US20060147545A1 - Volume maintaining osteoinductive/osteoconductive compositions - Google Patents
Volume maintaining osteoinductive/osteoconductive compositions Download PDFInfo
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- US20060147545A1 US20060147545A1 US11/284,539 US28453905A US2006147545A1 US 20060147545 A1 US20060147545 A1 US 20060147545A1 US 28453905 A US28453905 A US 28453905A US 2006147545 A1 US2006147545 A1 US 2006147545A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S606/00—Surgery
- Y10S606/907—Composed of particular material or coated
- Y10S606/909—Bone
Definitions
- This invention relates to an osteoinductive and osteoconductive composition containing demineralized fibrous bone elements in combination-with non-fibrous bone elements that are demineralized, partially demineralized or non-demineralized. More particularly, the invention relates to demineralized fibrous bone elements having a relatively high median length to median thickness ratio and relatively high surface area to volume ratio; demineralized, partially demineralized or non-demineralized non-fibrous bone elements that vary from “mostly irregular” to “mostly regular” in shape and not more than 10 mm in any measurable component of the shape to determine size, e.g., height, base, length, width, diameter or radius; and to a volume maintaining osteoinductive/osteoconductive composition containing such fibrous and non-fibrous elements within a biocompatible fluid carrier.
- bone matrix gelatin a water insoluble osteoinductive/osteoconductive substance referred to therein as “bone matrix gelatin” which was obtained by decalcifying (ire., demineralizing) bone was successfully employed as an alloimplant for the treatment of bone defects and other disorders.
- decalcified bone matrix An apparently similar water insoluble osteoinductive/osteoconductive material, referred to as “decalcified bone matrix”, is disclosed in McLaughlin et al., “Enhancement of Bone Ingrowth by the Use of Bone Matrix as a Biologic Cement”, Clinical Orthopaedics and Related Research, No. 183, pp. 255-261 (March, 1984).
- an osteoinductive/osteoconductive composition comprising: (a) a quantity of fibrous bone elements possessing an average surface area to volume ratio of about 100:1 to about 20:1, (b) a quantity of non-fibrous bone elements possessing an average surface area to volume ratio of about 10:1 or less and (c) a quantity of biocompatible fluid carrier sufficient to provide the composition as a deformable mass.
- a large bone defect e.g., one resulting from injury, infection, disease, malignancy or developmental malformation, leads to rapid new bone ingrowth by one or more mechanisms such as osteogenesis, osteoinduction and/or osteoconduction.
- fibrous bone elements imparts a higher level of cohesiveness to the osteoinductive/osteoconductive composition of this invention compared with that of an osteoinductive/osteoconductive composition containing the same ratio of bone elements to carrier but in which the bone elements are all, or substantially all, of the non-fibrous variety, e.g., the compositions of U.S. Pat. No. 5,073,373.
- non-fibrous bone elements provides an osteoinductive/osteoconducti-ve composition which requires a higher level of applied mechanical force to effect its deformation than that required to deform an osteoinductive/osteoconductive composition containing the same ratio of bone elements to carrier but in which all, or substantially all, of the bone elements possess a relatively high surface area to volume ratio, e.g., the osteoinductive/osteoconductive composition of aforesaid U.S. Pat. No. 5,314,476 in which all, or substantially all, of the bone elements are of the fibrous variety.
- median length to median thickness ratio as applied to the fibrous bone elements of the invention shall be understood to refer to the ratio of the longest median dimension of the fibrous bone element (its median length) to its shortest median dimension (its median thickness).
- osteoinductive/osteoconductiv-e composition shall be understood to refer to the ability of the composition to be shaped or packed into a coherent mass which retains its shape and volume and resists erosion from the implant site.
- fibrous refers to bone elements whose median length to median thickness ratio is at least about 10:1 and whose surface area to volume ratio is between about 100:1 and about 20:1.
- the fibrous bone elements can be described as fibers, threads, narrow strips, or thin sheets. Often, where thin sheets are produced, their edges tend to curl up toward each other.
- the fibrous bone elements can be substantially linear in appearance or they can be coiled to resemble springs.
- the fibrous bone elements are preferably demineralized however some of the original mineral content may be retained when desirable for a particular embodiment of the invention.
- partially demineralized bone elements refers to bone elements that are demineralized to the extent that only a small amount of mineral remains in the core. That is the residual calcium is between about 50 to 100% by weight.
- FIG. 1 are irregular non-fibrous bone elements
- FIG. 1A are mostly regular non-fibrous bone elements prepared as in Example 1.
- FIG. 1B represents a side-by-side comparison of the size and regular shape of the non-fibrous bone elements useful in the invention herein and the irregular non-fibrous elements of FIG. 1 .
- FIG. 2 represents the appearance of a prior art bone composition and FIG. 2A is a composition prepared as in Example 1.
- FIG. 3 is a relatively large defect site and FIG. 3A demonstrates the ability of a composition prepared as in Example 1 to fill a relatively large defect site.
- FIG. 4 represents the radiographic and biological results obtained in Example 4.
- the bone utilized in this invention is obtained utilizing methods well known in the art, e.g., aseptically procured allogenic donor bone that has been cleaned and disinfected.
- Fibrous bone elements whose median length to median thickness ratio is at least about 10:1 can be readily obtained by any one of several methods, e.g., shaving the surface of an entire bone or relatively large section of bone.
- a shaving technique fibrous bone elements ranging in median length from about 2 mm up to 400 mm or more (as in the case of the long bones) and in median thickness from about 0.05 mm to about 2 mm can be obtained.
- An apparatus useful for obtaining the fibrous bone elements useful herein is described in U.S. Pat. No. 5,607,269 the contents of which are incorporated herein by reference.
- the surface area to volume ratio of the fibrous bone elements will vary between about 100:1 and about 20:1, preferably between about 80:1 and about 40:1. If desired, the mass of fibrous bone elements bone can be graded into different sizes and/or any less desirable size(s) of fibrous bone elements which may be present can be reduced or eliminated.
- the fibrous bone elements can be obtained from cortical autogenic, cortical allogenic, cortical xenogenic, cortical transgenic, cancellous autogenic, cancellous allogenic, cancellous xenogenic, cancellous transgenic, corticocancellous autogenic, corticocancellous allogenic, corticocancellous xenogenic or corticocancellous transgenic bone.
- Porcine and bovine bone are a particularly advantageous type of xenogenic bone tissue which can be used as a source for the fibrous bone elements of this invention, although of course other sources of bone such as ovine, caprine and equine may also be suitable.
- the fibrous bone elements are subjected to demineralization in order to reduce their inorganic content to a very low level, e.g., to not more than about 5% by weight of residual calcium and preferably to not more than about 1% by weight residual calcium. Demineralization of the fibrous bone elements ordinarily results in their contraction to some extent.
- Demineralization of the fibrous bone elements can be conducted in accordance with known conventional procedures.
- the fibrous bone elements are subjected to an acid demineralization step that is followed by a defatting/disinfecting step.
- the bone is immersed in acid over time to effect its demineralization.
- Acids which can be employed in this step include inorganic acids such as hydrochloric acid and organic acids such as peracetic acid.
- the bone is rinsed with sterile water for injection, buffered with a buffering agent to a final predetermined pH and then finally rinsed with water for injection to remove residual amounts of acid and buffering agent or washed with water to remove residual acid and thereby raise the pH.
- a preferred defatting/disinfectant solution is an aqueous solution of ethanol, the ethanol being a good solvent for lipids and the water being a good hydrophilic carrier to enable the solution to penetrate more deeply into the bone.
- the aqueous ethanol solution also disinfects the bone by killing vegetative microorganisms and viruses.
- at least about 10 to 40 weight percent by weight of water i.e., about 60 to 90 weight percent of defatting agent such as alcohol should be present in the defatting/disinfecting solution to produce optimal lipid removal and disinfection within the shortest period of time.
- the preferred concentration range of the defatting solution is from about 60 to 85 weight percent alcohol and most preferably about 70 weight percent alcohol.
- the demineralized fibrous bone elements can be used immediately for preparation of the osteoinductive/osteoconductive composition or they can be stored under aseptic conditions, advantageously in a lyophilized state prior to such preparation.
- the fibrous bone elements can retain some of their original mineral content such that the composition is rendered capable of being imaged utilizing radiographic techniques such as disclosed in U.S. Pat. No. 5,676,146 the contents of which are incorporated herein by reference.
- the non-fibrous bone elements of this invention substantially display a relatively small surface area to volume ratio, e.g., less than about 10:1, preferably less than about 6:1, most preferably less than about 3:1.
- the median width of the non-fibrous bone elements is at least as large as the median thickness of the fibrous bone elements utilized in the composition of this invention but more preferably larger.
- the size and shape of the non-fibrous elements of the invention can be varied to tailor the composition to its intended application.
- the composition will contain non-fibrous elements that exhibit a substantially larger least dimension than the least dimension of the fibrous bone elements.
- the non-fibrous bone elements will display a “mostly regular” geometry, i.e.; the shape of the non-fibrous bone elements is a triangular prism, sphere, cube, cylinder, other regular shape or a combination of these shapes.
- Such shapes displaying a substantially regular geometry are to be distinguished from chips, shards, and powders which may have a relatively small surface area to volume ratio but which due to their “mostly irregular” shape are unable to lock into place when used in a composition intended to repair an appropriate size defect site.
- the shape of the non-fibrous elements will be substantially spheroid.
- Such non-fibrous elements can be obtained from cortical autogenic, cortical allogenic, cortical xenogenic, cortical transgenic, cancellous autogenic, cancellous allogenic, cancellous xenogenic, cancellous transgenic, corticocancellous autogenic, corticocancellous allogenic, corticocancellous xenogenic or corticocancellous transgenic bone.
- Porcine and bovine bone are a particularly advantageous type of xenogenic bone tissue which can be used as a source for the non-fibrous bone elements of this invention, although of course, ovine, caprine and equine bone may be entirely suitable.
- non-fibrous bone elements of the invention are non-fibrous bone elements having a median length to median width to median height ratio of at least about 1:0.3:1 and up to about 1:1:5, a median length of from about 0.25 mm to about 10 mm, a median width of from about 0.25 mm to about 10 mm and a median height of from about 0.25 mm to about 10 mm, the median width being the smallest dimension of the non-fibrous element and the median height being the io largest dimension of the non-fibrous element.
- Such non-fibrous elements are prepared utilizing methods well known in the art, e.g., cutting, milling, stamping, grinding.
- the size and shape of the non-fibrous elements can vary depending on the specific application the composition is intended for, e.g., large trauma defects will require relatively large non-fibrous elements, whereas small dental defects, e.g., sinus lifts, three-wall defects, furcations, etc., will require relatively small non-fibrous elements.
- Such variation of size and shape of the non-fibrous bone elements to tailor the composition to the specific application is intended to be within the scope of this invention.
- the non-fibrous bone elements useful herein can be fully mineralized, partially demineralized, or fully demineralized (i.e., ⁇ 5% calcium by weight).
- the composition contains from about 0 to about 50 percent by weight of the non-fibrous bone elements mineralized bone, from about 0 to about 80 percent by weight of the non-fibrous bone elements partially demineralized bone and from about 0 to about 100 percent by weight of the non-fibrous bone elements fully demineralized bone.
- the bone utilized in making the non-fibrous elements of the invention can be fully mineralized, partially demineralized or fully demineralized prior to the preparation of the non-fibrous elements.
- cortical bone is cut into slices, e.g., about 3 mm in width, and then demineralized to the extent that only a small amount of mineral remains in the core, i.e., less than 10% by weight residual calcium, preferably less than 5% by weight residual calcium.
- the bone is then cut with a stamping technique to yield substantially cuboid shapes about 3.times.3.times.3 mm in length, width and height.
- mineralized bone is cut into substantially cuboid shapes with a band saw.
- the bone cubes are then demineralized using techniques well known in the art, e.g., such as those described above. After the non-fibrous elements are obtained they can be used immediately for preparation of the osteoinductive/osteoconductive composition or they can be stored under aseptic conditions, advantageously in a lyophilized or frozen state prior to such preparation.
- a quantity of the fibrous and non-fibrous elements are combined with an amount of biocompatible fluid carrier which will provide a coherent mass.
- the carrier can be any of a number of compounds and/or polymers, e.g., polymer sugars, proteins, long chain hydrophilic block copolymers, reverse phase block copolymers, hyaluronic acid, polyuronic acid, mucopolysaccharide, proteoglycan, polyoxyethylene, surfactants, e.g., the pluronics series of nonionic surfactants, and peptide thickener.
- Suggested classes of biocompatible fluid carrier would include polyhydroxy compound, polyhydroxy ester, fatty alcohol, fatty alcohol ester, fatty acid, fatty acid ester, liquid silicone, mixtures thereof, and the like.
- suitable biocompatible fluid carrier include, but are not limited to:
- Polyhydroxy compound for example, such classes of compounds as the acyclic polyhydric alcohols, non-reducing sugars, sugar alcohols, sugar acids, monosaccarides, disaccharides, water-soluble or water dispersible oligosaccarides, polysaccarides and known derivatives of the foregoing.
- Specific polyhydroxy compounds include, 1,2-propanediol, glycerol, 1,4,-butylene glycol trimethylolethane, trimethylolpropane, erythritol, pentaerythritol, ethylene glycols, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, dipropylene glycol; polyoxyethylene-polyoxypropylene copolymer, e.g., of the type known and commercially available under the trade names Pluronic and Emkalyx; polyoxyethylene-polyoxypropylene block copolymer, e.g., of the type known and commercially available under the trade name Poloxamer; alkylphenolhydroxypolyoxyethylene, e.g., of the type known and commercially available under the trade name Triton, polyoxyalkylene glycols such as the polyethylene glycols, xylitol, sorbitol, mannitol, dulcitol,
- Polyhydroxy ester for example, liquid and solid monoesters and diesters of glycerol can be used to good effect, the solid esters being dissolved up to the limit of their solubilities in a suitable vehicle, e.g., propylene glycol, glycerol, polyethylene glycol of 200-1000 molecular weight, etc.
- Liquid glycerol esters include monacetin and diacetin and solid glycerol esters include such fatty acid monoesters of glycerol as glycerol monolaurate, glyceryl monopalmitate, glyceryl monostearate, etc.
- An especially preferred carrier herein comprises glyceryl monolaurate dissolved in glycerol or a 4:1 to 1:4 weight mixture of glycerol and propylene glycol, poly(oxyalkylene)glycol ester, and the like.
- Fatty alcohol for example primary alcohols, usually straight chain having from 6 to 13 carbon atoms, including caproic alcohol, caprylic alcohol, undecyl alcohol, lauryl alcohol, and tridecanol.
- Fatty alcohol ester for example, ethyl hexyl palmitate, isodecyl neopentate, octadodecyl benzoate, diethyl hexyl maleate, and the like.
- Fatty acid ester for example, polyoxyethylene-sorbitan-fatty acid esters; e.g., mono- and tri-lauryl, palmityl, stearyl, and oleyl esters; e.g., of the type available under the trade name Tween from Imperial Chemical Industries; polyoxyethylene fatty acid esters; e.g., polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj; propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate; propylene glycol dilaurate, propylene glycol hydroxy stearate, propylene glycol isostearate, propylene glycol laureate, propylene glycol ricinoleate, propylene glycol stearate, and propylene glycol caprylic-capric acid diester available under the trade name Miglyol; mono-, di-, and mono/di-glycerides, such as
- Liquid silicone for example, polyalkyl siloxanes such as polymethyl siloxane and poly (dimethyl siloxane) and polyalkyl arylsiloxane.
- the liquid carrier is a liquid polyhydroxy compound, liquid polyhydroxy compound derivative, liquid solution of solid polyhydroxy compound, liquid solution of solid polyhydroxy compound derivative or mixtures thereof.
- the liquid carrier can be dissolved or diluted with an appropriate solvent such that when combined with the fibrous and non-fibrous elements of the invention a composition capable of being shaped or packed into a coherent mass which retains its shape and volume over the relatively long term, e.g., until the bone formation and remodeling process is completed, is provided.
- the polyhydroxy compound or polyhydroxy derivatives can be a liquid in the pure or highly concentrated state at ambient temperature, e.g., 1.5 -50.degree.
- the liquid carrier can be made up of one or more liquid polyhydroxy compounds or derivatives in solution with one or more solid polyhdroxy compounds or derivatives.
- glycerol and its liquid monesters and diesters e.g. monacetin and diacetin, fructose, glucose and sucrose, and mixtures thereof are preferred.
- the polyhydroxy compound is a solid, e.g., sucrose
- a solvent such as water, glycerol, polyethylene glycol of from 200-1000 average molecular weight, or mixture thereof is used to provide a cohesive solution or paste of the compound.
- the fibrous and/or non-fibrous elements exhibit a tendency to quickly or prematurely separate from the carrier component or to otherwise settle out from the composition such that application of a fairly homogeneous composition is rendered difficult or inconvenient, it can be advantageous to include within the composition an optional substance whose thixotropic characteristics prevent or reduce this tendency.
- a thixotropic agent such as a solution of polyvinyl alcohol, polyvinylpyrrolidone, cellulosic ester such as hydroxypropyl methylcellulose, carboxyl methylcellulose, pectin, food-grade texturizing agent, gelatin, dextran, collagen, starch, hydrolyzed polyacrylonitrile, hydrolyzed polyacrylamide, polyelectrolyte such as polyacrylic acid salt, hydrogels, chitosan, other materials that can suspend particles, etc., can be combined with the carrier in an amount sufficient to significantly improve the suspension-keeping characteristics of the composition.
- the fibrous and/or non-fibrous bone elements of this invention can be modified in one or more ways, e.g., their protein content can be augmented or modified as described in U.S. Pat. Nos. 4,743,259 and 4,902,296 the contents of which are incorporated herein by reference. Any of a variety of medically and/or surgically useful optional substances can be incorporated in, or associated with, the bone elements before, during, or after preparation of the osteoinductive/osteoconductive composition.
- one or more of such substances can be introduced into the bone elements, e.g., by soaking or immersing the bone elements in a solution or dispersion of the desired substance(s), by adding the substance(s) to the carrier component of the osteoinductive/osteoconductive composition or by adding the substance(s) directly to the osteoinductive/osteoconductive composition.
- Medically/surgically useful substances which can be readily combined with the bone elements, fluid carrier and/or osteoinductive/osteoconductive composition of this invention include, e.g., demineralized bone powder as described in U.S. Pat. No. 5,073,373 the contents of which are incorporated herein by reference, collagen, insoluble collagen derivatives, hydroxyapatite, etc., and soluble solids and/or liquids dissolved therein, e.g., antiviricides, particularly those effective against HIV and hepatitis; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymyxin B, tetracyclines, viomycin, chloromycetin and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentainycin; etc.; amino acids, peptides, vitamins, inorganic elements, inorganic compounds, cofactors for protein
- the osteoinductive/osteoconductive composition of this invention can be freshly prepared just by mixing desired quantities of the demineralized fibrous bone elements, non-fibrous bone elements, fluid carrier and optional component(s), if any, in any suitable sequence of separate mixing, adsorption, rehydration or drying operations or all at once.
- the demineralized fibrous bone elements and/or non-fibrous bone elements can be mixed with the optional ingredients(s) and thereafter combined with the fluid carrier component
- the demineralized fibrous bone elements and/or non-fibrous bone elements can be mixed with the fluid carrier followed by addition of the optional ingredient(s) or the optional ingredients can be added to the fluid carrier followed by addition of the demineralized fibrous bone elements and/or non-fibrous bone elements.
- the fibrous and non-fibrous elements and fluid carrier are mixed substantially simultaneously such that the fibrous elements of the osteoinductive/osteoconductive composition are entangled and the non-fibrous bone elements are thoroughly mixed in the entangled fibrous bone elements.
- the amount of demineralized fibrous bone elements which can.be incorporated into the osteoinductive/osteoconductive composition can vary widely with amounts of from about 5 to about 90 weight percent, and preferably from about 20 to about 70 weight percent, being entirely suitable in most cases.
- the amount of the non-fibrous bone elements which can be incorporated into the osteoinductive/osteoconductiv-e composition can very widely with amounts from about 10 to about 90 weight percent, and preferably from about 20 to about 70 weight percent, being entirely suitable in most cases.
- the ratio of fibrous to non-fibrous bone elements can vary between about 0.2:1 to about 1:0.2. The balance of the composition being made up of fluid carrier and optional ingredient(s), if any.
- radiopaque material(s) may be incorporated into the composition.
- materials would include, e.g., barium sulfate, iodine-containing compounds, titanium and mineralized bone.
- the demineralized fibrous bone elements and non-fibrous bone elements preferably in lyophilized or frozen form, and fluid carrier (the latter containing one or more optional ingredients such as those identified above) can be stored in separate packages or containers under sterile conditions and brought together in intimate admixture at the moment of use for immediate application to an osseous defect site employing any suitable means such as spatula, forceps, syringe, tamping device, etc.
- the osteoinductive/osteoconductive composition can be prepared well in advance and stored under sterile conditions until required for use.
- the osteoinductive/osteoconductiv-e composition When the osteoinductive/osteoconductiv-e composition is prepared well in advance it is preferably lyophilized prior to packaging for storage.
- optional materials e.g., autograft bone marrow aspirate, autograft bone, preparations of selected autograft cells, autograft cells containing genes encoding bone promoting action, etc., can be combined with the composition of this invention.
- the osteoinductivelosteoconductive composition is packaged already mixed and ready for use in a suitable container, e.g., syringe, resealable non-toxic bottle, etc., or is provided as a kit which can be prepared at a surgeon's direction when needed.
- a suitable container e.g., syringe, resealable non-toxic bottle, etc.
- the osteoinductive/osteoconductive composition of this invention can be firmly placed into an appropriate size defect site to maintain volume and provide support for adjacent tissues. Such placement can be accomplished through the use of a variety of devices such as, e.g., spatula, forceps, syringe, tamping device, etc.
- the osteoinductive/osteoconductive composition of this invention can be tailored to be utilized for a variety of orthopaedic, neurosurgical, and oral and maxillofacial surgical indications in which it would be advantageous to be able to firmly place the composition into a bone defect site such as the repair of simple and compound fractures and nonunions, external fixations, joint reconstructions such as arthrodesis, general arthroplasty, acetabular repair, cup arthroplasty of the hip, femoral and humeral head replacement, femoral head surface replacement and total joint replacements, repairs of the vertebral column including spinal fusion and internal fixation, tumor surgery, e.g., deficit filling, discectomy, lain inectomy, excision of spinal cord tumors, anterior cervical and thoracic operations, repair of spinal injuries, scoliosis, lordosis and kyphosis treatments, intermaxillary fixation of fractures, mentoplasty, temporomandibular joint replacement, alveolar ridge augmentation and reconstruction
- the invention will be more fully understood by way of the following examples which are intended to illustrate but not limit methods of preparation of the demineralized fibrous bone elements and non-fibrous bone elements of the invention and the preparation of an osteoinductive/osteoconductive composition containing the fibrous and non-fibrous elements in accordance with the present invention.
- a comparison of the compressive force of prior art compositions and the composition of the invention is also provided, however, this comparison is intended to illustrate but not limit the differences between this invention and the prior art.
- Sections of defatted, disinfected allogenic cortical bone approximately 210-250 mm in length were cut on a band saw to yield 145.65 g of cuboid non-fibrous bone elements about 3 mm in size.
- the remaining allogenic cortical bone was processed in the bone milling apparatus described in U.S. Pat. No. 5,607,269 to yield 145.8 grams of fibrous bone elements.
- the non-fibrous bone elements were then placed in a reactor. A 0.6 N solution of HCl at 15 ml per gram of non-fibrous bone elements was introduced into the reactor, the reaction proceeded for 1 to 2 hours.
- the non-fibrous bone elements were covered with 0.6 N HCl/20 ppm-2000 ppm nonionic surfactant solution for 24 to 48 hours. The fibrous bone elements were then added to the reactor and allowed to soak for 5 to 10 minutes. Following drainage of the HCl/surfactant solution, 0.6 N HCl at 15 ml per gram of total bone was introduced into the reactor, the reaction proceeded for 40 to 50 minutes. Following drainage through a sieve the bone was rinsed three times with water for injection at 15 ml per gram non-fibrous element weight with the water for injection being replaced at 15-minute intervals. Following drainage of the water for injection, the bone was covered with alcohol and allowed to soak for at least 30 minutes.
- the alcohol was then drained and the bone was rinsed with water for injection.
- the bone was then contacted with a mixture of 3.5 ml of glycerol per gram of dry bone and 5 ml of water for injection per gram of dry bone for at least 2 hours.
- the composition was transferred to a lyophilization tray and frozen at ⁇ 70.degree. C. for at least 6 hours.
- the composition was then lyophilized following standard procedures for 24 to 48 hours.
- Example 1 The compressive force of the composition prepared as in Example 1 was compared with that of a like quantity of an osteoinductive/osteocondu-ctive composition prepared in accordance with U.S. Pat. No. 5,073,373 and an osteoinductive/osteoconductive composition prepared in accordance with U.S. Pat. No. 5,314,476.
- 5 cc of each material was placed into separate 10 cc syringe barrels.
- the compressive force i.e., the sustained force capable of deflecting a meter probe
- the results are contained in the following table.
- Material Compressive Force (N) U.S. Pat. No. 5,073,373 4.8 U.S. Pat. No. 5,314,476 7.9
- Example 1 10.3
- Example 1 Material prepared as in Example 1 was evaluated to determine its osteoinductive potential.
- the material was implanted in female athymic homozygous mu/mu rats according to the procedure described in Edwards et al., Osteoinduction of Human Demineralized Bone: Characterization in a Rat Model, Clinical Orthopedics and Related Research (No. 357, pp. 219-228) 1998, the contents of which are incorporated hereby by reference.
- the material was studied to analyze its bone formation response. After 28 days in the rat model it was determined that cells had accumulated in the porous region inside of the chips, differentiated into bone forming cells, and were in the process of laying down bone in remodeling the matrix from the inside out.
- the animals were sedated and serial radiographs of the forelimbs were taken every three weeks until 12 weeks post-operatively when the animals were sacrificed. At the time of sacrifice, the ulnas were removed, cleaned of soft tissue, and radiographed using a high resolution Faxitron. Bony union (Table 2) and quantitative bone formation (Table 3) was evaluated at each time point by 3 independent, blinded observers. Bony union was defined as bridging of the defect in excess of 25% of the diaphyseal diameter. The radiographs were digitized to normalize the bone area and intensity so that bone formation could be quantified using image analysis software.
Abstract
An osteoinductive/osteoconductive composition prepared from a quantity, of demineralized fibrous bone elements possessing an average surface area to volume ratio of about 100:1 to about 20:1, a quantity of mostly shaped regular non-fibrous bone elements possessing an average surface area to volume ratio of about 10:1 or less and a sufficient quantity of biocompatible fluid carrier sufficient to provide the composition as a deformable mass is provided herein. Also provided is a method of using the composition to repair a bone defect site.
Description
- This application is a continuation of U.S. application Ser. No. 10/413,324, filed on Apr. 14, 2003, which is a continuation of International Application No. PCT/US2000/28462, filed on Oct. 13, 2000, which claims priority to U.S. Provisional Application No. 60/159,774, filed on Oct. 15, 1999. The contents of all of the above-identified applications are incorporated in their entirety by reference herein.
- This invention relates to an osteoinductive and osteoconductive composition containing demineralized fibrous bone elements in combination-with non-fibrous bone elements that are demineralized, partially demineralized or non-demineralized. More particularly, the invention relates to demineralized fibrous bone elements having a relatively high median length to median thickness ratio and relatively high surface area to volume ratio; demineralized, partially demineralized or non-demineralized non-fibrous bone elements that vary from “mostly irregular” to “mostly regular” in shape and not more than 10 mm in any measurable component of the shape to determine size, e.g., height, base, length, width, diameter or radius; and to a volume maintaining osteoinductive/osteoconductive composition containing such fibrous and non-fibrous elements within a biocompatible fluid carrier.
- The use of pulverized exogenous bone growth material, e.g., derived from demineralized allogenic or xenogenic bone in the surgical repair or reconstruction of defective or diseased bone is known. See, in this regard, the disclosures of U.S. Pat. Nos. 4,394,370, 4,440,750, 4,472,840, 4,485,097, 4,678,470, and 4,743,259; Bolander et al., “The Use of Demineralized Bone Matrix in the Repair of Segmental Defects”, The Journal of Bone and Joint Surgery, Vol. 68-A, No. 8, pp. 1264-1273; Glowackie et al, “Demineralized Bone Implants”, Symposium on Horizons in Plastic Surgery, Vol. 12, No. 2; pp. 233-241 (1985); Gepstein et al., “Bridging Large Defects in Bone by Demineralized Bone Matrix in the Form of a Powder”, The Journal of Bone and Joint Surgery, Vol. 69-A, No. 7, pp. 984-991 (1987); Mellonig, “Decalcified Freeze-Dried Bone Allograft as an Implant Material In Human Periodontal Defects”, The International Journal of Periodontics and Restorative Dentistry, pp. 41-45 (June, 1984); Kaban et al., “Treatment of Jaw Defects with Demineralized Bone Implants”, Journal of Oral and Maxillofacial Surgery, pp.623-626 (Jun. 6, 1989); and, Todescan et al., “A Small Animal Model for Investigating Endosseous Dental Implants: Effect of Graft Materials on Healing of Endosseous, Porous-Surfaced Implants Placed in a Fresh Extraction Socket”, The International Journal of Oral & Maxillofacial Implants Vol. 2, No. 4, pp. 217-223 (1987). According to Kakincki et al., “Human bone matrix gelatin as a clinical alloimplant”, International Orthopaedics, 9, pp. 181-188 (1985), a water insoluble osteoinductive/osteoconductive substance referred to therein as “bone matrix gelatin” which was obtained by decalcifying (ire., demineralizing) bone was successfully employed as an alloimplant for the treatment of bone defects and other disorders. An apparently similar water insoluble osteoinductive/osteoconductive material, referred to as “decalcified bone matrix”, is disclosed in McLaughlin et al., “Enhancement of Bone Ingrowth by the Use of Bone Matrix as a Biologic Cement”, Clinical Orthopaedics and Related Research, No. 183, pp. 255-261 (March, 1984). However, the prior art demineralized bone products have proven to be unsatisfactory for applications requiring a bone product, which maintains the volume of bone defect sites and allows for firm packing. Thus, an osteoinductive/osteoconductive composition, which maintains its cohesiveness and volume and resists erosion, would be highly desirable.
- It is an object of the invention to provide a quantity of demineralized fibrous bone elements, a quantity of non-fibrous bone elements that are demineralized, partially demineralized or non-demineralized having a least dimension substantially larger than the thickness of the fibrous elements, and a cohesive osteoinductive/osteocon-ductive composition containing the fibrous and non-fibrous elements.
- It is a further object of the invention to provide a cohesive osteoinductive/osteoconductive composition, which is capable of wicking up blood and body fluids from the implant site, mixtures of bone marrow aspirate, autograft, etc.
- It is a further object of the invention to provide the cohesive osteoinductive/osteoconductive composition as an entangled mass with the non-fibrous elements maintained within the entangled fibrous elements of the composition.
- It is a further object of the invention to provide a cohesive osteoinductive/osteoconductive composition with superior surgical handling properties, e.g., the ability to pick up globs of it with forceps in order to place it at a surgical site.
- It is a further object of the invention to provide a volume maintaining osteoinductive/osteoconductive composition, which can be placed or injected into a hollow defect site.
- It is a further object of the invention to provide an osteoinductive/osteoconductive composition having superior volume maintaining properties, e.g., the ability to be packed firmly into large defect sites.
- It is a further object of the invention to provide an osteoinductive/osteoconductive composition that provides for rapid remodeling and incorporation of the non-fibrous elements into the host site, i.e., being turned into bone not only on the outside surfaces but also on the internal surfaces of the non-fibrous elements such that the composition remodels from inside out as well as outside in.
- It is a further object of the invention to provide a method of treating trauma indications, e.g., tibia plateau fractures, such that when the tibia plateau is elevated back to its normal anatomical configuration, the crushed area of the metaphysis can be easily filled with the composition of this invention to establish a solid fill that contributes to the maintenance of this normal anatomical reconstruction.
- It is a further object of the invention to provide an osteoinductive/osteoconductive composition in which the size and shape of the elements can be varied to suit the particular application.
- It is a further object of the invention to provide an osteoinductive/osteoconductive composition in which the ratio of fibrous elements to non-fibrous elements to carrier can be varied to suit the particular application.
- It is a further object of the invention to provide a composition that is capable of being viewed utilizing radiographic imaging techniques.
- The stated objects of the invention are not intended to be limiting in any way. Of course further objects of the invention herein will be obvious to those skilled in the art in view of the above stated objects and the foregoing specification.
- In keeping with these and related objects of the invention, there is provided an osteoinductive/osteoconductive composition comprising: (a) a quantity of fibrous bone elements possessing an average surface area to volume ratio of about 100:1 to about 20:1, (b) a quantity of non-fibrous bone elements possessing an average surface area to volume ratio of about 10:1 or less and (c) a quantity of biocompatible fluid carrier sufficient to provide the composition as a deformable mass. Application of the foregoing osteoinductive/osteoconductive composition to the site of a large bone defect, e.g., one resulting from injury, infection, disease, malignancy or developmental malformation, leads to rapid new bone ingrowth by one or more mechanisms such as osteogenesis, osteoinduction and/or osteoconduction.
- The inclusion of fibrous bone elements (a) imparts a higher level of cohesiveness to the osteoinductive/osteoconductive composition of this invention compared with that of an osteoinductive/osteoconductive composition containing the same ratio of bone elements to carrier but in which the bone elements are all, or substantially all, of the non-fibrous variety, e.g., the compositions of U.S. Pat. No. 5,073,373. The inclusion of non-fibrous bone elements (b) provides an osteoinductive/osteoconducti-ve composition which requires a higher level of applied mechanical force to effect its deformation than that required to deform an osteoinductive/osteoconductive composition containing the same ratio of bone elements to carrier but in which all, or substantially all, of the bone elements possess a relatively high surface area to volume ratio, e.g., the osteoinductive/osteoconductive composition of aforesaid U.S. Pat. No. 5,314,476 in which all, or substantially all, of the bone elements are of the fibrous variety.
- The expression “median length to median thickness ratio” as applied to the fibrous bone elements of the invention shall be understood to refer to the ratio of the longest median dimension of the fibrous bone element (its median length) to its shortest median dimension (its median thickness).
- The term “cohesive” as applied to the osteoinductive/osteoconductiv-e composition of this invention shall be understood to refer to the ability of the composition to be shaped or packed into a coherent mass which retains its shape and volume and resists erosion from the implant site.
- The term “fibrous” as applied to this invention refers to bone elements whose median length to median thickness ratio is at least about 10:1 and whose surface area to volume ratio is between about 100:1 and about 20:1. In overall appearance the fibrous bone elements can be described as fibers, threads, narrow strips, or thin sheets. Often, where thin sheets are produced, their edges tend to curl up toward each other. The fibrous bone elements can be substantially linear in appearance or they can be coiled to resemble springs. The fibrous bone elements are preferably demineralized however some of the original mineral content may be retained when desirable for a particular embodiment of the invention.
- The expression “non-fibrous” as applied to the elements of this invention refers to elements that have a median width substantially larger than the median thickness of the fibrous bone element. Such non-fibrous bone elements will have a surface area to volume ratio significantly smaller than the fibrous bone elements, e.g., about 10:1 or less. Preferably the non-fibrous bone elements are shaped in a substantially regular manner or specific configuration, e.g. triangular prism, sphere, cube, cylinder and other regular shapes. By contrast, particles such as chips, shards, or powders possess irregular or random geometries. It should be understood that some variation in dimension will occur in the production of the elements of this invention and elements demonstrating such variability in dimension are within the scope of this invention and are intended to be understood herein as being within the boundaries established by the expressions “mostly irregular” and “mostly regular”.
- The expression “partially demineralized bone elements” as applied to this invention refers to bone elements that are demineralized to the extent that only a small amount of mineral remains in the core. That is the residual calcium is between about 50 to 100% by weight.
- The expression “maintains its cohesiveness and volume and resists deformation” as applied to this invention refers to the ability of the composition to be packed into an appropriate size defect site and lock into place remaining as a coherent mass where it is placed. In addition, the invention resists substantial deformation when subjected to a force of up to about 10 N. This is in contrast to prior art compositions of paste-like or putty-like consistency as well as those of liquid or runny consistency.
- The following is a brief description of the drawings which are presented only for the purposes of further illustrating the invention and not for the purposes of limiting the same.
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FIG. 1 are irregular non-fibrous bone elements,FIG. 1A are mostly regular non-fibrous bone elements prepared as in Example 1.FIG. 1B represents a side-by-side comparison of the size and regular shape of the non-fibrous bone elements useful in the invention herein and the irregular non-fibrous elements ofFIG. 1 . -
FIG. 2 represents the appearance of a prior art bone composition andFIG. 2A is a composition prepared as in Example 1. -
FIG. 3 is a relatively large defect site andFIG. 3A demonstrates the ability of a composition prepared as in Example 1 to fill a relatively large defect site. -
FIG. 4 represents the radiographic and biological results obtained in Example 4. - The bone utilized in this invention is obtained utilizing methods well known in the art, e.g., aseptically procured allogenic donor bone that has been cleaned and disinfected. Fibrous bone elements whose median length to median thickness ratio is at least about 10:1 can be readily obtained by any one of several methods, e.g., shaving the surface of an entire bone or relatively large section of bone. Employing a shaving technique, fibrous bone elements ranging in median length from about 2 mm up to 400 mm or more (as in the case of the long bones) and in median thickness from about 0.05 mm to about 2 mm can be obtained. An apparatus useful for obtaining the fibrous bone elements useful herein is described in U.S. Pat. No. 5,607,269 the contents of which are incorporated herein by reference.
- Depending on the procedure employed for producing the fibrous bone elements, one can obtain a mass of fibrous bone elements containing at least about 50 weight percent, preferably at least about 70 weight percent and most preferably at least about 80 weight percent of the fibrous bone elements possessing a median length of from about 2 mm to about 400 mm or more and preferably from about 10 mm to about 100 mm, a median thickness of from about 0.05 mm to about 2 mm and preferably from about 0.08 mm to about 1.5 mm, and a median length to median thickness ratio of at least 10:1 up to about 500:1 or more and preferably from about 50:1 to about 100:1. The surface area to volume ratio of the fibrous bone elements will vary between about 100:1 and about 20:1, preferably between about 80:1 and about 40:1. If desired, the mass of fibrous bone elements bone can be graded into different sizes and/or any less desirable size(s) of fibrous bone elements which may be present can be reduced or eliminated. The fibrous bone elements can be obtained from cortical autogenic, cortical allogenic, cortical xenogenic, cortical transgenic, cancellous autogenic, cancellous allogenic, cancellous xenogenic, cancellous transgenic, corticocancellous autogenic, corticocancellous allogenic, corticocancellous xenogenic or corticocancellous transgenic bone. Porcine and bovine bone are a particularly advantageous type of xenogenic bone tissue which can be used as a source for the fibrous bone elements of this invention, although of course other sources of bone such as ovine, caprine and equine may also be suitable.
- Following shaving, milling or other technique whereby they are optionally obtained, the fibrous bone elements are subjected to demineralization in order to reduce their inorganic content to a very low level, e.g., to not more than about 5% by weight of residual calcium and preferably to not more than about 1% by weight residual calcium. Demineralization of the fibrous bone elements ordinarily results in their contraction to some extent.
- Demineralization of the fibrous bone elements can be conducted in accordance with known conventional procedures. For example, in a preferred demineralization procedure, the fibrous bone elements are subjected to an acid demineralization step that is followed by a defatting/disinfecting step. The bone is immersed in acid over time to effect its demineralization. Acids which can be employed in this step include inorganic acids such as hydrochloric acid and organic acids such as peracetic acid. After acid treatment, the bone is rinsed with sterile water for injection, buffered with a buffering agent to a final predetermined pH and then finally rinsed with water for injection to remove residual amounts of acid and buffering agent or washed with water to remove residual acid and thereby raise the pH. Following demineralization, the bone is immersed in solution to effect its defatting. A preferred defatting/disinfectant solution is an aqueous solution of ethanol, the ethanol being a good solvent for lipids and the water being a good hydrophilic carrier to enable the solution to penetrate more deeply into the bone. The aqueous ethanol solution also disinfects the bone by killing vegetative microorganisms and viruses. Ordinarily at least about 10 to 40 weight percent by weight of water (i.e., about 60 to 90 weight percent of defatting agent such as alcohol) should be present in the defatting/disinfecting solution to produce optimal lipid removal and disinfection within the shortest period of time. The preferred concentration range of the defatting solution is from about 60 to 85 weight percent alcohol and most preferably about 70 weight percent alcohol. Further in accordance with the invention, the demineralized fibrous bone elements can be used immediately for preparation of the osteoinductive/osteoconductive composition or they can be stored under aseptic conditions, advantageously in a lyophilized state prior to such preparation. In a preferred embodiment, the fibrous bone elements can retain some of their original mineral content such that the composition is rendered capable of being imaged utilizing radiographic techniques such as disclosed in U.S. Pat. No. 5,676,146 the contents of which are incorporated herein by reference.
- The non-fibrous bone elements of this invention substantially display a relatively small surface area to volume ratio, e.g., less than about 10:1, preferably less than about 6:1, most preferably less than about 3:1. The median width of the non-fibrous bone elements is at least as large as the median thickness of the fibrous bone elements utilized in the composition of this invention but more preferably larger. In further accordance with some of the objects of this invention, the size and shape of the non-fibrous elements of the invention can be varied to tailor the composition to its intended application. In preferred embodiments, the composition will contain non-fibrous elements that exhibit a substantially larger least dimension than the least dimension of the fibrous bone elements. In a preferred embodiment, the non-fibrous bone elements will display a “mostly regular” geometry, i.e.; the shape of the non-fibrous bone elements is a triangular prism, sphere, cube, cylinder, other regular shape or a combination of these shapes. Such shapes displaying a substantially regular geometry are to be distinguished from chips, shards, and powders which may have a relatively small surface area to volume ratio but which due to their “mostly irregular” shape are unable to lock into place when used in a composition intended to repair an appropriate size defect site. When it is desirable to have an embodiment capable of being injected or placed through, for example, a cannula or other similar device into a defect site, the shape of the non-fibrous elements will be substantially spheroid. Such non-fibrous elements can be obtained from cortical autogenic, cortical allogenic, cortical xenogenic, cortical transgenic, cancellous autogenic, cancellous allogenic, cancellous xenogenic, cancellous transgenic, corticocancellous autogenic, corticocancellous allogenic, corticocancellous xenogenic or corticocancellous transgenic bone. Porcine and bovine bone are a particularly advantageous type of xenogenic bone tissue which can be used as a source for the non-fibrous bone elements of this invention, although of course, ovine, caprine and equine bone may be entirely suitable.
- About 20 to about 80 weight percent of the non-fibrous bone elements of the invention are non-fibrous bone elements having a median length to median width to median height ratio of at least about 1:0.3:1 and up to about 1:1:5, a median length of from about 0.25 mm to about 10 mm, a median width of from about 0.25 mm to about 10 mm and a median height of from about 0.25 mm to about 10 mm, the median width being the smallest dimension of the non-fibrous element and the median height being the io largest dimension of the non-fibrous element. Such non-fibrous elements are prepared utilizing methods well known in the art, e.g., cutting, milling, stamping, grinding. The size and shape of the non-fibrous elements can vary depending on the specific application the composition is intended for, e.g., large trauma defects will require relatively large non-fibrous elements, whereas small dental defects, e.g., sinus lifts, three-wall defects, furcations, etc., will require relatively small non-fibrous elements. Such variation of size and shape of the non-fibrous bone elements to tailor the composition to the specific application is intended to be within the scope of this invention. The non-fibrous bone elements useful herein can be fully mineralized, partially demineralized, or fully demineralized (i.e., <5% calcium by weight). In a preferred embodiment of the invention, the composition contains from about 0 to about 50 percent by weight of the non-fibrous bone elements mineralized bone, from about 0 to about 80 percent by weight of the non-fibrous bone elements partially demineralized bone and from about 0 to about 100 percent by weight of the non-fibrous bone elements fully demineralized bone.
- The bone utilized in making the non-fibrous elements of the invention can be fully mineralized, partially demineralized or fully demineralized prior to the preparation of the non-fibrous elements. In a preferred embodiment cortical bone is cut into slices, e.g., about 3 mm in width, and then demineralized to the extent that only a small amount of mineral remains in the core, i.e., less than 10% by weight residual calcium, preferably less than 5% by weight residual calcium. The bone is then cut with a stamping technique to yield substantially cuboid shapes about 3.times.3.times.3 mm in length, width and height. Optionally, mineralized bone is cut into substantially cuboid shapes with a band saw. The bone cubes are then demineralized using techniques well known in the art, e.g., such as those described above. After the non-fibrous elements are obtained they can be used immediately for preparation of the osteoinductive/osteoconductive composition or they can be stored under aseptic conditions, advantageously in a lyophilized or frozen state prior to such preparation.
- To prepare an osteoinductive/osteoconductive composition utilizing the demineralized fibrous bone elements and non-fibrous bone elements of this invention, a quantity of the fibrous and non-fibrous elements are combined with an amount of biocompatible fluid carrier which will provide a coherent mass. The carrier can be any of a number of compounds and/or polymers, e.g., polymer sugars, proteins, long chain hydrophilic block copolymers, reverse phase block copolymers, hyaluronic acid, polyuronic acid, mucopolysaccharide, proteoglycan, polyoxyethylene, surfactants, e.g., the pluronics series of nonionic surfactants, and peptide thickener. Suggested classes of biocompatible fluid carrier would include polyhydroxy compound, polyhydroxy ester, fatty alcohol, fatty alcohol ester, fatty acid, fatty acid ester, liquid silicone, mixtures thereof, and the like.
- Examples of suitable biocompatible fluid carrier include, but are not limited to:
- (i) Polyhydroxy compound, for example, such classes of compounds as the acyclic polyhydric alcohols, non-reducing sugars, sugar alcohols, sugar acids, monosaccarides, disaccharides, water-soluble or water dispersible oligosaccarides, polysaccarides and known derivatives of the foregoing. Specific polyhydroxy compounds include, 1,2-propanediol, glycerol, 1,4,-butylene glycol trimethylolethane, trimethylolpropane, erythritol, pentaerythritol, ethylene glycols, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, dipropylene glycol; polyoxyethylene-polyoxypropylene copolymer, e.g., of the type known and commercially available under the trade names Pluronic and Emkalyx; polyoxyethylene-polyoxypropylene block copolymer, e.g., of the type known and commercially available under the trade name Poloxamer; alkylphenolhydroxypolyoxyethylene, e.g., of the type known and commercially available under the trade name Triton, polyoxyalkylene glycols such as the polyethylene glycols, xylitol, sorbitol, mannitol, dulcitol, arabinose, xylose, ribose, adonitol, arabitol, inositol, fructose, galactose, glucose, mannose, sorbose, sucrose, maltose, lactose, maltitol, lactitol, stachyose, maltopentaose, cyclomaltohexaose, carrageenan, agar, dextran, alginic acid, guar gum, gum tragacanth, locust bean gum, gum arabic, xanthan gum, amylose, mixtures of any of the foregoing, and the like.
- (ii) Polyhydroxy ester, for example, liquid and solid monoesters and diesters of glycerol can be used to good effect, the solid esters being dissolved up to the limit of their solubilities in a suitable vehicle, e.g., propylene glycol, glycerol, polyethylene glycol of 200-1000 molecular weight, etc. Liquid glycerol esters include monacetin and diacetin and solid glycerol esters include such fatty acid monoesters of glycerol as glycerol monolaurate, glyceryl monopalmitate, glyceryl monostearate, etc. An especially preferred carrier herein comprises glyceryl monolaurate dissolved in glycerol or a 4:1 to 1:4 weight mixture of glycerol and propylene glycol, poly(oxyalkylene)glycol ester, and the like.
- (iii) Fatty alcohol, for example primary alcohols, usually straight chain having from 6 to 13 carbon atoms, including caproic alcohol, caprylic alcohol, undecyl alcohol, lauryl alcohol, and tridecanol.
- (iv) Fatty alcohol ester, for example, ethyl hexyl palmitate, isodecyl neopentate, octadodecyl benzoate, diethyl hexyl maleate, and the like.
- (v) Fatty acid having from 6 to 11 carbon atoms, for example, hexanoic acid, heptanoic acid, octanoic acid, decanoic acid and undecanoic acid.
- (vi) Fatty acid ester, for example, polyoxyethylene-sorbitan-fatty acid esters; e.g., mono- and tri-lauryl, palmityl, stearyl, and oleyl esters; e.g., of the type available under the trade name Tween from Imperial Chemical Industries; polyoxyethylene fatty acid esters; e.g., polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj; propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate; propylene glycol dilaurate, propylene glycol hydroxy stearate, propylene glycol isostearate, propylene glycol laureate, propylene glycol ricinoleate, propylene glycol stearate, and propylene glycol caprylic-capric acid diester available under the trade name Miglyol; mono-, di-, and mono/di-glycerides, such as the esterification products of caprylic or caproic acid with glycerol; e.g., of the type known and commercially available under the trade name Imwitor; sorbitan fatty acid esters, e.g., of the type known and commercially available under the trade name Span, including sorbitan-monolauryl,-monopalmityl, -monostearyl, -tristearyl, -monooleyl and triolcylesters; monoglycerides, e.g., glycerol mono oleate, glycerol mono palmitate and glycerol monostearate, for example as known and commercially available under the trade names Myvatex, Myvaplex and Myverol, and acetylated, e.g., mono- and di-acetylated monoglycerides, for example, as known and commercially available under the trade name Myvacet; isobutyl tallowate, n-butylstearate, n-butyl oleate, and n-propyl oleate.
- (vii) Liquid silicone, for example, polyalkyl siloxanes such as polymethyl siloxane and poly (dimethyl siloxane) and polyalkyl arylsiloxane.
- In a preferred embodiment of the osteoinductive/osteoconductive composition, the liquid carrier is a liquid polyhydroxy compound, liquid polyhydroxy compound derivative, liquid solution of solid polyhydroxy compound, liquid solution of solid polyhydroxy compound derivative or mixtures thereof. If necessary or desirable, the liquid carrier can be dissolved or diluted with an appropriate solvent such that when combined with the fibrous and non-fibrous elements of the invention a composition capable of being shaped or packed into a coherent mass which retains its shape and volume over the relatively long term, e.g., until the bone formation and remodeling process is completed, is provided. Thus, the polyhydroxy compound or polyhydroxy derivatives can be a liquid in the pure or highly concentrated state at ambient temperature, e.g., 1.5 -50.degree. C., or it can be a solid or semi-solid at this temperature in which case it becomes necessary to dissolve the material in a solvent such as water, physiological saline, ethanol, glycerol, glucose, propylene glycol, polyethylene glycol of from 200-1000 molecular weight, polyvinyl alcohol, etc. Of course, the liquid carrier can be made up of one or more liquid polyhydroxy compounds or derivatives in solution with one or more solid polyhdroxy compounds or derivatives.
- Of the foregoing polyhydroxy compounds, glycerol and its liquid monesters and diesters, e.g. monacetin and diacetin, fructose, glucose and sucrose, and mixtures thereof are preferred. Where the polyhydroxy compound is a solid, e.g., sucrose, a solvent such as water, glycerol, polyethylene glycol of from 200-1000 average molecular weight, or mixture thereof is used to provide a cohesive solution or paste of the compound.
- Where, in a particular osteoinductive/osteoconductive composition, the fibrous and/or non-fibrous elements exhibit a tendency to quickly or prematurely separate from the carrier component or to otherwise settle out from the composition such that application of a fairly homogeneous composition is rendered difficult or inconvenient, it can be advantageous to include within the composition an optional substance whose thixotropic characteristics prevent or reduce this tendency. Thus, e.g., where the carrier component is glycerol and separation of fibrous and/or non-fibrous bone elements occurs to an excessive extent where a particular application is concerned, a thixotropic agent such as a solution of polyvinyl alcohol, polyvinylpyrrolidone, cellulosic ester such as hydroxypropyl methylcellulose, carboxyl methylcellulose, pectin, food-grade texturizing agent, gelatin, dextran, collagen, starch, hydrolyzed polyacrylonitrile, hydrolyzed polyacrylamide, polyelectrolyte such as polyacrylic acid salt, hydrogels, chitosan, other materials that can suspend particles, etc., can be combined with the carrier in an amount sufficient to significantly improve the suspension-keeping characteristics of the composition.
- If desired, the fibrous and/or non-fibrous bone elements of this invention can be modified in one or more ways, e.g., their protein content can be augmented or modified as described in U.S. Pat. Nos. 4,743,259 and 4,902,296 the contents of which are incorporated herein by reference. Any of a variety of medically and/or surgically useful optional substances can be incorporated in, or associated with, the bone elements before, during, or after preparation of the osteoinductive/osteoconductive composition. Thus, e.g., one or more of such substances can be introduced into the bone elements, e.g., by soaking or immersing the bone elements in a solution or dispersion of the desired substance(s), by adding the substance(s) to the carrier component of the osteoinductive/osteoconductive composition or by adding the substance(s) directly to the osteoinductive/osteoconductive composition.
- Medically/surgically useful substances which can be readily combined with the bone elements, fluid carrier and/or osteoinductive/osteoconductive composition of this invention include, e.g., demineralized bone powder as described in U.S. Pat. No. 5,073,373 the contents of which are incorporated herein by reference, collagen, insoluble collagen derivatives, hydroxyapatite, etc., and soluble solids and/or liquids dissolved therein, e.g., antiviricides, particularly those effective against HIV and hepatitis; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymyxin B, tetracyclines, viomycin, chloromycetin and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentainycin; etc.; amino acids, peptides, vitamins, inorganic elements, inorganic compounds, cofactors for protein synthesis, hormones; endocrine tissue or tissue fragments; synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.; polymer cell scaffolds with paraenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; biocompatible surface active agents; antigenic agents; cytoskeletal agents; cartilage fragments, living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, tissue transplants, bioadhesives, bone morphogenic proteins (BMPs), transforming growth factor (TGF-beta), insulin-like growth factor (IGF-1) (IGF-2), platelet derived growth factor (PDGF), fibroblast growth factors (FGF), vascular endothelial growth factor (VEGF), angiogenic agents, bone promoters, cytokines, interleukins, genetic material, genes encoding bone promoting action, cells containing genes encoding bone promoting action; growth hormones such as somatotropin; bone digestors; antitumor agents; fibronectin; cellular attractants and attachment agents; immuno-suppressants; permeation enhancers, e.g., fatty acid esters such as laureate, myristate and stearate monesters of polyethylene glycol, surface active agents, enamine derivatives, .alpha.-keto aldehydes, etc.; nucleic acids; epidermal growth factor (EGF); all collagen types (not just type 1); non-collagenous proteins such as osteopontin, osteonectine, bone sialo proteins, vitronectin, thrombospondin, proteoglycans, decorin, biglycan, aggrecan, versican, tenascin, matrix gla protein hyaluronan; soluble- and insoluble components of the immune system, soluble and insoluble receptors including truncated forms, soluble, insoluble and cell surface bound ligands including truncated forms; chemokines, bioactive compounds that are endocytosed; compounds capable of altering the membrane potential of cells, compounds capable of altering the monovalent and divalent cation/anion channels of cells; bone resportion inhibitors and stimulators; angiogenic and mitogenic factors; bioactive factors that inhibit and stimulate second messenger molecules; integrin adhesion molecules; clotting factors; externally expanded autograft or xenograft cells and any combinations thereof. The amounts of such optionally added substances can vary widely with optimum-levels being readily determined in a specific case by routine experimentation.
- As previously indicated, the osteoinductive/osteoconductive composition of this invention can be freshly prepared just by mixing desired quantities of the demineralized fibrous bone elements, non-fibrous bone elements, fluid carrier and optional component(s), if any, in any suitable sequence of separate mixing, adsorption, rehydration or drying operations or all at once. Thus, the demineralized fibrous bone elements and/or non-fibrous bone elements can be mixed with the optional ingredients(s) and thereafter combined with the fluid carrier component, the demineralized fibrous bone elements and/or non-fibrous bone elements can be mixed with the fluid carrier followed by addition of the optional ingredient(s) or the optional ingredients can be added to the fluid carrier followed by addition of the demineralized fibrous bone elements and/or non-fibrous bone elements. Variations of these and other sequences of mixing are, of course, possible. Advantageously, the fibrous and non-fibrous elements and fluid carrier are mixed substantially simultaneously such that the fibrous elements of the osteoinductive/osteoconductive composition are entangled and the non-fibrous bone elements are thoroughly mixed in the entangled fibrous bone elements.
- The amount of demineralized fibrous bone elements which can.be incorporated into the osteoinductive/osteoconductive composition can vary widely with amounts of from about 5 to about 90 weight percent, and preferably from about 20 to about 70 weight percent, being entirely suitable in most cases. Likewise, the amount of the non-fibrous bone elements which can be incorporated into the osteoinductive/osteoconductiv-e composition can very widely with amounts from about 10 to about 90 weight percent, and preferably from about 20 to about 70 weight percent, being entirely suitable in most cases. The ratio of fibrous to non-fibrous bone elements can vary between about 0.2:1 to about 1:0.2. The balance of the composition being made up of fluid carrier and optional ingredient(s), if any.
- In embodiments where it is desirable to improve the ability of the osteoinductive/osteoconductive composition to be imaged, e.g., by x-ray, radiopaque material(s) may be incorporated into the composition. Such materials would include, e.g., barium sulfate, iodine-containing compounds, titanium and mineralized bone.
- To facilitate on-site preparation and/or usage of the composition herein, the demineralized fibrous bone elements and non-fibrous bone elements, preferably in lyophilized or frozen form, and fluid carrier (the latter containing one or more optional ingredients such as those identified above) can be stored in separate packages or containers under sterile conditions and brought together in intimate admixture at the moment of use for immediate application to an osseous defect site employing any suitable means such as spatula, forceps, syringe, tamping device, etc. Alternatively, the osteoinductive/osteoconductive composition can be prepared well in advance and stored under sterile conditions until required for use. When the osteoinductive/osteoconductiv-e composition is prepared well in advance it is preferably lyophilized prior to packaging for storage. At the time just prior to when the osteoinductive/osteoconductive composition of the invention is to be placed in a defect site optional materials, e.g., autograft bone marrow aspirate, autograft bone, preparations of selected autograft cells, autograft cells containing genes encoding bone promoting action, etc., can be combined with the composition of this invention. Preferably, the osteoinductivelosteoconductive composition is packaged already mixed and ready for use in a suitable container, e.g., syringe, resealable non-toxic bottle, etc., or is provided as a kit which can be prepared at a surgeon's direction when needed.
- The osteoinductive/osteoconductive composition of this invention can be firmly placed into an appropriate size defect site to maintain volume and provide support for adjacent tissues. Such placement can be accomplished through the use of a variety of devices such as, e.g., spatula, forceps, syringe, tamping device, etc.
- The osteoinductive/osteoconductive composition of this invention can be tailored to be utilized for a variety of orthopaedic, neurosurgical, and oral and maxillofacial surgical indications in which it would be advantageous to be able to firmly place the composition into a bone defect site such as the repair of simple and compound fractures and nonunions, external fixations, joint reconstructions such as arthrodesis, general arthroplasty, acetabular repair, cup arthroplasty of the hip, femoral and humeral head replacement, femoral head surface replacement and total joint replacements, repairs of the vertebral column including spinal fusion and internal fixation, tumor surgery, e.g., deficit filling, discectomy, lain inectomy, excision of spinal cord tumors, anterior cervical and thoracic operations, repair of spinal injuries, scoliosis, lordosis and kyphosis treatments, intermaxillary fixation of fractures, mentoplasty, temporomandibular joint replacement, alveolar ridge augmentation and reconstruction, inlay bone grafts, implant placement and revision, sinus lifts, furcation defects, periodontal defects, dental defects, ulna defects, metaphyseal defects, tibia plateau defects, wrist defects, ankle defects, etc.
- The invention will be more fully understood by way of the following examples which are intended to illustrate but not limit methods of preparation of the demineralized fibrous bone elements and non-fibrous bone elements of the invention and the preparation of an osteoinductive/osteoconductive composition containing the fibrous and non-fibrous elements in accordance with the present invention. A comparison of the compressive force of prior art compositions and the composition of the invention is also provided, however, this comparison is intended to illustrate but not limit the differences between this invention and the prior art.
- Sections of defatted, disinfected allogenic cortical bone approximately 210-250 mm in length were cut on a band saw to yield 145.65 g of cuboid non-fibrous bone elements about 3 mm in size. The remaining allogenic cortical bone was processed in the bone milling apparatus described in U.S. Pat. No. 5,607,269 to yield 145.8 grams of fibrous bone elements. The non-fibrous bone elements were then placed in a reactor. A 0.6 N solution of HCl at 15 ml per gram of non-fibrous bone elements was introduced into the reactor, the reaction proceeded for 1 to 2 hours. Following drainage of the HCl, the non-fibrous bone elements were covered with 0.6 N HCl/20 ppm-2000 ppm nonionic surfactant solution for 24 to 48 hours. The fibrous bone elements were then added to the reactor and allowed to soak for 5 to 10 minutes. Following drainage of the HCl/surfactant solution, 0.6 N HCl at 15 ml per gram of total bone was introduced into the reactor, the reaction proceeded for 40 to 50 minutes. Following drainage through a sieve the bone was rinsed three times with water for injection at 15 ml per gram non-fibrous element weight with the water for injection being replaced at 15-minute intervals. Following drainage of the water for injection, the bone was covered with alcohol and allowed to soak for at least 30 minutes. The alcohol was then drained and the bone was rinsed with water for injection. The bone was then contacted with a mixture of 3.5 ml of glycerol per gram of dry bone and 5 ml of water for injection per gram of dry bone for at least 2 hours. After draining, the composition was transferred to a lyophilization tray and frozen at −70.degree. C. for at least 6 hours. The composition was then lyophilized following standard procedures for 24 to 48 hours.
- The compressive force of the composition prepared as in Example 1 was compared with that of a like quantity of an osteoinductive/osteocondu-ctive composition prepared in accordance with U.S. Pat. No. 5,073,373 and an osteoinductive/osteoconductive composition prepared in accordance with U.S. Pat. No. 5,314,476. In this example, 5 cc of each material was placed into separate 10 cc syringe barrels. The compressive force (i.e., the sustained force capable of deflecting a meter probe) was then measured using the meter, to determine deflective force. The results are contained in the following table.
Material Compressive Force (N) U.S. Pat. No. 5,073,373 4.8 U.S. Pat. No. 5,314,476 7.9 Example 1 10.3 - Material prepared as in Example 1 was evaluated to determine its osteoinductive potential. The material was implanted in female athymic homozygous mu/mu rats according to the procedure described in Edwards et al., Osteoinduction of Human Demineralized Bone: Characterization in a Rat Model, Clinical Orthopedics and Related Research (No. 357, pp. 219-228) 1998, the contents of which are incorporated hereby by reference. The material was studied to analyze its bone formation response. After 28 days in the rat model it was determined that cells had accumulated in the porous region inside of the chips, differentiated into bone forming cells, and were in the process of laying down bone in remodeling the matrix from the inside out.
- Twenty-four 6 month-old (3.5-4.0 kg) male New Zealand white rabbits (Covance: Denver, Pa.) were used. The animals received a standard rabbit diet (Purina, Ind.) and received standard tap water ad libitum. The animals were kept on a 12 h light/dark cycle.
- The animals underwent surgery to create bilaterial 1.5 cm ulnar defects by the method described by Bostrom et al., Use of Bone morphogenic Protein-2 in the Rabbit Ulnar Nonunion Modelz, Clinical Orthopedics and Related Research (No. 327, pp. 272-282) 1996, the contents of which are incorporated herein by reference. The 48 defects were randomly assigned and implanted with one of the four grafting materials (Table 1). The final volume of each implant was 1 cc. The animals were not restricted from full weight bearing after surgery.
TABLE 1 EVALUATION TREATMENT GROUP PERIODS SAMPLE SIZE 1 cc of autogenous bone graft 6 and 12 weeks N = 1 at 6 weeks from the iliac crest Demineralized fibers with 6 and 12 weeks N = 9 at 12 weeks demineralized cortical chips Demineralized fibers with non- 6 and 12 weeks N = 3 at 6 weeks demineralized cortical chips N = 8 at 12 weeks DBM Putty with non- 6 and 12 weeks N = 3 at 6 weeks demineralized cancellous chips N = 9 at 12 weeks Empty 12 weeks N = 2 at 12 weeks - The animals were sedated and serial radiographs of the forelimbs were taken every three weeks until 12 weeks post-operatively when the animals were sacrificed. At the time of sacrifice, the ulnas were removed, cleaned of soft tissue, and radiographed using a high resolution Faxitron. Bony union (Table 2) and quantitative bone formation (Table 3) was evaluated at each time point by 3 independent, blinded observers. Bony union was defined as bridging of the defect in excess of 25% of the diaphyseal diameter. The radiographs were digitized to normalize the bone area and intensity so that bone formation could be quantified using image analysis software. Bone formation was evaluated on a standardized 5-point scale measuring percent of new bone seen in defect: 0=no new bone evident in defect, 1=1-25%, 2=26-50%, 3=51-75%, 4=76-99%, 5=100%.
TABLE 2 RADIOGRAPHIC UNIONS BY TIME POINT 9 Weeks 12 Weeks TREATMENT GROUP Union Nonunion Union Nonunion Autograft 5 4 8 1 Demin Fibers/Demin 1 7 7 1 Cortical Chips 2 6 7 1 DBM Putty/Non-Demin C/C Chips 0 9 6 3 Demin Fibers/Non- Demin Cortical Chips -
TABLE 3 BONE FORMATION EVALUATED RADIOGRAPHICALLY AREA OF DEFECT OCCUPIED BY BONE (MEDIAN SCORE) TREATMENT GROUP Week 3 Week 6Week 9 Week 12Autograft 0 4 4 5 Demin Fibers/Demin 0 3 3.5 4 Cortical Chips DBM Putty/Non-Demin 1 3 4 4 C/C Chips Demin Fibers/Non- 1 3 3 4 Demin Cortical Chips - All limbs from each group were prepared for histological analysis. Tissue samples were dehydrated over a course of several weeks with daily changes of the alcohol solutions. After dehydration was complete, tissue samples were embedded in methylmethacrylate. The blocks were cut in the longitudinal direction of the bone in 5 .mu.m sections using a microtome. Serial sections were stained with one of the following stains: Hematoxylin and eosin, Goldner-Masson trichrome, or Von Kossa. The sections were examined for cellular characteristics indicative of new bone formation and callus formation. Groups using the Fisher's exact test compared radiographic union data. Bone formation was verified with a nonparametic analysis of variance (ANOVA), the Kruskal-Wallis H-test.
- Experimental protocols were followed without incidence. There was one postoperative death resulting in the loss of 2 experimental defects. One defect was lost from demineralized fibers and demineralized cortical chips. Radiographic evaluation showed no statistically significant differences between the four groups. Some bone formation was evident in all groups by six weeks. At 12 weeks, all groups displayed similar quantities of new bone formation as assessed by radiodensity scale. (Table 3).
- Union of the defect sites occurred in a similar fashion in all groups (Table 2). The autogenous bone graft (“ABG”) group did show higher union rates at earlier point times, but at 12 weeks there is no statistically significant difference between the three groups. Strong bony bridges were seen in all four groups at 12 weeks. The only exceptions were in the demineralized fibers with non-demineralized chip. In this group, though 6 out of 9 were united, the defects tended not to have maintained their three-dimensional space and showed sagging in the middle.
- It shall be understood, however, that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other than as particularly described and still be within the scope of the accompanying claims.
Claims (23)
1. An osteoinductive and osteoconductive composition comprising: (a) a quantity of demineralized fibrous bone elements possessing an average surface area to volume ratio of about 100:1 to about 20:1, (b) a quantity of shaped non-fibrous bone elements possessing an average surface area to volume ratio of about 10:1 or less, and (c) a biocompatible fluid carrier, wherein the composition withstands a compressive force greater than 7.9 N without substantial deformation.
2. The osteoinductive and osteoconductive composition of claim 1 of which about 50 to about 100 percent by weight of the fibrous bone element is made up of demineralized fibrous bone elements having a median length of from about 2 mm to about 400 mm, a median thickness of from about 0.05 mm to about 2 mm and a median length to median thickness ratio of at least 10:1 up to about 500:1.
3. The osteoinductive and osteoconductive composition of claim 1 in which a shape of the non-fibrous bone elements is selected from the group consisting of triangular prism, sphere, cube, cylinder and other regular shapes.
4. The osteoinductive and osteoconductive composition of claim 1 wherein the bone elements are obtained from cortical autogenic, cortical allogenic, cortical xenogenic cancellous autogenic, cancellous allogenic, cancellous xenogenic, cortical transgenic, cancellous transgenic, corticocancellous autogenic, corticocancellous allogenic, corticocancellous xenogenic or corticocancelldus transgenic bone.
5. The osteoinductive and osteoconductive composition of claim 1 of which about 20 to about 80 weight percent of the non-fibrous bone elements of the invention are non-fibrous bone elements having a median length to median width to median height ratio of at least about 1:0.3:1 and up to about 1:5:1, a imedian length of from about 1 mm to about 10 mm, a median width of from about 1 mm to about 10 mm and a median height of from about 1 mm to about 10 mm.
6. The osteoinductive and osteoconductive composition of claim 1 wherein about 0 to about 50 percent by weight of the bone elements are mineralized.
7. The osteoinductive and osteoconductive composition of claim 1 wherein about 0 to about 80 percent by weight of the bone elements are partially demineralized.
8. The osteoinductive and osteoconductive composition of claim 1 wherein about 0 to about 100 percent by weight of the bone elements are demineralized.
9. The osteoinductive and osteoconductive composition of claim 1 further comprising a thixotropic agent.
10. The osteoinductive and osteoconductive composition of claim 1 further comprising at least one medically/surgically useful substance.
11. The osteoinductive and osteoconductive composition of claim 1 wherein the fibrous bone elements are entangled.
12. The osteoinductive and osteoconductive composition of claim 11 wherein the non-fibrous bone elements are thoroughly mixed in the entangled fibrous bone elements.
13. The osteoinductive and osteoconductive composition of claim 1 containing from about 20 to about 70 weight percent demineralized fibrous bone elements, from about 20 to about 70 weight percent non-fibrous bone elements, and from about 10 to about 80 weight percent fluid carrier.
14. The osteoinductive and osteoconductive composition of claim 1 wherein the ratio of fibrous to non-fibrous elements is about 0.2:1 to about 1:0.2.
15. The osteoinductive and osteoconductive composition of claim 1 further comprising at least one additive selected from the group consisting of autograft bone marrow aspirate, autograft bone, preparations of selected autograft cells, autograft cells containing genes encoding bone promoting action and autograft cells expanded outside the body and returned.
16. The osteoinductive and osteoconductive composition of claim 1 wherein the composition withstands a compressive force of at least about 10.3 N without significant deformation.
17. The osteoinductive and osteoconductive composition of claim 1 wherein the amount of mineral remaining in the elements allows for radiographic imaging of the composition.
18. The osteoinductive and osteoconductive composition of claim 1 further comprising at least one radiopaque material selected from the group consisting of barium sulfate, iodine containing compounds, titanium and mineralized bone.
19. method of using the osteoinductive and osteoconductive composition of claim 1 wherein the composition is packed appropriately into an appropriate size bone defect site.
20. The method of claim 19 wherein the composition is packed into the defect site utilizing at least one means selected from the group consisting of spatula, forceps, syringe and dental equipment.
21. The method of claim 19 wherein the defect site is selected from the group consisting of ulna defects, metaphyseal defects, tibia plateau defects, acetabular defects, sinus defects, long bone cortical defects, cranial defects, ilium defects, wrist/hand defects, ankle/foot defects and oral/maxillofacial defects.
22. The method of claim 19 wherein the composition further comprises at least one additional additive selected from the group consisting of autograft bone marrow aspirate, autograft bone, autograft cell preparations, autograft cells containing genes encoded for bone stimulating activity and autograft cells expanded outside the body and returned.
23. The osteoinductive and osteoconductive composition of claim 1 containing about X weight units of component (a), about Y weight units of component (b) and about Z weight units of component (c) a given amount of the composition exhibiting a greater resistance to deformation than the identical amount of a second osteoinductive and osteoconductive composition containing X+Y weight units of component (a), no amount of component (b) and Z weight units of component (c).
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US9675645B2 (en) | 2013-01-22 | 2017-06-13 | Warsaw Orthopedic, Inc. | Method of preparing bone material having enhanced osteoinductivity |
US20140212390A1 (en) * | 2013-01-30 | 2014-07-31 | NuTech Medical, Inc. | Placental Membrane Preparation and Methods of Making and Using Same |
EP3798226A1 (en) | 2013-02-01 | 2021-03-31 | Children's Medical Center Corporation | Collagen scaffolds |
WO2014130953A1 (en) | 2013-02-22 | 2014-08-28 | Lifenet Health | Packaging assembly for storing tissue and cellular material |
CA2894750C (en) | 2013-02-22 | 2021-12-14 | Allosource | Cartilage mosaic compositions and methods |
AU2014225458A1 (en) | 2013-03-07 | 2015-07-09 | Allosource | Consistent calcium content bone allograft systems and methods |
EP2967874B1 (en) | 2013-03-15 | 2019-11-20 | AlloSource | Perforated osteochondral allograft compositions |
CA2899713C (en) | 2013-03-15 | 2022-07-19 | Allosource | Cell repopulated collagen matrix for soft tissue repair and regeneration |
US9730796B2 (en) | 2014-05-16 | 2017-08-15 | Allosource | Composite bone constructs and methods |
WO2016115625A1 (en) * | 2015-01-19 | 2016-07-28 | Ammolite Biomodels Inc. | Simulated bone materials and methods of making same |
US11052175B2 (en) | 2015-08-19 | 2021-07-06 | Musculoskeletal Transplant Foundation | Cartilage-derived implants and methods of making and using same |
WO2017218545A1 (en) | 2016-06-13 | 2017-12-21 | Lifenet Health | Demineralized bone fibers and preparation thereof |
US11452796B2 (en) | 2017-06-30 | 2022-09-27 | Allosource | Cellular bone grafts, and methods of manufacture and use |
Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4059684A (en) * | 1975-03-14 | 1977-11-22 | Kulzer & Co. Gmbh | Bone cement compositions containing gentamycin |
US4355331A (en) * | 1981-01-28 | 1982-10-19 | General Electric Company | X-ray image subtracting system |
US4394370A (en) * | 1981-09-21 | 1983-07-19 | Jefferies Steven R | Bone graft material for osseous defects and method of making same |
US4440750A (en) * | 1982-02-12 | 1984-04-03 | Collagen Corporation | Osteogenic composition and method |
US4472840A (en) * | 1981-09-21 | 1984-09-25 | Jefferies Steven R | Method of inducing osseous formation by implanting bone graft material |
US4485097A (en) * | 1982-05-26 | 1984-11-27 | Massachusetts Institute Of Technology | Bone-equivalent and method for preparation thereof |
US4678470A (en) * | 1985-05-29 | 1987-07-07 | American Hospital Supply Corporation | Bone-grafting material |
US4743259A (en) * | 1986-10-29 | 1988-05-10 | The University Of Virginia Alumni Patents Foundation | Use of demineralized bone matrix in the repair of segmental defects |
US4857269A (en) * | 1988-09-09 | 1989-08-15 | Pfizer Hospital Products Group Inc. | High strength, low modulus, ductile, biopcompatible titanium alloy |
US4902296A (en) * | 1986-10-29 | 1990-02-20 | The University Of Virginia Alumni Patents Foundation | Use of demineralized bone matrix in the repair of segmental defects |
US5073373A (en) * | 1989-09-21 | 1991-12-17 | Osteotech, Inc. | Flowable demineralized bone powder composition and its use in bone repair |
US5284655A (en) * | 1989-09-21 | 1994-02-08 | Osteotech, Inc. | Swollen demineralized bone particles, flowable osteogenic composition containing same and use of the composition in the repair of osseous defects |
US5314476A (en) * | 1992-02-04 | 1994-05-24 | Osteotech, Inc. | Demineralized bone particles and flowable osteogenic composition containing same |
US5405390A (en) * | 1989-11-09 | 1995-04-11 | Osteotech, Inc. | Osteogenic composition and implant containing same |
US5507813A (en) * | 1993-12-09 | 1996-04-16 | Osteotech, Inc. | Shaped materials derived from elongate bone particles |
US5607269A (en) * | 1995-11-21 | 1997-03-04 | Osteotech, Inc. | Bone milling apparatus |
US5676146A (en) * | 1996-09-13 | 1997-10-14 | Osteotech, Inc. | Surgical implant containing a resorbable radiopaque marker and method of locating such within a body |
US5707962A (en) * | 1994-09-28 | 1998-01-13 | Gensci Regeneration Sciences Inc. | Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof |
US6123731A (en) * | 1998-02-06 | 2000-09-26 | Osteotech, Inc. | Osteoimplant and method for its manufacture |
US6294187B1 (en) * | 1999-02-23 | 2001-09-25 | Osteotech, Inc. | Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same |
Family Cites Families (166)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US159334A (en) | 1875-02-02 | Improvement in machines for crushing bones | ||
US781882A (en) | 1904-11-22 | 1905-02-07 | William Hinckle Smith | Compressed product from bone. |
US2516438A (en) | 1947-05-26 | 1950-07-25 | Norton L Wheeler | Dental pulp capping preparation |
US2968593A (en) | 1957-12-09 | 1961-01-17 | Armour & Co | Preparation of anorganic bone |
US3739773A (en) | 1963-10-31 | 1973-06-19 | American Cyanamid Co | Polyglycolic acid prosthetic devices |
US3458397A (en) | 1966-12-08 | 1969-07-29 | Squibb & Sons Inc | Process for producing osteogenic material |
US3609867A (en) | 1969-03-10 | 1971-10-05 | Research Corp | Plastic bone composition |
US3790507A (en) | 1969-03-10 | 1974-02-05 | Research Corp | Plastic bone composition |
GB1409051A (en) | 1971-09-24 | 1975-10-08 | Nat Research Department Corp | Hip joint prostheses |
US3947287A (en) | 1971-11-15 | 1976-03-30 | Badische Anilin- & Soda-Fabrik Aktiengesellschaft | Aqueous pigment dispersions |
US4209434A (en) | 1972-04-18 | 1980-06-24 | National Research Development Corporation | Dental cement containing poly(carboxylic acid), chelating agent and glass cement powder |
IT992109B (en) | 1973-08-27 | 1975-09-10 | Ente Ospedal Spec | HIP ENDOPROTESIS |
FR2260980B1 (en) | 1974-02-20 | 1976-12-03 | Herbert Jules | |
US4172128A (en) | 1975-03-26 | 1979-10-23 | Erhard Thiele | Process of degrading and regenerating bone and tooth material and products |
US4134792A (en) | 1976-12-06 | 1979-01-16 | Miles Laboratories, Inc. | Specific binding assay with an enzyme modulator as a labeling substance |
DE2657370C2 (en) | 1976-12-17 | 1982-11-11 | Hans Dr.med. Dr.med.dent. 8000 München Scheicher | Means for covering and / or filling in bone defects |
US4123806A (en) | 1977-01-31 | 1978-11-07 | Regents Of The University Of California | Total hip joint replacement |
DE2843963A1 (en) | 1978-10-09 | 1980-04-24 | Merck Patent Gmbh | BODY-RESORBABLE SHAPED MATERIAL BASED ON COLLAGEN AND THEIR USE IN MEDICINE |
US4224698A (en) | 1979-04-05 | 1980-09-30 | Hopson Clark N | Acetabular cup for total hip replacements |
US4512038A (en) | 1979-04-27 | 1985-04-23 | University Of Medicine And Dentistry Of New Jersey | Bio-absorbable composite tissue scaffold |
DE2967060D1 (en) | 1979-12-18 | 1984-07-19 | Oscobal Ag | Bone replacement material and process for producing a bone replacement material |
US4363319A (en) | 1980-06-30 | 1982-12-14 | Applied Medical Devices, Inc. | Ready-to-use bandage incorporating a coagulant composition and method of preparing same |
US4294753A (en) | 1980-08-04 | 1981-10-13 | The Regents Of The University Of California | Bone morphogenetic protein process |
US4430760A (en) | 1981-12-18 | 1984-02-14 | Collagen Corporation | Nonstress-bearing implantable bone prosthesis |
CH648747A5 (en) | 1981-02-20 | 1985-04-15 | Sulzer Ag | JOINT PAN, ANCHORABLE IN THE POOL. |
US4411662A (en) | 1982-04-06 | 1983-10-25 | Baxter Travenol Laboratories, Inc. | Sterile coupling |
US4440370A (en) | 1982-09-28 | 1984-04-03 | Rood Robert M | Securing stake |
US4581030A (en) | 1982-09-30 | 1986-04-08 | Massachusetts General Hospital | Collagen replacement prothesis for the cornea |
US4932973A (en) | 1983-09-30 | 1990-06-12 | El Gendler | Cartilage and bone induction by artificially perforated organic bone matrix |
US4563489A (en) | 1984-02-10 | 1986-01-07 | University Of California | Biodegradable organic polymer delivery system for bone morphogenetic protein |
DE3479402D1 (en) | 1984-06-12 | 1989-09-21 | Oscobal Ag | Method of producing a bone replacement material |
US4620327A (en) | 1984-07-05 | 1986-11-04 | Caplan Arnold I | Process of adapting soluble bone protein for use in stimulating osteoinduction |
US5032445A (en) | 1984-07-06 | 1991-07-16 | W. L. Gore & Associates | Methods and articles for treating periodontal disease and bone defects |
US4795463A (en) | 1984-10-03 | 1989-01-03 | Baylor College Of Medicine | Labeled breast prosthesis and methods for detecting and predicting rupture of the prosthesis |
US4637931A (en) | 1984-10-09 | 1987-01-20 | The United States Of America As Represented By The Secretary Of The Army | Polyactic-polyglycolic acid copolymer combined with decalcified freeze-dried bone for use as a bone repair material |
US4888366A (en) | 1984-10-24 | 1989-12-19 | Collagen Corporation | Inductive collagen-based bone repair preparations |
US4563350A (en) | 1984-10-24 | 1986-01-07 | Collagen Corporation | Inductive collagen based bone repair preparations |
US5001169A (en) | 1984-10-24 | 1991-03-19 | Collagen Corporation | Inductive collagen-based bone repair preparations |
US4595713A (en) | 1985-01-22 | 1986-06-17 | Hexcel Corporation | Medical putty for tissue augmentation |
US4842604A (en) | 1985-02-19 | 1989-06-27 | The Dow Chemical Company | Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics |
US5007930A (en) | 1985-02-19 | 1991-04-16 | The Dow Chemical Company | Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics |
US4698375A (en) | 1985-02-19 | 1987-10-06 | The Dow Chemical Company | Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics |
US4636526A (en) | 1985-02-19 | 1987-01-13 | The Dow Chemical Company | Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics |
CA1260391A (en) | 1985-03-28 | 1989-09-26 | Karl A. Piez | Xenogeneic collagen/mineral preparations in bone repair |
US5053049A (en) | 1985-05-29 | 1991-10-01 | Baxter International | Flexible prostheses of predetermined shapes and process for making same |
US4627853A (en) | 1985-05-29 | 1986-12-09 | American Hospital Supply Corporation | Method of producing prostheses for replacement of articular cartilage and prostheses so produced |
US4709703A (en) | 1985-11-12 | 1987-12-01 | Mayo Foundation | Imaging system and method using radiopaque microspheres for evaluation of organ tissue perfusion |
US6311690B1 (en) | 1986-03-27 | 2001-11-06 | Gensci Orthobiologics, Inc. | Bone repair material and delayed drug delivery system |
EP0243151B1 (en) | 1986-04-22 | 1992-12-16 | Ajinomoto Co., Inc. | Modified microbially-produced cellulose gel and complex thereof with animal cell |
US4919939A (en) | 1986-04-29 | 1990-04-24 | Pharmetrix Corporation | Periodontal disease treatment system |
FI81010C (en) | 1986-09-05 | 1990-09-10 | Biocon Oy | Benomplaceringsimplants |
US4824939A (en) | 1986-10-09 | 1989-04-25 | Eastman Kodak Company | Process for leaching particulate solid materials |
NZ235556A (en) | 1986-11-05 | 1991-06-25 | Ethicon Inc | Breast milk substitute containing recombinant human egf |
US4865602A (en) | 1986-11-06 | 1989-09-12 | Collagen Corporation | Gamma irradiation of collagen/mineral mixtures |
AT398373B (en) | 1987-12-17 | 1994-11-25 | Immuno Ag | BIOLOGICAL RESORBABLE IMPLANTATION MATERIAL AND METHOD FOR PRODUCING THE SAME |
US5139527A (en) | 1987-12-17 | 1992-08-18 | Immuno Aktiengesellschaft | Biologic absorbable implant material for filling and closing soft tissue cavities and method of its preparation |
US4961707A (en) | 1987-12-22 | 1990-10-09 | University Of Florida | Guided periodontal tissue regeneration |
GB2215209B (en) | 1988-03-14 | 1992-08-26 | Osmed Inc | Method and apparatus for biodegradable, osteogenic, bone graft substitute device |
US4950296A (en) | 1988-04-07 | 1990-08-21 | Mcintyre Jonathan L | Bone grafting units |
US5162114A (en) | 1989-02-23 | 1992-11-10 | Stryker Corporation | Bone collagen matrix for xenogenic implants |
US4975526A (en) | 1989-02-23 | 1990-12-04 | Creative Biomolecules, Inc. | Bone collagen matrix for zenogenic implants |
US5015247A (en) | 1988-06-13 | 1991-05-14 | Michelson Gary K | Threaded spinal implant |
US4994030A (en) | 1988-06-28 | 1991-02-19 | Osteotech, Inc. | Reconstitution of human bone and tissue |
DE3831657A1 (en) | 1988-09-17 | 1990-03-22 | Boehringer Ingelheim Kg | DEVICE FOR THE OSTEOSYNTHESIS AND METHOD FOR THE PRODUCTION THEREOF |
US5207710A (en) | 1988-09-29 | 1993-05-04 | Collagen Corporation | Method for improving implant fixation |
EP0366029B1 (en) | 1988-10-25 | 1994-09-07 | Takao Yamamuro | Bone repairing material and artificial bone fixing agent |
US5700479A (en) | 1988-12-23 | 1997-12-23 | Guidor Ab | Surgical element and method for selective tissue regeneration |
US5432000A (en) | 1989-03-20 | 1995-07-11 | Weyerhaeuser Company | Binder coated discontinuous fibers with adhered particulate materials |
IT216721Z2 (en) | 1989-06-30 | 1991-09-19 | Euroresearch S R L Milano | TUTOR CONSTITUTED BY A HETEROLOGICAL COLLAGEN TUBULAR, SUITABLE FOR USE IN THE SUTURE OF CABLE ORGANS. |
CA2020654A1 (en) | 1989-07-07 | 1991-01-08 | Yohko Akiyama | Stabilized fgf composition and production thereof |
US5077049A (en) | 1989-07-24 | 1991-12-31 | Vipont Pharmaceutical, Inc. | Biodegradable system for regenerating the periodontium |
ES2109230T3 (en) | 1989-08-02 | 1998-01-16 | Univ North Carolina | PROCEDURE FOR RETICULATING COLLAGOUS MATERIALS AND THE RESULTING PRODUCT. |
US5061286A (en) | 1989-08-18 | 1991-10-29 | Osteotech, Inc. | Osteoprosthetic implant |
US4946792A (en) | 1989-08-18 | 1990-08-07 | Osteotech, Inc. | Process for debriding bone |
US5112354A (en) | 1989-11-16 | 1992-05-12 | Northwestern University | Bone allograft material and method |
US5204055A (en) | 1989-12-08 | 1993-04-20 | Massachusetts Institute Of Technology | Three-dimensional printing techniques |
US5197882A (en) | 1990-05-14 | 1993-03-30 | Gary R. Jernberg | Periodontal barrier and method for aiding periodontal tissue regeneration agents |
US5723117A (en) | 1990-08-10 | 1998-03-03 | Otsuka Pharmaceutical Co., Ltd. | Use of interleukin-1 (IL-1) to inhibit development of hepatitis |
JPH0497747A (en) | 1990-08-17 | 1992-03-30 | Osteotech Inc | Artificial bone for transplanting application |
ES2076467T3 (en) | 1990-10-31 | 1995-11-01 | El Gendler | FLEXIBLE MEMBRANES PRODUCED WITH ORGANIC BONE MATTER FOR THE REPAIR AND RECONSTRUCTION OF PARTS OF THE SKELETON. |
EP1142581A3 (en) | 1990-11-27 | 2002-09-11 | American National Red Cross | Tissue sealant and growth factor containing compositions that promote accelerated wound healing |
US5171278A (en) | 1991-02-22 | 1992-12-15 | Madhavan Pisharodi | Middle expandable intervertebral disk implants |
US5656593A (en) | 1991-03-11 | 1997-08-12 | Creative Biomolecules, Inc. | Morphogen induced periodontal tissue regeneration |
JP3007903B2 (en) | 1991-03-29 | 2000-02-14 | 京セラ株式会社 | Artificial disc |
DE4121043A1 (en) | 1991-06-26 | 1993-01-07 | Merck Patent Gmbh | BONE REPLACEMENT MATERIAL WITH FGF |
FR2679778B1 (en) | 1991-08-02 | 1995-07-07 | Coletica | USE OF CROLAGEN CROSSLINKED BY A CROSSLINKING AGENT FOR THE MANUFACTURE OF A SLOW RESORPTIVE, BIOCOMPATIBLE, SUTURABLE MEMBRANE, AS WELL AS SUCH A MEMBRANE. |
US5329846A (en) | 1991-08-12 | 1994-07-19 | Bonutti Peter M | Tissue press and system |
US5092887A (en) | 1991-08-12 | 1992-03-03 | El Gendler | Artificial ligament produced from demineralized bone for the replacement and augmentation of ligaments, tendons and other fibrous connective tissue |
US6503277B2 (en) | 1991-08-12 | 2003-01-07 | Peter M. Bonutti | Method of transplanting human body tissue |
US5282827A (en) | 1991-11-08 | 1994-02-01 | Kensey Nash Corporation | Hemostatic puncture closure system and method of use |
EP0552579B1 (en) | 1992-01-22 | 1996-01-03 | Guy-Henri Muller | Prosthetic implants for plastic surgery |
DE69304092T2 (en) | 1992-02-10 | 1997-01-02 | Matsumoto Dental College Shioj | Bone replacement material and process for its manufacture |
US5336699A (en) | 1992-02-20 | 1994-08-09 | Orthopaedic Research Institute | Bone cement having chemically joined reinforcing fillers |
US5366507A (en) | 1992-03-06 | 1994-11-22 | Sottosanti John S | Method for use in bone tissue regeneration |
CA2118520C (en) | 1992-04-24 | 1999-08-10 | Dirkjan Bakker | Devices for preventing tissue adhesion |
CA2093836A1 (en) | 1992-04-24 | 1993-10-25 | Wayne Gombotz | Biodegradable tgf-.beta. delivery system for bone regeneration |
FR2691901B1 (en) | 1992-06-04 | 1995-05-19 | Centre Nat Rech Scient | Use of mixtures of polymers derived from lactic acids in the preparation of bioresorbable membranes for guided tissue regeneration, in particular in periodontology. |
US5343877A (en) | 1992-09-09 | 1994-09-06 | University Of Iowa Research Foundation | Orthopedic implant and method |
US5641518A (en) | 1992-11-13 | 1997-06-24 | Purdue Research Foundation | Method of repairing bone tissue |
US5334216A (en) | 1992-12-10 | 1994-08-02 | Howmedica Inc. | Hemostatic plug |
US5336507A (en) | 1992-12-11 | 1994-08-09 | Sterling Winthrop Inc. | Use of charged phospholipids to reduce nanoparticle aggregation |
US5405402A (en) | 1993-04-14 | 1995-04-11 | Intermedics Orthopedics, Inc. | Implantable prosthesis with radiographic marker |
US5447725A (en) | 1993-06-11 | 1995-09-05 | The Procter & Gamble Company | Methods for aiding periodontal tissue regeneration |
US5531791A (en) | 1993-07-23 | 1996-07-02 | Bioscience Consultants | Composition for repair of defects in osseous tissues, method of making, and prosthesis |
US5455041A (en) | 1993-09-13 | 1995-10-03 | Research Foundation Of State University Of New York At Buffalo | Method for inducing periodontal tissue regeneration |
US5490962A (en) | 1993-10-18 | 1996-02-13 | Massachusetts Institute Of Technology | Preparation of medical devices by solid free-form fabrication methods |
US5518680A (en) | 1993-10-18 | 1996-05-21 | Massachusetts Institute Of Technology | Tissue regeneration matrices by solid free form fabrication techniques |
US5425639A (en) | 1994-05-03 | 1995-06-20 | Anders; Irving | Dental implant with shock absorbent cushioned interface |
IL110367A (en) | 1994-07-19 | 2007-05-15 | Colbar Lifescience Ltd | Collagen-based matrix |
US5496375A (en) | 1994-09-14 | 1996-03-05 | Zimmer, Inc. | Prosthetic implant with circumferential porous pad having interlocking tabs |
DE4434459C2 (en) | 1994-09-27 | 1996-07-25 | Uwe Dr Richter | membrane |
US6599515B1 (en) | 1995-01-16 | 2003-07-29 | Baxter International Inc. | Fibrin porous structure |
US5782919A (en) | 1995-03-27 | 1998-07-21 | Sdgi Holdings, Inc. | Interbody fusion device and method for restoration of normal spinal anatomy |
EP0880345B1 (en) | 1996-01-17 | 2006-04-05 | Osteotech, Inc. | Process for producing flexible sheets from demineralized, elongate, bone particles |
DE29608321U1 (en) | 1996-05-08 | 1996-08-08 | Aesculap Ag | Marker element |
US5727945A (en) | 1996-08-26 | 1998-03-17 | Dannenbaum; Richard M. | Impregnated barrier and method of assisting bone or tissue regeneration |
US5922753A (en) | 1996-10-23 | 1999-07-13 | Zymogenetics, Inc. | Methods for treating bone deficit conditions with benzothiazole |
US5846484A (en) | 1997-03-20 | 1998-12-08 | Osteotech, Inc. | Pressure flow system and method for treating a fluid permeable workpiece such as a bone |
US20020137890A1 (en) | 1997-03-31 | 2002-09-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US5910315A (en) | 1997-07-18 | 1999-06-08 | Stevenson; Sharon | Allograft tissue material for filling spinal fusion cages or related surgical spaces |
US6652592B1 (en) | 1997-10-27 | 2003-11-25 | Regeneration Technologies, Inc. | Segmentally demineralized bone implant |
US6090998A (en) | 1997-10-27 | 2000-07-18 | University Of Florida | Segmentally demineralized bone implant |
US5899939A (en) | 1998-01-21 | 1999-05-04 | Osteotech, Inc. | Bone-derived implant for load-supporting applications |
US7087082B2 (en) | 1998-08-03 | 2006-08-08 | Synthes (Usa) | Bone implants with central chambers |
US6437018B1 (en) | 1998-02-27 | 2002-08-20 | Musculoskeletal Transplant Foundation | Malleable paste with high molecular weight buffered carrier for filling bone defects |
USRE38522E1 (en) | 1998-02-27 | 2004-05-25 | Musculoskeletal Transplant Foundation | Malleable paste for filling bone defects |
US6030635A (en) | 1998-02-27 | 2000-02-29 | Musculoskeletal Transplant Foundation | Malleable paste for filling bone defects |
US6326018B1 (en) | 1998-02-27 | 2001-12-04 | Musculoskeletal Transplant Foundation | Flexible sheet of demineralized bone |
US6911212B2 (en) | 1998-02-27 | 2005-06-28 | Musculoskeletal Transplant Foundation | Malleable putty and flowable paste with allograft bone having residual calcium for filling bone defects |
US7045141B2 (en) | 1998-02-27 | 2006-05-16 | Musculoskeletal Transplant Foundation | Allograft bone composition having a gelatin binder |
US6458375B1 (en) | 1998-02-27 | 2002-10-01 | Musculoskeletal Transplant Foundation | Malleable paste with allograft bone reinforcement for filling bone defects |
US6224630B1 (en) | 1998-05-29 | 2001-05-01 | Advanced Bio Surfaces, Inc. | Implantable tissue repair device |
WO2000007639A1 (en) | 1998-08-07 | 2000-02-17 | Tissue Engineering, Inc. | Bone precursor compositions |
CA2355046A1 (en) | 1998-12-14 | 2000-06-22 | Osteotech, Inc. | Bone graft and guided bone regeneration method |
US6206923B1 (en) | 1999-01-08 | 2001-03-27 | Sdgi Holdings, Inc. | Flexible implant using partially demineralized bone |
WO2000045753A1 (en) | 1999-02-04 | 2000-08-10 | Sdgi Holdings, Inc. | Improved interbody fusion device with anti-rotation features |
US6375663B1 (en) | 1999-03-17 | 2002-04-23 | Maxilon Laboratories, Inc. | Bone grafting material |
EP1194086A4 (en) | 1999-06-08 | 2003-03-19 | Osteotech Inc | Keyed intervertebral dowel |
US6599520B2 (en) | 1999-10-14 | 2003-07-29 | Osteotech, Inc. | Method of inducing new bone growth in porous bone sites |
US20030228288A1 (en) | 1999-10-15 | 2003-12-11 | Scarborough Nelson L. | Volume maintaining osteoinductive/osteoconductive compositions |
US6630153B2 (en) | 2001-02-23 | 2003-10-07 | Smith & Nephew, Inc. | Manufacture of bone graft substitutes |
AR027685A1 (en) | 2000-03-22 | 2003-04-09 | Synthes Ag | METHOD AND METHOD FOR CARRYING OUT |
US6340477B1 (en) | 2000-04-27 | 2002-01-22 | Lifenet | Bone matrix composition and methods for making and using same |
US6863694B1 (en) | 2000-07-03 | 2005-03-08 | Osteotech, Inc. | Osteogenic implants derived from bone |
TR200400527T4 (en) | 2000-07-03 | 2004-07-21 | Osteotech Inc. | Bone-derived osteogenic implants |
US7001551B2 (en) | 2000-07-13 | 2006-02-21 | Allograft Research Technologies, Inc. | Method of forming a composite bone material implant |
US9387094B2 (en) | 2000-07-19 | 2016-07-12 | Warsaw Orthopedic, Inc. | Osteoimplant and method of making same |
US20020026244A1 (en) | 2000-08-30 | 2002-02-28 | Trieu Hai H. | Intervertebral disc nucleus implants and methods |
US6432436B1 (en) | 2000-10-03 | 2002-08-13 | Musculoskeletal Transplant Foundation | Partially demineralized cortical bone constructs |
AU2002243270B2 (en) | 2000-10-25 | 2006-03-09 | Warsaw Orthopedic, Inc. | Vertically expanding intervertebral body fusion device |
WO2002036049A2 (en) | 2000-11-03 | 2002-05-10 | Osteotech, Inc. | Spinal intervertebral implant and method of making |
US6752831B2 (en) | 2000-12-08 | 2004-06-22 | Osteotech, Inc. | Biocompatible osteogenic band for repair of spinal disorders |
US7323193B2 (en) | 2001-12-14 | 2008-01-29 | Osteotech, Inc. | Method of making demineralized bone particles |
US6855169B2 (en) | 2001-02-28 | 2005-02-15 | Synthes (Usa) | Demineralized bone-derived implants |
US6723131B2 (en) | 2001-02-28 | 2004-04-20 | The Cleveland Clinic Foundation | Composite bone marrow graft material with method and kit |
US6595998B2 (en) | 2001-03-08 | 2003-07-22 | Spinewave, Inc. | Tissue distraction device |
KR20040047746A (en) | 2001-10-12 | 2004-06-05 | 오스테오테크, 인코포레이티드 | Improved bone graft |
US6733534B2 (en) | 2002-01-29 | 2004-05-11 | Sdgi Holdings, Inc. | System and method for spine spacing |
US7582309B2 (en) | 2002-11-15 | 2009-09-01 | Etex Corporation | Cohesive demineralized bone compositions |
US7507257B2 (en) | 2003-02-04 | 2009-03-24 | Wright Medical Technology, Inc. | Injectable resorbable bone graft material, powder for forming same and methods relating thereto for treating bone defects |
EP2462957B1 (en) | 2003-09-23 | 2019-04-24 | Abyrx, Inc. | Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects |
US7955616B2 (en) | 2003-09-23 | 2011-06-07 | Orthocon, Inc. | Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects |
CN1856283A (en) | 2003-09-23 | 2006-11-01 | 奥斯治疗有限公司 | Bioabsorbable putty-like hemostatic implants |
US8603528B2 (en) | 2004-09-16 | 2013-12-10 | Abyrx, Inc. | Compositions and method for the reduction of post-operative pain |
IS7572A (en) | 2004-11-29 | 2006-05-30 | Genis Ehf | Method and materials for healing |
CN101141934B (en) | 2005-01-14 | 2010-11-24 | 骨骼技术股份有限公司 | Expandable osteoimplant |
-
2003
- 2003-04-14 US US10/413,324 patent/US20030228288A1/en not_active Abandoned
-
2005
- 2005-11-22 US US11/284,539 patent/US20060147545A1/en not_active Abandoned
-
2009
- 2009-08-26 US US12/548,029 patent/US8002813B2/en not_active Expired - Fee Related
-
2011
- 2011-07-19 US US13/185,553 patent/US8197474B2/en not_active Expired - Lifetime
Patent Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4059684A (en) * | 1975-03-14 | 1977-11-22 | Kulzer & Co. Gmbh | Bone cement compositions containing gentamycin |
US4355331A (en) * | 1981-01-28 | 1982-10-19 | General Electric Company | X-ray image subtracting system |
US4394370A (en) * | 1981-09-21 | 1983-07-19 | Jefferies Steven R | Bone graft material for osseous defects and method of making same |
US4472840A (en) * | 1981-09-21 | 1984-09-25 | Jefferies Steven R | Method of inducing osseous formation by implanting bone graft material |
US4440750A (en) * | 1982-02-12 | 1984-04-03 | Collagen Corporation | Osteogenic composition and method |
US4485097A (en) * | 1982-05-26 | 1984-11-27 | Massachusetts Institute Of Technology | Bone-equivalent and method for preparation thereof |
US4678470A (en) * | 1985-05-29 | 1987-07-07 | American Hospital Supply Corporation | Bone-grafting material |
US4743259A (en) * | 1986-10-29 | 1988-05-10 | The University Of Virginia Alumni Patents Foundation | Use of demineralized bone matrix in the repair of segmental defects |
US4902296A (en) * | 1986-10-29 | 1990-02-20 | The University Of Virginia Alumni Patents Foundation | Use of demineralized bone matrix in the repair of segmental defects |
US4857269A (en) * | 1988-09-09 | 1989-08-15 | Pfizer Hospital Products Group Inc. | High strength, low modulus, ductile, biopcompatible titanium alloy |
US5073373A (en) * | 1989-09-21 | 1991-12-17 | Osteotech, Inc. | Flowable demineralized bone powder composition and its use in bone repair |
US5284655A (en) * | 1989-09-21 | 1994-02-08 | Osteotech, Inc. | Swollen demineralized bone particles, flowable osteogenic composition containing same and use of the composition in the repair of osseous defects |
US5298254A (en) * | 1989-09-21 | 1994-03-29 | Osteotech, Inc. | Shaped, swollen demineralized bone and its use in bone repair |
US5405390A (en) * | 1989-11-09 | 1995-04-11 | Osteotech, Inc. | Osteogenic composition and implant containing same |
US5314476A (en) * | 1992-02-04 | 1994-05-24 | Osteotech, Inc. | Demineralized bone particles and flowable osteogenic composition containing same |
US5510396A (en) * | 1992-02-04 | 1996-04-23 | Osteotech, Inc. | Process for producing flowable osteogenic composition containing demineralized bone particles |
US5507813A (en) * | 1993-12-09 | 1996-04-16 | Osteotech, Inc. | Shaped materials derived from elongate bone particles |
US5707962A (en) * | 1994-09-28 | 1998-01-13 | Gensci Regeneration Sciences Inc. | Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof |
US5607269A (en) * | 1995-11-21 | 1997-03-04 | Osteotech, Inc. | Bone milling apparatus |
US5676146A (en) * | 1996-09-13 | 1997-10-14 | Osteotech, Inc. | Surgical implant containing a resorbable radiopaque marker and method of locating such within a body |
US5676146B1 (en) * | 1996-09-13 | 2000-04-18 | Osteotech Inc | Surgical implant containing a resorbable radiopaque marker and method of locating such within a body |
US6123731A (en) * | 1998-02-06 | 2000-09-26 | Osteotech, Inc. | Osteoimplant and method for its manufacture |
US6294187B1 (en) * | 1999-02-23 | 2001-09-25 | Osteotech, Inc. | Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same |
Cited By (37)
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US8002813B2 (en) | 1999-10-15 | 2011-08-23 | Warsaw Orthopedic, Inc. | Volume maintaining osteoinductive/osteoconductive compositions |
US8197474B2 (en) | 1999-10-15 | 2012-06-12 | Warsaw Orthopedic, Inc. | Volume maintaining osteoinductive/osteoconductive compositions |
US8663672B2 (en) | 2000-07-19 | 2014-03-04 | Warsaw Orthopedic, Inc. | Osteoimplant and method of making same |
US9999520B2 (en) | 2000-07-19 | 2018-06-19 | Warsaw Orthopedic, Inc. | Osteoimplant and method of making same |
US20030009235A1 (en) * | 2000-07-19 | 2003-01-09 | Albert Manrique | Osteoimplant and method of making same |
US9387094B2 (en) | 2000-07-19 | 2016-07-12 | Warsaw Orthopedic, Inc. | Osteoimplant and method of making same |
US8529962B2 (en) | 2000-12-14 | 2013-09-10 | Warsaw Orthopedic, Inc. | Method of making demineralized bone particles |
US7939108B2 (en) | 2000-12-14 | 2011-05-10 | Osteotech, Inc. | Method of making demineralized bone particles |
US8740987B2 (en) | 2001-06-04 | 2014-06-03 | Warsaw Orthopedic, Inc. | Tissue-derived mesh for orthopedic regeneration |
US7959941B2 (en) | 2001-10-12 | 2011-06-14 | Warsaw Orthopedic, Inc. | Bone graft comprising a demineralized bone matrix and a stabilizing agent |
US8753689B2 (en) | 2001-12-14 | 2014-06-17 | Warsaw Orthopedic, Inc. | Method of making demineralized bone particles |
US8268008B2 (en) | 2003-06-11 | 2012-09-18 | Warsaw Orthopedic, Inc. | Osteoimplants and methods for their manufacture |
US9393116B2 (en) | 2003-06-11 | 2016-07-19 | Warsaw Orthopedic, Inc. | Osteoimplants and methods for their manufacture |
US20080091270A1 (en) * | 2005-01-14 | 2008-04-17 | Miller Timothy R | Expandable osteoimplant |
US20070000802A1 (en) * | 2005-06-21 | 2007-01-04 | Cervitech, Inc. | Holder for intervertebral prostheses |
US8545864B2 (en) | 2005-11-02 | 2013-10-01 | Warsaw Orthopedic, Inc. | Hemostatic bone graft |
US9066994B2 (en) | 2006-08-31 | 2015-06-30 | Warsaw Orthopedic, Inc. | Demineralized cancellous strip DBM graft |
US9642936B2 (en) | 2006-08-31 | 2017-05-09 | Warsaw Orthopedic, Inc. | Demineralized cancellous strip DBM graft |
US20080058953A1 (en) * | 2006-08-31 | 2008-03-06 | Scarborough Nelson L | Demineralized cancellous strip DBM graft |
US8722075B2 (en) | 2008-10-24 | 2014-05-13 | Warsaw Orthopedic, Inc. | Compositions and methods for promoting bone formation |
US10207027B2 (en) | 2012-06-11 | 2019-02-19 | Globus Medical, Inc. | Bioactive bone graft substitutes |
US10792397B2 (en) | 2012-06-11 | 2020-10-06 | Globus Medical, Inc. | Bioactive bone graft substitutes |
US20180207317A1 (en) * | 2013-08-06 | 2018-07-26 | Mark Schumacher | Method for fusion of fractured or voided sternum post sternotomy |
US11179497B2 (en) * | 2013-08-06 | 2021-11-23 | Fusion Innovations, Llc | Method for fusion of fractured or voided sternum post sternotomy |
US10022474B2 (en) | 2013-10-18 | 2018-07-17 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
US9486483B2 (en) | 2013-10-18 | 2016-11-08 | Globus Medical, Inc. | Bone grafts including osteogenic stem cells, and methods relating to the same |
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US10531957B2 (en) | 2015-05-21 | 2020-01-14 | Musculoskeletal Transplant Foundation | Modified demineralized cortical bone fibers |
US11596517B2 (en) | 2015-05-21 | 2023-03-07 | Musculoskeletal Transplant Foundation | Modified demineralized cortical bone fibers |
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US11426489B2 (en) | 2015-06-10 | 2022-08-30 | Globus Medical, Inc. | Biomaterial compositions, implants, and methods of making the same |
US11772126B2 (en) * | 2016-02-01 | 2023-10-03 | Theradep Technologies Inc. | Systems and methods for delivering therapeutic agents |
US11896736B2 (en) | 2020-07-13 | 2024-02-13 | Globus Medical, Inc | Biomaterial implants and methods of making the same |
Also Published As
Publication number | Publication date |
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US20030228288A1 (en) | 2003-12-11 |
US8197474B2 (en) | 2012-06-12 |
US20100111906A1 (en) | 2010-05-06 |
US8002813B2 (en) | 2011-08-23 |
US20110274668A1 (en) | 2011-11-10 |
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