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Title:  Bioactive spinal implant material and method of manufacture thereof
United States Patent: 
6,987,136
Issued: 
January 17, 2006
Inventors:
 Erbe; Erik M. (Berwyn, PA); Murphy; James P. (Broomall, PA); Pomrink; Gregory J. (Lansdale, PA)
Assignee: 
Vita Special Purpose Corporation (Wilmington, DE)
Appl. No.: 
127947
Filed: 
April 23, 2002


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

Bioactive spinal implant materials having optimized radiopacity, stiffness, and bioactivity properties for formulation of shaped bodies capable of withstanding large dynamic, compressive loads are provided. The invention also provides methods of making the optimized implant materials.

SUMMARY OF THE INVENTION

The present invention provides synthetic spinal implant materials that have a radiopacity similar to bone for facilitating radiographic assessment of fusion. The implant materials of the present invention are capable of withstanding physiologic dynamic, compressive loads and is bioactive and biocompatible. As defined herein, bioactive relates to the chemical formation of a calcium phosphate layer via ion exchange between surrounding fluid and the implant materials. Bioactive can also relate to materials that elicits a reaction which leads to bone formation or attachment into or adjacent to implants or to bone formation or apposition directly to the implants usually without intervening fibrous tissue. Biocompatible as defined herein relates to materials that do not invoke a prolonged adverse immunologic or host response. The present invention also provides methods for making such implant materials.

In certain embodiments of the present invention, the implant materials of the present invention can be comprised of a biocompatible polymeric matrix reinforced or coated with bioactive fillers and fibers. The implants can probably be comprised of a diurethane dimethacrylate (DUDMA) and tri-ethylene glycol dimethacrylate (TEGDMA) blended resin and a plurality of fillers and fibers including bioactive fillers and E-glass fibers. The implants may also be comprised of a variety of other monomers and fillers as described herein.

This invention teaches synthetic, bioactive spinal implant materials having a range of radiopacity from about 30 to about 55 and a range of stiffness from about 6 GPa to about 20 GPa. The invention also provides a synthetic, artificial shaped bodies in the form of a spinal implant, said implant shaped body having a radiopacity of about 30 to about 55 and a range of stiffness of about 6 GPa to about 20 GPa. Another embodiment discloses synthetic spinal implant materials that are optimized for radiopacity, stiffness, and bioactivity, comprising: a polymerizable resin matrix of DUDMA and TEGDMA resins and at least one filler.

The implant materials can be formed from a polymerized resin matrix and can include at least one filler that can be bioactive. A bioactive filler can comprise combeite. The polymerized matrix can comprise about 20% to about 50% of the total composition of the implant material. Fifty to about 80% of the filler can comprise the total composition of the implant material. The radiopacity of the implants can range from about 38 to about 50. Also, the stiffness can range from about 8 GPa to about 17 GPa.

Also included are methods of making a synthetic spinal implant material that is optimized for radiopacity, stiffness and bioactivity comprising: mixing a resin blend of DUDMA and TEGDMA mixing said resin blend with at least one filler, and agitating the to form said implant material.

The embodiment of this invention can be used to form a variety of different orthopaedic implants, particularly spinal implants having various shapes and sizes.

The present invention provides bioactive and biocompatible implant materials for formulation of shaped bodies capable of withstanding large dynamic, compressive loads, especially spinal implants. Further, the implant materials of the present invention overcome the risks associated with disease transmission present with allograft devices. Moreover, the implant materials of the present invention exhibit a radiopacity similar to that of bone.

The materials of this invention are preferably comprised of a biocompatible, hardenable polymeric matrix reinforced with bioactive and non-bioactive fillers. The materials can be comprised of about 10% to about 90% by weight of the polymeric matrix and about 10% to about 90% by weight of one or more fillers. The materials can also be comprised of about 20% to about 50% by weight of the polymeric matrix and about 50% to about 80% by weight of one or more fillers. In order to promote bone bonding to the implants, the implants of the present invention can be comprised of a bioactive material that can comprise a polymeric blended resin reinforced with bioactive ceramic fillers. Examples of such bioactive materials can be found, for example, in U.S. Pat. Nos. 5,681,872 and 5,914,356 and pending application U.S. Ser. No. 60/305,070, which is assigned to the assignee of the present invention and incorporated herein by reference in its entirety.

The polymeric matrixes of the implant materials are comprised of polymerizable monomer, monomers, dimers or trimers. They can comprise ethylenically unsaturated monomers or even an acrylate functional group. The term "monomers," as used herein, can also represent dimers, trimers, resins, resin components or any other polymerizable component. Examples of the monomers include, but are not limited to, DUDMA, bisphenol-A-glycidyl methacrylate (bis GMA), TEGDMA, ethoxylated bisphenol-A-dimethacrylate (bis-EMA), or combinations thereof. Still, further examples of monomers that can be used in the present invention include the adducts of 2,2,3-trimethylhexane diisocyanate with hydroxyethyl methacrylate, hydroxypropyl methacrylate, and other hydroxyacrylic acrylic species can also be used. Other examples of polymerizable species that can be used in the present invention include those disclosed in U.S. Pat. Nos. 5,681,872 and 5,914,356, and pending application U.S. Ser. No. 60/305,070, which are incorporated herein by reference in their entirety.

Methyl methacrylate, ethyl methacrylate, propyl methacrylate, higher methacrylates, acrylates, ethacrylates, and similar species can be employed as all or part of the polymerizable materials of the implant materials of the present invention. It is also possible to employ other types of polymerizable material such as epoxide compounds, polyurethane-precursor species and a wide host of other materials. For example, other monomers useful in the production of hardenable compositions of this invention include methyl-, ethyl, isopropyl-, tert-butyloctyl-, dodecyl-, cyclohexyl-, chloromethyl-, tetrachloroethyl-, perfluorooctyl-, hydroxyethyl-, hydroxypropyl-, hydroxybutyl-, 3-hydroxyphenyl-, 4-hydroxphenyl-, aminoethyl-, aminophenyl-, thiophenyl-, acrylate, methacrylate, ethacrylate, propacrylate, butacrylate, and chloromethacrylate, as well as the homologous mono-acrylic acid esters of bisphenol-A, dihydroxydiphenyl sulfone, dihydroxydiphenyl ether, dihydroxybiphenyl, dihydroxydiphenyl sulfoxide, and 2,2 bis(4-hydroxy-2,3,5,6-tetrafluorophenyl)propane. Polymerizable monomers capable of sustaining a polymerization reaction such as the di-, tri-, and higher acrylic ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, trimethylene glycol dimethacrylate, trimethylol propane trimethacrylate, analogous acrylates and similar species are also useful. It is also possible to employ mixtures of more than two polymerizable species to good effect.

The implant materials of the present invention can further comprise polymeric additives that include, but are not limited to, polymerization inhibitors, polymerization activators, polymerization initiators, stabilizers such as UV-9, radiopacifiers, reinforcing components (i.e., fibers, particles, micro spheres, flakes, etc.), bioactive fillers, neutralizing resins, diluting resins, antibiotic agents, coloring agents, plasticizers, coupling agents, free radical generators, radiographic contrast agents, and antibiotics.

In many embodiments, the implant materials include a monomeric blended resin of DUDMA to impart strength, TEDGMA to impart flexibility, a benzoyl peroxide initiator (BPO) or any peroxide initiator that is consumed during the polymerization reaction, and at least one polymer stabilizer. The implant materials can also include a plurality of fillers and fibers. The fillers can be of the combeite type, such as the combeite filler described in U.S. Pat. No. 5,681,872 to render the material bioactive and encourage direct bone bonding. Alternatively, the filler can be selected from a group of fillers including, but not limited to, borosilicate, silica, Wollastonite, hydroxyapatite (HA), beta-tricalcium phosphate, calcium sulfate, alumina, and the like. In embodiments where the implants further comprise fibers, the fibers can further include E-glass fibers of the composition type [SiO2 CaO Al2O3 B2O3, A-glass fibers, silica or a plurality of other fibers including but not limited to Kevlar and carbon fibers for imparting toughness and strength to the implant. In certain embodiments, the fillers and fibers are surface treated for incorporation and bonding between them and the resin. For example, the fillers and fibers can be silanated, silicone-oil treated, or provided with coupling agents such alumina, titania, or zirconia coupling agents.

Certain embodiments have optimized radiopacity and stiffness and display bioactivity. As defined herein and in ASTM standards, radiopacity is calculated as an optical density ratio of the material versus an aluminum standard of the same thickness, both of which are normalized by the background sample optical density. The resultant number is multiplied by 100 and then referred to as the percent relative linear attenuation coefficient, α, which is dimensionless. Embodiments of the present invention are synthetic, bioactive spinal implant materials having a radiopacity between about 30 to about 55 and stiffness between about 6 GPa to about 20 GPa. Other embodiments provide a synthetic, artificial shaped body in the form of a spinal implant, said shaped body having a radiopacity of about 30 to about 55 and a stiffness of about 6 GPa to about 20 GPa.

The radiopacity of bone ranges between about 24 to about 52 as reported by Brantigan, et al., "Compression Strength of Donor Bone for Posterior Interbody Fusion," Spine, 18, 1213-1221 (1983), with a stiffness ranging from about 3 GPa to about 17 GPa. Similar to bone, which is naturally bioactive, the present inventions also display bioactivity.

In other embodiments, the spinal implant materials can have a radiopacity of about 30 to 55 and a range of stiffness of about 8 GPa to 17 GPa. The spinal implant can be formed from a polymerized resin matrix. At least one filler can be included in other embodiments and any of the fillers can be bioactive. The bioactive filler can be combeite glass ceramic or another type of ceramic filler. In some embodiments, the polymerized resin matrix comprises about 20% to about 50% of the total composition of the implant material. About 50% to about 80% of the total composition of the implant material can be filler.

Certain embodiments are synthetic spinal implant materials that are optimized for radiopacity, stiffness, and bioactivity, comprising a polymerizable resin matrix of DUDMA and TEGDMA resins and at least one filler.

While the present invention material has been described in terms of polymeric matrices comprised of polymerizable monomers and the like, it should be understood that the disclosed radiopacity and stiffness ranges may be achieved by using a variety of materials. For instance, the polymeric matrix may be composed of any polymeric material and include an additional organic or inorganic component. The matrix may be thermoplastic, thermoset, polymerizable, or non-polymerizable. Epoxies, polyurethanes, polyphosphates, polyesters, polyamides, polyphosphazenes, polycarbonates, polyureas, polyamides, polyacrylonitriles, polysulfones, polysulfides, polysiloxanes, polyacetals, polyethers such as polyetheretherketone (PEEK), fluoropolymers, polyketals, polyolefins such as polyethylene (PE), polypropylene (PP), polystyrene, and polyvinylchloride (PVC), and the like may also be used. These materials may be used either alone, in combination, or with various fillers to form a copolymer or terpolymer with the present invention to provide an implant material that yields desired radiopacity and stiffness comparable to bone as described herein.

Also included as a part of the present invention are methods of making a synthetic implant material that is optimized for radiopacity, stiffness, and bioactivity, comprising mixing a resin blend of DUDMA, TEGDMA, and a stabilizer, mixing said resin blend with at least one filler, and agitating the resultant mixture to form said implant material. The resin blend can also comprise an initiator. Both mixing steps can occur under vacuum. The fillers can be added in the range of about 15% by weight to about 80% by weight of the total mixture composition. If vacuum is applied at this stage, it can be applied upon the addition of each filler. Agitation of the resultant mixture can be added to further eliminate bubbles or voids.

In one embodiment of the present invention, the monomers, fillers, and other additives are blended together to form a paste composition. The paste compositions are easily mixed via a low speed, high shear rotary mixer. The duration of the blending operation will vary depending upon the constituents that comprise the paste composition precursors. In one embodiment, the blending of the monomers and other additives within the paste composition precursors activates the polymerization of the composition. In another embodiment, exposure to heat either during or after blending activates the polymerization. The exposure can occur in temperature ranges of about 40° C. to about 180° C. or about 60° C. to about 120° C. in some instances.

The implant materials of the present invention can be comprised of a one paste system or combined with two or more paste compositions to form a multiple paste system. Depending upon whether the implant material is a one paste or multiple paste system determines the hardening of the material. The paste compositions of the present invention can be hardened under the influence of heat, photochemical energy, chemically, or in a controlled fashion. In certain embodiments wherein the implant materials comprise a one paste system, the paste composition is hardened or cured via exposure to heat or light. Alternatively, the paste composition could be cured via gamma radiation. In some embodiments, additional exposure to gamma radiation can impart additional strength. In other embodiments wherein the implant materials comprise a multiple paste system, the paste compositions are admixed and hardened via thermal energy or heat cured. The paste compositions can also be chemically cured via catalyst or redox systems. It will be understood, however, that a wide variety of polymerization systems and materials for use therein can be employed to good advantage in connection with the present invention and all such systems are contemplated hereby. Depending upon the system that is employed, the paste composition can generally comprise heat-curing catalysts, photopolymerization, or redox (i.e. N,N(dihydroxyethyl)-p-toluidine(DHEPT), BPO, FeII, tertiary butyl hydroperoxide (t-BHP)) initiators. Each type is well-known and any catalytic system known for restorative use can be employed so long as the same is consistent with the objects of the invention.

In multiple paste systems where heat curing is used to harden the composition, a catalytic system is employed such that when two components of the hardenable composition are mixed together, the catalytic action begins, leading to hardening. This system is familiar and can be applied to a wide variety of polymerizable species including many which are suitable in the present invention. Radical initiators such as peroxides, especially benzoyl peroxide (also called dibenzoyl peroxide) are conventional, economic and convenient. A stabilizer such as butyl hydroxy toluene is customary, as is employment of co-catalysts like dimethyl-p-toluidine, N-N-substituted toluidine, and other conventional catalysts including tertiary amine structures with double bond functionality like diethyl aminoethyl methacrylate and N,N-dimethyl-p-toluidine. In general, one of the pastes incorporates both the radical initiator and stabilizer, such as a peroxide, and the other paste incorporates the accelerator, such as an amine or toluidine. Curing is initiated by an oxidation-reduction mechanism upon mixing the two pastes together.

In paste systems where curing via exposure to heat or other means is used to harden the composition, a photoinitiation system can be included with the hardenable compositions and the same caused to be activated by exposure to actinic light of a suitable wavelength. Both ultraviolet and visible photocuring systems are known for use in restorative surgery and dentistry and any such system can be employed herein. Exemplary systems are described in U.S. Pat. No. 4,110,184 to Dart et al., U.S. Pat. No. 4,698,373 to Tateosian et al., U.S. Pat. No. 4,491,453 to Koblitz et al., and U.S. Pat. No. 4,801,528 to Bennett, which are incorporated herein by reference in their entirety to provide enablement for such, known systems.

A particularly useful system employs visible light curing, thus avoiding the potential danger inherent in curing with ultraviolet radiation. Visible light curing has been well refined in the dental field and the same can also be applied to restorations of bony tissues. Quinones, as a class, find wide utility as photochemical initiators for visible light sensitizing systems, preferably when the same are admixed with tertiary amines. Some skilled artisans may prefer that an alpha diketone (quinone) such as camphoroquinone or biacetyl be admixed with an amine reducing agent such as n-alkyl dialkanolamine or trialkanolamine. Other such photo-initiator systems include a 2-Benzyl-2-(dimethylamino)-4′-morpholinobutyrophenone, or 50%/50% weight composition of 2-Hydroxyethyl-2-methyl-1-phenyl-1-propanone and Diphenyl (2,4,6-trimethylbenzyl) phosphine oxide. However, other such curing systems or combinations of curing systems can also be employed with the materials of the present invention.

In some embodiments, the paste system is not cured or hardened but used in situations in which the paste form is preferred. In those cases, the paste may be dispensed from a tube or the like. In other embodiments, one or more fillers are blended into the paste composition after the monomers and other additives comprising the resin blend have been combined. The fillers can be added incrementally to avoid binding during the blending process. A vacuum can be applied during blending to minimize porosity and dusting. Some embodiments comprise multiple fillers, which may include E-glass fibers and fillers or fibers of borosilicate, silica, and combeite. In particular embodiments, the E-glass fibers can be added first followed by the remaining fillers in a designated order. Alternatively, one or more fillers can be pre-blended together prior to incorporation into the resin blend. After the filler has been combined with the resin mixture, the completed paste mixture can be agitated via a vibrating table, ultrasonic or similar means for a period of time ranging from about 5 minutes to about 60 minutes to further reduce porosity. A vacuum can be applied during the agitation step.

Table I shows a number of compositions in accordance with certain preferred embodiments of the present invention together with salient data showing suitability for orthopaedic, especially spine implant use. Six exemplary implant materials were made in accordance with the present invention. The weight percentage of each composition is presented in the table. As the following table illustrates, the Examples 2-4 are multiple paste systems wherein Examples 5-7 are one paste systems.

The implant materials of Examples 2-7 can be fashioned into standard shapes, which include cylinders, bricks, and dog bones, for testing. Along with radiopacity, the compressive strength, compressive yield, and compressive modulus were tested, as were the tensile strength and tensile modulus. Compressive testing was conducted in accordance with ASTM D 695-91 using 6 mm diameter×12 mm height cylindrical specimens. Tensile testing was conducted in accordance with ASTM D 638-95, using Type IV specimen geometry of flat tensile bars or "dog bone". Lastly, radiopacity was conducted in accordance with ASTM F 640-79 ("Radiopacity of Plastics for Medical Use").

TABLE I
 
Comparison
  Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7
   
Formulation Comparison            
[Product (%)]
Bis-GMA 12-14 13-15 0-1 0-1 0-1 0-1
Bis-EMA 5-7 6-8 0-1 0-1 0-1 0-1
TEGDMA 11-13 12-14  8-10 7-9 7-9 7-9
DUDMA 0-1 0-1 24-28 24-28 24-28 24-28
t-Butylhydroxytoluene 0-1 0-1 0-1 0-1 0-1 0-1
DHEPT 0-1 0-1 0-1 0-1 0-1 0-1
UV-9 (C14H12O3) 0-1 0-1 0-1 0-1 0-1 0-1
BPO 0-1 0-1 0-1 0-1 0-1 0-1
Silane Treated Amorphous 7-9 6-8 6-8 4-6 4-6 4-6
Silica
Silane Treated Orthovita 28-31 18-21 18-21 20-23 22-24 19-21
Combeite [OC] Filler
Silane Treated
Bariaboroaluminosilicate 29-32 0-1 0-1 0-1 0-1 0-1
Glass
Silane Treated Alkali Leached 0-1 16-19 16-19 20-23 19-21 0-1
OC Filler
Silane Treated E-Glass 0-1 19-21 19-21 19-21 19-21 19-21
Silane Treated Borosilicate 0-1 0-1 0-1 0-1 0-1 22-24
Filler
Approx. Test Parameter
before Gamma Irradiation
Compressive Strength (MPa) 211 195.6 216.3 238.4
Compressive Yield (MPa) 127 105 125 150 170 182
Compressive Modulus (MPa) 5800 6998 7875 8456 8403 8516
Tensile Strength (MPa) 52.5 60.2 54.3 63.4 86.7
Tensile Modulus (MPa) 9800 10306 11976 14839 16290
Radiopacity 118.6 50 46.3 57.3
 

Although the uses described above are exemplary for the present invention, there are other embodiments that may be foreseen by those skilled in the art. Within the dental field, the implants of the present invention can have use as dental crowns (temporary or crown) and dental implants, including Maryland bridges. The implant materials can also have use as implants for other areas of the animal body. Such foreseeable implants include cochlear, cranial, tumor, sternum, or other custom implants that can be MRI compatible or functional shapes made for the body. Other embodiments can be used for formulation of universal plates for orthopedic use, bone screws, rods, and pins for orthopedic use (IM nails, femoral rods or plugs, long bone fractures, etc.), tendon anchors, suture anchors and tacks, graft retainers, and marrow sampling ports.

Other pharmaceutical uses include non-articulating artificial joint surfaces, sensor anchors or housings, bone spacers or wedges (tibial, femoral), cartilage beds or anchors, or drug delivery. It is also foreseeable that the implant materials can be used in methods for repairing the iliac harvest site. The materials can be incorporated into drug delivery beads into bone or in interbody balls. There can also be applications for mandibular joints (TMJ) and orbital reconstruction.

One embodiment of the present invention involves machining of the implantable materials into morsels for use in methods to treat segmental defects. The morsels can also be used for minimally invasive load bearing applications. The material can be made into a mesh for postero-lateral fusion or cages for other materials. Other embodiments involve the material being used as a cannulated screw with peripheral holes used in methods for treating vertebral augmentation. The present invention can have embodiments involving synthetic bones.
 

Claim 1 of 21 Claims

1. An implant comprising a synthetic, bioactive spinal implant material formed from a one-paste, 0% by weight bisphenol-A-glycidyl methacrylate polymerized resin matrix comprising about 10% by weight to about 60% by weight of the total composition of the implant material, the polymerized resin matrix comprising diurethane dimethacrylate and tri-ethylene glycol dimethacrylate resins, the resin matrix further comprising silane treated borosilicate filler, the implant material having a range of radiopacity from about 30 to about 55 and a range of stiffness from about 6 GPa to about 20 GPa.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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