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WO2010050935A1 - Dispositifs contenant des particules de matrice osseuse déminéralisée - Google Patents

Dispositifs contenant des particules de matrice osseuse déminéralisée Download PDF

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Publication number
WO2010050935A1
WO2010050935A1 PCT/US2008/081544 US2008081544W WO2010050935A1 WO 2010050935 A1 WO2010050935 A1 WO 2010050935A1 US 2008081544 W US2008081544 W US 2008081544W WO 2010050935 A1 WO2010050935 A1 WO 2010050935A1
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WO
WIPO (PCT)
Prior art keywords
bone
dbm
demineralized bone
particles
polysaccharide
Prior art date
Application number
PCT/US2008/081544
Other languages
English (en)
Inventor
Susan J. Drapeau
Kathy L. Remsen
William F. Mckay
Daniel Shimko
Original Assignee
Warsaw Orthopedic, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warsaw Orthopedic, Inc. filed Critical Warsaw Orthopedic, Inc.
Priority to PCT/US2008/081544 priority Critical patent/WO2010050935A1/fr
Publication of WO2010050935A1 publication Critical patent/WO2010050935A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • A61L27/365—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates generally to medical implants.
  • the present invention relates to osteoinductive medical devices containing demineralized bone matrix.
  • a wide variety of implant formulations have been suggested in the art for the treatment of bone defects.
  • a number of synthetic bone graft substitutes have been used or explored, including some materials that contain demineralized bone matrix.
  • Demineralized bone matrix has been shown to exhibit the ability to induce and/or conduct the formation of bone. It is thus desirable to implant and maintain demineralized bone matrix at a site at which bone growth is desired.
  • demineralized bone matrix is susceptible to disruption by the incorporation of incompatible materials or techniques when formulating the medical implant material.
  • implant devices exhibiting good physical integrity to retain the demineralized bone matrix at the implant site, and that handle well in the operating environment and during implantation.
  • the formulation be manufacturable without undue cost, equipment or material burdens.
  • the present invention provides a demineralized bone matrix (DBM) device comprising a dried, flexible aggregate of bone-derived particles retained in a unitary body by an ionically-crosslinked polysaccharide gel, with the bone-derived particles including DBM particles alone or in combination with demineralized bone chips.
  • the bone-derived particles may constitute at least 90% by weight of the body on a dry weight basis, and the polysaccharide may constitute no more than 10% by weight of the body on a dry weight basis.
  • the present invention provides a method for preparing a DBM device.
  • the method comprises providing wetted bone-derived particles, wherein the particles have pores occupied by a wetting liquid.
  • the wetted bone-derived particles are blended into a gellable liquid medium comprising an ionically-crosslinkable polysaccharide under conditions wherein the gellable liquid medium does not displace the wetting liquid from the pores.
  • the polysaccharide is ionically crosslinked to form a unitary body comprising an ionically-crosslinked polysaccharide gel and the bone-derived particles.
  • the unitary body is dried to form a dried material in which bone-derived particles have pores free from the ionically-crosslinked polysaccharide gel.
  • the present invention provides a DBM device comprising a dried, flexible unitary body comprising an ionically-crosslinked polysaccharide gel and bone-derived particles having pores free from the ionically-crosslinked polysaccharide gel.
  • the present invention provides a sheet-form DBM device that may provide a persistent collagen scaffold in use.
  • the device may comprise a resilient, porous sheet including particulate solids, wherein the particulate solids contain a particulate collagen material and a bone-derived particle, e.g., DBM particles and demineralized bone chips.
  • Particles of the particulate collagen material may be individually chemically or otherwise crosslinked, and the solids are retained in the resilient, porous sheet form by an ionically-crosslinked polysaccharide gel.
  • the DBM material retained in the resilient, porous sheet may exhibit osteoinductivity.
  • the invention provides a DBM device that includes a three- dimensionally stable, porous implant structure which comprises particulate solids.
  • the particulate solids may include a particulate collagen material and a particulate DBM material in a weight ratio of 1:12 to about 1:2, respectively.
  • the particulate solids are retained in the porous implant structure form by an ionically-crosslinked polysaccharide gel.
  • the bone-derived particles retained in the porous implant structure may exhibit osteoinductivity.
  • the invention provides a DBM device that includes a three- dimensionally stable, porous implant structure.
  • the three-dimensionally stable, porous implant structure comprises particulate solids which include a fragmented bioresorbable sponge material and a particulate DBM material.
  • the fragmented bioresorbable sponge material may comprise a sponge material that has been rendered to particulate form, such as a randomly fragmented (e.g., milled) sponge material.
  • the particulate solids are retained in the porous implant structure form by an ionically-crosslinked polysaccharide gel.
  • the DBM material retained in the porous implant structure may exhibit osteoinductivity.
  • the invention provides a method for preparing a DBM implant material.
  • the method includes preparing an admixture including DBM particles in a liquid medium containing a polysaccharide susceptible to ionic crosslinking, optionally the method may also include admixing individually chemically or otherwise crosslinked collagen particles.
  • the admixture is contacted with a liquid medium containing a multivalent ionic agent effective to ionically crosslink the polysaccharide so as to form an ionically-crosslinked gel incorporating the DBM and, optionally, the collagen particles.
  • the method may include the steps of freezing the ionically-crosslinked gel to form a frozen precursor material, and drying the frozen precursor material.
  • the invention provides a method for preparing a DBM implant material.
  • the method includes providing an admixture including collagen particles and DBM particles in a liquid medium containing a polysaccharide susceptible to ionic crosslinking, with the collagen particles and DBM particles present in a weight ratio of about 1:12 to about 1:2.
  • the admixture is contacted with a liquid medium containing a multivalent ionic agent effective to ionically crosslink the polysaccharide, so as to form an ionically-crosslinked gel incorporating the DBM particles and collagen particles.
  • the method may include the further steps of freezing the ionically-crosslinked gel to form a frozen precursor material, and drying the frozen precursor material.
  • the invention provides a method for preparing a DBM implant material.
  • the method includes providing an admixture including a particulated bioresorbable sponge material and osteoinductive DBM particles in a liquid medium containing a polysaccharide susceptible to ionic crosslinking.
  • the admixture is contacted with a liquid medium containing a multivalent ionic species effective to ionically crosslink the polysaccharide, so as to form an ionically-crosslinked gel incorporating the particulated bioresorbable sponge material and DBM particles.
  • the method may include the additional steps of freezing the ionically-crosslinked gel to form a frozen precursor material, and drying the frozen precursor material.
  • the invention provides a bioactive demineralized bone matrix (DBM) implant device comprising a dried, porous implant body including osteoinductive DBM particles held in intimate contact with one another by an ionically- crosslinked polysaccharide matrix.
  • DBM demineralized bone matrix
  • the invention provides methods of treating patients comprising implanting in the patients DBM devices as described herein, and the manufacture of a bone graft substitute and/or bone void filler for the treatment of voids or gaps in bone.
  • Bone voids or gaps can be surgically created defects or bony defects resulting from traumatic injury and/or cancer.
  • compositions of the invention provide excellent handling characteristics, osteoinductivity, validated viral inactivation and/or device-level sterility.
  • compositions of the invention are prepared and packaged in a sterile condition.
  • FIG. 1 provides a perspective view of a DBM-containing medical device of the invention.
  • the present invention relates to implantable medical devices, and to methods for making and using the devices.
  • the present invention provides osteoinductive medical devices that include a three-dimensionally stable structure incorporating particulate solids.
  • the solids include bone-derived particles that in particular embodiments are osteoinductive when implanted in a mammalian patient, including a human patient.
  • the solids may optionally include a particulate collagen material, such as collagen fibers or a randomly fragmented bioresorbable material such as a collagen sponge.
  • the collagen particles that are incorporated in the device are individually populated with non-native crosslinks, e.g., by chemical, dehydrothermal, radiation or other crosslinking techniques, to increase their persistence as a scaffold at the implant site after implantation.
  • Devices of the invention include an ionically-crosslinked polysaccharide matrix which advantageously facilitates holding the solids in a defined form or shape.
  • the inventive devices desirably retain the DBM in its bioactive, osteoinductive condition, while also providing beneficial properties during handling and implantation.
  • the incorporated solids or bone-derived particles of the disclosed devices include demineralized bone matrix particles (DBM particles) and demineralized bone chips.
  • DBM particles refers to a matrix material prepared by demineralizing any bone source, including cortical and/or cancellous bone. More desirable demineralized bone matrix materials will contain less than about 5% by weight of residual calcium, less than about 4% by weight residual calcium, less than about 3% by weight residual calcium, less than about 2% by weight residual calcium, less than about 1% by weight residual calcium, less than about 0.5% by weight residual calcium, less than about 0.25% by weight residual calcium, less than about 0.1% by weight residual calcium, or less than about 0.05% by weight residual calcium.
  • the source bone may be from any suitable source including autogenic, allogeneic, and/or xenogenic bone.
  • DBM demineralized bone matrix
  • osteoinductive refers to the ability of the material to induce bone growth.
  • DBM or bone-derived particles may be provided lacking osteoinductive character, and nonetheless be used as osteoconductive materials that provide a scaffold capable of receiving bone growth induced by natural healing processes or other materials implanted in the patient.
  • DBM materials for use in the present invention may be obtained commercially or may be prepared by known techniques.
  • osteoinductive DBM materials may be prepared by decalcification of cortical and/or cancellous bone, which is often done by way of an acid extraction technique. This process may be conducted so as to retain collagen, noncollagenous proteins, and growth factors in the solid matrix. Methods for preparing such bioactive demineralized bone matrix are well known, for example, see U.S. Patent Nos. 5,073,373; 5,484,601; and 5,284,655.
  • DBM products are also available commercially, including for instance, from sources such as Regeneration Technologies, Inc. (Alachua, FL), The American Red Cross (Arlington, VA), and others.
  • the particulate DBM material may have an average particle size of less than about 1,000 ⁇ m.
  • the DBM material may have particle sizes in the range of 50 to 850 ⁇ m.
  • DBM materials that are solely osteoinductive may be prepared using similar techniques that have been modified or supplemented to remove or inactivate (e.g. by crosslinking or otherwise denaturing) components in the bone matrix responsible for osteoinductivity.
  • Osteoinductive and/or osteoconductive DBM materials used in the present invention may desirably be derived from human donor tissue, especially in regard to implant devices intended for use in human subjects.
  • the sponge material of the invention may be made completely or in part from a bioresorbable material other than collagen.
  • the device is produced without the addition of collagen.
  • the particulated sponge material may be made from any of the other natural or synthetic polymers disclosed herein.
  • another binder material or technique may be used instead of the ionically-crosslinked polysaccharide matrix, including for example other gel-forming substances which may, for example, be thermally reversible gel forming agents such as gelatin.
  • the particulated sponge material may be used in the same relative amounts disclosed herein for the optional collagen materials.
  • a sponge starting material has been chemically crosslinked with an aldehyde crosslinker such as formaldehyde or glutaraldehyde, or another suitable chemical crosslinker such as a carbodiimide, or by other techniques such as dehydrothermal or radiation-induced crosslinking
  • an aldehyde crosslinker such as formaldehyde or glutaraldehyde
  • another suitable chemical crosslinker such as a carbodiimide
  • the particulated collagen or other bioresorbable material retains the chemical crosslinking and provides an advantageous, lasting scaffold for bone ingrowth.
  • These crosslinked particulate materials may be provided as starting materials for preparing devices as disclosed herein, and therefore as incorporated in the device these particles are individually crosslinked.
  • the term "individually crosslinked” means that the particles include non-native crosslinks other than those which might be introduced by any crosslinking technique used to hold the solids of the device together as a unitary structure, e.g. by introducing crosslinks between respective particles after they have been cast or otherwise formed into the shape of the device.
  • the bioresorbable solids include an optional particulate solid collagen material and the DBM material at a collagen material:DBM material weight ratio (dry basis) of about 1:12 to about 1:2, or about 1:12 to about 1:5, or about 1:10 to about 1:5, or about 1:8 to about 1:5.
  • the particulate DBM material may constitute about 20% to about 90% of a device in some embodiments, more preferably about 50% to about 90%, and most preferably about 70% to about 85% by weight.
  • inventive devices of the invention are comprised of dried, flexible aggregate bodies containing a major amount by weight of bone-derived particles that include DBM particles alone or in combination with demineralized bone particles, and a minor amount by weight of an ionically-crosslinked polysaccharide, especially alginate.
  • Dried DBM-containing devices of the invention may comprise at least about 70%, by weight, particulate bone-derived material(s), and/or at least 90%, by weight, particulate bone-derived material(s).
  • the bone-derived particles may include DBM only in certain embodiments, and a combination of DBM and larger demineralized bone particles in other embodiments.
  • the device may comprise no more than about 30% by weight of a polysaccharide, and in other embodiments, no more than about 10% by weight of the polysaccharide.
  • Devices of such embodiments are desirably free from any particulate collagen material as disclosed herein, or at least free from any particulate collagen material derived from a tissue source other than bone, and may, in certain embodiments, have a dried, flexible matrix that consists or consists essentially of DBM and polysaccharide components, or DBM, demineralized bone chips and polysaccharide components.
  • the invention provides devices that may have relatively high levels of DBM and very low levels of polysaccharide, where these devices are highly bioactive, posses good integrity during handling and implant, and provide ready cellular access to concentrated volumes of the bioactive DBM (and optionally the demineralized bone particles) upon implant.
  • such devices may have a bulk density in the range of about 0.2 g/cc to about 0.6 g/cc, more preferably in the range of about 0.3 g/cc to about 0.6 g/cc.
  • the dried devices of the invention may be rehydrated prior to use in a mammal.
  • the device may be rehydrated with bone marrow aspirate, other bone derived liquids, blood cells, blood product, a liquid preparation containing stem cells or any other desirable fluid.
  • the bone-derived particles of the device include both DBM particles and demineralized bone (MB) particles
  • the DBM particles and MB particles may be used in a dry weight ratio of about 1:4 to 4:1, more preferably about 1:2 to 2:1.
  • the MB particles may be obtained from human or animal donors, and may suitably be bone chips having a maximum particle dimension of about 1 to about 5 mm, or about 2 to about 4 mm.
  • relatively large demineralized bone particles such as demineralized bone chips having a maximum particle dimension of about 1 to about 5 mm, or about 2 to about 4 mm, may be used instead of or in addition to the demineralized bone chips or other particles.
  • the particulate collagen and DBM materials may at least largely make up the weight of the device on a dry weight basis, for example, these two materials may constitute at least about 50%, at least about 70%, or at least about 80% by weight of the overall device on a dry weight basis.
  • the water- insoluble solids in the composition may consist or consist essentially of DBM particles.
  • all of the water- insoluble solids in the composition will be bioresorbable. It will be understood, however, that these parameters are not necessary to all aspects of the invention.
  • medical devices which comprise one or more polysaccharides used to form an ionically-crosslinked gel or matrix which participates in providing three-dimensional stability to the devices.
  • Preferred are ionic polysaccharides that are capable of forming thermally irreversible ionically-crosslinked gels upon combination with divalent or other polyvalent cationic materials.
  • Suitable polysaccharides include, as examples, plant-derived polysaccharides such as alginates and pectins, and gel-forming derivatives thereof.
  • Aqueous solutions of such ionic polysaccharides form ionically-crosslinked gels upon contact with aqueous solutions of counter-ions.
  • useful agents for ionically crosslinking alginate and pectin polysaccharides include cationic gelling agents, preferably including divalent or trivalent cations.
  • Useful divalent cations for these purposes include the alkaline earth metals, especially calcium and strontium.
  • Aluminum is a useful crosslinking trivalent cation.
  • Useful anionic counter- ions for the calcium or other salts are desirably selected from pharmaceutically-acceptable anions such as chlorides, gluconates, fluorides, citrates, phosphates, tartrates, sulphates, acetates, borates, and the like.
  • An especially preferred ionic crosslinking agent for use with an alginate or pectin compound is provided by calcium chloride.
  • the ionic polysaccharide chitosan may also be used, and may be ionically crosslinked with multivalent, anionic gelling agents.
  • Such agents include metal polyphosphates, such as an alkali metal or ammonium polyphosphate, pyrophosphates or metaphosphates. Citrates may also be used.
  • These anionic crosslinking agents will also usually be provided by salts.
  • the cationic counter-ion for the polyphosphate or other salt may be any suitable, biocompatible or pharmaceutically-acceptable cation including for instance sodium, potassium, or ammonium.
  • Many other biocompatible polysaccharides, including plant- derived and animal-derived materials, as well as corresponding ionic crosslinking agents, are known and may also be used in aspects of the present invention.
  • the polysaccharide will typically be incorporated into devices of the invention at a relatively low level. Accordingly, in certain embodiments, when considered on a dry weight basis, the device may contain a polysaccharide at a level of about 1% to about 20%, about 5% to about 15%, and/or about 8% to about 12%. It will be understood, however, that other amounts of polysaccharide may be used within the broader aspects of the invention. Further, in additional embodiments, the polysaccharide, and especially alginate, will be included at a level of less than about 8% by dry weight, for example about 2% to about 8% by dry weight, or about 3% to about 7% by dry weight.
  • the polysaccharide material when ionically crosslinked, holds the incorporated particulate solids together and contributes by providing integrity to the overall three-dimensional structure of the device.
  • the particulate solids may be bound together to form the device without the use of any chemical crosslinker, such as glutaraldehyde, formaldehyde or a carbodiimide, to covalently link the solid particles to one another.
  • the solid particulates are thus held together in the substantial or complete absence of covalent chemical crosslinks between the particles.
  • covalent chemical crosslinks may be introduced by such chemical crosslinking agents; however, where osteoinductive DBM material is used and preservation of its osteoinductive character is desired, such chemical crosslinking is desirably used at a low, controlled level that does not abrogate such osteoinductive character.
  • Medical grade polysaccharides suitable for use in aspects of the invention may be prepared using known techniques or purchased from commercial sources.
  • purification techniques for preparing medical grade polysaccharides may include conventional separation techniques such as chromatography, membrane filtration, precipitation, extraction, or other suitable techniques.
  • Medical grade sodium alginate may be commercially obtained, for example, from Medipol SA (Lausanne, Switzerland), or from NovaMatrix FMC Biopolymer (Philadelphia, Pennsylvania, Ultrapure PRONOVA brand (endotoxin level ⁇ 100 endotoxin units per gram)).
  • one or more alginate polymers may contain more than 50% alpha-L-guluronic acid, for example, in malleable compositions of the invention. In other embodiments, one or more alginate polymers may contain more than 60% alpha-L- guluronic acid. In yet other embodiments, one or more alginate polymers may contain 60% to 80% alpha-L-guluronic acid.
  • alginate polymers used in the invention may have average molecular weights ranging from 2 to 1000 kilodaltons (kD).
  • the molecular weight of alginates may be utilized to affect the properties of the malleable composition. Generally, lower molecular weight alginates will be more biodegradable.
  • the alginate polymers have an average molecule weight of from 5 to 350 kD. In some embodiments, the alginate polymers have an average molecule weight of from 2 to 100 kD. In some embodiments, the alginate polymers have an average molecule weight of from 50 to 500 kD. In some embodiments, the alginate polymers have an average molecule weight of from 100 to 1000 kD.
  • the molecular weights identified in this paragraph may similarly apply to other polysaccharides when used in the invention.
  • the alginate when used, may possess a viscosity in a 1% solution measured at 20 degrees centigrade of from 25 to 1000 mPas and in some embodiments, 50 to 1000 mPas (1% solution, 20 0 C).
  • the ready-to-use medical product may be a porous, sheet- form product 11.
  • the sheet- form material may be configured as a strip or other parallelepiped three dimensional structure.
  • Sheet-form product 11 includes a first face 12, a second face 13, and sidewalls 14 interconnecting the first and second faces 12 and 13.
  • Sheet-form product may have any suitable length (L), width (W) and thickness (T). In certain embodiments, the length and width will range from about 1 mm to about 200 mm, and the thickness will range from about 0.1 mm to about 10 mm.
  • the length and width will each range from about 1 mm to about 100 mm, and the thickness from about 0.2 mm to about 1 mm.
  • devices may have a unitary body defining a volume of about 0.1 mm 3 to about 40 cm 3 , in the range of about 500 mm 3 to about 10,000 mm 3 , and/or in the range of about 600 mm 3 to about 10,000 mm 3 .
  • Exemplary dimensions include, but are not limited to, approximately 100mm x 20mm x 5mm; approximately 50 mm x 20 mm x 5 mm; approximately 10 mm x 12 mm x 5 mm and/or approximately 8 mm x 25 mm x 5 mm. It will be understood however that other linear and volumetric dimensions may also be employed within the scope of the present invention.
  • the bulk densities of the devices of the invention may vary, depending upon factors such as the extent of their porosity, the densities of the incorporated materials, and the state of the device (e.g., hydrated or dehydrated condition).
  • the device will be in a dried condition (containing less than about 5% by weight of water or other liquid), and will have a bulk density in the range of about 0.1 g/cc to about 0.4 g/cc, more typically in the range of about 0.1 g/cc to about 0.3 g/cc, and in certain embodiments about 0.15 g/cc to about 0.25 g/cc. Nonetheless, as noted above these densities may vary with many factors, and bulk densities within these ranges, or that are lower or higher, may be exhibited by devices within aspects of the invention.
  • Devices of the invention may be substantially porous. Devices of the invention may have a void volume of at least about 40%, about 40% to 90%, especially when in a dried condition. Moderate void volume levels of about 50% to less than 70%, or higher levels in the range of 70% to 90% or more, may be controllably achieved, for instance by varying the amount of water or other liquid included in a slurry used to prepare the devices and/or varying the lyophilization conditions.
  • Devices of the invention may be manufactured by preparing a mixture including the DBM material, the polysaccharide, and, when used, the collagen material (or the particulated bioresorbable sponge material, be it collagenous or otherwise), along with any other liquid or solid materials to be incorporated into the device upon original manufacture.
  • This mixture may then be contacted with a liquid medium (e.g., solution) containing the ionic crosslinking agent so as to form a wetted ionically-crosslinked gel material.
  • This wet gel material may be sterilized and packaged in a wetted state; or, the wet gel material may be dried.
  • Such drying advantageously utilizes lyophilization or other sublimation drying techniques that involve freezing the wet gel material and drying the material while frozen.
  • the non-crosslinked admixture of materials is charged to a liquid-penetrable mold, such as a porous mold, in a desired shape.
  • a liquid-penetrable mold such as a porous mold
  • the filled mold is then immersed in a solution of the ionic crosslinking agent to form the ionically-crosslinked gel in the shape of the mold.
  • the resultant wetted crosslinked gel may then be packaged and sterilized as the final product, or may be dried and potentially additionally processed as described herein to provide the final product.
  • one or more of the solid particulates to be bound in a crosslinked polysaccharide matrix may first be impregnated with a wetting liquid prior to admixture with the polysaccharide-containing medium.
  • the impregnating liquid may for example be an aqueous medium, such as water or phosphate buffered saline, and may occupy pores located in the internal volume of the particles.
  • the resulting admixture of the wetted particulate and the polysaccharide medium may then be processed under conditions wherein the impregnating liquid substantially remains within the pores of the particles, thus preventing or reducing the level of polysaccharide medium infiltrating into the pores.
  • the internal pores of the DBM or other particulate will remain free or substantially free from the polysaccharide. In this manner, the pores will be more readily accessible to cells upon implant of the material in a patient.
  • the devices of the invention may be implanted in a patient in a dried or wetted condition.
  • any medically acceptable wetting agent may be used. These include, for example, aqueous substances such as sterile water, physiological saline, phosphate buffered saline, blood, bone marrow, bone marrow fractions or other liquid mediums, emulsions or suspensions that provide adequate wetting characteristics.
  • Biocompatible organic liquids may also be used, alone or in combination with water. A wide variety of biocompatible organic liquids are known and suitable for these purposes, including for instance liquid polyols such as glycerol.
  • molecules of the wetting agent e.g.
  • Devices of the invention may also contain other beneficial substances including for example preservatives, cosolvents, suspending agents, buffering agents (e.g. carrying active agents to be added to the device) viscosity enhancing agents, ionic strength and osmolality adjusters and/or other excipients.
  • beneficial substances including for example preservatives, cosolvents, suspending agents, buffering agents (e.g. carrying active agents to be added to the device) viscosity enhancing agents, ionic strength and osmolality adjusters and/or other excipients.
  • Devices of the invention may also include other biocompatible and/or bioresorbable substances. These materials may include, for example, natural polymers such as proteins and polypeptides, glycosaminoglycans, proteoglycans, elastin, hyaluronic acid, dermatan sulfate, or mixtures or composites thereof. Synthetic polymers may also be incorporated into the devices of the invention.
  • biodegradable synthetic polymers such as polylactic acid, polyglycolide, polylactic polyglycolic acid copolymers (“PLGA”), polycaprolactone (“PCL”), poly(dioxanone), poly(trimethylene carbonate) copolymers, polyglyconate, poly ⁇ ropylene fumarate), poly(ethylene terephthalate), poly(butylene terephthalate), polyethyleneglycol, polycaprolactone copolymers, polyhydroxybutyrate, polyhydroxyvalerate, tyrosine-derived polycarbonates and any random or (multi-)block copolymers, such as bipolymer, terpolymer, quaterpolymer, etc., that may be polymerized from the monomers related to previously- listed homo- and copolymers.
  • biodegradable synthetic polymers such as polylactic acid, polyglycolide, polylactic polyglycolic acid copolymers (“PLGA”), polycaprolactone (“PCL”), poly(dio
  • the devices of the invention may also include a mineral component.
  • the mineral used may include a natural or synthetic mineral that is effective to provide a scaffold for bone ingrowth.
  • the mineral matrix may be selected from one or more materials consisting of bone particles, Bioglass®, tricalcium phosphate, biphasic calcium phosphate, hydroxyapatite, corraline hydroxyapatite, and biocompatible ceramics.
  • Biphasic calcium phosphate is a particularly desirable synthetic ceramic for use in the invention.
  • Such biphasic calcium phosphate may have a tricalcium phosphate:hydroxyapatite weight ratio of about 50:50 to about 95:5, about 70:30 to about 95:5, about 80:20 to about 90:10, and/or about 85:15.
  • the mineral material may be a granular particulate having an average particle diameter between about 0.2 and 5.0 mm, more typically between about 0.4 and 3.0 mm, and desirably between about 0.4 and 2.0 mm.
  • the demineralized bone particles may be obtained from cancellous and/or cortical bone that is ground to provide an average particle diameter among as described herein.
  • Both human and non-human sources of bone are suitable for use in the instant invention, and the bone may be autograft, allograft or xenograft in nature relative to the mammal to receive the implant. Appropriate pre- treatments known in the art may be used to minimize the risks of disease transmission and/or immunogenic reaction when using bone particles as or in the mineral material.
  • xenogenic bone that has been pretreated to reduce or remove its immunogenicity is used to provide a porous mineral matrix in the implant device.
  • the bone may be calcined or deproteinized to reduce the risks of immunogenic reactions to the implant material.
  • Bioactive agents may be delivered with devices of the invention. These bioactive agents may include, for example, antimicrobials, antibiotics, antimyobacterial, antifungals, antivirals, antineoplastic agents, antitumor agents, agents affecting the immune response, blood calcium regulators, agents useful in glucose regulation, anticoagulants, antithrombotics, antihyperlipidemic agents, cardiac drugs, thyromimetic and antithyroid drugs, adrenergics, antihypertensive agents, cholnergics, anticholinergics, antispasmodics, antiulcer agents, skeletal and smooth muscle relaxants, prostaglandins, general inhibitors of the allergic response, antihistamines, local anesthetics, analgesics, narcotic antagonists, antitussives, sedative-hypnotic agents, anticonvulsants, antipsychotics, anti-anxiety agents, antidepressant agents, anorexigenics, non-steroidal anti-inflammatory agents, steroidal anti-
  • Bioactive agents may also be provided by tissue materials incorporated into the devices, including for instance autologous or allogenic tissue materials, which are incorporated into the material to be implanted in the patient.
  • tissue materials may include blood or blood fractions, bone marrow or bone marrow fractions, and/or other sources of cells or other beneficial tissue components derived from the patient to be treated or another suitable animal source. These substances can, for example, be added to the device just prior to implantation into the patient.
  • Bioactive agents such as those described herein may be incorporated homogeneously or regionally into the implant devices by simple admixture or otherwise. Further, they may be incorporated alone or in conjunction with another carrier form or medium such as microspheres or another microp articulate formulation. Suitable techniques for forming microparticles are well known in the art, and may be used to entrain or encapsulate bioactive agents, whereafter the microparticles may be incorporated within or upon the inventive device during or after its preparation.
  • a device of the invention will include one or more substances, additional to the osteoinductive DBM material, that induces or generates the formation of bone.
  • Suitable osteogenic materials may include a growth factor that is effective in inducing formation of bone.
  • the growth factor will be from a class of proteins known generally as bone morphogenic proteins (BMPs), and may in certain embodiments be recombinant human (rh) BMPs.
  • BMP proteins which are known to have osteogenic, chondrogenic and other growth and differentiation activities, include rhBMP-2, rhBMP-3, rhBMP4 (also referred to as rhBMP-2B), rhBMP-5, rhBMP-6, rhBMP-7 (rhOP-1), rhBMP-8, rhBMP-9, rhBMP-12, rhBMP-13, rhBMP-15, rhBMP-16, rhBMP-17, rhBMP-18, rhGDF-1, rhGDF-3, rhGDF-5, rhGDF-6, rhGDF-7, rhGDF-8, rhGDF-9, rhGDF-10, rhGDF-11, rhGDF-12, rhGDF-14.
  • BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 disclosed in U.S. Pat. Nos. 5,108,922; 5,013,649; 5,116,738; 5,106,748; 5,187,076; and 5,141,905; BMP-8, disclosed in PCT publication WO91/18098; and BMP-9, disclosed in PCT publication WO93/00432, BMP-10, disclosed in U.S. Pat. No. 5,637,480; BMP-Il, disclosed in U.S. Pat. No. 5,639,638, or BMP-12 or BMP-13, disclosed in U.S. Pat. No. 5,658,882, BMP-15, disclosed U.S. Pat. No.
  • compositions which may also be useful include Vgr-2, and any of the growth and differentiation factors, including those described in PCT applications WO94/15965; WO94/15949; WO95/01801; WO95/01802; WO94/21681; WO94/15966; WO95/10539; WO96/01845; WO96/02559 and others.
  • Also useful in the present invention may be BIP, disclosed in WO94/01557; HP00269, disclosed in JP Publication number: 7-250688; and MP52, disclosed in PCT application WO93/16099.
  • the BMP may be recombinantly produced, or purified from a protein composition.
  • the BMP may be homodimeric, or may be heterodimeric with other BMPs (e.g., a heterodimer composed of one monomer each of BMP-2 and BMP-6) or with other members of the TGF-beta superfamily, such as activins, inhibins and TGF-beta 1 (e.g., a heterodimer composed of one monomer each of a BMP and a related member of the TGF- beta superfamily).
  • BMPs e.g., a heterodimer composed of one monomer each of BMP-2 and BMP-6
  • TGF-beta 1 e.g., a heterodimer composed of one monomer each of a BMP and a related member of the TGF- beta superfamily.
  • Examples of such heterodimeric proteins are described for example in Published PCT Patent Application WO 93/09229, the specification of which is
  • Other therapeutic growth factors or substances may also be used in devices of the present invention, especially those that may be used to stimulate bone formation.
  • proteins are known and include, for example, platelet-derived growth factors, insulin-like growth factors, cartilage-derived morphogenic proteins, growth differentiation factors such as growth differentiation factor 5 (GDF-5), and transforming growth factors, including TGF- ⁇ and TGF- ⁇ .
  • the osteogenic proteins or other biologically active agents when used in the present invention, may be provided in liquid formulations, for example buffered aqueous formulations.
  • liquid formulations may be received upon and/or within, or otherwise combined with a dry- form device by a health care provider just prior to implantation.
  • such liquid formulations may be included within wet materials used to prepare a dry-form or wetted device during its manufacture.
  • rhBMP-2 formulation is available from Medtronic Sofamor Danek, Memphis, TN, with its INFUSE® Bone Graft product.
  • Osteoinductive devices of the present invention may also comprise progenitor and/or stem cells derived from embryonic or adult tissue sources and/or taken from culture.
  • compositions of the invention may incorporate cells derived from blood, bone marrow, or other tissue sources from the patient to be treated (autologous cells) or from a suitable allogenic or xenogenic donor source.
  • the conformable compositions incorporate an enriched bone marrow fraction, prepared for example as described in US Patent Publication No. 2005/0130301 to McKay et al. published June 16, 2005, which is hereby incorporated herein by reference in its entirety.
  • the devices of the invention may incorporate a bone marrow fraction enriched in connective tissue growth components, which may be prepared by centrifuging a biological sample (e.g., from the patient to be treated) to separate the sample into fractions including a fraction rich in connective tissue growth components.
  • the isolated fraction that is rich in connective tissue growth components may then be incorporated into or onto a device of the invention, e.g. by using the fraction in or as a wetting medium applied to the device by a health care provider prior to implantation.
  • an osteoinductive DBM device may be implanted at a site at which tissue growth is desired, e.g., to treat a disease, defect or location of trauma, and/or in some instances to promote artificial arthrodesis.
  • the medical devices of the invention may be used as surgical implants at, in, on, or near bone defect sites, cartilage repair sites, or other musculoskeletal sites.
  • the device will exhibit a conformable or flexible character that enables its introduction and shaping within voids, defects or other areas in which new tissue growth is desired, and/or in certain embodiments in which the delivery of a bioactive agent is desired.
  • the device may have compression-resistant properties sufficient to resist substantial compression when impinged by adjacent soft tissues of the body at a bony implant site, for instance at a posterolateral spinal fusion implant site.
  • Illustrative bone repair sites that may be treated with medical devices of the invention include, for instance, those resulting from injury, defects brought about during the course of surgery, infection, malignancy or developmental malformation.
  • the devices may be used in a wide variety of orthopedic, periodontal, neurosurgical and oral and maxillofacial surgical procedures including, but not limited to: the repair of simple and compound fractures and non-unions; external and internal fixations; joint reconstructions such as arthrodesis; general arthroplasty; cup arthroplasty of the hip; femoral and humeral head replacement; femoral head surface replacement and total joint replacement; repairs of the vertebral column including spinal fusion and internal fixation; tumor surgery, e.g., deficit filing; discectomy; laminectomy; excision of spinal cord tumors; anterior cervical and thoracic operations; repairs of spinal injuries; scoliosis, lordosis and kyphosis treatments; intermaxillary fixation of fractures; mentoplasty; temporomandibular joint
  • Specific bones which may be repaired or replaced with the device include, but are not limited to: the ethmoid; frontal; nasal; occipital; parietal; temporal; mandible; maxilla; zygomatic; cervical vertebra; thoracic vertebra; lumbar vertebra; sacrum; rib; sternum; clavicle; scapula; humerus; radius; ulna; carpal bones; metacarpal bones; phalanges; ilium; ischium; pubis; femur; tibia; fibula; patella; calcaneus; tarsal and metatarsal bones.
  • the osteoinductive DBM device may be used as a bone void filler, or may be incorporated in, on or around a load bearing implants such as spinal implants, hip implants (e.g. in or around implant stems and/or behind acetabular cups), knee implants (e.g. in or around stems).
  • Some embodiments provide an osteoinductive DBM device that may be incorporated in, on or around a load-bearing spinal implant device having a compressive strength of at least about 10000 N, such as a fusion cage, dowel, or other device potentially having a pocket, chamber or other cavity for containing the osteoinductive material of the invention, and used in a spinal fusion such as an interbody fusion.
  • a spinal fusion such as an interbody fusion.
  • One illustrative such use is in conjunction with a load-bearing interbody spinal spacer to achieve interbody fusion. In these applications, the device may be placed in and/or around the spacer to facilitate the fusion.
  • Illustrative cartilage repair sites that may be treated with devices of the invention include, as examples, articular cartilage surfaces occurring in articular joints having at least two major bones. Examples include, but are not limited to the elbow, wrist, phalanx, knee, and ankle. Additionally, cartilage surfaces within shoulder and hip joints may be treated.
  • the present invention also provides medical kits or other products that include one or more osteoinductive DBM devices of the invention.
  • Such products may include the device(s) of the invention in a dried (e.g. having less than about 5% residual water) or wet format, received in sterile condition in medical packaging.
  • Such products may also include one or more additional surgical instruments or implants, for example a load- bearing implant (e.g. a spinal spacer), and/or a fluid transfer device such as a syringe, and/or a therapeutic substance, for example an osteogenic substance such as a BMP.
  • a medical kit may include a dried device of the invention, a BMP in lyophilized form (e.g. rhBMP-2), and an aqueous medium for reconstitution of the BMP to prepare an aqueous formulation that may then be added to the dried device.
  • a DBM strip device comprising 8.3% by dry weight of sodium alginate and 91.7% by dry weight of DBM material was prepared as follows.
  • Example mold dimensions may be sized to produce a product that is approximately 100mm x 20mm x 5mm; approximately 50 mm x 20 mm x 5 mm; approximately 10 mm x 12 mm x 5 mm or approximately 8 mm x 25 mm x 5 mm.
  • the molds were transferred to a freezer and the slurry was allowed to freeze.
  • the frozen slurry was then unmolded and transferred into a continuously agitated pool of 1-10% by weight solution of calcium chloride dihydrate for a period of 1 to 24 hours to ionically crosslink the alginate.
  • the resulting cross-linked blocks of alginate and DBM were then removed from the crosslinking solution, and placed into a pool of water of sufficient volume to extract any residual calcium chloride solution from the cross-linked blocks.
  • the rinsed cross-linked blocks were then lyophilized under conditions that substantially preserved the original volume of the cross-linked blocks.
  • the resulting lyophilized materials were, porous strip devices having a thickness of about 5 mm and exhibiting a bulk density in the range of about 0.3 g/cc to 0.6 g/cc.
  • the strips were then packaged in dual barrier trays or equivalent and terminally sterilized with an E- beam to a level of 25 kiloGrays (kGy). Strip materials prepared as described above were evaluated for osteoinductivity in the widely- accepted athymic rat model.
  • Implants were placed singularly in the muscle pouch of each hind limb near the femur to allow for blood supply but not adjacent to the bone. At 28 days post-operative, the rats were sacrificed via carbon dioxide inhalation. The implants were then harvested. The explanted devices were then placed in labeled histology cassettes in 10% neutral buffered formalin. Samples were decalcified, embedded in paraffin, sectioned & stained. Three sections per implant were taken at 100 micrometer intervals and stained with H&E. Semi-quantitative scoring of the samples versus controls confirmed that the implant materials were osteoinductive.
  • a DBM strip device comprising 7.7% by dry weight of sodium alginate, 42.2% by dry weight of small DBM particles, and 50.1% by dry weight of demineralized bone chips (2-4 mm maximum particle dimension) was prepared using the procedures described in Example 1, except that pre-hydrated human allograft demineralized bone chips were mixed into the water/alginate material along with the DBM particles prior to transfer to the molds.
  • a DBM strip device comprising 4.3% by dry weight of sodium alginate and 95.7% by dry weight of DBM particles was prepared as follows.
  • 4.5g of sodium alginate (Ultrapure Pronova MVG grade, NovaMatrix) was combined with 144 cc of water in a blender. The materials were mixed in the blender until all of the alginate was incorporated, producing WFI. Approximately lOOg of lyophilized demineralized bone matrix (DBM, 710 micron powder) was added to a mixing bowl and was combined with 200cc of WFI. Optionally, demineralized bone chips may be added to, or substituted for, the DBM powder. The DBM was mixed with the WFI until all DBM was fully hydrated. The combined WFI/alginate solution was then transferred to the mixer bowl containing the hydrated DBM and mixing was initiated.
  • DBM demineralized bone chips
  • Example mold dimensions may be sized to produce a product that is approximately 100mm x 20mm x 5mm; approximately 50 mm x 20 mm x 5 mm; approximately 10 mm x 12 mm x 5 mm or approximately 8 mm x 25 mm x 5 mm.
  • the molds were transferred to a freezer and the slurry was allowed to freeze. The frozen slurry was then unmolded and transferred into a continuously agitated pool of 1-10% by weight calcium chloride dihydrate solution for a period of 1 to 24 hours to ionically crosslink the alginate.
  • the resulting cross-linked blocks of alginate and DBM were then removed from the crosslinking solution, and placed into a sufficient volume of water to extract any residual calcium chloride solution from the cross-linked blocks.
  • the rinsed cross-linked blocks were then lyophilized under conditions to substantially preserve the original volume of the cross-linked blocks.
  • the resulting lyophilized materials were, porous strip materials having a thickness of about 5 mm and exhibiting a bulk density in the range of about 0.3 g/cc to 0.6 g/cc.
  • the strips were then packaged in dual barrier trays or equivalent and terminally sterilized with E-beam to a level of 25 kiloGrays (kGy).
  • a DBM strip device constituted 4.0% by dry weight of sodium alginate, 44.0% by dry weight of small DBM particles, and 52.0% by dry weight of demineralized bone chips (2-4 mm maximum particle dimension) was prepared using the procedures described in Example 3, except that pre-hydrated human allograft demineralized bone chips were mixed into the water/alginate material along with the DBM particles prior to transfer to the molds.
  • a DBM strip device constituted 3.0% by dry weight of sodium alginate and 97.0% by dry weight of DBM particles is prepared as follows.
  • 3.1g of sodium alginate (Ultrapure Pronova MVG grade, NovaMatrix) are combined with 144 cc of water for injection (WFI) in a blender. The materials are mixed in the blender until all of the alginate is incorporated.
  • Approximately lOOg of lyophilized demineralized bone matrix (DBM, 710 micron powder) is added to a mixing bowl and is combined with 200cc of WFI.
  • the DBM is mixed with the WFI until all DBM is fully hydrated.
  • the combined WFI/alginate solution is then transferred to the mixer bowl containing the hydrated DBM and mixing is initiated. Mixing is allowed to proceed until a uniform slurry is obtained. The uniform slurry was then decanted into pre-sized molds.
  • Example mold dimensions may be sized to produce a product that is approximately 100mm x 20mm x 5mm; approximately 50 mm x 20 mm x 5 mm; approximately 10 mm x 12 mm x 5 mm or approximately 8 mm x 25 mm x 5 mm.
  • the molds are transferred to a freezer and the slurry is allowed to freeze.
  • the frozen slurry is then unmolded and transferred into a continuously agitated pool of 1-10% by weight solution of calcium chloride dihydrate for a period of 1 to 24 hours to ionically crosslink the alginate.
  • the resulting cross-linked blocks of alginate and DBM are then removed from the crosslinking solution, and placed into a pool of water for injection in sufficient volume to extract any residual calcium chloride solution from the cross-linked blocks.
  • the rinsed cross-linked blocks are then lyophilized under conditions to substantially preserve the original volume of the cross-linked blocks.
  • the resulting lyophilized materials are porous strip materials having a thickness of about 5 mm and exhibiting a bulk density in the range of about 0.3 g/cc to 0.6 g/cc.
  • the strips are then packaged in dual barrier trays or equivalent and terminally sterilized with E-beam to a level of 25 kiloGrays (kGy).
  • a DBM strip device constituted 3.0% by dry weight of sodium alginate, 45.0% by dry weight of small DBM particles, and 52.0% by dry weight of demineralized bone chips (2-4 mm maximum particle dimension) is prepared using the procedures described in Example 5, except that pre-hydrated human allograft demineralized bone chips are mixed into the water/alginate material along with the DBM particles prior to transfer to the molds.
  • a retch grinder operating at 8000 rpm with a 1 mm sieve was used for this purpose, resulting in the collection of the randomized sponge particulate as a wispy mass.
  • 100 g of osteoinductive demineralized bone matrix having a particle size of 55-850 ⁇ m were then slowly added to the bowl while mixing, which was allowed to proceed until a uniform mixture was obtained.
  • 260 cc aliquats of the resulting slurry were measured in a graduated cylinder and transferred to 260 cc capacity stainless steel screen molds (270 mesh screen size). The dimensions of the molds were 8 inches (-20.3 cm) by 10 inches (-25.4 cm), and the slurry was pooled to a depth of about 0.5 cm.
  • the molds were capped with a screen top and completely submerged in a vessel containing a 1% by weight solution of calcium chloride dihydrate for a period of 6 to 24 hours in order the ionically crosslink the alginate.
  • the molds were then removed from the cross-linking solution, placed into individual lyophilization pouches, and lyophilized under conditions to substantially preserve the original volume of the charged material.
  • the resulting lyophilized materials were flexible, solid sheet materials having a thickness of about 5 mm and exhibiting a bulk density in the range of about 0.17 g/cc to 0.21 g/cc.
  • the sheets were cut to desired strip sizes (some 8 mm X 25 mm; some 10 mm X 12 mm; some 50 mm X 20 mm and some 100 mm X 20 mm) and packaged in trays in a double-pouch format.
  • the packaged products were terminally sterilized with E-beam to a level of 25 kiloGrays (kGy).
  • the packaged product may contain any number of product strips, for example, a single strip, two strips, three strips, or four stips.
  • Strip materials prepared as described above were evaluated for osteoinductivity in the widely- accepted athymic rat model. Implants were placed singularly in the muscle pouch of each hind limb near the femur to allow for blood supply but not adjacent to the bone. At 28 days post-operative, the rats were sacrificed via carbon dioxide inhalation. The implants were then harvested. Explants were placed in labeled histology cassettes in 10% neutral buffered formalin. Samples were decalcified, embedded in paraffin, sectioned & stained. Three sections per implant were taken at 100 micrometer intervals and stained with H&E. Semi-quantitative scoring of the samples versus controls confirmed that the implant materials were osteoinductive.

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Abstract

L'invention concerne des dispositifs d'implant médical qui comprennent des particules dérivées d'os. Ces matériaux et d'autres matériaux potentiels sont maintenus ensemble dans une structure ayant une stabilité tridimensionnelle, comme une feuille résiliente poreuse, au moyen d'un gel polysaccharidique réticulé par les ions. Elle concerne également des procédés pour fabriquer et utiliser ces dispositifs médicaux.
PCT/US2008/081544 2008-10-29 2008-10-29 Dispositifs contenant des particules de matrice osseuse déminéralisée WO2010050935A1 (fr)

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WO2014130953A1 (fr) * 2013-02-22 2014-08-28 Lifenet Health Ensemble d'emballage pour stocker du tissu ou matériau cellulaire
US10905801B2 (en) 2002-06-26 2021-02-02 Lifenet Health Device and process for producing fiber products and fiber products produced thereby
US11365395B2 (en) 2003-05-01 2022-06-21 Lifenet Health In vitro growth of tissues suitable to the formation of bone and bone forming tissue formed thereby

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US20010014667A1 (en) * 1998-01-05 2001-08-16 Chen Charles C. Compositions with enhanced osteogenic potential, methods for making the same and therapeutic uses thereof
US6340477B1 (en) * 2000-04-27 2002-01-22 Lifenet Bone matrix composition and methods for making and using same
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US10905801B2 (en) 2002-06-26 2021-02-02 Lifenet Health Device and process for producing fiber products and fiber products produced thereby
US11365395B2 (en) 2003-05-01 2022-06-21 Lifenet Health In vitro growth of tissues suitable to the formation of bone and bone forming tissue formed thereby
CN102895703A (zh) * 2012-11-08 2013-01-30 北京鑫康辰医学科技发展有限公司 脱钙骨基质材料及其制备方法
WO2014130953A1 (fr) * 2013-02-22 2014-08-28 Lifenet Health Ensemble d'emballage pour stocker du tissu ou matériau cellulaire
CN105163704A (zh) * 2013-02-22 2015-12-16 莱福奈特海尔斯公司 用于储存组织和细胞材料的包装组件
US20160000062A1 (en) * 2013-02-22 2016-01-07 Lifenet Health Packaging assembly for storing tissue and cellular material
CN105163704B (zh) * 2013-02-22 2019-07-26 莱福奈特海尔斯公司 用于储存组织和细胞材料的包装组件
CN110371486A (zh) * 2013-02-22 2019-10-25 莱福奈特海尔斯公司 用于储存组织和细胞材料的包装组件
US10932464B2 (en) 2013-02-22 2021-03-02 Lifenet Health Packaging assembly for storing tissue and cellular material
US11730163B2 (en) 2013-02-22 2023-08-22 Lifenet Health Packaging assembly for storing tissue and cellular material

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