United States Patent [191
`Prewett et a1.
`
`llllllllllllllllllllllIIIIIllllllllllllllllllllllllllllllIllllllllIllllllll
`
`USOO5298254A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,298,254
`Mar. 29, 1994
`
`[54] SHAPED, SWOLLEN DEMINERALIZED
`BONE AND ITS USE IN BONE REPAIR
`_
`_
`[75] Inventors: Annmarie B. Prewett, Llttle S1lver,
`
`5,053,049 10/1991 Campbell ............................ .. 623/16
`5,073,373 12/1991 O’Leary ..... ..
`424/423
`5,162,114 11/1992 Kuberasampath et a1. ...... .. 424/423
`
`N_J_; Roger (2I s?keleather, Doylestown, Pa; Simon Bosdmslfy,
`
`Marlboro; Robert K. O’Leary, Spnng
`Lake, both of NJ.
`.
`'
`[73] Asslgnee: Osteotech, Inc., Shrewsbury, N].
`[211 APPI‘ N°-‘ 80958“
`[221 F11=d=
`Dec- 17’ 1991
`_
`_
`Related U's' Apphcatlon Data
`Continuation-impart of Ser. No. $73,458, Aug. 27,
`1990, which is a continuation-impart of S61‘. No.
`410'596’ Sep- 21’ 19891?“ N°' 5'073’373-
`[51] 1111.01; ............................................ .. A61K 35/32
`[52] us. Cl. .................................. .. 424/422; 424/423;
`424/549; 514/ 772.3; 514/777; 514/ 779;
`514/780; 514/785; 514/801; 514/802; 514/953;
`623/16
`[58] Field of Search ..................... .. 424/422, 423, 549;
`623/16
`
`[63]
`
`[56]
`
`References'cited
`U.S. PATENT DOCUMENTS
`2,968,593 l/l961 Rapkin ..... ..
`3,458,397 7/1969 Myersetal.
`4,172,128 10/1979 T111616 et al.
`
`0082621 6/1983 European Pal. Off. .
`90591986 3/1986 Japan .
`8607265 12/1986 PCT Int’l Appl. .
`8904646 6/1989 PCT Int’l A l. .
`2175807 10/1986 United Kingggm ‘
`OTHER PUBLICATIONS
`Covey 6181., “Clinical 11160611611 0f B0118 Repair With
`Demineralized Bone Matrix or :3 Bone Morphogenetic
`Protein”, Orthopaedic Review, v01. XVIII, No. 8, pp.
`857-863 (Aug, 1989).
`Gekko e1; 31,, “Mechanism of Protein Stabilization by
`Glycerol: Preferential Hydration in Glycerol-Water
`Mixtures”, vol- 20, No- 16, pp- 4667-5676 (1981)
`Habal et 91-, “Autologous Cortiwcanoellous Bone
`Paste for Long Bone Discontinuity Devects: An Exper
`imental Approach”, Annals of Plastic Surgery, vol. 15,
`NO. 2, pp. 138-142 (Aug., 1985).
`McLaughlin et aL, “Enhancement of Bone Ingrowth by
`the use of Bone Matrix as a Biologic Cement”, Clinical
`Orthopaedics and Related Research, No. 183, pp. 255
`M ., 1984 .
`( a’
`)
`424/549 Pm?” Ex“’""_’e'_Th“rma“ K- Page
`195/2
`Aswan’ Ex“"""e’";'am¢$ M- Spear
`424/549
`Attorney, Agent, or FIrm—D11W0rth & Barrese
`
`4,191,747 3/1980 Scheicher . . . . . . .
`
`. . . .. 424/549
`
`4,430,760 2/1984 Smestad ................. .. 3/19
`1,513,322
`Slowackl e181
`4,563,489 V1986 Urist ________ N
`
`,
`
`,
`
`yons ............... ..
`
`524/21
`
`[57]
`ABSTRACT
`A shaped piece of swollen demineralized bone which
`lineal-1051c p1ast1c1zed 1s provided for use 1n surgical
`
`-
`
`-
`
`~
`
`'
`
`-
`
`'
`
`4,595,713 6/1986 51.161111 . . . . . . . . .
`. . . .. 523/105
`4,946,792 8/1990 O’Leary ............................ .. 424/549
`4,994,030 2/1991 Glowczewskie, Jr. ct a1.
`604/84
`
`‘1
`
`P 1r‘
`
`30 Claims, 3 Drawing Sheets
`
`2
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`1 of 10
`
`

`
`U.S. Patent
`
`Mar. 29, 1994
`
`Sheet 1 of 3
`
`5,298,254
`
`2
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`2 of 10
`
`

`
`US. Patent
`
`Mar. 29, 1994
`
`Sheet 2 of 3
`
`5,298,254
`
`F/G.7
`
`FIG. 9
`
`FIG. /2
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`3 of 10
`
`

`
`US. Patent
`
`Mar. 29, 1994
`
`Sheet 3 of 3
`
`5,298,254
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`4 of 10
`
`

`
`1
`
`SHAPED, SWOLLEN DEMINERALIZED BONE
`AND ITS USE IN BONE REPAIR
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`This application is a continuation~in-part of copend
`ing US. patent application Ser. No. 07/573,458 ?led
`Aug. 27, 1990 which is, in turn, a continuation-in-part of
`copending U.S. patent application Ser. No. 07/4l0,596
`?led Sep. 21, 1989, now US. Pat. No. 5,073,373.
`
`5
`
`10
`
`15
`
`25
`
`BACKGROUND OF THE INVENTION
`This invention relates to shaped, swollen, demineral
`ized bone and to the use of the bone in the surgical
`repair of bone defects.
`The use of demineralized bone powder in the repair
`of bone defects has been a subject of investigation for
`some time. Bone powder contains one or more sub
`stances, possibly bone morphogenic protein (BMP),
`which induce bone regeneration at the defect site. See,
`e.g., Covey et al., “Clinical Induction of Bone Repair
`with Demineralized Bone Matrix or a Bone Morphoge
`netic Protein”, Orthopaedic Review, Vol. XVII, No. 8,
`pp. 857-863 (August, 1989).
`According to I-Iabal et al., “Autologous Corticocan
`cellous Bone Paste for Long Bone Discontinuity De
`fects: An Experimental Approach”, Annals of Plastic
`Surgery, Vol 15, No.2, pp. 138-142 (Aug. 1985), autoge
`nous bone which has been granulated into a pastelike
`material and combined with autogenous blood has been
`used in the repair of long bone defects in dogs.
`
`5,298,254
`2
`FIG. 2 is a perspective view of another embodiment
`and application of the osteogenic bone of the present
`invention;
`FIG. 3 is a plan view of a third embodiment of the
`osteogenic bone of the present invention;
`FIG. 4 is a plan view of a fourth embodiment of the
`osteogenic bone of the present invention;
`FIG. 5 is a side elevational view of the application of
`the embodiment illustrated in FIG. 4;
`FIG. 6 is an enlarged view'of part of FIG. 5;
`FIG. 7 is a perspective view of a ?fth embodiment of
`the osteogenic bone of the present invention;
`FIG. 8 is a perspective view of a sixth embodiment of
`the osteogenic bone of the present invention;
`FIG. 9 is a perspective view of the seventh embodi
`ment of the osteogenic bone of the present invention;
`FIG. 10 is a side elevational view of the application of
`the embodiment illustrated in FIG. 7;
`FIG. 11 is a side elevational view of the application of
`the embodiment illustrated in FIG. 8;
`FIG. 12 is a side elevational view of the application of
`the embodiment illustrated in FIG. 9;
`FIG. 13 is a perspective view of an eighth embodi
`ment of the osteogenic bone of the present invention;
`FIG. 14 is a side elevational view of the application of
`the embodiment illustrated in FIG. 13;
`FIG. 15 is a plan view of a ninth embodiment of the
`osteogenic bone of the present invention; and
`FIGS. 16-18 are schematic views illustrating a tenth
`embodiment of the osteogenic bone of the present in
`vention and application thereof.
`DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`The demineralized bone component of the composi
`tion herein is a known type of material and is prepared
`in accordance with known procedures. The bone can be
`obtained from cortical, cancellous and/or corticocan
`cellous autogenous, allogeneic or xenogeneic bone tis
`sue. In general, cortical allogeneic bone tissue is pre
`ferred as the source of bone.
`In a preferred bone demineralization procedure, the
`bone is ?rst cut, machined and/or shaped. to the desired
`size and dimensions followed by defatting/disinfecting
`and acid demineralization treatments. The operations of
`cutting, machining, extruding or otherwise shaping a
`bone piece in accordance with this invention are to be
`distinguished from known bone pulverizing procedures
`which result in bone particles not exceeding about 12
`mm. in size. In the present invention, the pieces of bone
`are at a minimum greater than about 12 mm. in size
`along at least one dimension thereof, with the geometry
`thereof being substantially regular in that the pieces are
`shaped to various speci?c con?gurations such as illus
`trated in the accompanying ?gures. By contrast, parti
`cles such as chips or powders possess irregular or ran
`dom geometries. The bone pieces of the present inven- .
`tion are of sizes which provide uni?ed structure for easy
`manipulation upon implantation.
`A preferred defatting/ disinfectant solution is an aque
`ous solution of ethanol and nonionic surfactant, 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 vege
`tative microorganisms and viruses For example, the
`nonionic surfactant destroys the lipid toga viruses such
`as HIV and HBV. Ordinarily at least about 10% to 40%
`
`40
`
`35
`
`SUMMARY OF THE INVENTION
`It is an object of the invention to provide swollen
`demineralized bone in a variety of desired shapes for use
`as surgical implants.
`It is also an object of the invention to provide
`swollen, demineralized bone which has been plasticized
`so that the bone can be readily shaped or formed for use
`in a variety of surgical applications.
`It is a speci?c object of the present invention to pro
`45
`vide swollen demineralized bone which is optionally
`?exibilized and which acts as an osteoinductive and/or
`osteoconductive allograft upon implantation in a body.
`In keeping with these and related objects of the in
`vention, there is provided a shaped piece of swollen
`demineralized bone, the bone being swollen by a bi
`ocompatible swelling agent. Application of the forego
`ing bone to the site of a bone defect, e.g., one resulting
`from injury, infection, malignancy or developmental
`malformation, leads to rapid new bone ingrowth by one
`or more mechanisms such as osteogenesis, osteoconduc
`tion and osteoinduction. The bone of this invention can
`be readily prepared with the swelling agent along with
`means for disinfecting the bone before applying the
`bone to a bone defect site, in the form of a unitary kit.
`Alternatively, the bone can be prepared beforehand and
`stored in the swelling agent for later use, i.e., later disin
`fecting.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a perspective view of one embodiment and
`application of the osteogenic bone of the present inven
`tion;
`
`50
`
`55
`
`65
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`5 of 10
`
`

`
`5,298,254
`3
`water (i.e., about 60% to 90% defatting agent such as
`alcohol) should be present in the defatting, disinfecting
`solution to produce optimal lipid removal and disinfec
`tion within the shortest period of time. The preferred
`concentration range of the defatting solution is about
`60% to 85% alcohol and most preferably about 70%
`alcohol.
`Following viricidal defatting, the bone is immersed in
`acid over time to effect demineralization. Acids which
`can be employed in this operation 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 ?nal predetermined pH and then
`?nally rinsed with water for injection to remove resid
`ual amounts of acid and buffering agent. The demineral
`ized bone is then stored under aseptic conditions, i.e., in
`the swelling agent.
`If desired, the bone can be modi?ed in one or more
`ways, e.g., the porosity of the bone can be increased
`20
`and/or the bone can be treated with one or more modi
`fying agents, e.g., glutaraldehyde, as disclosed in U.S.
`Pat. No. 4,678,470. Another optional treatment involves
`augmenting or altering the bone protein content of the
`bone as described in U.S. Pat. Nos. 4,743,259 and
`4,902,296.
`Any of a variety of medically/surgically useful sub
`stances can be incorporated in the preserved, swollen
`bone herein, e.g., by adding the substance(s) to the bone
`component, e.g., by soaking or immersing the bone in a
`solution or dispersion of the desired substance prior to
`adding the swelling agent, by adding the substance(s) to
`the swelling agent, i.e., polyhydroxy compound compo
`nent prior to immersing the bone therein or by adding
`the substances directly to the swelling agent after the
`bone has been incorporated therein. Alternatively, these
`medically/surgically useful substances can be added to
`the bone after the bone has been removed from the
`swelling agent, e.g., by dipping the preserved and
`swollen bone in a sterilizing solution containing one or
`more of these medically/surgically useful substances.
`Medically/surgically useful substances which can be
`readily incorporated in the bone of this invention in
`clude, e.g., collagen and insoluble collagen derivatives,
`hydroxy apatite, 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, neo
`mycin, penicillin, polymyxin B, tetracyclines, viomycin,
`chloromycetin and streptomycins, cefazolin, ampicillin,
`azactam, tobramycin, clindamycin and gentamycin,
`etc.; amino acids, magainins, peptides, vitamins, inor
`ganic elements, co-factors for protein synthesis; hor—
`mones; endocrine tissue or tissue fragments; synthesiz
`ers; enzymes such as collagenase, peptidases, oxidases,
`etc.; polymer cell scaffolds with parenchymal cells;
`surface cell antigen eliminators; angiogenic drugs and
`polymeric carriers containing such drugs; collagen lat
`tices; biocompatible surface active agents; antigenic
`agents; cytoskeletal agents; cartilage fragments, living
`cells such as chondrocytes, bone marrow cells, mesen
`chymal stem cells, natural extracts, tissue transplants,
`bioadhesives, bone morphogenic proteins (BMPs),
`transforming growth factor (TGF-beta), insulin-like
`growth factor (lGF-l); growth hormones such as so
`matotropin; bone digestors; antitumor agents; ?bronec
`tin; cellular attractants and attachment agents; immuno
`suppressants; permeation enhancers, e.g., fatty acid
`
`40
`
`45
`
`50
`
`55
`
`65
`
`4
`esters such as laureate, myristate and stearate monoes
`ters of polyethylene glycol, enamine derivatives, alpha
`keto aldehydes, etc.; nucleic acids; and, bioerodable
`polymers such as those disclosed in U.S. Pat. Nos.
`4,764,364 and 4,765,973 and European Patent Applica
`tion 168,277. The amounts of such optionally added
`substances can vary widely with optimum levels being
`readily determined in a speci?c case by routine experi
`mentation.
`To provide the swollen demineralized bone piece of
`this invention, the demineralized bone is contacted with
`a biocompatible swelling agent for a period of time
`suf?cient to cause swelling of the piece. A preferred
`swelling agent and one which also serves as a preserva
`tive for the bone is any one or mixture of biocompatible
`liquid polyhydroxy compounds hereinafter identi?ed.
`These compounds can be hypertonic, isotonic or hypo
`tonic and are thought to function by penetrating and
`permeating the demineralized bone matrix and causing
`polymerized collagen crystallites contained therein to
`swell and the ?bers contained within the matrix to be
`come ?lamentous.
`>
`
`10
`
`25
`
`35
`
`The expressions “liquid polyhydroxy compound”
`and “liquid polyhydroxy compound derivative” as em
`ployed herein are intended to include those compounds
`of this type which in the pure or highly concentrated
`state and at ambient temperature, e.g., l5°—40° C., are
`?owable liquids. The expressions “solid polyhydroxy
`compound" and “solid polyhydroxy compound deriva
`tive” as employed herein are intended to include those
`compounds of this type which in the pure orconcen
`trated state and at ambient temperature are normally
`solid or semi-solid but are soluble in a suitable solvent,
`e.g., water, physiological saline, ethanol, glycerol, glu
`cose, propylene glycol, polyethylene glycol of from
`200-1000 molecular weight, etc., or mixtures thereof, to
`provide a liquid composition.
`Useful polyhydroxy swelling agents possess from 2 to
`about 18 carbons and include such classes of com
`pounds as the acyclic polyhydric alcohols, non-reduc
`ing sugars, sugar alcohols, sugar acids, monosaccha
`rides, disaccharides, water-soluble or water dispersible .
`-oligosaccharides, polysaccharides and known deriva
`tives of the foregoing. Speci?c polyhydroxy com
`pounds include ethylene glycol, diethylene glycol, tri
`ethylene glycol, 1,2-propanediol, trimethylolethane,
`trimethylopropane, erythritol, pentaerythritol, polyal
`kylene glycols such as the polyethylene glycols, xylitol,
`sorbitol, mannitol, dulcitol, arabinose, xylose, ribose,
`adonitol, arabitol, rhamose, inositol, fructose, galactose,
`glucose, mannose, sorbose, sucrose, maltose, lactose,
`maltitol, lactitol, stachyose, maltopentaose, cyclomal
`tohexaose, carrageenan, agar, alginic acid, guar gum,
`gum tragacanth, locust bean gum, gum arabic, xanthan
`gum, amylose, mixtures of any of the foregoing, and the
`like.
`Derivatives of the foregoing polyhydroxy com
`pounds, in particular, ester derivatives thereof, are also
`useful as swelling agents. 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 mo
`lecular weight, etc. Liquid glycerol esters include mo
`nacetin and diacetin and solid glycerol esters include
`such fatty acid monoesters of glycerol as glycerol
`monolaurate which is preferred, glyceryl monopalmi
`tate, glyceryl monostearate, etc. An especially pre
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`6 of 10
`
`

`
`20
`
`5,298,254
`5
`6
`ferred carrier herein comprises glyceryl monolaurate
`_ cin, polymyxin B, neomycin, sodium cefazolin and gen
`tamicin sulfate, with gentamicin sulfate being especially
`dissolved in glycerol or a 4:1 to 1:4 mixture of glycerol
`preferred.
`and propylene glycol.
`Of the foregoing polyhydroxy compounds, glycerol
`The disinfecting solution can be applied to the bone in
`any number of ways, e.g., by spraying, by brushing, by
`and its liquid monoesters and diesters, e.g., monacetin
`dipping the bone into the solution, etc. As noted supra,
`and diacetin, fructose, glucose and sucrose, and mix
`the disinfecting solution and preserved, swollen bone
`tures thereof are preferred. Where the polyhydroxy
`can be constituted together in the form of a kit such as
`compound is a solid, e.g., sucrose, a solvent such as
`water, glycerol, polyethylene glycol of from 200-1000
`shown in U.S. Pat. No. 4,994,030 the contents of which
`are incorporated by reference herein. In this regard, the
`average molecular weight, or mixture thereof is used to
`bone is stored in one vessel along with the swelling
`preferably provide a ?owable solution or paste of the
`compound.
`medium which is drained out of the vessel, e. g., through
`As previously indicated, the bone composition of this
`a double—ended needle puncturing the vessel. Then, the
`disinfecting/plasticizing medium contained in another
`invention can be freshly demineralized just prior to
`swelling by mixing the demineralized bone, swelling
`vial, is introduced into the vessel containing the pre—
`served, swollen bone, e.g., by way of a double-ended
`agent and optional component(s) in any suitable se
`needle illustrated in FIG. 7 of U.S. Pat. No. 4,994,030.
`quence of separate mixing operations or all at once.
`Thus, the optional ingredient(s) can ?rst be applied to
`U.S. Pat. No. 4,994,030 also discloses suitable disinfect
`ing medium for the bone.
`the bone and thereafter the bone can be combined with
`After the demineralized bone has been stored in the
`the swelling agent, the bone can be mixed with the
`swelling agent followed by addition of the optional
`swelling agent for some time, the swollen bone becomes
`fairly rigid because the swelling medium, i.e., liquid
`ingredient(s) or the optional ingredients can be added to
`polyhydroxy compound, is extremely hydrophilic and
`the swelling agent followed by inclusion of the demin
`hypertonic and absorbs water out from the demineral
`eralized bone. Variations of these sequences of mixing
`ized bone. While the water absorption serves to swell
`operations are, of course, possible.
`the demineralized bone collagen matrix upon storage
`The amount of bone which can be incorporated into
`the swelling agent of this invention can vary widely
`over a period of time, it also renders the swollen bone
`fairly rigid. However, upon contact with the aqueous
`with the amounts of from about 5 to about 90 weight
`disinfecting solution, water is restored into the deminer—
`percent, and preferably from about 20 to about 80
`alized bone tissue which increases the plasticity of the
`weight percent, being entirely- suitable in most cases, the
`balance of the composition being made up of swelling
`same (i.e., the ?exibility or resilient nature thereof).
`Therefore, the ?exibility of the demineralized bone
`agent. Furthermore, the optional ingredient(s) can be
`existing right after demineralization is restored, while at
`added to the bone after the bone has been removed from
`the swelling agent, i.e., just prior to implantation into a
`the same time the bone has been suitably swollen for a
`length of time and is now in condition for being pressed
`bone defect site. For example, the swollen bone can also
`and/or shaped e.g., into a surgical implant site.
`be dipped in a solution containing these optional ingre
`dients after removal from the swelling agent.
`The bone of the present invention can be machined,
`cut, extruded, and/or otherwise formed into any de
`To facilitate on-site preparation of the bone for im
`sired shape or dimension for implantation into a body.
`plantation into a bone defect site, the bone in the swell
`ing agent and a plasticizing and/ or disinfecting solution
`For example, the bone can be sliced into a very thin
`(the latter containing any of the optional ingredients
`sheet, cut into the shape of a disc, ring, cube, cylinder
`etc., or sliced and wrapped into a tubular shape. While
`identi?ed above) can be stored in separate packages or
`such shaping can be carried out before the bone is pre
`containers under sterile conditions as part of a kit, with
`the bone removed from the swelling agent and brought
`served and swelled, the bone can first be preserved and -
`together with the disinfecting solution in intimate ad
`swelled and then appropriately cut, shaped, or even
`extruded after removal from the swelling agent and
`mixture at the moment of use for immediate application
`before implantation into a body.
`to a bone defect site employing any suitable means, e.g.,
`More speci?cally, several examples of suitable forms
`a syringe, spatula, etc. Alternatively, the demineralized
`of the demineralized bone for implantation into a body
`bone can be prepared well in advance and stored in the
`swelling agent under sterile conditions until required
`are shown in FIGS. 1-18. FIG. 1 illustrates the demin
`eralized bone having been sliced and wrapped into a
`for use, when the bone can be removed from the swell
`ing agent and then dipped into a separately-provided
`substantially tubular shape to form a sleeve or stabilizer
`disinfecting solution.
`1 for a screw 2. The screw 2 is inserted into the sleeve
`or stabilizer 1 and then introduced into an orifice within
`More speci?cally, as noted supra, the demineralized
`bone to affix a plate or other osteoprosthetic implant to
`bone, after removal from the swelling agent and prior to
`the bone. This immediately improves the screw’s hold
`implantation into a body such as into a bone defect site,
`ing power. Then, over time, the screw becomes calci
`is preferably contacted with an aqueous composition,
`?ed within the bone. FIG. 2 illustrates the demineral
`e.g., a plasticizing and disinfecting solution to ensure
`ized bone having been cut into a substantially cylindri
`total removal of vegetative organisms of the bone upon
`cal shape to form a plug 3 to fill defects within bone.
`implantation in a body. The disinfecting solution itself is
`For example, the plug 3 can be used to fill a hole 5 left
`preferably aqueous and can include any of the optional
`ingredients enumerated supra. A preferred composition
`in bone 4 by removal of a screw such as screw 2 of FIG.
`1. The plug 3 is introduced into the hole 5 by way of
`of the disinfecting solution is an aqueous solution in
`forceps 6 as illustrated in FIG. 2.
`cluding from about 250 to about 1000 mg/ml, and most
`FIG. 3 illustrates the demineralized bone having been
`preferably from about 500 to about 600 mg/ml disinfec
`cut into four substantially thin parallelepipeds which
`tant. The disinfectant includes antibiotics and other
`are wafer-like and are termed pledgets 7. These pledgets
`bactericides and/or bacteriostats. More particularly,
`7 can be substantially rectangular. FIG. 4 illustrates the
`the disinfectant is selected from at least one of bacitra
`
`50
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`
`60
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`65
`
`25
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`30
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`35
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`40
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`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`7 of 10
`
`

`
`5,298,254
`8
`7
`500 ml of 0.6N HCl was added to a piece of the corti
`demineralized bone having been cut into several
`wedges 8. Both pledgets 7 and wedges 8 can be used as
`cal bone remaining in the iliac crest and was stirred.
`invertebral support blocks. For example, FIGS. 5 and 6
`This HCl solution was replaced with another 500 ml of
`0.6N HC] solution after about 1} hours, with stirring for
`illustrate one of the wedges 8 being inserted between
`adjacent vertebrae 9 and 10 in a spinal column 11 in
`approximately 14 hours. The ileum bone structure ap'
`place of an invertebral disk that has been removed.
`peared to collapse. The second 0.6N HCl solution was
`More speci?cally, FIG. 6 illustrates insertion of the
`discarded and the remaining cortical bone was washed
`wedge 8 in the direction of arrow A by forceps 12.
`three times with 500 ml of water for injection (WFI).
`Wedges 22, which are cross-sections of ?bula, are illus
`500 ml of 0.1M phosphate buffer with 0.01% sodium
`trated in FIG. 15 which have been prepared from cor
`azide was added to the cortical ileum bone with stirring
`ticocancellous bone, with the cancellous centers having
`for i hour. The ileum bone was then removed from the
`been removed to leave openings 23 and with just the
`phosphate buffer and dried until no more liquid could
`outer cortical bone remaining.
`be removed from the ileum bone. The ileum bone was
`FIG. 7 illustrates the demineralized bone having been
`?exible, i.e., felt soft to the touch. This cortical ileum
`sliced into a thin ?exible tape 13 which can be tightly
`bone was weighed, with 2.62 g thereof being placed into
`wrapped around a fracture in a femur bone 27 as illus
`a wide mouth plastic container. 60.43 g of 95% glycerol
`trated in FIG. 10. FIG. 8 illustrates the demineralized
`was then added to the container with continuous stir
`bone having been cut and/or extruded or otherwise
`ring to ensure that the cortical ileum bone remained
`shaped into a piece of ?exible rope 15 which can be used
`immersed in the glycerol.
`for securing bone fractures in extremely mobile or hard
`to-reach bones, such as the metacarpus bone 16 of the
`thumb as illustrated in FIG. 11. FIG. 9 illustrates the
`demineralized bone having been sliced into a thin sheet
`17 which can be used to patch an injury to the ilium 18
`as illustrated in FIG. 12.
`FIG. 13 illustrates the demineralized bone having
`been sliced or shaped into the form of a ?exible ?bro
`blast liner 19 which can be used to prevent ingrowth of
`fibroblasts in an area from which bone has been excised.
`More particularly, when a diseased or injured tooth
`including the adjacent maxilla and/or mandible has
`been removed from the jaw 20 as illustrated in FIG. 14,
`it is necessary to block ingrowth of fibroblasts into the
`gap left by the removed tooth, at least until new bone
`growth permits a replacement denture to be anchored
`or otherwise fit into the gap. In order to prevent the
`ingrowth of fibroblasts which immediately begin to
`occur upon removal of the natural tooth, the liner 19 is
`introduced into the gap in the jaw 20 in the direction of
`arrow B and by way of forceps 21.
`A bone clip 24 can be fashioned and used to secure a
`bone fracture 25 as illustrated in FIGS. 16-18 respec
`tively. More particularly, the clip 24, which is substan
`tially in the shape of a U, is inserted over the location of
`the fracture 25 of a femur bone 26 as illustrated in FIG.
`45
`17, with the ends of the clip then being tied together,
`e.g., with a suture 28, as illustrated in FIG. 18, thus
`securing the fracture.
`Thus, the demineralized, swollen and plasticized
`bone of this invention can be applied to the bone defect
`in a variety of ways. Among the bone repair applica
`tions for which the use of the treated bone in accor
`dance with the present invention is eminently suited are:
`standard or custom arthroplasty prosthesis; reconstruc
`tion of skeletal or other osseous defects; enhancing or
`augmenting the effectiveness of internal and external
`?xation devices, bone plates, etc., as a replacement of
`corticocancellous strips, and so forth.
`The following examples are illustrative of the prepa
`ration of the swollen, demineralized and plasticized
`bone composition of the present invention.
`
`EXAMPLE 2
`After being stored with the glycerol in the container
`of Example 1 for one day, the swollen cortical iliac bone
`was removed and was found to be quite rigid. Next, this
`bone was dipped in an aqueous disinfecting solution
`comprising 500 mg/ml gentamicin sulfate for 15 min
`utes. It was found that the ?exibility returned to the
`demineralized bone, so that the bone can then be cut or
`sliced into any con?guration such as shown in FIGS.
`1—4, 7-9, 13, 15 and 17 which is suitable for implantation
`into bone defect sites.
`
`EXAMPLE 3
`The steps of the Examples 1 and 2 are repeated but
`with the bone being cut, sliced or shaped into various
`con?gurations just after demineralization and then im
`mersed into the glycerol swelling agent and stored in
`the same.
`What is claimed is:
`1. A shaped piece of swollen demineralized bone
`having substantially regular geometry and/or greater
`than 12 mm. in size along at least one dimension thereof,
`the bone being combined with a biocompatible swelling
`agent,
`wherein the swelling agent is selected from the group
`consisting of ethylene glycol, diethylene glycol,
`triethylene glycol, 1,2-propanediol, trimethyloleth
`ane, trimethylopropane, erythritol, pentaerythritol,
`polyethylene glycols, xylitol, sorbitol, mannitol,
`dulcitol, arabinose, xylose, ribose, adonitol, arabi
`tol, rhamose, inositol, fructose, galactose, glucose,
`mannose, sorbose, sucrose, maltose, lactose, mal
`titol, lactitol, stachyose, maltopentaose, cyclomal
`tohexaose, carrageenan, agar, alginic acid, guar
`gum, gum tragacanth, locust bean gum, gum ara
`bic, xanthan gum, amylose and mixtures thereof.
`2. A shaped piece of a swollen demineralized bone
`having substantially regular geometry and/or greater
`than 12 mm. in size along at least one dimension thereof,
`the bone being combined with a biocompatible swelling
`agent,
`wherein the swelling agent is selected from a member
`of the group consisting of liquid polyhydroxy com
`pound, liquid polyhydroxy compound ester, liquid
`solution of solid polyhydroxy compound, liquid
`solution of solid polyhydroxy compound ester and
`mixtures thereof, and
`
`20
`
`25
`
`55
`
`60
`
`EXAMPLE I
`Cancellous bone in an iliac crest of a human donor
`was drilled out, leaving behind cortical bone from the
`iliac crest. This cortical bone from the iliac crest was
`demineralized in 0.6N HCl overnight in the following
`
`manner.
`
`_
`
`DePuy Synthes Sales, Inc. & Depuy Synthes Products, Inc.
`Exhibit 1006
`8 of 10
`
`

`
`20
`
`25
`
`5,298,254
`10
`nosuppressant, nucleic acid, surface active agent, hy
`the potlyhydroxy compound is selected from the
`droxyapatite and penetration enhancer.
`group consisting of acyclic polyhydric alcohols,
`19. The bone of claim 1 which is additionally plasti
`non-reducing sugars, sugar alcohols, sugar acids,
`cized before being applied to a bone defect site.
`monosaccharides, disaccharides, water-soluble or
`water dispersible oligosaccharides, polysaccha
`20. The bone of claim 19 wherein said demineralized
`osteogenic bone is plasticized with an aqueous composi
`rides, polyalkylene glycols and mixtures thereof.
`3. The bone of claim 2 wherein the swelling agent is
`tion.
`selected from the group consisting of glycerol, glycerol
`21. The bone of claim 20 wherein said aqueous com
`position additionally includes at least one disinfectant
`monoester and glycerol diester.
`selected from the group consisting of gentamicin sul
`4. The bone of claim 2 wherein the swelling agent is
`fate, bacitracin, polymyxin B, neomycin and sodium
`selected from the group consisting of monosaccharide,