obezvozhivani through 4 times washing with acetone, every time - within 8 hours. Then the cartilage was degreased by 4-fold extraction with n-hexane. Each treatment lasted for at least 8 hours. The ratio of hexane and cartilage was 1:10.

After degreasing the cartilage was allowed to swell in water. The ratio of water : the material was equal to 10:1. Processing time is 24 hours.

Then the material was treated with NaOH (5 weight%), moreover, the ratio of the cartilage and fluid was equal to 1: 4, and the processing time was 32 hours. During processing, the pieces of cartilage are well mixed. Then, from the cartilage was washed alkali. The initial pH of 14, it was down to 9-11. Dissolved contaminants washed and separated from the cartilage. The liquid formed by treatment with alkali, Cl (about 3 wt.%), at pH values below 1.0. Processing time is 4-6 hours.

Then the material was washed with cold water long enough to ensure that the pH value increased to 3-3 .5. All impurities were removed, and the product was represented by collagen mass, not containing salts, suitable for the manufacture of sponges or other collagenous materials. To this end, the mass derived from cartilage, can be, depending on the desired result, degassed, frozen and subjected to freeze-drying.

The extract formed by the above treatment with alkali, contains glycosaminoglycan, alkalis, denatured proteins and salts. First, the extract was neutralized using Hcl, pH after neutralization was equal to 6. Then the extract was processed by the filtering device, namely, the diatomaceous earth, which removes denatured proteins. To the extract was added to 0.5 weight percent of diatomaceous earth and deleted it by filtering with denatured protein.

Then the supernatant was subjected to ultrafiltration using a membrane separating particles with a molecular weight of about 10,000 daltons. Thus was removed salt and left cleared of glycosaminoglycan.

The mass of collagen II had the following properties:

TG = 2.8 wt.%,

GAG = 3 wt.% (calculated in terms of collagen),

The pH value of 3.5.

(C) Freshly prepared peritoneal membrane, prepared as described in paragraph (a), uniformly soaked in water and spread on a glass plate fibrous side up. Next, the membrane was thoroughly moistened mass of collagen II, prepared as described in paragraph (B) above. The membrane stretched on a plane in all directions so that it remained attached to the plate. Then in the membrane rubbed a lot of collagen II.

The membrane was applied a very thick layer of pulp, and the plate was left overnight in a refrigerator at a temperature of about 4oC. during this period he formed a paste.

The paste was frozen under the following conditions:

Bath temperature: -12oWITH,

Time: 40 minutes.

Next frozen pasta was subjected to freeze-drying and then was heated to 125oC.

Time freeze-drying: 14 hours.

Then the matrix layer of collagen II were cut to a thickness of 1 mm

1. Multilayer membrane, suitable for use in vivo in the reconstruction of bone or cartilage, and above the membrane contains a matrix layer, consisting mainly of collagen II and having a loose spongy structure, and at least one barrier layer having a dense, relatively impermeable structure.

2. The membrane under item 1, characterized in that it contains one barrier layer.

3. The membrane under item 1, characterized in that the matrix layer it is located between two barrier layers.

4. The membrane according to any one of paragraphs.1-3, characterized in that the matrix layer made of collagen II is derived from natural cartilage.

7. The membrane according to any one of paragraphs.1-6, characterized in that the barrier layer or barrier layers made primarily of collagen I and III.

8. The membrane under item 7, characterized in that the barrier layer or barrier layers obtained from peritoneal membrane calves or pigs.

9. The membrane according to any one of paragraphs.1-6, characterized in that the barrier layer or barrier layers include synthetic soluble polymer network, which can be covered with a collagen material.

10. The membrane under item 9, characterized in that the above-mentioned collagen material consists of collagen type I and/or type III.

11. The membrane under item 9 or 10, characterized in that the synthetic polymer is a polymer selected from the group consisting of polyesters, homopolymers and copolymers polyglycolic and polylactic acid, copolymers of glycolide and lactide, polyarteritis and consistent.

12. The membrane under item 11, wherein the polymer is poly(D, L-lactic acid) in which the ratio of D-lactide to L-lactide is approximately 70:30.

13. The membrane according to any one of the preceding paragraphs, characterized in that chatengine stem cells from the bone marrow.

14. The membrane according to any one of the preceding paragraphs, characterized in that the matrix layer and/or barrier layers impregnated with glycosaminoglycans.

15. The membrane under item 14, characterized in that glycosaminoglycan is hyaluronic acid, chondroitin-6-sulfate, keratomalacia, dermatosurgical.

16. The membrane according to any one of the preceding paragraphs, characterized in that the matrix layer and the barrier layers contain virtually no proteoglycans.

17. The membrane according to any one of the preceding paragraphs, characterized in that the matrix layer and/or barrier layers additionally contain chondroitin, laminin, fibronectin, calcium alginate, anchorin II, growth factors or morphogenetic factors bones.

18. A method of manufacturing a membrane under item 1, in which a paste made of collagen II is applied to the surface of the barrier membrane having a dense, relatively impermeable structure, with subsequent freeze-drying, resulting in a matrix layer having a loose spongy structure.

19. An implant for use in directed tissue regeneration, characterized in that it includes a membrane as defined in any of paragraphs.1-17.

the AET overlay membrane according to any one of paragraphs.1-17 on the defect, as above, the membrane is oriented so that the barrier layer or layers prevent ingrowth of unwanted tissue types in the zone of regeneration of bone or cartilage.

 

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