An implantable biodegradable device is disclosed containing a fibrous matrix, the fibrous matrix being constructed from fibers A and fibers B, wherein fibers A biodegrade faster than fibers B, fibers A and fibers B are present in relative amounts and are organized such that the fibrous matrix is provided with properties useful in repair and/or regeneration of mammalian tissue.

SUMMARY OF THE INVENTION

Implantable, biodegradable devices of the present invention comprise a fibrous matrix comprising first fibers A and second fibers B, wherein fibers A biodegrade faster than fibers B and wherein fibers A and fibers B are present in relative amounts and are organized such that the fibrous matrix is provided with properties useful, desirable or required for use in the repair and/or regeneration of mammalian tissue.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes bioabsorbable, implantable medical devices containing a fibrous matrix that possesses certain properties that are highly desirable, or even necessary, for use in the repair and/or regeneration of diseased or damaged musculoskeletal tissue in mammals.

The matrix must be biodegradable and resorbable by the body. The matrix must facilitate tissue in-growth in order for tissue to replace the resorbing matrix. In addition, the matrix must be capable of providing and maintaining structural support required for a particular device in a particular procedure for so long as is required to effect the repair and/or regeneration of the tissue, including that time in which the matrix is being resorbed by the body. Accordingly, the rate of resorption of the fibrous matrix by the body preferably approximates the rate of replacement of the fibrous matrix by tissue. That is to say, the rate of resorption of the fibrous matrix relative to the rate of replacement of the fibrous matrix by tissue must be such that the structural integrity, e.g. strength, required of the scaffold is maintained for the required period of time. If the fibrous matrix degrades and is absorbed unacceptably faster than the matrix is replaced by tissue growing therein, the scaffold may exhibit a loss of strength and failure of the device may occur. Additional surgery then may be required to remove the failed scaffold and to repair damaged tissue. Thus, devices of the present invention advantageously balance the properties of biodegradability, resorption, structural integrity over time and the ability to facilitate tissue in-growth, each of which is desirable, useful or necessary in tissue regeneration or repair. Such devices provide synergistic improvements over devices of the prior art.

Examples of such devices include tissue scaffolds as exemplified herein. The scaffolds facilitate tissue infiltration therein and ultimately are biodegraded and resorbed by the body when placed in the body of a mammal. The scaffolds comprise a fibrous matrix constructed from at least two different fibrous materials, e.g. fibers, one of which biodegrades faster than the other. The fibers are of such composition and structure and are combined, or organized, in such a way, both with respect to relative fiber amounts and matrix structure, that the response of musculoskeletal tissue to the scaffold is enhanced and, in fact, infiltration and growth of musculoskeletal tissue therein is facilitated. In this way, the biodegrading scaffold fibrous matrix may be replaced by tissue at a rate that maintains the structural integrity of the scaffold throughout the treatment period.

Biodegradable polymers that may be used to prepare fibrous matrices and fibers used to prepare same are selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylene oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, poly(anhydrides), polyphosphazenes and biopolymers. Certain of the polyoxaester copolymers further comprise amine groups.

Biodegradable and bioabsorbable glasses that may be used to prepare fibers and fibrous matrices may be selected from the group consisting of biologically active glasses comprising a silicate-containing calcium phosphate glass, e.g. BIOGLASS.TM. (University of Florida, Gainesville, Fla.), or calcium phosphate glasses wherein some of the calcium ions are replaced by varying amounts of iron, sodium, magnesium, potassium, aluminum, zirconium or other ions. This partial replacement of calcium ions is used to control the resorption time of the glass. For example, in a calcium phosphate glass, with a phosphate concentration between about 50 and about 70 weight percent, substituting iron for calcium, e.g. from about 0 weight percent to about 35 weight percent iron, while keeping the phosphate level constant, will increase the time for the glass to degrade and resorb in the body.

In addition, the present invention embodies a construct comprising porous biocompatible constructs having interconnecting pores or voids to facilitate the transport of nutrients and/or invasion of cells into the scaffold. The interconnected voids range in size from about 20 to 400 microns, preferably 50 to 250 microns, and constitute about 70 to 95 percent of the total volume of the construct. The range of the void size in the construct can be manipulated by changing process steps during construct fabrication.

In devices according to the present invention, the fibrous matrix comprises an organized network selected from the group consisting of threads, yarns , nets, laces, felts and nonwovens. A preferred method of combining the bioabsorbable fibrous materials, e.g. fibers, to make the fibrous matrix for use in devices of the present invention is known to one skilled in the art as the wet lay process of forming nonwovens. The wet lay method has been described in "Nonwoven Textiles," by Radko Krcma, Textile Trade Press, Manchester, England, 1967 pages 175 176, the contents of which are incorporated herein by reference.

In one embodiment of the invention, a continuous multifilament yarn (Yarn A) is formed from a copolymer comprising from about of 50 to about 95 weight percent PGA and from about 5 to about 50 weight percent PLA. Yarn A is cut into uniform lengths between 1/4'' and 2''. Fiber in this form is known as "staple fiber". In a similar fashion, a continuous multifilament yarn (Yarn B) is formed from a copolymer comprising from about 2 to about 50 weight percent PGA and from about 50 to about 98 weight percent PLA. Yarn B is cut into uniform lengths of between 1/4'' and 2'' staple fiber. Both Yarn A and Yarn B comprise filaments of from about 2 to about 200 microns in diameter, preferably from about 5 to about 100 microns.

In another embodiment of the invention, a continuous multifilament yarn (Yarn A) is formed from a biodegradable glass comprising about 65.9 weight percent P.sub.2O.sub.5, about 17.0 weight percent CaO and about 17.1 weight percent iron. The glass filament diameter was approximately 15 to 30 microns. In a similar fashion, a continuous multifilament yarn (Yarn B) is formed from biodegradable glass fibers comprising 25 about 60 weight percent P.sub.2O.sub.5, about 34 weight percent iron, about 5.7 weight percent CaO and about 0.3 percent impurities. All of these filaments were cut into uniform lengths of 0.5-inch staple fiber. Both Yarn A and Yarn B comprise filaments of from about 2 to about 200 microns in diameter, preferably from about 5 to about 100 microns.

It should also be understood that Yarn A could comprise a continuous multifilament yarn formed from a biodegradable polymer, while Yarn B could comprise a continuous multifilament yarn formed from a biodegradable glass.

Likewise, Yarn A could comprise a continuous multifilament yarn formed from a biodegradable glass, while Yarn B could comprise a continuous multifilament yarn formed from a biodegradable polymer. The key is that Yarn A biodegrades faster than Yarn B.

Predetermined amounts of staple fiber produced from Yarn A and Yarn B are dispersed into water. The predetermined relative amounts of Yarn A and B are selected in order to provide the fibrous matrix to be fabricated from the organized Yarn A and B with properties noted herein. Preferably, the weight ratio of fibers, e.g. Yarn A, to fibers, e.g. Yarn B, will range from about 19:1 to about 1:19, more preferably from about 9:1 to about 1:9.

The predetermined amounts of fibers from Yarn A and Yarn B, respectively, will vary depending upon, for example, the composition of the respective fibers, the construction of the respective fibers, and the particular organization of the respective fibers, which determines the structure of the fibrous matrix produced from the organized fibers. Considering such factors, the relative amounts of fibers are selected such that the matrix prepared therefrom not only possesses the structural integrity, i.e. strength, required for its intended purpose in tissue repair and/or regeneration, but also enhances tissue growth and infiltration into the matrix. In addition, the selection must be such that the rate of resorption of the biodegradable fibrous matrix approximates the rate of replacement of the fibrous matrix by tissue when placed in the body, thus preserving the structural integrity of the implant throughout the treatment period.

Additional processing aids, such as viscosity modifiers, surfactants and defoaming agents, may be added to the water. The purpose of such processing aids is to allow a uniform dispersion of the filaments within the water without causing foaming, which in turn may cause defects in the final product.

A bioabsorbable thermoplastic polymer or copolymer, such as Polycaprolactone (PCL) in powder form, also may be added to the water. This powder possesses a low melting temperature and acts as a binding agent later in the process to increase the tensile strength and shear strength of the nonwoven structure, or fibrous matrix. The preferred particulate powder size of PCL is in the range of 10 500 microns in diameter, and more preferably 10 150 microns in diameter. Additional binding agents include biodegradable polymeric binders selected from the group consisting of polylactic acid, polydioxanone and polyglycolic acid.

Once the fibers are uniformly dispersed within the water, the mixture is drained through a screen. The screen allows water to pass through, but traps the fiber. If PCL powder is included in the mixture, some of the powder is trapped as well within the organized mat of fibers. After the water has drained through the screen, the mat of fibers is removed. The mat containing PCL powder fibers is then subjected to heat in order to melt the PCL. The melt temperature range is between about 60.degree. C. and about 100.degree. C., preferably between 60 80.degree. C. It is crucial to perform this step at a temperature that is above the melting point of PCL powder or similar binding agent, and below the softening point of the fibers. This is necessary to avoid damaging the staple fibers. The powder is melted, flows around the filaments and subsequently cools to a solid state. As seen in FIG. 1, fibers 2 are bonded together at intersecting points via particles 4 of binding agent when the molten powder returns to a solid state. Thus the intersecting fibers are encapsulated at that point in solid polymer and locked in place. The powder thus acts as a binding agent, increasing the strength of the matrix.

The matrix is rinsed overnight in water, followed by another overnight incubation in ethanol to remove any residual chemicals or processing aids used during the manufacturing process. The matrix may then be sterilized by a number of standard techniques, such as exposure to ethylene oxide or gamma radiation.

The nonwoven fibrous matrices of the present invention may be formed into different shapes, or configurations, such as disks, rectangles, squares, stars and tubes, by thermal or non-thermal punching of the nonwoven sheets with dies of appropriate shape and dimension.

Tubular structures having gradient degradation profiles also are included among devices of the present invention. In vascular grafts, having a tube with pores in the outer diameter which transitions to smaller pores on the inner surface, or visa versa, may be useful in the culturing of endothelial cells and smooth muscle cells for the tissue culturing of vessels.

Multilayered tubular structures that allow the regeneration of tissue that mimics the mechanical and/or biological characteristics of blood vessels will have utility as vascular grafts. Concentric layers, made from different fiber compositions under different processing conditions, could have tailored mechanical properties, bioabsorption properties and tissue in-growth rates. The inner, or luminal, layer would be optimized for endothelialization through control of the porosity of the surface and the possible addition of a surface treatment. The outermost, or adventitial, layer of the vascular graft would be tailored to induce tissue in-growth, again by optimizing the porosity (percent porosity, pore size, pore shape and pore size distribution) and by incorporating bioactive factors, pharmaceutical agents, or cells. There may or may not be a barrier layer with low porosity disposed between these two porous layers to increase strength and decrease leakage.

The biodegradable fibers used to prepare fibrous matrices and devices according to the present invention may be solid, or hollow, or may be of a sheath/core construction. Filaments may be co-extruded to produce a sheath/core construction. Additionally, such constructs may be formed by coating a biodegradable fiber, e.g. a biodegradable glass fiber, with a biodegradable polymer. Methods for making each construct of filament are well known to those skilled in the art. In a co-extruded construction, each filament comprises a sheath of biodegradable polymer that surrounds one or more cores comprising another biodegradable polymer. Filaments with a fast-absorbing sheath surrounding a slow-absorbing core may be desirable in instances where extended support is necessary for tissue in-growth.

A further embodiment may include fibers with circular cross-section comprising a combination of fibers ranging from rapidly to slowly resorbing fibers. It has been observed that, in a large articular cartilage defect (7 mm) in a goat model, cartilage formation occurs at the periphery of the rapidly degrading implant. However, the center of the implant was devoid of tissue because the scaffold resorbed too quickly to allow cell migration from the periphery of the implant to the center. Having slower degrading fibers at the center of the defect would allow for complete filling of the defect by tissue in-growth, including the central portion. An example of such a system would be a nonwoven structure comprising a majority of fibers in the center that are prepared from a PLA-based polymer rich in PLA. The periphery would contain a majority of filaments prepared from a PGA-based polymer rich in PGA. Because the PLA-based polymer absorbs more slowly than the PGA-based polymer, the center of the structure will absorb at a slower rate than the periphery of the structure.

In yet another embodiment, the fibrous matrix may comprise a gradient structure. For example, a fibrous implant may have a gradual or rapid, but continues, transition from rapidly degrading fibers at the periphery of the implant, to slowly degrading fibers at the center, relatively speaking. In another embodiment, the transition may occur between the top of the matrix to the bottom of the matrix. One profile for transition from rapidly degrading fibers to slowly degrading fibers may be, for instance, from about 100% rapidly degrading fibers, to about 75% rapidly degrading fibers/25% slowly degrading fibers, to about 50% rapidly degrading fibers/50% slowly degrading fibers, to about 25% rapidly degrading fibers/75% slowly degrading fibers, to about 100% slowly degrading fibers, proceeding from the periphery of the implant to the center.

In yet another embodiment, the three-dimensional structures of the present invention may be coated with a biodegradable, fibrous and porous polymer coating, e.g. a sheet, preferably produced by an electrostatic spinning process. As seen in FIG. 3, the fibrous matrix 10 comprising organized fibers 12 has applied to a surface thereof polymeric coating 14. The electrostatically spun polymer coating can provide the nonwoven matrices with enhanced mechanical properties and the ability to hold sutures. Exemplary biodegradable polymeric coats may be prepared from polymers selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof.

Embodiments of the invention thus far describe a homogenous mixture of filaments in the form of a sheet, or nonwoven matrix. However, the mixture need not be homogenous and the final form need not be a sheet.

A non-homogenous mixture of filaments may be desirable in applications where total absorption time and/or loss of strength over time varies throughout the material.

Therefore, in yet another embodiment, a multi-layered device comprising a first layer that comprises a majority of filaments prepared from a (90/10) PGA/PLA copolymer and second layer that comprises a majority of filaments prepared from a (95/5: wt/wt) PLA/PGA copolymer, will provide a structure that, when implanted, will have a first, e.g. top, layer that is absorbed more quickly than the second, e.g. bottom, layer.

Similar structures may be produced in any shape. In other embodiments, cylinders or prisms with fast (or slow) absorbing cores may be produced during a nonwoven process by segregating the different filaments during the forming process.

In yet another embodiment of the invention, the porous nonwoven matrix can be chemically crosslinked or combined with hydrogels, such as alginates, hyaluronic acid, collagen gels, and poly(N-isopropylacryalmide).

In still another embodiment of the invention, the porous nonwoven matrix can be penetrated with a polymer melt or a polymer solvent solution. Such penetration provides the construct with the ability to maintain bundle coherence and retain potentially loose fibers. Biodegradable polymers that may be used to penetrate the porous nonwoven matrix are selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylene oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, poly(anhydrides), polyphosphazenes and biopolymers.

In another embodiment of the invention, the matrix may be modified, either through physical or chemical means, to contain biological or synthetic factors that promote attachment, proliferation, differentiation, and/or matrix synthesis of targeted cell types. Furthermore, the bioactive factors may also comprise part of the matrix for controlled release of the factor to elicit a desired biological function. Growth factors, extracellular matrix proteins, and biologically relevant peptide fragments that can be used with the matrices of the current invention include, but are not limited to, members of TGF-.beta. family, including TGF-.beta.1, 2, and 3, bone morphogenic proteins (BMF-2, -12, and -13), fibroblast growth factors-1 and -2, platelet-derived growth factor-AA, and -BB, platelet rich plasma, vascular endothelial cell-derived growth factor (VEGF), plelotrophin, endothelin, tenascin-C, fibronectin, vitronectin, V-CAM, I-CAM, N-CAM, selectin, cadherin, integrin, laminin, actin, myosin, collagen, microfilament, intermediate filament, antibody, elastin, fibrillin, and fragments thereof, and biological peptides containing cell- and heparin-binding domains of adhesive extracellular matrix proteins such as fibronectin and vitronectin. The biological factors may be obtained either through a commercial source or isolated and purified from a tissue.

In yet another embodiment, the three-dimensional structures of the present invention can be seeded or cultured with appropriate cell types prior to implantation for the targeted tissue. Cells which can be seeded or cultured on the matrices of the current invention include, but are not limited to, bone marrow cells, stromal cells, stem cells, embryonic stem cells, chondrocytes, osteoblasts, osteocytes, osteoclasts, fibroblasts, pluripotent cells, chondrocyte progenitors, endothelial cells, macrophages, leukocytes, adipocytes, monocytes, plasma cells, mast cells, umbilical cord cells, mesenchymal stem cells, epithelial cells, myoblasts, and precursor cells derived from adipose tissue. The cells can be seeded on the scaffolds of the present invention for a short period of time, e.g. less than one day, just prior to implantation, or cultured for longer a period, e.g. greater than one day, to allow for cell proliferation and matrix synthesis within the seeded scaffold prior to implantation.

Cells typically have at their surface, receptor molecules which are responsive to a cognate ligand (e.g., a stimulator). A stimulator is a ligand which when in contact with its cognate receptor induce the cell possessing the receptor to produce a specific biological action. For example, in response to a stimulator (or ligand) a cell may produce significant levels of secondary messengers, like Ca.sup.+2, which then will have subsequent effects upon cellular processes such as the phosphorylation of proteins, such as (keeping with our example) protein kinase C. In some instances, once a cell is stimulated with the proper stimulator, the cell secretes a cellular messenger usually in the form of a protein (including glycoproteins, proteoglycans, and lipoproteins). This cellular messenger can be an antibody (e.g., secreted from plasma cells), a hormone, (e.g., a paracrine, autocrine, or exocrine hormone), or a cytokine.

The unique properties of the matrices of the present invention can be shown by in vitro experiments that test for adhesion, migration, proliferation, and matrix synthesis of primary bovine chondrocytes by conventional culturing for 4 weeks followed by histological evaluation.

Claim 1 of 28 Claims

1. An implantable, biodegradable device, comprising a fibrous matrix, said fibrous matrix comprising first fibers A and second fibers B, wherein fibers A biodegrade faster than fibers B, fibers A and B are present in relative amounts and are organized such that the fibrous matrix is provided with properties useful in repair and/or regeneration of mammalian tissue, wherein one of fibers A and B comprises a biodegradable polymer and one of fibers A and B comprises a biodegradable glass, and wherein the fibrous matrix comprises a gradient structure comprising a transition in the relative concentration of fibers A to fibers B.
 

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