Bioactive Load-bearing Composites

Abstract

Methods of preparing bioactive composites are described. Also described are methods of molding such composites. Shaped bodies comprising bioactive composites are further described.

Claims

1. (canceled)

2. A bioactive composite comprising a substantially homogenous mixture of polyetheretherketone and an alkali containing bioactive glass, wherein the bioactive glass is a nanoparticulate or has a particle size ranging from about 1 to about 400 microns, and wherein the bioactive glass is present in an amount of from about 5% to about 60% by weight of the bioactive composite.

3. The bioactive composite of claim 2, wherein the polyetheretherketone has a particle size ranging from about 1 to about 400 microns.

4. The bioactive composite of claim 2, wherein the bioactive glass is combeite having a particle size ranging from about 1 to about 200 microns.

5. The bioactive composite of claim 2, wherein the bioactive glass is combeite having a particle size ranging from about 90 to about 150 microns.

6. The bioactive composite of claim 2, wherein the bioactive glass is combeite having a particle size of less than 53 microns.

7. The bioactive composite of claim 2, wherein the bioactive glass is present in an amount from about 45% to about 55% by weight of the bioactive composite.

8. The bioactive composite of claim 2, wherein the bioactive composite further comprises a filler.

9. The bioactive composite of claim 8, wherein the filler is a reinforcing fiber, a carbon, a glass, a radiopaque material, a barium glass, or a resorbable material.

10. The bioactive composite of claim 8, wherein the filler is a calcium phosphate material.

11. A shaped body prepared by melting the polyetheretherketone in the bioactive composite of claim 2.

12. The shaped body of claim 11, wherein the melting is performed using heat, vibrational, radiofrequency or microwave energy or a combinations thereof.

13. The shaped body of claim 11, wherein the shape body is an intracorporeal implant.

14. The shaped body of claim 11, wherein the shape body is a spinal implant.

15. A shaped body prepared by molding the bioactive composite of claim 2.

16. The shaped body of claim 15, wherein the shape body is an intracorporeal implant.

17. The shaped body of claim 15, wherein the shape body is a spinal implant.

18. A shaped body prepared by molding the bioactive composite of claim 2 to form a generic shape and then machining to an implant shape.

19. The shaped body of claim 18, wherein the shape body is an intracorporeal implant.

20. The shaped body of claim 18, wherein the shape body is a spinal implant.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1A depicts a SEM (100) of a sample of PEEK after immersion in simulated body fluid (SBF) for 1 day.

[0013] FIG. 1B depicts a SEM (1000) of a sample of PEEK after immersion in SBF for 1 day.

[0014] FIG. 1C depicts an energy dispersive spectroscopy (EDS) spectrum of a sample of PEEK after immersion in SBF for 1 day. The spectrum corresponds to the sample region shown in FIG. 2B.

[0015] FIG. 2A depicts a SEM (100) of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 1 day.

[0016] FIG. 2B depicts a SEM (1000) of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 1 day.

[0017] FIG. 2C depicts an EDS spectrum of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 1 day. The spectrum corresponds to the boxed area of FIG. 2B.

[0018] FIG. 3A depicts a SEM (100) of a sample of PEEK after immersion in simulated body fluid (SBF) for 7 days.

[0019] FIG. 3B depicts a SEM (1000) of a sample of PEEK after immersion in SBF for 7 days.

[0020] FIG. 3C depicts an EDS spectrum of a sample of PEEK after immersion in SBF for 7 days. The spectrum corresponds to the sample region shown in FIG. 3B.

[0021] FIG. 4A depicts a SEM (100) of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 7 days.

[0022] FIG. 4B depicts a SEM (1000) of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 7 days.

[0023] FIG. 4C depicts an EDS spectrum of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 7 days. The spectrum corresponds to the boxed area of FIG. 4B.

[0024] FIG. 5A depicts a SEM (100) of a sample of PEEK after immersion in simulated body fluid (SBF) for 14 days.

[0025] FIG. 5B depicts a SEM (1000) of a sample of PEEK after immersion in SBF for 14 days.

[0026] FIG. 5C depicts an EDS spectrum of a sample of PEEK after immersion in SBF for 14 days. The spectrum corresponds to the sample region shown in FIG. 5B.

[0027] FIG. 6A depicts a SEM (100) of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 14 days.

[0028] FIG. 6B depicts a SEM (1000) of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 14 days.

[0029] FIG. 6C depicts an EDS spectrum of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 14 days. The spectrum corresponds to the sample region shown in FIG. 6B.

[0030] FIG. 7 depicts a SEM of a cross-section of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight), after immersion in SBF for 14 days. The arrows demarcate deposition of calcium phosphate along the surface of the composite.

[0031] FIGS. 8A-8E depict FTIR spectra of an exemplary embodiment of the present invention comprising PEEK and combeite glass-ceramic (50% by weight). FIG. 8A is an FTIR spectra taken after 1 day of immersion in SBF. FIG. 8B is an FTIR spectra taken after 3 days of immersion in SBF, FIG. 8C is an FTIR spectra taken after 7 days of immersion in SBF. FIG. 8D is an FTIR spectra taken after 10 days of immersion in SBF. FIG. 8E is an FTIR spectra taken after 14 days of immersion in SBF.

[0032] FIG. 8F is an FTIR spectrum of hydroxyapatite.

[0033] FIG. 9A is an example of one embodiment of a shaped body of the present invention.

[0034] FIG. 9B is an example of one embodiment of a shaped body of the present invention.

[0035] FIG. 9C is an example of one embodiment of a shaped body of the present invention.

[0036] FIGS. 10A-10C illustrate exemplary composite structures of the present invention. Bioactive materials are represented by filled gray circles, FIG. 10A is a representation of a cross-section of homogeneous composite structure wherein the bioactive filler particles are roughly evenly distributed throughout the composite, FIG. 10B is a representation of a cross-section of a gradient composite structure wherein the bioactive filler particles are concentrated toward the surface of the composite and diminish toward the interior of the composite. FIG. 10C is a representation of a cross-section of a composite structure with surface adhered bioactive layers.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0037] According to the present invention, methods for preparing bioactive molding composites comprising polyetheretherketone (PEEK), or similar types of polymers in this family, and bioactive glass are described. Also described are methods of preparing bioactive implants comprising PEEK and bioactive glass, as well as shaped bodies for intercorporeal implantation that comprise PEEK and bioactive glass.

[0038] Preferably, medical grade PEEK is used in the present invention, although industrial-grade PEEK can also be incorporated. PEEK is available as a powder and a desirable PEEK material for use in the present invention has an average particle size of about 1 to about 200 microns. PEEK material having an average particle size of about 1 to about 400 microns is also suitable. Preferably, the PEEK material has an average particle size of about 10 to about 100 microns.

[0039] The bioactive glass used in the present invention may be any alkali-containing ceramic (glass, glass-ceramic, or crystalline) material that reacts as it comes in contact with physiological fluids including, but not limited to, blood and serum, which leads to bone formation. In preferred embodiments, bioactive glasses, when placed in physiologic fluids, form an apatite layer on their surface.

[0040] Preferably, the bioactive glass comprises at least one alkali metal, for example, lithium, sodium, potassium, rubidium, cesium, francium, or combinations thereof. In a preferred embodiment, the bioactive glass comprises regions of combeite crystallite morphology. Such bioactive glass is referred to herein as combeite glass-ceramic. Examples of preferred bioactive glasses suitable for use in the present invention are described in U.S. Pat. Nos. 5,914,356 and 5,681,872, each of which is incorporated by reference herein in its entirety. Other suitable bioactive materials include 45S5 glass and compositions comprising calcium-phosphorous-sodium silicate and calcium-phosphorous silicate. Further bioactive glass compositions that may be suitable for use in the present invention are described in U.S. Pat. No. 6,709,744, incorporated herein by reference. Other suitable bioactive glasses include borosilicate, silica, and Wollastonite. Suitable bioactive glasses include, but are not limited to, silica-, borate-, and phosphate-containing materials. It is understood that some non-alkali-containing bioactive glass materials are within the spirit of the invention. Bioactive glasses, as defined herein, do not include calcium phosphate materials, for example, hydroxyapatite and tri-calcium phosphate.

[0041] In exemplary embodiments of the present invention, the bioactive glass possesses osteoproductive properties. As used herein, osteoproductive refers to an ability to allow osteoblasts to proliferate, allowing bone to regenerate. Osteoproductive may also be defined as conducive to a process whereby a bioactive surface is colonized by osteogenic stem cells and which results in more rapid filling of defects than that produced by merely osteoconductive materials. Combeite glass-ceramic is an example of an osteoproductive material.

[0042] Preferably, the bioactive glass has an average particle size of about 1 to about 400 microns. Bioactive glass may have an average particle size of about 1 to about 200 microns, about 1 to about 100 microns, or about 10 to about 100 microns. More preferably, the bioactive glass has an average particle size of about 5 to about 40 microns. Most preferred are bioactive glasses having an average particle size of about 10 to about 25 microns. In some embodiments, the bioactive glass has an average particle size of less than or about 53 microns. It is envisioned that in certain embodiments of the present invention, the bioactive particles are nanoparticulate. In some embodiments, nanoparticulate bioactive glass is substantially excluded. In some embodiments, the bioactive glass has average particle sizes larger than about 500 nm. It is also contemplated that a blend of bioactive particles of differing average particle sizes may be employed.

[0043] Methods of determining particle sizes are known in the art. Some methods include passing the particles through several sieves to determine general particle size ranges. Other methods include laser light scattering, and still others are known to persons skilled in the art. Determination of particle size is conveniently accomplished by sieving and such may be used here. Particle size may also be appreciated via SEM image analysis. It will be appreciated that recitation of averages or size ranges is not meant to exclude every particle with a slightly higher or lower dimension. Rather, sizes of particles are defined practically and in the context of this invention.

[0044] According to the present invention, PEEK particles and bioactive glass particles are blended to form a particle mixture. The blending of the bioactive component with PEEK particles may be accomplished using any methods known in the art per se, including mixing, milling, spinning, tumbling, vibrating, or shaking. In certain embodiments, the bioactive glass is present in an amount of about 5-60% by weight of the particle mixture. In other embodiments, the bioactive glass is present in an amount of about 45-55% by weight of the particle mixture. In other embodiments, the bioactive glass is present in an amount of about 50% by weight of the particle mixture. In certain variations of the present invention, the number of PEEK particles is greater than the number of bioactive glass particles. In other variations, the ratio of PEEK particles to bioactive glass particles is between about 6:1 and about 10:1, inclusive. In certain preferred embodiments, the particle size ratio of PEEK particles to bioactive glass particles is about 1:1.5.

[0045] While not desiring to be bound to any particular theory, it is believed that the combination, of PEEK and bioactive glass using conventional methods is inhibited due to the reactivity of the surface of the bioactive glass with PEEK. In such situations, it may be desirable to prepare the bioactive component prior to its combination with PEEK, or similar polymers. In one embodiment, preparation of the bioactive component may comprise treatment with an agent which serves to remove at least a portion of reactive alkali which may be present at the surface of the bioactive particle component. Aqueous solutions, such as those containing a mildly acidulating agent, may be employed for this purpose. In another embodiment, the bioactive particles can be coated with PEEK or other polymers compatible with PEEK. In yet another embodiment, at least a portion of the surface alkali of the bioactive component may be depleted, leached, or washed, such that the surface alkali is minimized. Such minimization can be achieved by coating, flame spheroidization, or chemical treatment. It is understood that such surface treatments serve to reduce reactivity at the surface of the bioactive component. In one embodiment, the reactive constituent, such as alkali, for example, is reduced at the surface of the bioactive component and up to about 5 to about 10 microns into the bioactive component. Such bioactive components retain bioactivity.

[0046] In certain embodiments of the present invention, the bioactive glass particles and polymer (for example, PEEK) particles may be prepared prior to their combination. For example, the bioactive glass particles may be prepared by rinsing, adjusting particle size, spheroidizing, coating, and/or chemically treating. The polymer (for example, PEEK) particles may be prepared by determining particle size, particle size distribution, composition, molecular weight, purity, viscosity, and/or particle shape. In certain, embodiments, the combination of the prepared bioactive glass particles and the polymer (for example, PEEK) particles may be achieved by blending. Blending sufficient to obtain substantial homogeneity of the mixture may be accomplished using techniques known in the art, for example, sonicating, rolling, milling, impact milling, and/or a chemical slurry. In certain embodiments, the blending may be sufficient to provide a composite having a gradient of bioactive material. In others, the blending may be sufficient to provide a composite having at least one layer of bioactive material. In yet others, the blending may be sufficient to form a coating. According to the present invention, the blended material may be fused. Such fusion may be accomplished using techniques known in the art, including molding, compacting, and/or pressure molding. Thus, provided herein is a method of preparing a bioactive composite article comprising preparing bioactive glass particles, preparing PEEK particles, blending the PEEK particles with the bioactive glass particles to form a particle mixture, and fusing the mixture to form the article.

[0047] In the present invention, a polar organic solvent is added to the particle mixture. Preferably, the weight ratio of solvent to particle mixture is about 1:1 to about 4:1. Most preferably, the weight ratio of solvent to particle mixture is about 2:1. Certain preferred solvents include alcohols, for example ethanol, methanol, and isopropanol. Other solvents include ketones, such as acetone, and halogenated solvents such as chloroform. It is desirable that the solvent contain less than about 5% by weight of water. Preferably, the solvent contains less than about 1% by weight of water. Most preferably, the solvent is anhydrous.

[0048] The particle mixture and solvent is preferably agitated for a period of time and under conditions sufficient to achieve substantial homogeneity of the mixture. In an exemplary embodiment, the mixture and solvent is tumbled on rollers for about one to about two hours. As used herein, homogeneity and homogeneous describe a composition that is substantially uniform in structure and/or composition throughout. The agitation may comprise sonication or mechanical vibration, or both. The agitation may further comprise stirring. The term substantially homogeneous is to be understood within the context of the invention and is not to be taken as an absolute.

[0049] In the present invention, substantially all of the solvent is removed from the mixture. Methods of removing solvent are known in the art per se. In certain embodiments, the solvent can be removed under reduced pressure. In other embodiments, the solvent can be removed by evaporation. The mixture may optionally be re-blended to further ensure homogeneity. For example, the dried powder may be tumbled for about one to about two hours on rollers.

[0050] Also in accordance with the present invention, at least one filler may be added to the mixture of polymer and bioactive glass. Such fillers can comprise, at least partially, reinforcing fibers. Examples of preferred fillers include carbon, glass, radiopaque material, barium glass, resorbable material, or mixtures thereof. In certain, embodiments, the filler may comprise calcium phosphate having macro-, meso-, and microporosity. More preferably, the porosity of the calcium phosphate is interconnected. The preparation of preferred forms of calcium phosphate for use in the present invention is described in U.S. Pat. Nos. 6,383,519 and 6,521,246, incorporated herein by reference in their entireties. An exemplary calcium phosphate product is Vitoss Scaffold Synthetic Cancellous Bone Void Filler (Orthovita, Inc., Malvern, Pa.).

[0051] In accordance with the present invention, the steps described for preparing the bioactive composite may be repeated to achieve substantial homogeneity of the composite.

[0052] Having prepared the bioactive particle composite according to the methods described herein, the composite can be molded using conventional molding techniques to form an integral shaped bioactive implant body, such as those shown in FIGS. 9A-9C. Alternatively, the composite may be molded such that after further machining, a shaped body for implantation is prepared. For example, the composite may be molded to form a generic shape, for example a cylinder or block, which is then machined to a pre-selected implant shape. A mold can be filled with the composite and pressure, for example about 2 to about 80 MPa, can be applied to form a bioactive implant or a generic shape suitable for further machining. Heat sufficient to melt at least one component of the composite can also be used. In addition to using heat to melt at least one component of the composite, vibrational, radiofrequency, or microwave energy, or combinations thereof, can be used to melt at least one component of the composite.

[0053] Once the bioactive spinal implant has been molded, treatment of the implant can be performed to alter the mechanical properties of the composite. For example, after molding, the implant can be held at a temperature above room temperature for a period of time. In other instances, the molded implant can be cooled to room temperature or below by, for example, immersion in water or liquid nitrogen.

[0054] Once the composite has been molded into a desired shaped body, conventional finishing techniques may be employed, such as milling, cutting, drilling, and/or sanding of the shaped body.

[0055] Composite structures contemplated by the present invention include homogeneous composites prepared by blending PEEK, or a related polymer, with bioactive glass, using the methods described herein. Also within the scope of the present invention are composites comprising a gradient of bioactive material. For example, the gradient can vary along one or more dimensions. In another example, there may be greater concentrations of bioactive material in one or more portions of the composite as compared with other portions. Also envisioned are composites comprising layers of one or more types or concentrations of bioactive material, so long as at least one layer is in accordance with the invention. Structures prepared from such composites may have a bioactive portion of the composite at one or more specific locations, such that the bioactive material occurs where design specifications call for bone bonding. In other embodiments, structures prepared using the composites of the present invention may have bioactive materials adhered to the surface. In further embodiments of the present invention, the structures may be coated with materials described herein and such coatings may be useful on metals, polymeric, or ceramic intracorporeal implants.

[0056] Composites and shaped bodies of the present invention preferably demonstrate load-bearing and mechanical properties suitable for use in spinal implants. Composites and shaped bodies of the present invention also preferably demonstrate bioactivity. As used herein, bioactive relates to the chemical formation of a calcium phosphate layer (amorphous, partially crystalline, or crystalline) via ion exchange between surrounding fluid and the composite material. Bioactive also pertains to materials that, when subjected to intracorporeal implantation, elicit a reaction. Such a reaction leads to bone formation, attachment into or adjacent to implants, and/or bone formation or apposition directly to the implants, usually without intervening fibrous tissue. Referring to FIGS. 1-8, a composite, comprising PEEK and 50% by weight of combeite glass-ceramic (having <53 micron average particle size), was prepared using the methods set forth herein. In vitro bioactivity studies were performed with the composites, prepared as described herein, using the method of Kokubo, How useful is SBF is predicting in vivo bone bioactivity, Biomaterials (2006) 27:2907-2915. After immersion in simulated body fluid (SBF) for 1 day, the formation of calcium phosphate can be observed (FIGS. 2A-2C). By comparison, a sample of PEEK, without the bioactive component, immersed in SBF for 1 day, does not result in the formation of calcium phosphate (FIGS. 1A-1C). After 7 days of immersion in SBF, increasing amounts of calcium phosphate formation can be observed in the composite (FIGS. 4A-4C), whereas no calcium phosphate formation is observed in the PEEK sample (FIGS. 3A-3C). After 14 days of immersion in SBF, calcium phosphate can still be observed in the composite sample (FIGS. 6A-6C), but no calcium phosphate formation is observed in the PEEK sample (FIGS. 5A-5C), A cross section of a composite sample which had been immersed in SBF is shown in FIG. 7. As denoted by arrows, calcium phosphate formation is observed on the surface of the composite material. The distribution of bioactive glass within the sample can also be appreciated in this view.

[0057] FIGS. 8A-8E are fourier transform infrared (FTIR) spectra of composites comprising PEEK and 50% by weight of combeite glass-ceramic, prepared using the methods set forth herein. As can be seen, characteristic peaks for calcium phosphate (1000, 600, and 560 cm.sup.1, see FIG. 8F) increase over time, indicative of bioactivity and progression to a mature crystalline hydroxyapatite. Thus, an embodiment of the present invention is a composite comprising PEEK and bioactive glass wherein the composite is bioactive.

[0058] The following examples are set forth to further describe the invention and are not intended to be limiting.

Example 1

[0059] 1500 grams of PEEK powder (GoodFellow Corp., Devon, Pa. nominal 80 micron) and 1500 grams of combeite glass-ceramic (Orthovita, Inc., Malvern, Pa., average particle size <53 micron, non-silanated) were combined in a polyethylene bottle and tumbled on rollers for about 1 to 2 hours. Anhydrous ethanol (2:1, ethanol:powder mixture) was added and the resulting mixture was sonicated in a glass beaker for about 5 minutes while stirring. The excess alcohol was decanted and the mixture was transferred to a glass tray and dried at about 70 C. for about 12 hours. The mixture was then transferred to a polyethylene bottle and tumbled on rollers for about 1 to 2 hours.

Example 2

[0060] The material obtained from Example 1 was loaded into a stainless steel mold. A piston was inserted and about 80 MPa of pressure was applied. The mold was heat pressurized to above 340 C. and was held until the material melted. The mold was then held at 270 C. for about 4 hours before being cooled to room temperature. After cooling, the molded article was removed from the mold and milled.

Example 3

[0061] The material obtained from Example 1 was loaded into a stainless steel mold. A piston was inserted and about 80 MPa of pressure was applied. The mold was heat pressurized to above 340 C. and was held until the material melted. The mold was then cooled to room temperature and the molded article was removed from the mold and milled.

[0062] Those skilled in the art will appreciate that numerous changes and modifications can be made to the many embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all such equivalent variations as falling within the true spirit and scope of the invention.