MXPA96003990A - Bio remodelable collagen fabrics, three-dimensional - Google Patents

Abstract

The invention relates to three-dimensional bioremodellable fabrics, made from collagen threads that are used to replace or repair organic fabrics.

Description

COLLAGEN FABRIC BIOREMODELABLES THREE-DIMENSIONAL Field of the Invention The invention is in the field of implantable medical devices for tissue engineering, and is directed to three-dimensional bioremovable fabrics, made of collagen threads that are used to replace or repair tissues or organs.

Background of the Invention One of the most important attributes of living organisms is their ability to self-repair. Various mechanisms have evolved to achieve this, including wound healing, compensatory growth and epimorphic regeneration. Although all tissues and organs (with the possible exception of teeth) are capable of a certain level of repair, mammals have unfortunately lost the ability to faithfully regenerate severely damaged body parts. In an effort to overcome this deficiency, numerous synthetic devices have been developed, with the intention that the implants are biologically inert, and still work during the lifetime of the recipient. The experience with REF: 22969 synthetic devices, however, has shown that not only is the seemingly impossible inert biological quality, but that the interaction between a biomaterial and the surrounding living tissue can now contribute to the long-term success of the implant.

The concept of a resorbable scaffold or support for tissue repair and regeneration has received considerable attention in recent years, and has been attempted using synthetic and natural resorbable polymers. Yannas et al., In the U.S. 4,060,081, fabricated implants from lyophilized sponges of collagen and glycosaminoglycans. Nyiles et al, Trans Am. Soc. Artif. Intern. Organs, 29: 307-312 (1983), used resorbable polyesters for peripheral nerve regeneration. Li used a porous semipermeable collagen conduit for nerve regeneration, as described in U.S. Pat. 4,963,146, and used the collagen fibers to form a resorbable prosthesis ligament as described in U.S. Pat. 5,263,984.

Collagen has long been used as a biomaterial. (Chvapil, et al., "Medical and Surgical Applications of Collagen", International Review of Connective Tissue Research, volume 6, pp. 1-60 (1973); Stenzel et al., "Collagen as a Biomaterial", Annual Review of Biophysi cs and Bioengineering, p. 231-253 (1974); E.E. Sableman, "Biology, Biotechnology and Biocompatibility of Collagen ", volume 1, pp. 27-65 (19).) In these structures, collagen has been formed into fibers, threads, membranes, gels and sponges.

Independently of the extensive research during the last fifty years, these reconstituted structures of collagen, do not possess the same mechanical properties of the connective tissues, for which they try to imitate and, therefore, it is often necessary to reinforce them with synthetic materials. In this way, Chvapil and colleagues reinforced a collagen cylinder with Dacron, to function as a vascular graft. (Chvapil M. and Krajice M., J. Surg. Res., 3: 358 (1963); Chvapil et al., J. Biomed. Mat. Res. , 3: 315 (1969)). The Dacron was also used to reinforce a bandage for collagen-based wounds. (Song et al., Surgery, 59: 576 (1966)). Collagen has also been mixed with glycol methacrylate to form a material for its possible use in orthopedic surgery.

(Chvapil et al., J. Biomed, Mat. Res., 3: 315 (1969)).

The reconstituted collagen fibers were first produced in the 1940s, and this technology was exploited to produce an extruded collagen suture. These collagen fibers were woven or interlaced into a mesh for use in surgery. An open collagen tissue (log), formed of 4-0 suture materials, was used by Adler et al. (Adler et al., "A Collagen Mesh Prosthesis for Wound Repairing and Hernia Reinforcement," Surgical Foru, 13: 29-30 (1962)). A similar material was also used by Friedman and Meltzer to repair endopelvic bandage defects. (Friedman and Meltzer, "Collagen mesh prosthesis for repair of endopelvic fascial defects", Gynecology, 106: 430-433 (1970)).

Green and Patterson demonstrated in 1968 that an open tissue of collagen fibers stained with formalin and laminated between layers of a fibrillar collagen dispersion could be used for reconstruction of the pelvic floor. (Green and Patterson, "Collagen Film Pelvic Floor Reconstruction Following Total Pelvic Exenteration", Surgery, Gynecology &Obstetrics, pp. 309-314 (February 1968)). A similar device was used by Janetta and Whayne (1965) as a dural substitute in dogs.

A device made of an open mesh of collagen, through which three long ribbons of collagen were intertwined, was used by Girgis and Veenema (1965).

Schonbauer and Fanta (1958), implanted a mesh made of catgut sutures stained with chromium inside the dorsal and abdominal band of dogs. All these materials were simple layers of collagen tissue, as can be seen in Figure 2 of Girgis and Veenema (1965) and in drawing 1 of Schonbauer and Fanta (1958).

Weslo ski et al., Surgery, 50:91 (1963) investigated the production of a composite vascular graft, in which some of the monofilament fibers were replaced with cat gut or with reconstituted collagen suture. These researchers however, found that this graft did not work properly due to the fact that the collagen material was not completely absorbed during the healing time of the fibrous capsule.

The connective tissues derive their mechanical strength and physical character mainly from the three-dimensional assembly of fibrils and collagen fibers, long, intertwined and intertwined, formed of one or more of the 18 different types of collagen, each of which has its own structure and properties. The same type of collagens synthesized by different tissues, organize themselves into different organizational structures. Thus, in type I skin collagen, the collagen fibers form a structure in which type I collagen fibers lie at various acute angles in relation to the surface of the skin. In tendons and ligaments, however, most collagen fibers of type I are arranged with their longitudinal axis parallel to the longitudinal axis of the tissue. In the cornea, type I collagen fibers are oriented in orthogonal layers. In cylindrical organs such as the blood vessels and the intestine, the collagen fibers lie in a cross-layered arrangement, with the two arrays of fibers running diagonally in a direction in the direction and in the opposite direction of the clock hands. In bones, the large collagen fibers are arranged in a way that best opposes the charges imposed on the tissue. By using collagen fibers and three-dimensional fabric forming technology, this organization can be imitated to a certain degree in the formation of implantable bioprostheses that are designed to act as remodelable scaffolds to promote the establishment of new tissues that maintain, restore or improve , the normal biological function.

It is easier to achieve a variety of fiber orientations in three dimensions, if you are not limited by the need to interlock the fibers. (See Figure 4 of Mohamed). This fabric lacks structural integrity since the individual fibers do not interact, and the material needs to be impregnated with a matrix, in order to produce an integrated structure. This technique has been used with synthetic materials to form structures with wall thicknesses of up to 20.32 cm. (Mohamed, American Scientist, 78: 530-541 (1990)).

Machines that can form woven fabrics, cylindrical, three-dimensional, in which the two layers can be bonded together have also been developed. (Williams, Advanced Composition Engineering, volume 2 (1987)). The twisted fabric, with multiple re-reinforcing filaments, can be used to produce a fabric that is multi-layered. (Mohamed, supra.) Braiding can also be used to produce highly complex three-dimensional shapes. (Florentine, U.S. Patent 4,312,261). Three-dimensional fabrics have also been formed. The fabrics can be woven with a space between the layers (core fabrics) or woven as dense and thick structures as seen in Figure 8 of Mohamed, supra.

Brief Description of the Invention The inventors have combined the fibrilogenic capacity of collagen with textile technologies, in order to bioengineered custom-made, three-dimensional bio-removable fabrics to fit a variety of applications with varied porosity, elongation, and resistance requirements based on knowledge. acquired from bioimitation studies. The bioremolability of the collagen fabrics of this invention allows them to be subjected to a biodegradation in a controlled manner, so that the production of the endogenous structural collagen, the vascularization and the epithelization of the fabric through the growth of host cells, occurs at a speed faster than the loss of biomechanical resistance of the implanted fabric due to the biodegradation of the host enzymes. By the time the implanted collagen fabric of this invention is reabsorbed by the body, the endogenous host tissue is in place and is able to maintain the integrity and normal function of the tissue.

The invention provides for the production of three-dimensional bioremogable collagen fabrics of various configurations. These fabrics are then implants and bioengineering devices that serve the required physical function while facilitating the remodeling of the repaired or replaced tissue or the implant of the organ.

Detailed description of the invention I. Tissue Engineering This invention is directed to three-dimensional bioremodellable fabrics that are formed from collagen threads. The invention is directed to implantable medical devices that can be used to replace or repair tissues or organs. More particularly, the invention is directed towards devices that can serve as scaffolds in vivo for the regeneration of new tissue. In the textile industry, three-dimensional fabrics reach their greatest strength when the threads intertwine or interlock in the transverse, longitudinal or thickness direction. These directions are also called axes X-, Y- and Z-. The three-dimensional bioremovable fabrics of this invention are applications of the textile technique with an understanding of the fibrillogenic capacity of collagen and ability to bioremodelar. The three-dimensional bioremovable fabrics are made from collagen threads and, using textile techniques, are woven and / or knitted in the desired configurations to replace or repair organs and tissues.

The three-dimensional fabrics of this invention means that they include collagen strands in multiaxial directions, as compared to two-dimensional fabrics having only width and length directions. A two-dimensional fabric has, of course, some depth based on the diameter of the yarns used in the construction, but it is not a true three-dimensional multiaxial fabric.

As the term "fabric" is used herein, it means a structure that is used as a three-dimensional framework or stage for bioremoving, which can be formed in a number of patterns or shapes according to the dictates of the bioimitation approach of tissue engineering. . Thus for example, as explained in detail below, a three-dimensional bioremoveable fabric can be formed into a structure resembling a bone, with a hollow core. Additionally, the collagen strands can be formed in a solid configuration, such as a structure that resembles a sling for hernia repair. The term "cloth" is used, because it describes a construction made of collagen threads using textile techniques. For example, the term sgnifica that includes braids that can be made within a wide range of geometric shapes where the braided wires are assembled with the complete structure.

Various types of structures are described in detail in the co-pending application, serial number U.S. 08 / 216,527, filed simultaneously with this, as "Biocompatible Devices", the content of which is fully incorporated herein by reference.

The bioremodable collagen fabric is designed not only to perform an immediate physical function, but equally important, to guide and promote proper formation of host tissues, dissolve, and gradually transfer the load to newly formed collagen. The term "bioremovelable" means the ability of the implanted collagen fabric to function as a scaffold for the incarnated new host tissue, by facilitating the production of endogenous structural collagen, vascularization and the epithelization of the incarnated host cells to a speed greater than the loss of biomechanical resistance of the implanted fabric, due to biodegradation. As the bioremoveable fabric biodegrades, a new tissue is formed, thus creating a permanent functional analog of the original tissue or organ.

A three-dimensional fabric is a woven and / or woven product that is multiaxial, with X-, Y-, and z- axes. Typically, three-dimensional fabrics are formed continuously by weaving a plurality of filaments together, some of which are at an angle to the plane of traditional flat fabric of the fabric. An inherent disadvantage of fabric constructions made of two-dimensional fabric sheets is their limited strength. Two-dimensional fabrics are anisotropic, exhibiting unequal resistance properties when measured along the X- and Y- axis. To extend the use and value of textile technology within bioremovable collagen constructions, resistance is required in more than two directions. The three-dimensional fabrics of this invention can be constructed from collagen fabrics using textile techniques.

The formation of three-dimensional fabrics in the textile industry has been used to produce a number of different items. These techniques are described in detail in the following patents, which are not intended to be limiting: U.S. 5,019,435 4,917,756 4,863,660 4,848,414 4,834,144 4,805,422 4,805,421 4,779,429 4,346,741 5,067,525 4,936,186 4,881,444 4,800,796 4,719,837 4,615,256 4,312,261, all of which are incorporated herein by reference.

The construction of three-dimensional bioremovable fabrics can be carried out using textile techniques of knitting and knitting. Using these techniques, the three-dimensional bioremovable fabrics of this invention can be made in a variety of forms: (1) a solid fabric; (2) a tissue 10 open; (3) a solid knitted fabric; and (4) a fabric * open point. All these fabrics can be manufactured with threads of the same size or with threads of different sizes in the same construction. In addition, threads can first be layered, braided, or manipulated 15 otherwise, to increase the diameter or strength of the yarns, such as by interlacing, before being used in the construction of bio-removable fabrics. Additionally, a combination of knit construction and fabric construction 20 can be used in the same construction of the fabric. These collagen fabrics can be used for a variety of applications with varied porosity, elongation and resistance requirements. 25 II. Construction of three-dimensional fabrics A. Fabric A woven cloth is defined in textile terms, as a fabric made by interlacing or interweaving warp filaments, with filler filaments, the weft. A warp, is a series of filaments that extend along a loom and are crossed by the plot, the filler filaments.

Woven multilayer fabrics are composed of different series of warps and filler filaments that form different layers, one above the other. Fabrics can be woven with a space between the layers (core fabrics) or woven as thick and dense structures. The layers can be bonded together by warp ends entangled in the structure, with the filling of the adjacent layers (angle assembly) or by having the ends interlaced between the front and back layers (warp assembly). The bonding filaments can also be interlaced vertically between the layers, producing an orthogonal weave.

Multilayer woven fabrics need not be interlaced through the fabric: the sum of the vertical filaments interlaced with the upper and lower horizontal filaments, provide the same type of reinforcement in a three-dimensional structure that is supplied by the lower and upper interlacing in the flat tissue.

The multilayer structures, provide additional resistance by inserting in each layer filler filaments, which remain straight and contribute to their complete resistance in the direction in which they are oriented. The filaments that are interlaced between the layers as bonding filaments contribute partially to the resistance of their direction; in orthogonal woven fabrics, they contribute immensely to the resistance in the thickness direction. There are some exchanges that must be made, however, since only one filament can occupy any position within the structure. An increase in the fiber volume fraction (the fraction of the total volume occupied by the fiber) in one direction can be achieved only at the expense of one or both of the other directions.

More commonly, shuttle looms are used and the warp filaments are taken from a top hat, since the warp comes from several individual coils, can be taken from different sources, an arrangement that allows the filaments to mix and allow flexibility at the speeds at which they feed.

Traditional weaving machines adapt well to make multi-layered panels in this form, but the complexities of creating other three-dimensional textile structures require special considerations, including maintaining consistency in filament tension.

A key step to ensure the strength of the finished structure, occurs every time the needles cross the warp, A vertical needle, spun with the filament that will secure the selvedge loops on the vertical edge, is inserted from below the weaving area, reaching to catch the filler filament that has been brought through the warp. This selvedge needle holds a loop of each filler filament at the warp edge, as the filler needles return to their original position. Then, a double length of padding is inserted with each cycle. The selvage needles retract for the next stage, but the selvedge filament - which now holds the filler loops - is hooked and held in its vertical position by a knitting needle. To form a finished corner edge, the ties of the selvedge filaments are woven together as the process continues.

The stage called "weft adjustment" in the traditional fabric, is used in the three-dimensional fabric to position the vertical filaments (z). These filaments are spun through needles suspended from the frames of the harness (similar to those used in traditional looms), and are passed through vertical openings in a tongue at angles, crossing the opposite end of the filling needles. Once each cycle, as the z-filaments are suspended diagonally, the tongue moves horizontally to push the filling against the length of already woven textile. This action pushes the crossed z-strands in a vertical arrangement. The harnesses that hold the filaments z, then move up and down, to reverse the positions of the filaments before the process starts again. In this way, the vertical filament that has been stretched from the bottom to the top of the textile is passed over the top filler filament and is held in this position, to be placed in the opposite direction in the next weaving stage. .

With additional frames of harness, and devices for weaving machine or Jacquard, it is possible to weave various structures.

It is also possible to vary the fiber volume fraction to give the composition the ability to withstand extra efforts in a particular direction. Since in this system the filler filament is inserted in the form of a bent loop, a balanced structure is reached when the filler filaments are half the size of the warp and z filaments. The structure can be maintained balanced in this way but the sizes of the filaments used in each of the three directions vary. In addition, the fraction of fiber volume can vary in the vertical direction using more than one warp filament for each filament z. This proportion may not be required for each application.

B. Knitted Fabric A woven fabric is formed by interlocking the thread or filament in a series of connected loops. Knitting stitch is a basic knitting stitch, which is usually made with filament at the back of the work, by inserting the right needle into the front of the loop over the left needle on the left side, rescuing the filament with the point of the right needle, and bringing it through the first loop to form a new loop. The inverted stitch forms a pointed fabric stitch usually made with the filament at the front of the work, by inserting the right needle into the front of the loop on the left needle from the right, rescuing the filament with the right needle and bringing it to form a new bond.

Knitting is a versatile technique for producing strong and porous structures, and is the preferred method for making three-dimensional bioremovable collagen fabrics. The main advantage of knitting over normal fabric is that the knitted fabric introduces closed loops at the crossing points of the filament, allowing the product to hold the sutures with very few roughnesses and without the need to bend the material in the suture line. In contrast, normal fabric interferes with parallel filaments that result in a fabric more subject to wear when cut. In addition, knitting offers more options by varying the physical nature of the final material compared to normal fabric.

There are two basic types of knitting machines. The knitting machines use only one end of the filament and the individual needles release the stitches sequentially. The warp knitting machines use different ends of the filament woven in parallel on a cylinder (the warp) and the needles as a whole (a "needle bar") release the stitches simultaneously to produce the fabric.

The warp knit fabric, however, offers different advantages. Since woven fabrics are formed from a single end, they can be unraveled if the end is pulled, or if the fabric is cut in half and the free end is pulled. Most warp knit fabrics do not unravel when pulled. Moreover, by using additional warps and additional needle bars at the same time, complex fabrics can be designed in which a more complex fabric of heavier weight results with new mechanical properties.

There are two main categories of warp knitting machines. The Raschel type has a hooking needle to hold the filament. The type of tricot, holds the filament with a flexible bent tip, called "beard". Raschel machines offer a more versatile arrangement of knitting patterns, but Tricot machines exert less effort on the fibers. Both flat and tubular structures can be made on Raschel machines; Tricot machines are mainly used to produce flat structures. Collagen fabrics can be made by tubular and flat knit fabric, and by Raschel knit fabric and Tricot. A variety of knitwear designs range from the range of open stretch knits, to stable dense fabrics, to tubular structures, using starting materials from multiple or single monofilament yarns to braided or twisted filaments.

Variations of knitting techniques can be used to make three-dimensional constructions in conical or cylindrical forms. In this approach, the axial rods are placed to create the shape of the structure; after the radial filaments are added, the knitting needles trap the radial filaments and create chain stitches to link these filaments around the axial rods, which are replaced with axial reinforcing fibers when the preform is removed from the machine.

C. Braiding Braiding techniques have been developed to produce complex shapes (Florentine 1982). In essence, these are multilayer structures in which some strands of braid traverse the inner layers to link together the two outer layers. Complex shapes can be formed by braiding on a removable mandrel where the contour of the final braid is coupled with those of the mandrel, as can be seen in Figure 7 of Mohamed, supra.

III. Collagen Threads The collagen that can be used in this invention can be formed from the collagen parts derived from animals, or from collagen produced by cells in tissue culture. Collagen can be extracted in various forms from animal parts. Appropriate sources of collagen include, but are not limited to, skin, tendons, bone, cartilage, ligaments, bandage (fascia), intestinal submucosa, placenta. The extraction methods that have been commercialized for the production of the collagen preparations can be divided into the categories of dispersion, digestion and dissolution.

Dispersion techniques generally involve sing and crushing of connective tissue. This results in a heterogeneous material with a high solids content, formed from portions of collagen fibrils. The digestion uses proteolytic enzymes that adhere to the telopeptides down the interlacing. This method produces a partially degraded monomeric collagen solution which, although still containing intact triple helic regions, has now lost most or all of the telopeptide region. The collagen solution is supported by the labile acid nature of the newly formed covalent crosslinks. This technique, which employs low pH solutions, results in the extraction of the intact collagen molecule. Although the yields are relatively low compared to the enzymatic digestion methods, there are major benefits of this technique due to the fact that the complete original structure is maintained.

Various types of collagen strands can be used in this invention. The different types of collagen strands are described in various patents, for example, Silver, U.S. Pat. No. 5,171,273; Shu Tun Li, U.S. Patent No. 5,263,984; PCT application WO93 / 06791 and the copending patent application, U.S. series No. 08 / 216,527, "Biocompatible Devices", all of which are incorporated herein by reference. Collagen sutures are also included in the definition of collagen strands and can be used in this invention. Collagen sutures are described in U.S. Pat. Nos. 3,114,593 and 3,114,591, which are incorporated herein by reference.

The size of the yarn can be measured in two ways. The diameter can be measured microscopically (10X), using a measuring eyepiece, by averaging the readings taken on at least five samples of yarn at least five points at random. Another way to measure the diameter, which is more characteristic of textile fibers, is to measure the mass of yarn per length, or denier (mass in grams per 9000 meters in length). For use in this invention, the denier may be in the range from about 15 to about 300, typically about 80.

Wire strength can be determined by mounting a 50 mm length in a force gauge (Chatillon Corp., Agawam, Massachusetts) and pulling at 50% effort per minute until failure. The final elongation and the load to the break can then be characterized.

The ease of knitting of the yarn can be evaluated by knitting a tubular fabric 5 mm in diameter on a circular knitting machine (Lamb, Chicopee, MA).

The shrinkage temperature, a measure of the stability of the triple collagen helix, can be measured by dipping a loop of thread 5 to 7, loaded with 2.5 g. in 1.0 mM monobasic potassium phosphate, dibasic sodium phosphate, and 150 mM NaCl at a pH of 7.30, and heating at 1 ° C per minute, until shrinkage occurs. The temperature at which the sample shrinks by at least 10% is the shrinkage temperature.

IV. Uses of three-dimensional bioremovable fabrics The three-dimensional bioremodable collagen fabrics of this invention have many uses as organ implants or in the repair or replacement of tissues.

The bioremoveable collagen constructions can be braided or wrapped for use as orthopedic prostheses for load support, such as bone, cartilage, tendon or ligament substitutions. When used as a bone prosthesis, collagen constructions can be formed in a structure with a hollow core. Alternatively, the bone prosthesis may be formed of (1) an outer, hollow, tubular structure with the desired strength and biomechanical properties required to support the load exerted on the particular bone being replaced, and the necessary diameter required to achieve a appropriate coupling at the site of implantation; and (2) an internal matrix of collagen fabric of the desired porosity to allow it to be seeded with hematopoetic stem cells.

Knitted or conventional knitted collagen fabrics, in tabular forms, can also be used as a support for a vascular prosthesis, provided that a luminal uniform flow surface is also provided. Similarly, larger diameter tubes can be woven for use as implants in restorative-reconstructive surgery of tubular organs such as larynx, trachea, bronchi, esophagus, urethra, intestine, colon or bile ducts.

Collagen fabric constructions can also be formed in the form of a wedge to be implanted in synovial joints, to replace a damaged articular meniscus or in the form of a disc to replace damaged intravertebral discs. The implants will be biorelated with endogenous fibrocartilages to create a new meniscus or disc.

The collagen fabric constructions of this invention can also be atomized or coated with antibiotics, antiviral agents, growth factors, thrombosis-resistant agents or the like, prior to implantation to increase remodeling or to prevent infection.

The collagen fabric can also be produced from collagen strands that have been formed from a mixture of collagen and one or more of the following: (a) Proteoglycans or other extracellular matrix components such as fibronectin, laminin and tenascin; (b) Cytokines, such as members of beta transforming growth factors (TGFbs), growth factor-factor platelets (PDGF), insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), morphogenic proteins of bone (BMPs) or interleukin families (IL): these factors can be incorporated uniformly within the collagen thread or coextruded so that the gradient of a factor is formed from the center to the edge of the thread. (C) antifungal, antibacterial or antiviral agents.

The collagen fabric can also be produced from non-interlaced collagen and implanted in this state. The collagen fabric can also be entangled by any of the known interlacing agents described in U.S. Pat. No. 5,263,984, Column 3, lines 54-62. Additionally, the individual threads can be interlaced prior to construction formation in order to control the biomechanical properties of the construction and the response to the cells, and the fabric can be made from mixed interlaced and non-interlaced yarns.

The following examples are presented by way of illustration and are not in any way limiting.

EXAMPLE 1 Formation of an abdominal wall repair system.

This fabric was first made by producing a 2-plate collagen filament. The collagen threads were manufactured by the process described in the copending patent application, serial number U.S. 08 / 216,527, presented in parallel with this, as "Biocompatible Devices". Two strand monofilament strands twisted to 1.5 twists per inch (tpi) in the Z direction; later, they were twisted to 2.5 tpi in the S direction. The result was a two-layered filament that does not unravel or bend. This filament was then woven using a conventional single and a warper (more convenient for test quantities than a top hat) on an ordinary knit beam. The hernia repair fabric under investigation used three such beams on a 20 gauge knitting machine, in a pattern designated for low extensibility and high volume. The stitch design is as follows: • Front bar (# 1): 0-1 / 1-0 // • Medium bar (# 2): 1-0 / 4-5 // • Rear bar (# 3) : 4-5 / 1-0 // This fabric was evaluated as a substitute for the abdominal wall in the rat model, using a complete muscle layer defect measuring 2 cm by 2 cm. Before implantation, the fabric was cleaned with acetone, entangled with 50mM EDC in 90% acetone at room temperature overnight, depyrogenated in 0.1 N NaOH at 4 ° C overnight, and chemically cold sterilized.

The fabric could also be sterilized (dry) by gamma radiation or ethylene oxide.

In this study, the collagen fabric was examined for its ability to close a full thickness abdominal excision in the rat model. A full-thickness abdominal wall defect of 2 cm x 2 cm was created in each of the 5 Sprague-Dawley rats. A 2.5 cm x 2.5 cm piece of collagen fabric was sutured over the defect, using six 4-0 polypropylene, with 0.25 cm of partial coverage around the perimeter. Additional continuous sutures were placed around the perimeter of the fabric, through the fabric and muscle. At 3 weeks and 12 weeks, the animals were examined for herniation and mechanical stability of the implant: the implants, together with a margin of surrounding tissue, were then separated and fixed for histological processing as described below. The area of repair was evaluated by tracing the perimeter of the wound.

All the animals were healthy during the experiment. No abdominal hernia was observed until 12 weeks after the postimplantation. On visual inspection at 3 weeks, the cloth had a dark pink color, suggesting good neovascularization. The blood supply to the tissue within the fabric was supplied from a simple small projection of the abdominal connective tissue (about 2 mm wide) to the lower part of the fabric. No visceral adhesions were observed. Histology at 3 weeks showed a vigorous cell infiltrate, with numerous fibroblasts and some macrophages. An abundant deposition of the matrix could be observed in the interstices of the fabric.

This fabric has a high volume and thickness with low extensibility, and would be useful for space filling applications with moderate load bearing requirements. In addition, various layers of three-dimensional fabrics can then be joined to supply composite fabrics of any desired thickness.

EXAMPLE 2 Training of a meniscus repair device for knees.

When the knee is bent, the menisci stretch to accommodate movement. When the knee bends and turns, the meniscus can overstretch and tear. The medial meniscus is especially vulnerable to tearing due to its anchoring with the tibial collateral ligament, and is therefore less mobile than the lateral meniscus. The medial or lateral meniscus can be repaired using the meniscus repair device of the invention.

To form the meniscus repair device, the knitted fabric described in Example 1 above is wound by placing the fabric on a flat surface, and taking the length of one side of the fabric and winding it end to end. The fabric is rolled up to approximate the total length and diameter of the meniscus to be repaired. The rolled meniscus repair device is crimped to conform to the original contour of the meniscus.

The rolled meniscus repair device is then interlaced with standard techniques using l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), 50mM, for 8 hours in 90% acetone, then rinsing thoroughly with water. Before implantation, the device is depyrogenated by rinsing in 0.1 M NaOH overnight at 4 ° C and sterilized by treatment with ethylene oxide (EtO) at room temperature.

The device is implanted in the lateral or middle meniscus, or both, surrounding the knee cap.

EXAMPLE 3 Formation of tubular structures for bone repair.

Fabric constructions with hollow structures are also produced by direct tubular knitting. The filament described in Example 1 above is knitted by Raschel with two needle bars inside a tube that uses the following pattern: • Front bar: 1-0 / 1-2 • Rear bar: 1-2 / 1 -0 A tubular fabric has its dimensions of external and internal diameter, mechanical strength and porosity determined by the specific knitted fabric design employed. If necessary, the nesting structures of progressively larger diameters can be joined to provide a hollow tube of any desired wall thickness. The center of the cylinder can be filled with collagen in any form, for example, a parallel package of collagen strands formed as described above, a paste of homogenized collagen fibers, or a collagen gel. Any of the elements of the structure can be coated with various agents such as morphogenic bone proteins to stimulate bone repair. A knitted device can be placed over any non-union fracture end in order to stimulate bone repair.

EXAMPLE 4 Formation of a braided tubular structure for bone repair.

A tubular structure can be formed from more than one coaxial layer of braided collagen so that the outer diameter of the braid is coupled with that of the bone being repaired. The braid may be hollow or completely filled with braided material. If a hollow braid is used, the center of the cylinder can be filled with collagen in any form, for example, with a parallel package of collagen strands formed as described above; a paste of homogenized collagen fibers; a collagen gel; and similar. Any of the elements of the structure can be coated with various agents, such as morphogenic bone proteins to stimulate bone repair. A braided medical device formed in this way can be placed on either end of a non-union fracture to stimulate bone repair.

EXAMPLE 5 Formation of a woven fabric to fill a deep skin wound. 1. They can be used to weave the fabric, collagen threads formed from any of the yarns described above in the description. 2. The threads are woven by coil loading sets with collagen threads. One set supplies the warp filaments (lengthwise). These will be stationary during the weaving process. A harness suspends the vertical filaments at oblique angles (some from above and some from below). Two additional sets of filaments are used: "filling filaments" that are inserted from the side by means of two horizontal sets of needles and "edge filaments" inserted from below by a pair of vertical needles. Two knitting needles are also positioned, so that they can knit edge stitches together, at the corners of the woven structure. To weave the structure, the filling needles move between the layers of the warp and vertical filaments to introduce the filling filaments in a transverse direction. Before these needles are retracted, the vertical selvedge needles move to trap the filling; A horizontal bar, in turn, traps the selvedge filaments at the top. The filling needles are then retracted and a pair of knitting needles secure the selvedge filaments to allow the transverse bar to also retract. The warper, which is a comb-shaped device in front of the harness, then moves horizontally to pack the filaments into their final configuration. While this occurs, the vertical filaments are pushed from their diagonal position into a vertical alignment. At the end of each knitting cycle, the knitting needles pass the new yarn filament loop through the previous loop and the harnesses are changed to reverse the position of the vertical filaments for the next cycle.

Although the above invention has been described in some detail by way of illustration with examples for purposes of clarity of understanding, it is obvious that certain changes and modifications may be practiced within the scope of the appended claims.

Claims (20)

1. A three-dimensional bioremodellable fabric, made from collagen threads.

2. The three-dimensional bioremoveable fabric according to claim 1, characterized in that the fabric is woven.

3. The three-dimensional bioremoveable fabric according to claim 1, characterized in that the fabric is knitted.

4. The three-dimensional bioremoveable fabric according to claim 2, characterized in that the fabric is woven in a solid fabric.

5. The three-dimensional bioremoveable fabric according to claim 3, characterized in that the fabric is knitted in a knitted fabric.

6. The three-dimensional bioremovelable fabric according to claim 2, characterized in that the fabric is woven in the form of an open weave.

7. The three-dimensional bioremoveable fabric according to claim 3, characterized in that the fabric is knitted in the form of an open knitted fabric.

8. The fabric according to any of claims 1-3, characterized in that the fabric is made with threads of the same size.

9. The fabric according to any of claims 1-3, characterized in that the fabric is made with yarns of different size.

10. The fabric according to any of claims 1-3, characterized in that the fabric is made with a combination of yarns of equal or different size.

11. The three-dimensional bioremoveable fabric according to any of claims 1-3, characterized in that the fabric is formed in a cylinder.

12. The three-dimensional bioremoveable fabric according to claim 11, characterized in that the cylinder has a diameter suitable for the repair or reconstruction of tubular organs selected from the group consisting of vascular prosthesis, larynx, trachea, bronchi, esophagus, urethra, intestine, colon or bile ducts.

13. The three-dimensional bioremoveable fabric according to any of claims 1-3, characterized in that the fabric is formed as a wedge for implantation in synovial joints to replace a meniscus articular dan? i.

14. The three-dimensional bioremoveable fabric according to any of claims 1-3, wherein the fabric is formed as an intervertebral disc.

15. A three-dimensional bioremodellable tubular medical device made from braided collagen threads.

16. The medical device according to claim 15, characterized in that the tis hollow or full.

17. The medical device according to claim 16, characterized in that the tis filled with collagen in any form.

18. A tissue or an organ implant made of three-dimensional bioremovable fabric constructed from collagen threads.

19. The three-dimensional bioremoveable fabric according to any of claims 1-18, characterized in that the fabric further comprises antibiotics, antiviral agents, growth factors or agents resistant to thrombosis.

20. The three-dimensional bioremoveable fabric according to any of claims 1-18, characterized in that the fabric further comprises the following components: (a) proteoglycans or other extracellular matrix components such as fibronectin, laminin and tenascin; (b) cytokines, such as members of transforming growth beta-factors (TGFbs), platelet-derived growth factors (PDGF), insulin-like growth factors (IGFs), fibroplast growth factors (FGFs), morphogenic proteins of bone (BMPs) or interleukin families 'IL); Y, (c) antibacterial, antiviral or fungicidal agents,