WO2000050102A1 - Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same - Google Patents

Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same Download PDF

Info

Publication number
WO2000050102A1
WO2000050102A1 PCT/US2000/004408 US0004408W WO0050102A1 WO 2000050102 A1 WO2000050102 A1 WO 2000050102A1 US 0004408 W US0004408 W US 0004408W WO 0050102 A1 WO0050102 A1 WO 0050102A1
Authority
WO
WIPO (PCT)
Prior art keywords
osteoimplant
bone particles
bone
group
particles
Prior art date
Application number
PCT/US2000/004408
Other languages
French (fr)
Inventor
Todd M. Boyce
Lawrence A. Shimp
Albert Manrique
Original Assignee
Osteotech, 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 Osteotech, Inc. filed Critical Osteotech, Inc.
Priority to JP2000600712A priority Critical patent/JP4658331B2/en
Priority to EP00915821A priority patent/EP1152777B1/en
Priority to AU37033/00A priority patent/AU758828B2/en
Priority to CA2363153A priority patent/CA2363153C/en
Priority to DE60027698T priority patent/DE60027698T2/en
Publication of WO2000050102A1 publication Critical patent/WO2000050102A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/28Bones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/32Joints for the hip
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/46Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
    • A61F2/4644Preparation of bone graft, bone plugs or bone dowels, e.g. grinding or milling bone material
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials 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
    • A61L27/3604Materials 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
    • A61L27/3608Bone, e.g. demineralised bone matrix [DBM], bone powder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials 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
    • A61L27/3641Materials 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
    • A61L27/3645Connective tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials 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
    • A61L27/3683Materials 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 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials 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
    • A61L27/3683Materials 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 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3691Materials 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 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials 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
    • A61L27/38Materials 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 containing added animal cells
    • A61L27/3839Materials 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 containing added animal cells characterised by the site of application in the body
    • A61L27/3843Connective tissue
    • A61L27/3847Bones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/005Ingredients of undetermined constitution or reaction products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30316The prosthesis having different structural features at different locations within the same prosthesis; Connections between prosthetic parts; Special structural features of bone or joint prostheses not otherwise provided for
    • A61F2002/30535Special structural features of bone or joint prostheses not otherwise provided for
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/02Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to an osteoimplant for use in the repair, replacement and/or augmentation of various portions of animal or human skeletal systems, to a method for manufacturing the osteoimplant and to a method of using the osteoimplant. More particularly, this invention relates to an osteogenic osteoimplant which provides mechanical or structural support to a bone repair site.
  • Shaped or cut bone segments have been used extensively to solve various medical problems in human and animal orthopaedic surgical practice, and their application has also extended to the field of cosmetic and reconstructive surgery, dental reconstructive surgery, and other medical fields involving surgery of hard tissues.
  • autograft bone where the patient provides the source
  • allograft bone where another individual of the same species provides the source
  • xenograft bone where another individual of a different species provides the source
  • transplanted bone is known to provide support, promote healing, fill bony cavities, separate bony elements (such as vertebral bodies), promote fusion (where bones are induced to grow together into a single, solid mass), or stabilize the sites of fractures.
  • processed bone has been developed into shapes for use in new surgical applications, or as new materials for implants that were historically made of non-biologically derived materials.
  • Bone grafting applications are differentiated by the requirements of the skeletal site. Certain applications require a "structural graft" in which one role of the graft is to provide mechanical or structural support to the site. Such grafts contain a substantial portion of mineralized bone tissue to provide the strength needed for load- bearing. The graft may also have beneficial biological properties, such as incorporation into the skeleton, osteoinduction, osteoconduction, or angiogenesis. Structural grafts are conventionally made by processing, and then cutting or otherwise shaping cortical bones collected for transplant purposes. The range of bone grafts that might be thus prepared is limited by the size and shape limitations of the bone TISSUE from which the bone graft originated. Certain clinically desirable shapes and sizes of grafts may thus be unattainable by the cutting and shaping processes, due to the dimensional limitations of the bone. For some shapes they may also be available only in limited amounts, due to the large variations inherent in the human or animal donor source
  • a load-bearing osteoimplant which comprises a shaped, compressed composition of bone particles.
  • the osteoimplant possesses a bulk density of greater than about 0.7 g/cm 3 and a wet compressive strength of at least about 3 MPa.
  • the osteoimplant of this invention is fabricated by the method which comprises providing a composition comprising bone particles optionally in combination with one or more biocompatible components and applying compressive force of greater than about 1000 psi to the composition to provide a load-bearing osteoimplant.
  • the bone particles utilized in the fabrication of the osteoimplant of this invention are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and combinations thereof.
  • the bone particles are remodeled and replaced by new host bone as incorporation of the osteoimplant progresses in vivo.
  • bone particles can be fully demineralized by removing substantially all of the inorganic mineral content of the bone particles, can be partially demineralized by removing a significant amount, but less than all, of the inorganic mineral content of the bone particles, or can be only superficially demineralized by removing a minor amount of the inorganic mineral content of the bone particles.
  • demineralized as applied to the bone particles utilized in the practice of the present invention is intended to cover all bone particles which have had some portion of their original mineral content removed by a demineralization process.
  • Nondemineralized bone particles provide strength to the osteoimplant and allow it to initially support load.
  • Demineralized bone particles induce new bone formation at the site of the demineralized bone and permit adjustment of the overall mechanical properties of the osteoimplant.
  • the osteoimplant of this invention optionally includes additional biocompatible component(s) such as wetting agents, biocompatible
  • binders fillers, fibers, plasticizers, biostatic biocidal agents, surface active agents, bioactive agents, and the like.
  • osteoimplant herein is utilized in its broadest sense and is not intended to be limited to any particular shapes, sizes, configurations or applications.
  • shaped refers to a determined or regular form or configuration, in contrast to an indeterminate or vague form or configuration (as in the case of a limp or other solid mass of no special form) and is characteristic of such materials as sheets, plates, disks, cores, pins, screws, tubes, teeth, bones, portion of bone, wedges, cylinders, threaded cylinders, and the like.
  • wet compressive strength refers to the compressive strength of the osteoimplant after the osteoimplant has been immersed in physiological saline (water containing 0.9 g NaCl/100 ml water) for a minimum of 12 hours and a maximum of 24 hours. Compressive strength is a well known measurement of mechanical strength and is measured using the procedure described herein.
  • osteoogenic as applied to the osteoimplant of this invention shall be understood as referring to the ability of the osteoimplant to enhance or accelerate the ingrowth of new bone tissue by one or more mechanisms such as osteogenesis, osteoconduction and/or osteoinduction.
  • incorporación utilized herein refers to the biological mechanism whereby host tissue gradually removes portions of the osteoimplant of the invention and replaces those removed portions with native host bone tissue while maintaining strength. This phenomenon is also known in the scientific literature as “creeping substitution”.
  • incorporación utilized herein shall be understood as embracing what is known by those skilled in the art as “creeping substitution”.
  • FIGS, la-h show various configurations of an osteoimplant of the present
  • FIGS. 2a and 2b are views of a vertebrae and the osteoimplant of the invention sized and shaped as a disc (FIG. 2a) and threaded cylinder (FIG. 2b) for installation at an intervertebral site;
  • FIG. 3 is a view of human cervical vertebrae showing an osteoimplant of the invention affixed thereto as a cervical plate;
  • FIG. 4 is a view of the human skull showing an osteoimplant of the invention fashioned as a mandibular replacement;
  • FIG. 5 is a cross-sectional view of a human femur showing implanted therein an osteoimplant fashioned as a femoral implant;
  • FIGS. 6a and 6b show an embodiment of the osteoimplant of the present invention configured and dimensioned as an acetabular cup;
  • FIG. 7 is a view of a total hip replacement using the femoral implant depicted in FIG. 5 and the acetabular cup depicted in FIG. 6;
  • FIGS. 8a and 8b are views of a human radius and ulna showing an osteoimplant of the invention fashioned as a diaphyseal plate being implanted at a bone fracture site (FIG. 8a) and as an intercalary implant implanted at a diaphyseal segment missing due to trauma or tumor (FIG. 8b);
  • FIG. 9 is a view of a human femur and an osteoimplant of the invention fashioned as an intramedullary rod positioned for installation in the medullary canal of the femur;
  • FIG. 10 is a view of a femoral head and an osteoimplant of the invention positioned for installation in a core decompression site in the femoral head;
  • FIG. 11 is a view of a human skull and an osteoimplant of the present invention positioned for implantation as a parietal bone replacement;
  • FIGS. 12a and 12b show a cylindrical press-mold which can be utilized in the fabrication of the osteoimplant of the invention;
  • FIG. 13 shows a press which can be utilized in the fabrication of the osteoimplant of the invention.
  • FIG. 14 shows a press and heating apparatus which can be utilized in the fabrication of the osteoimplant of the invention.
  • the load-bearing osteoimplant of the present invention is produced by providing a composition comprising bone particles optionally in combination with one or more biocompatible components, and thereafter applying compressive force of at least about 1000 psi to the composition to provide a load-bearing osteoimplant.
  • the osteoimplant fabricated in accordance with the invention possesses a bulk density of at least about 0.7 g/cm 3 and a wet compressive strength of at least about 3 MPa.
  • the bone particle-containing composition can be heated, lyophilized and/or cross-linked either before, during or after the step of applying a compressive force to the bone particle-containing composition.
  • the bone particles employed in the preparation of the bone particle- containing composition can be obtained from cortical, cancellous and/or corticocancellous bone which may be of autogenous, allogenic and/or xenogeneic origin.
  • the bone particles are obtained from cortical bone of allogenic origin.
  • Porcine and bovine bone are particularly advantageous types of xenogeneic bone tissue which can be used individually or in combination as sources for the bone particles.
  • Particles are formed by milling whole bone to produce fibers, chipping whole bone, cutting whole bone, fracturing whole bone in liquid nitrogen, or otherwise disintegrating the bone tissue. Particles can optionally be sieved to produce those of a specific size.
  • the bone particles employed in the composition can be powdered bone particles possessing a wide range of particle sizes ranging from relatively fine powders to coarse grains and even larger chips.
  • powdered bone particles can range in average particle size from about 0.05 to about 1.2 cm and preferably from about 0.1 to about 1 cm and possess an average median length to median thickness ratio of from about 1 : 1 to about 3:1.
  • powdered bone particles can be graded into different sizes to reduce or eliminate any less desirable size(s) of particles which may be present.
  • bone particles generally characterized as elongate and possessing relatively high median length to median thickness ratios can be utilized herein.
  • elongate particles can be readily obtained by any one of several methods, e.g., by milling or shaving the surface of an entire bone or relatively large section of bone.
  • a mass of elongate bone particles containing at least about 60 weight percent, preferably at least about 70 weight percent, and most preferably at least about 80 weight percent of elongate bone particles possessing a median length of from about 2 to about 200 mm or more and preferably from about 10 to about 100 mm, a median thickness of from about 0.05 to about 2 mm, and preferably from about 0.2 to about 1 mm and a median width of from about 1 mm to about 20 mm, and preferably from about 2 to about 5 mm.
  • These elongate bone particles can possess a median length to median thickness ratio of at least about 50:1 up to about 500:1 or more, and preferably from about 50:1 to about 100:1, and a median length to median width ratio of from about 10:1 and about 200: 1 , and preferably from about 50: 1 to about 100: 1.
  • Another procedure for obtaining elongate bone particles, particularly useful for pieces of bone of up to about 100 mm in length, is the bone processing mill described in commonly assigned U.S. Patent No. 5,607,269. Use of this bone mill results in the production of long, thin strips which quickly curl lengthwise to provide tubular-like bone particles.
  • elongate bone particles can be graded into different sizes to reduce or eliminate any less desirable size(s) of particles which may be present.
  • elongate bone particles can be described as filaments, fibers, threads, slender or narrow strips, etc.
  • At least about 60 weight percent, more preferably at least about 75 weight percent, and most preferably at least about 90 weight percent of the bone particles utilized in the preparation of the bone particle-containing composition herein are elongate. It has been observed that elongate bone particles provide an osteoimplant possessing particularly good compressive strength.
  • the bone particles are optionally demineralized in accordance with known and conventional procedures in order to reduce their inorganic mineral content.
  • Demineralization methods remove the inorganic mineral component of bone by employing acid solutions. Such methods are well known in the art, see for example, Reddi et al., Proc. Nat. Acad. Sci. 69, ppl601-1605 (1972), incorporated herein by reference herein.
  • the strength of the acid solution, the shape of the bone particles and the duration of the demineralization treatment will determine the extent of demineralization. Reference in this regard may be made to Lewandrowski et al., J. Biomed Materials Res,
  • the bone particles are subjected to a defatting/disinfecting step which is followed by an acid demineralization step.
  • a preferred defatting/disinfectant solution is an aqueous solution of ethanol, the ethanol being a good solvent for lipids and the water being a good hydrophilic carrier to enable the solution to penetrate more deeply into the bone particles.
  • the aqueous ethanol solution also disinfects the bone by killing vegetative microorganisms and viruses.
  • the defatting disinfecting solution should be present in the defatting disinfecting solution to produce optimal lipid removal and disinfection within the shortest period of time.
  • the preferred concentration range of the defatting solution is from about 60 to about 85 weight percent alcohol and most preferably about 70 weight percent alcohol.
  • Acids which can be employed in this step include inorganic acids such as hydrochloric acid and organic acids such as peracetic acid. After acid treatment, the demineralized bone particles are rinsed with sterile water to remove residual amounts of acid and thereby raise the pH.
  • the wet demineralized bone particles can then be immediately shaped into any desired configuration or stored under aseptic conditions, advantageously in a lyophilized state, for processing at a later time.
  • the particles can be shaped into a desired configuration and sterilized using known methods.
  • the phrase "superficially demineralized" as applied to the bone particles refers to bone particles possessing at least about 90 weight percent of their original inorganic mineral content.
  • the phrase “partially demineralized” as applied to the bone particles refers to bone particles possessing from about 8 to about 90 weight percent of their original inorganic mineral content, and the phrase “fully demineralized” as applied to the bone particles refers to bone particles possessing less than about 8, preferably less than about 1 , weight percent of their original inorganic mineral content.
  • the unmodified term “demineralized” as applied to the bone particles is intended to cover any one or combination of the foregoing types of demineralized bone particles. Mixtures or combinations of one or more of the foregoing types of bone particles can be employed.
  • one or more of the foregoing types of demineralized bone particles can be employed in combination with nondemineralized bone particles, i.e., bone particles that have not been subjected to a demineralization process.
  • Nondemineralized bone particles possess an initial and ongoing mechanical role, and later a biological role, in the osteoimplant of this invention.
  • Nondemineralized bone particles act as a stiffener, providing strength to the osteoimplant and enhancing its ability to support load. These bone particles also play a biological role in bringing about new bone ingrowth by the process known as osteoconduction. Thus, these bone particles are gradually remodeled and replaced by new host bone as incorporation of the osteoimplant progresses over time.
  • the use of nondemineralized bone particles is highly preferred, albeit not essential, in the fabrication of the osteoimplant of the present invention.
  • Demineralized bone particles likewise possess an initial and ongoing mechanical role, and later a biological role, in the osteoimplant of this invention.
  • Superficial or partial demineralization produces particles containing a mineralized core. Particles of this type actually can contribute to the strength of the osteoimplant, through their mineralized core. These particles also play a biological role in bringing about new bone ingrowth by the process known as osteoinduction. Full demineralization produces particles in which nearly all of the mineral content has been removed from the particles. Particles treated in this way do not directly contribute to the strength of the osteoimplant; however, they do contribute to the osteoinductivity of the osteoimplant and provide a coherency or binding effect.
  • the osteoimplant herein When prepared from bone particles that are almost exclusively nondemineralized and/or superficially demineralized the osteoimplant herein will tend to possess a fairly high compressive strength, e.g., one approaching and even exceeding that of natural bone. Accordingly, when an osteoimplant exhibiting a wet compressive strength of on the order of from about 20 to about 200 MPa, is desired, a predominant amount of nondemineralized bone particles and/or superficially demineralized bone particles can be advantageously employed. In order to lower the compressive strength of the osteoimplant, a quantity of partially or fully demineralized bone particles can be employed in combination with nondemineralized bone particles or superficially demineralized bone particles.
  • the use of various types of bone particles can be used to control the overall mechanical and biological properties, i.e., the strength, osteoconductivity and/or osteoinductivity, etc., of the osteoimplant.
  • the differential in compressive strength, osteogenicity and other properties between partially and/or fully demineralized bone particles on the one hand and non-demineralized and/or superficially demineralized bone particles on the other hand can be exploited.
  • nondemineralized and/or superficially demineralized bone particles can be concentrated in that region of the osteoimplant which will be directly subjected to applied load upon implantation.
  • the walls of the mold can be coated with a slurry or paste containing partially and/or fully demineralized bone particles followed by addition of a slurry or paste containing nondemineralized and/or superficially demineralized bone particles (or vice versa) to provide an osteoimplant which contains at least one discrete region, e.g., an outer surface, composed of partially and/or fully demineralized bone particles and at least one discrete region, e.g., a core, composed of nondemineralized and/or superficially demineralized bone particles.
  • the amount of each individual type of bone particle employed can vary widely depending on the mechanical and biological properties desired.
  • the weight ratio of nondemineralized to demineralized bone particles can broadly range from about 20:1 to about 1 :20 and the weight ratio of superficially and/or partially demineralized bone particles to fully demineralized bone particles can broadly range from about 20:1 to about 1 :20.
  • Suitable amounts can be readily determined by those skilled in the art on a case-by-case basis by routine experimentation.
  • the bone particles can be modified in one or more ways, e.g., their protein content can be augmented or modified as described in U.S. Patent Nos. 4,743,259 and 4,902,296, the contents of which are incorporated by reference herein.
  • the bone particle-containing composition fabricated in accordance with this disclosure will typically possess a bone particle content ranging from about 5 to about
  • weight percent preferably from about 40 to about 99 weight percent, and more preferably from about 50 to about 95 weight percent, based on the weight of the entire composition calculated prior to compression of the composition.
  • the bone particles can be combined with one or more biocompatible components such as wetting agents, biocompatible binders, fillers, fibers, plasticizers, biostatic/biocidal agents, surface active agents, bioactive agents, and the like, prior to, during, or after compressing the bone particle-containing composition.
  • biocompatible components such as wetting agents, biocompatible binders, fillers, fibers, plasticizers, biostatic/biocidal agents, surface active agents, bioactive agents, and the like, prior to, during, or after compressing the bone particle-containing composition.
  • One or more of such components can be combined with the bone particles by any suitable means, e.g., by soaking or immersing the bone particles in a solution or dispersion of the desired component, by physically admixing the bone particles and the desired component, and the like.
  • Suitable wetting agents include biocompatible liquids such as water, organic protic solvent, aqueous solution such as physiological saline, concentrated saline solutions, sugar solutions, ionic solutions of any kind, and liquid polyhydroxy compounds such as glycerol and glycerol esters, and mixtures thereof.
  • biocompatible liquids such as water, organic protic solvent, aqueous solution such as physiological saline, concentrated saline solutions, sugar solutions, ionic solutions of any kind, and liquid polyhydroxy compounds such as glycerol and glycerol esters, and mixtures thereof.
  • wetting agents in general is preferred in the practice of the present invention, as they improve handling of bone particles.
  • wetting agents will typically represent from about 20 to about 80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
  • Certain wetting agents such as water can be advantageously removed from the osteoimplant, e.g., by heating and lyophilizing the
  • Suitable biocompatible binders include biological adhesives such as fibrin glue, fibrinogen, thrombin, mussel adhesive protein, silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin or chitosan; cyanoacrylates; epoxy-based compounds; dental resin sealants; bioactive glass ceramics (such as apatite-wollastonite), dental resin cements; glass ionomer cements (such as Ionocap ® and Inocem ® available from Ionos
  • bioabsorbable polymers such as starches, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters, polyamino acids, polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly (propylene glycol-co- fumaric acid), tyrosine-based polycarbonates, pharmaceutical tablet binders (such as Eudragit ® binders available from H ⁇ ls America, Inc.), polyvinylpyrrolidone, cellulose, ethyl cellulose, micro-crystalline cellulose and blends thereof; starch ethylenevinyl alcohols, polycyanoacrylates; polyphosphazenes; nonbioabsorbable polymers such as poly
  • biocompatible binder acts as a matrix which binds the bone particles, thus providing coherency in a fluid environment and also improving the mechanical strength of the osteoimplant.
  • Suitable fillers include graphite, pyrolytic carbon, bioceramics, bone powder, demineralized bone powder, anorganic bone (i.e., bone mineral only, with the organic constituents removed), dentin tooth enamel, aragonite, calcite, nacre, amorphous calcium phosphate, hydroxyapatite, tricalcium phosphate, Bioglass ® and other calcium phosphate materials, calcium salts, etc.
  • Preferred fillers are demineralized bone powder and hydroxyapatite. When employed, filler will typically represent from about 5 to about
  • Suitable fibers include carbon fibers, collagen fibers, tendon or ligament derived fibers, keratin, cellulose, hydroxyapatite and other calcium phosphate fibers. When employed, fiber will typically represent from about 5 to about 75 weight percent of the bone particle-containing composition, calculated prior to compression of the
  • Suitable plasticizers include liquid polyhydroxy compounds such as
  • glycerol monoacetin, diacetin, etc.
  • Glycerol and aqueous solutions of glycerol are preferred.
  • plasticizer will typically represent from about 20 to about 80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
  • Suitable biostatic/biocidal agents include antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin, povidone, sugars, mucopolysaccharides, etc.
  • Preferred biostatic/biocidal agents are antibiotics.
  • biostatic/biocidal agent will typically represent from about 10 to about 95 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
  • Suitable surface active agents include the biocompatible nonionic, cationic, anionic and amphoteric surfactants.
  • Preferred surface active agents are the nonionic surfactants.
  • surface active agent will typically represent from about 1 to about 80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
  • Any of a variety of bioactive substances can be incorporated in, or associated with, the bone particles.
  • one or more bioactive substances can be combined with the bone particles by soaking or immersing the bone particles in a solution or dispersion of the desired bioactive substance(s).
  • Bioactive substances include physiologically or pharmacologically active substances that act locally or systemically in the host.
  • Bioactive substances which can be readily combined with the bone particles include, e.g., collagen, insoluble collagen derivatives, etc., and soluble solids and/or liquids dissolved therein; antiviricides, particularly those effective against HIV and hepatitis; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin, etc.; biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids; peptides; vitamins; inorganic elements; co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.; polymer cell scaffolds with parenchymal cells; angi
  • biocompatible components are not intended to be exhaustive and that other biocompatible components may be admixed with bone particles within the practice of the present invention.
  • the total amount of such optionally added biocompatible substances will typically range from about 0 to about 95, preferably from about 1 to about 60, more preferably from about 5 to about 50, weight percent of the bone particle-containing composition, based on the weight of the entire composition prior to compression of the composition, with optimum levels being readily determined in a specific case by routine experimentation.
  • One method of fabricating the bone particle-containing composition which can be advantageously utilized herein involves wetting a quantity of bone particles, of which at least about 60 weight percent preferably constitute elongate bone particles, with a wetting agent as described above to form a composition having the consistency of a slurry or paste.
  • the wetting agent can comprise dissolved or admixed therein one or more biocompatible substances such as biocompatible binders, fillers, plasticizers, biostatic/biocidal agents, surface active agents, bioactive substances, etc., as previously described.
  • Preferred wetting agents for forming the slurry or paste of bone particles include water, liquid polyhydroxy compounds and their esters, and polyhydroxy compounds in combination with water and/or surface active agents, e.g., the Pluronics ® series of nonionic surfactants.
  • Water is the most preferred wetting agent for utilization herein.
  • the preferred polyhydroxy compounds possess up to about 12 carbon atoms and, where their esters are concerned, are preferably the monoesters and diesters.
  • Specific polyhydroxy compounds of the foregoing type include glycerol and its monoesters and diesters derived from low molecular weight carboxylic acids, e.g., monoacetin and diacetin (respectively, glycerol monoacetate and glycerol diacetate), ethylene glycol, diethylene glycol, triethylene glycol, 1 ,2-propanediol, trimethylolethane, trimethylolpropane, pentaerythritol, sorbitol, and the like.
  • glycerol is especially preferred as it improves the handling characteristics of the bone particles wetted therewith and is biocompatible and easily metabolized.
  • slurry or paste e.g., by applying the slurry or paste to a form such as a flat sheet, mesh screen or three-dimensional mold and draining away excess liquid.
  • the bone particles have a tendency to quickly or prematurely separate or to otherwise settle out from the slurry or paste such
  • a thickener such as a solution of polyvinyl alcohol, polyvinylpyrrolidone, cellulosic ester such as hydroxypropyl methylcellulose, carboxy methylcellulose, pectin, xanthan gum, food- grade texturizing agent, gelatin, dextran, collagen, starch, hydrolyzed polyacrylonitrile, hydrolyzed polyacrylamide, polyelectrolyte such as polyacrylic acid salt, hydrogels, chitosan, other materials that can suspend particles, etc., can be combined with the wetting agent in an amount sufficient to significantly improve the suspension-keeping characteristics of the composition.
  • the composition is subjected to a compressive force of at least about 1,000 psi to produce the osteoimplant of this invention.
  • compressive forces of from about 2,500 to about 60,000 psi can be employed with particularly good effect, with compressive forces of from about 2,500 to about 20,000 psi presently being preferred.
  • the compression step will typically be conducted for a period of time ranging from about 0.1 to about 180 hours, preferably from about 4 to about 72 hours.
  • the resulting osteoimplant possesses a bulk density (measured by dividing the weight of the osteoimplant by its volume) of at least about 0.7g/cm 3 , preferably at least about 1.0 g/cm 3 .
  • the osteoimplant of this invention After being immersed in physiological saline for 12-24 hours, the osteoimplant of this invention possesses a wet compressive strength (as measured by the method described hereinbelow) of at least about 3 MPa. Typically, the wet compressive strength of the osteoimplant substantially exceeds 3 MPa. In most cases (and especially where a predominant amount of nondemineralized elongate bone particles are utilized in the fabrication of the osteoimplant), the inventors have found that wet compressive strength normally exceeds about 15 MPa and typically ranges from about 15 to about 100 MPA.
  • the wet compressive strength of the osteoimplant of this invention allows the osteoimplant to provide significant mechanical or structural support to a bone repair site in a body fluid environment over an extended period of time in vivo.
  • the composition can be placed in a mold possessing any suitable or desired shape or configuration and compressed in a press, e.g., a Carver ® manual press.
  • FIGS. 12a and 12b depict a cylindrical press-mold 10 which is suitable for use in the present invention.
  • Mold 10 consists of three parts, a hollow cylinder 12, an end cap 14 and a plunger 16.
  • Mold 10 is assembled by placing hollow cylinder 10 on top of end cap 12. The interior of hollow cylinder 12 is then filled with the bone particle- containing composition described herein, shown at 18. Thereafter, plunger 16 is placed on top of cylinder 10 which has been filled with bone particle-containing composition 18.
  • bone particle-containing composition 18 is filled to a height inside cylinder 12 which results in plunger 16 coming to a rest on composition 18 instead of cylinder 12.
  • mold 10 is placed inside a manual hydraulic press, generally depicted at 20.
  • Press 20 is equipped with two plates 22 and 24.
  • Plate 24 remains stationary while plate 22 moves in an upward direction as indicated by the arrow in FIG. 13. Movement of plate 22 is hydraulically controlled by means of a handle or other means (not shown) which is operated by the user. As plate 22 moves upward, plunger 16 is forced against plate 24 and moves downward to apply compressive force against composition 18 inside mold 10.
  • the osteoimplant produced by the method of this invention can be described as a hard, chalk-like material.
  • the osteoimplant may possess tiny pores or cavities which permit the osteoimplant to be properly revascularized and incorporated by the host. It can be easily shaped or machined into any of a wide variety of configurations.
  • the osteoimplant is provided with macroporosity, i.e., holes, which enhance blood flow through the osteoimplant or can be filled with a medically useful substance (such as Grafton ® putty available from Osteotech Inc., Eatontown, NJ).
  • macroporosity can be provided, e.g., by drilling or by using a mold which possesses spikes therein.
  • the composition can be subjected to an additional operation selected from heating, lyophilizing and cross-linking to further enhance the mechanical and/or biological properties of the osteoimplant. Incorporation of biocompatible component(s), if any, to the composition can precede or come after the step(s) of subjecting the composition to such additional operation(s).
  • the composition is heated during or after the compression step.
  • the composition can be heated at a suitable temperature, e.g., one ranging from about 30° to about 70°C, preferably from about 40° to about 50°C, for 1 to 72 hours preferably 24 to 48 hours.
  • a presently preferred mode of heating involves placing the bone particle-containing composition in a mold and immersing the mold in a heated biocompatible liquid, e.g., water, glycerol, solution of glycerol and water, ionic solutions of any kind, saline, concentrated saline, etc., such that the liquid can communicate with the composition being compressed. Concentrated saline is preferred.
  • the composition inside the mold is compressed to provide an osteoimplant in accordance with the present invention.
  • mold 10 is placed in container 30 which is filled with biocompatible liquid 32.
  • a heat tape 34 which contains electric heating elements (not shown) which are controlled by an electrostat (not shown).
  • electrostat an electrostat
  • biocompatible liquid 32 By raising the temperature of biocompatible liquid 32, heat is transferred to the composition (not shown) inside mold 10.
  • plate 22 moves upward, plunger 16 is compressed against plate 24 and exerts downward compressive force against the composition.
  • biocompatible liquid 32 actually enters mold 10 through seams formed by the connection between end cap 14 and cylinder 12 and contacts the composition. It has been discovered that this mode of heating provides osteoimplants possessing particularly good strength characteristics.
  • the osteoimplant can be lyophilized, advantageously after the bone particle-containing composition has been compressed in accordance with this disclosure, under conditions that are well known in the art, e.g., a shelf temperature of from about - 20° to about -55 °C, a vacuum of from about 150 to about 100 mTorr for a period of time ranging from about 4 to about 48 hours.
  • Crosslinking can be performed in order to improve the strength of the osteoimplant.
  • Crosslinking of the bone particle-containing composition can be effected by a variety of known methods including chemical reaction, the application of energy such as radiant energy, which includes irradiation by UV light or microwave energy, drying and/or heating and dye-mediated photo-oxidation; dehydrothermal treatment in which water is slowly removed while the bone particles are subjected to a vacuum; and, enzymatic treatment to form chemical linkages at any collagen-collagen interface.
  • the preferred method of forming chemical linkages is by chemical reaction.
  • Chemical crosslinking agents include those that contain bifunctional or multifunctional reactive groups, and which react with surface-exposed collagen of adjacent bone particles within the bone particle-containing composition. By reacting with multiple functional groups on the same or different collagen molecules, the chemical crosslinking agent increases the mechanical strength of the osteoimplant.
  • Chemical crosslinking involves exposing the bone particles presenting surface-exposed collagen to the chemical crosslinking agent, either by contacting bone particles with a solution of the chemical crosslinking agent, or by exposing bone particles to the vapors of the chemical crosslinking agent under conditions appropriate for the particular type of crosslinking reaction.
  • the osteoimplant of this invention can be immersed in a solution of cross-linking agent for a period of time sufficient to allow complete penetration of the solution into the osteoimplant.
  • Crosslinking conditions include an appropriate pH and temperature, and times ranging from minutes to days, depending upon the level of crosslinking desired, and the activity of the chemical crosslinking agent. The resulting osteoimplant is then washed to remove all leachable traces of the chemical.
  • Suitable chemical crosslinking agents include mono- and dialdehydes, including glutaraldehyde and formaldehyde; polyepoxy compounds such as glycerol polyglycidyl ethers, polyethylene glycol diglycidyl ethers and other polyepoxy and diepoxy glycidyl ethers; tanning agents including polyvalent metallic oxides such as titanium dioxide, chromium dioxide, aluminum dioxide, zirconium salt, as well as organic tannins and other phenolic oxides derived from plants; chemicals for esterification or carboxyl groups followed by reaction with hydrazide to form activated acyl azide functionalities in the collagen; dicyclohexyl carbodiimide and its derivatives as well as other heterobifunctional crosslinking agents; hexamethylene diisocyante; sugars, including glucose, will also crosslink collagen.
  • polyepoxy compounds such as glycerol polyglycidyl ethers, polyethylene glycol diglycidyl
  • Glutaraldehyde crosslinked biomaterials have a tendency to over-calcify in the body.
  • calcification-controlling agents can be used with aldehyde crosslinking agents.
  • These calcification-controlling agents include dimethyl sulfoxide (DMSO), surfactants, diphosphonates, aminooleic acid, and metallic ions, for example ions of iron and aluminum.
  • DMSO dimethyl sulfoxide
  • surfactants diphosphonates
  • aminooleic acid aminooleic acid
  • metallic ions for example ions of iron and aluminum.
  • concentrations of these calcification-controlling agents can be determined by routine experimentation by those skilled in the art.
  • useful enzymes include those known in the art which are capable of catalyzing crosslinking reactions on proteins or peptides, preferably collagen molecules, e.g., transglutaminase as described in Jurgensen et al., The Journal of Bone and Joint Surgery, 79-a (2), 185-193 (1997), herein incorporated by reference.
  • Formation of chemical linkages can also be accomplished by the application of energy.
  • One way to form chemical linkages by application of energy is to use methods known to form highly reactive oxygen ions generated from atmospheric gas, which in turn, promote oxygen crosslinks between surface-exposed collagen. Such methods include using energy in the form of ultraviolet light, microwave energy and the like.
  • Another method utilizing the application of energy is a process known as dye- mediated photo-oxidation in which a chemical dye under the action of visible light is used to crosslink surface-exposed collagen.
  • Another method for the formation of chemical linkages is by dehydrothermal treatment which uses combined heat and the slow removal of water, preferably under vacuum, to achieve crosslinking of bone particles.
  • the process involves chemically combining a hydroxy group from a functional group of one collagen molecule and a hydrogen ion from a functional group of another collagen molecule reacting to form water which is then removed resulting in the formation of a bond between the collagen molecules.
  • the resulting osteoimplant can assume a determined or regular form or configuration such as a sheet, plate, disk, cone, pin, screw, tube, tooth, tooth root, bone or portion of bone, wedge or portion of wedge, cylinder, threaded cylinder (dowel), to name but a few.
  • the osteoimplant can be machined or shaped by any suitable mechanical shaping means.
  • Computerized modeling can, for example, be employed to provide an intricately-shaped osteoimplant which is custom-fitted to the bone repair site with great precision.
  • the osteoimplant possesses the configuration of a threaded cylinder (dowel).
  • the osteoimplant herein is applied at a bone repair site, e.g., one resulting from injury, defect brought about during the course of surgery, infection, malignancy or developmental malformation, which requires mechanical support.
  • the osteoimplant can be utilized in a wide variety of orthopaedic, periodontal, neurosurgical and oral and maxillofacial surgical procedures such as 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 filling, 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
  • Specific bones which can be repaired or replaced with the bone- derived implant herein include 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.
  • FIGS, la-h depict various embodiments of an osteoimplant according to the present invention configured and dimensioned in the shape of a cylinder 40, wedge 50, plate 60, threaded cylinder (dowel) 70, fibular wedge 62, femoral struts 64, 66 and tibial strut 68.
  • cylinder 20 and wedge 30 are provided with macroporosity, namely holes 42 and 52, respectively, which have been drilled into cylinder 40 and wedge 50.
  • Macroporosity promotes blood flow through the osteoimplant and enhances and accelerates the incorporation of the osteoimplant by the host.
  • macroporous holes 42 and 52 can be advantageously filled with an osteogenic material, e.g., Grafton ® putty available from Osteotech, Inc., Eastontown, NJ.
  • osteoimplant 80 is configured and dimensioned as a disk to be inserted into the intervertebral fibrocartilage site 82 on the anterior side of vertebral column 84.
  • osteoimplant 70 is configured and dimensioned as a threaded cylinder (as depicted in FIG. Id) to be inserted into the intervertebral site 72 on the anterior side of vertebral column 84.
  • the osteoimplant of the invention is configured and dimensioned as a cervical plate 90 and is shown affixed to cervical vertebrae 94, 96 by bone screws 92.
  • bone screws 92 form yet another embodiment of the osteoimplant of the present invention.
  • the osteoimplant 100 of the invention is sized and shaped to form the mandible of skull 102.
  • the osteoimplant 110 of the invention is sized and shaped as a femoral implant.
  • Osteoimplant 110 comprises head 112 which is attached to ball 114.
  • Ball 114 is fabricated from plastic or metal and is affixed to osteoimplant 110 by any suitable means, e.g, screw 116.
  • Osteoimplant is inserted into intramedullary canal 118 of femur 120.
  • the osteoimplant 130 of the invention is sized and shaped as an acetabular cup which is configured and dimensioned to receive plastic or metallic liner 132.
  • FIG. 7 a total hip replacement with the osteoimplant 110 depicted in FIG. 5 and the osteoimplant 130 of FIGS. 6a and 6b is depicted.
  • the osteoimplant 140 of the invention is sized and shaped as a diaphyseal implant and is shown being implanted via bone screws 142 on a fracture 144 along the diaphyseal segment of a human radius 146.
  • screws 142 can be fabricated from compressed bone particles in accordance with this disclosure.
  • osteoimplant 180 of the invention is sized and shaped as an intercalary implant and is shown already implanted at a diaphyseal segment of human radius 146 that is missing due to trauma or tumor.
  • the osteoimplant 150 of the invention is sized and shaped as an intramedullary rod for insertion into the medullary canal 154 of femur 152.
  • osteoimplant 186 is sized and shaped as a reinforcement rod for insertion into a core decompression site 184 formed by drilling a hole into femoral head 182.
  • osteoimplant 160 is sized and shaped to form part of the parietal bone 162 for skull 164. Osteoimplant 160 promotes fusion with parietal bone 88.
  • the present invention is intended to embrace all such devices which are constructed as the osteoimplant of the present invention and the attendant uses of such devices.
  • Initial density is determined by measuring specimen dimensions with a caliper to determine volume, and then weighing the specimen on a laboratory balance. The specimen is then placed in a container with 0.9% NaCl solution at room temperature for 12-24 hours. After the hydration period, the specimen is measured again to determine dimensions, and dimensions are recorded. The specimen is then centered on a compression platen (MTS 643.10A-01) in a servohydraulic testing system (MTS 858 Bionix). The top platen is lowered onto the specimen until a compressive preload of 0.1 kN is achieved. The system displacement transducer is then zeroed (MTS 358.10), defining zero displacement as the displacement associated initially with 0.1 kN preload.
  • the specimen is loaded in the displacement mode, using a ramp compressive load of 0.5 mm/s, until an endpoint of 4 mm displacement is achieved. After the 4 mm displacement is achieved, the loading is stopped automatically, and the specimen is unloaded. During testing, load (from the system load cell MTS 661.20E-03) and displacement data are collected every 0.05 sec.
  • Elongate bone particles were prepared using a milling machine. Half of the volume of the particles was fully demineralized using two charges of 0.6N HC1 acid. The nondemineralized and the fully demineralized particles were then combined together in an aqueous solution containing glycerol and allowed to soak for 4-12 hours at room temperature. The particles were then removed from the solution by straining, and placed into a 28 mm diameter cylindrical press-mold while still moist. The particles were pressed to 10,000 psi for 15 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45 °C. The osteoimplant was then frozen in a -70°C freezer (1.5 hours), and freeze-dried overnight, after which it was removed from the mold. The bulk density of the osteoimplant produced was 1.34 g/cm 3 . The height of the osteoimplant was 29 mm. The wet compressive strength of the osteoimplant exceeded 3 MPa.
  • Example 1 The procedure of Example 1 was used except the ratio of fully demineralized to nondemineralized bone particles was 2:1, the pellet was heated in situ in an oven for 4 hours at 40°C and the pressure was 2,500 psi. The resulting compressed pellet was cut into two portions and each portion was treated with crosslinking agent: 10% neutral buffered formalin (both dipped and in vapor phase) and 4% Denacol EX313
  • Example 3 The procedure of Example 1 was followed except that all of the particles were partially demineralized by using 225 ml of 0.6N HC1 and allowing the acid to react to depletion. Additionally, the mold was hexagonal in configuration (with each side of the hexagon measuring 18 mm). After completing the freeze-drying step, the resulting osteoimplant was placed in a bath of 10% neutral buffered formalin and the exposed collagen of the partially demineralized bone particles was allowed to cross-link for 48 hours. The resulting dry osteoimplant was tested mechanically and was found to possess a dry compressive strength of about 85 MPa. The bulk density of the osteoimplant was 1.05 g/cm 3 .
  • Example 3 The procedure of Example 3 was repeated and the resulting osteoimplant was immersed in physiological saline for 12-24 hours and was found to possess an ultimate wet compressive strength of about 45 MPa.
  • the bulk density of the osteoimplant was 1.05 g/cm 3 .
  • Elongate bone particles were prepared using a milling machine. The nondemineralized particles were then combined with ethyl cellulose (3:2 ratio by weight), and covered with 70% ethanol for 30 minutes, with stirring. The elongate bone particles were then removed from the solution by straining, and placed into a press-mold while still moist. The elongate bone particles were pressed to 10,000 psi for 15 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45 °C. The implant was then frozen in a -70 °C freezer (overnight), and freeze-dried, after which it was removed from the mold. The osteoimplant was immersed in physiological saline overnight and was found to possess a wet compressive strength of 20 MPa. EXAMPLE 6
  • Bone particles were prepared by using a block plane on the periosteal surface of cortical bone. Half of the volume of the bone particles was fully demineralized using two changes of 0.6N HC1 acid. The mineralized (25 g) and the demineralized particles (25 g based on original weight) were then combined together in a 70% ethanol solution with 20 g ethyl cellulose. This mixture was stirred for 30 minutes at room temperature. The particles were then removed form the solution by straining, and placed into a cylindrical press-mold while still moist. The particles were pressed to 18,000 psi for 10 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45°C.
  • the implant was then frozen in a -70°C freezer (1.5 hours), and freeze-dried overnight, after which it was removed from the mold.
  • the dry compressive strength of the osteoimplant was 6.5 MPa and the wet compressive strength of the osteoimplant was 4.0 MPa.
  • Elongate bone particles were prepared using a milling machine (30g). An equivalent amount by weight of cortical bone chips were also prepared by grinding in a bone mill. Chips were sieved between screens having dimensions between 4.0 mm and 1.8 mm. The elongate particles and the chips were then combined together in a container with 70% Ethanol (1 liter) and ethyl cellulose (20g). The components were mixed together thoroughly and allowed to soak for 30 minutes at room temperature. The mixture was then removed from the excess solution by straining, and placed into a press- mold while still moist. The particles were pressed to 10,000 psi for 10 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45 °C. The implant was then frozen in a -70 °C freezer (1.5 hours), and freeze-dried overnight, after which it was removed from the mold. The wet compressive strength of the osteoimplant exceeded 3 MPa.
  • elongate bone particles Twenty grams of elongate bone particles were produced by milling from diaphyseal bone. The nondemineralized elongate bone particles were mixed with 10 grams dry ethyl cellulose. To this mixture, 150 ml of 95% ethanol was added, and the mixture was stirred for 30 minutes. The fluid was then drained off, and 20 ml of elongate bone particles was measured out and placed in a cylindrical press-mold. The elongate bone particles were pressed for 10 minutes at 56,000 psi. After pressing, the pellet, still in its mold, was placed in an oven at 45 °C for 4 hours, and then in a -70 °C freezer overnight. The pellet was freeze-dried for about 3 days.
  • the resulting osteoimplant (10 mm dia. by 9.1 mm high cylinder) was then re-hydrated overnight in physiological saline (water containing 0.9g NaCl/100 ml water).
  • physiological saline water containing 0.9g NaCl/100 ml water.
  • the wet compressive strength of the osteoimplant was 31.9 MPa.
  • An osteoimplant was prepared as in Example 9, except that the bone particles used were 100-500 ⁇ m powder, superficially demineralized with 0.6N HCl.
  • the mold size was 10 mm diameter for this example.
  • the resulting osteoimplant had a bulk density of 1.9 g/cm 3 and a wet compressive strength of 17.6 MPa.
  • An osteoimplant was prepared as in Example 9, except that the elongate bone particles were pressed in a 10 mm diameter mold for 24 hours at 40°C.
  • the resulting osteoimplant had a bulk density of 1.8 g/cm 3 , and a wet compressive strength of 41.6 MPa.
  • An osteoimplant was prepared as in Example 9, except that the elongate bone particles were placed in a 50% aqueous solution of glycerol and were pressed in a 10mm diameter mold surrounded by heated 50% aqueous solution of glycerol at 40 °C.
  • the implant was pressed to 40,000 psi for 24 hours.
  • the resulting osteoimplant had a bulk density of 1.6 g/cm 3 , and a wet compressive strength of 12.5 MPa.

Abstract

A load-bearing osteoimplant, method of making the osteoimplant and method for repairing bone using the osteoimplant are provided. The osteoimplant comprises a shaped, compressed composition of bone particles. The osteoimplant possesses a bulk density of greater than about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa.

Description

LOAD-BEARING OSTEOIMPLANT, METHOD FOR ITS MANUFACTURE AND METHOD OF REPAIRING BONE USING SAME
FIELD OF THE INVENTION
The present invention relates to an osteoimplant for use in the repair, replacement and/or augmentation of various portions of animal or human skeletal systems, to a method for manufacturing the osteoimplant and to a method of using the osteoimplant. More particularly, this invention relates to an osteogenic osteoimplant which provides mechanical or structural support to a bone repair site.
BACKGROUND OF THE INVENTION
Shaped or cut bone segments have been used extensively to solve various medical problems in human and animal orthopaedic surgical practice, and their application has also extended to the field of cosmetic and reconstructive surgery, dental reconstructive surgery, and other medical fields involving surgery of hard tissues. The use of autograft bone (where the patient provides the source), allograft bone (where another individual of the same species provides the source) or xenograft bone (where another individual of a different species provides the source) is well known in both human and veterinary medicine. In particular, transplanted bone is known to provide support, promote healing, fill bony cavities, separate bony elements (such as vertebral bodies), promote fusion (where bones are induced to grow together into a single, solid mass), or stabilize the sites of fractures. More recently, processed bone has been developed into shapes for use in new surgical applications, or as new materials for implants that were historically made of non-biologically derived materials.
Bone grafting applications are differentiated by the requirements of the skeletal site. Certain applications require a "structural graft" in which one role of the graft is to provide mechanical or structural support to the site. Such grafts contain a substantial portion of mineralized bone tissue to provide the strength needed for load- bearing. The graft may also have beneficial biological properties, such as incorporation into the skeleton, osteoinduction, osteoconduction, or angiogenesis. Structural grafts are conventionally made by processing, and then cutting or otherwise shaping cortical bones collected for transplant purposes. The range of bone grafts that might be thus prepared is limited by the size and shape limitations of the bone TISSUE from which the bone graft originated. Certain clinically desirable shapes and sizes of grafts may thus be unattainable by the cutting and shaping processes, due to the dimensional limitations of the bone. For some shapes they may also be available only in limited amounts, due to the large variations inherent in the human or animal donor source
populations.
Many structural allografts are never fully incorporated by remodeling and replacement with host tissue due, in part, to the difficulty with which the host's blood supply may penetrate cortical bone, and partly to the poor osteoinductivity of nondemineralized bone. To the extent that the implant is incorporated and replaced by living host bone tissue, the body can then recognize and repair damage, thus eliminating failure by fatigue. In applications where the mechanical load-bearing requirements of the graft are challenging, lack of replacement by host bone tissue may compromise the graft by subjecting it to repeated loading and cumulative unrepaired damage (mechanical fatigue) within the implant material. Thus, it is highly desirable that the graft have the capacity to support load initially, and be capable of gradually transferring this load to the host bone tissue as it remodels the implant.
SUMMARY OF THE INVENTION It is an object of the present invention to provide an osteoimplant possessing sufficient strength in a body fluid environment to enable the osteoimplant to bear loads.
It is a further object of the present invention to provide a load-bearing osteoimplant which contains pores or cavities which permit the osteoimplant to be properly revascularized and incorporated by the host.
It is yet a further object of the present invention to provide a load-bearing osteoimplant which is osteogenic and thereby promotes new host bone tissue formation within and around the osteoimplant.
It is yet an even further object of the invention to provide a load-bearing osteoimplant which supports load initially and is capable of gradually transferring this load to the host bone tissue as it remodels the osteoimplant. It is yet an even further object of the invention to provide a method for fabricating an osteoimplant which meets the foregoing objectives.
It is yet an even further object of the present invention to provide a method which enables the fabrication of osteoimplants of any size and/or shape. It is yet an even further object of the present invention to provide a method for preparing osteoimplants which is not limited by constraints imposed by the shape and size of the original bone tissue from which the osteoimplants are derived.
These and further objects of the invention are obtained by a load-bearing osteoimplant which comprises a shaped, compressed composition of bone particles. The osteoimplant possesses a bulk density of greater than about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa. The osteoimplant of this invention is fabricated by the method which comprises providing a composition comprising bone particles optionally in combination with one or more biocompatible components and applying compressive force of greater than about 1000 psi to the composition to provide a load-bearing osteoimplant.
The bone particles utilized in the fabrication of the osteoimplant of this invention are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and combinations thereof. The bone particles are remodeled and replaced by new host bone as incorporation of the osteoimplant progresses in vivo. As described more fully hereinbelow, bone particles can be fully demineralized by removing substantially all of the inorganic mineral content of the bone particles, can be partially demineralized by removing a significant amount, but less than all, of the inorganic mineral content of the bone particles, or can be only superficially demineralized by removing a minor amount of the inorganic mineral content of the bone particles.
The term "demineralized" as applied to the bone particles utilized in the practice of the present invention is intended to cover all bone particles which have had some portion of their original mineral content removed by a demineralization process.
Nondemineralized bone particles provide strength to the osteoimplant and allow it to initially support load. Demineralized bone particles induce new bone formation at the site of the demineralized bone and permit adjustment of the overall mechanical properties of the osteoimplant. The osteoimplant of this invention optionally includes additional biocompatible component(s) such as wetting agents, biocompatible
binders, fillers, fibers, plasticizers, biostatic biocidal agents, surface active agents, bioactive agents, and the like.
The term "osteoimplant" herein is utilized in its broadest sense and is not intended to be limited to any particular shapes, sizes, configurations or applications.
The term "shaped" as applied to the osteoimplant herein refers to a determined or regular form or configuration, in contrast to an indeterminate or vague form or configuration (as in the case of a limp or other solid mass of no special form) and is characteristic of such materials as sheets, plates, disks, cores, pins, screws, tubes, teeth, bones, portion of bone, wedges, cylinders, threaded cylinders, and the like. The phrase "wet compressive strength" as utilized herein refers to the compressive strength of the osteoimplant after the osteoimplant has been immersed in physiological saline (water containing 0.9 g NaCl/100 ml water) for a minimum of 12 hours and a maximum of 24 hours. Compressive strength is a well known measurement of mechanical strength and is measured using the procedure described herein.
The term "osteogenic" as applied to the osteoimplant of this invention shall be understood as referring to the ability of the osteoimplant to enhance or accelerate the ingrowth of new bone tissue by one or more mechanisms such as osteogenesis, osteoconduction and/or osteoinduction.
The term "incorporation" utilized herein refers to the biological mechanism whereby host tissue gradually removes portions of the osteoimplant of the invention and replaces those removed portions with native host bone tissue while maintaining strength. This phenomenon is also known in the scientific literature as "creeping substitution". The term "incorporation" utilized herein shall be understood as embracing what is known by those skilled in the art as "creeping substitution".
BRIEF DESCRIPTION OF THE DRAWINGS
Various embodiments are described below with reference to the drawings wherein: FIGS, la-h show various configurations of an osteoimplant of the present
invention: FIGS. 2a and 2b are views of a vertebrae and the osteoimplant of the invention sized and shaped as a disc (FIG. 2a) and threaded cylinder (FIG. 2b) for installation at an intervertebral site;
FIG. 3 is a view of human cervical vertebrae showing an osteoimplant of the invention affixed thereto as a cervical plate;
FIG. 4 is a view of the human skull showing an osteoimplant of the invention fashioned as a mandibular replacement;
FIG. 5 is a cross-sectional view of a human femur showing implanted therein an osteoimplant fashioned as a femoral implant; FIGS. 6a and 6b show an embodiment of the osteoimplant of the present invention configured and dimensioned as an acetabular cup;
FIG. 7 is a view of a total hip replacement using the femoral implant depicted in FIG. 5 and the acetabular cup depicted in FIG. 6;
FIGS. 8a and 8b are views of a human radius and ulna showing an osteoimplant of the invention fashioned as a diaphyseal plate being implanted at a bone fracture site (FIG. 8a) and as an intercalary implant implanted at a diaphyseal segment missing due to trauma or tumor (FIG. 8b);
FIG. 9 is a view of a human femur and an osteoimplant of the invention fashioned as an intramedullary rod positioned for installation in the medullary canal of the femur; FIG. 10 is a view of a femoral head and an osteoimplant of the invention positioned for installation in a core decompression site in the femoral head;
FIG. 11 is a view of a human skull and an osteoimplant of the present invention positioned for implantation as a parietal bone replacement; FIGS. 12a and 12b show a cylindrical press-mold which can be utilized in the fabrication of the osteoimplant of the invention;
FIG. 13 shows a press which can be utilized in the fabrication of the osteoimplant of the invention; and
FIG. 14 shows a press and heating apparatus which can be utilized in the fabrication of the osteoimplant of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The load-bearing osteoimplant of the present invention is produced by providing a composition comprising bone particles optionally in combination with one or more biocompatible components, and thereafter applying compressive force of at least about 1000 psi to the composition to provide a load-bearing osteoimplant. The osteoimplant fabricated in accordance with the invention possesses a bulk density of at least about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa. In accordance with further embodiments of the invention, the bone particle-containing composition can be heated, lyophilized and/or cross-linked either before, during or after the step of applying a compressive force to the bone particle-containing composition. The bone particles employed in the preparation of the bone particle- containing composition can be obtained from cortical, cancellous and/or corticocancellous bone which may be of autogenous, allogenic and/or xenogeneic origin. Preferably, the bone particles are obtained from cortical bone of allogenic origin. Porcine and bovine bone are particularly advantageous types of xenogeneic bone tissue which can be used individually or in combination as sources for the bone particles. Particles are formed by milling whole bone to produce fibers, chipping whole bone, cutting whole bone, fracturing whole bone in liquid nitrogen, or otherwise disintegrating the bone tissue. Particles can optionally be sieved to produce those of a specific size. The bone particles employed in the composition can be powdered bone particles possessing a wide range of particle sizes ranging from relatively fine powders to coarse grains and even larger chips. Thus, e.g., powdered bone particles can range in average particle size from about 0.05 to about 1.2 cm and preferably from about 0.1 to about 1 cm and possess an average median length to median thickness ratio of from about 1 : 1 to about 3:1. If desired, powdered bone particles can be graded into different sizes to reduce or eliminate any less desirable size(s) of particles which may be present.
Alternatively, or in combination with the aforementioned bone powder, bone particles generally characterized as elongate and possessing relatively high median length to median thickness ratios can be utilized herein. Such elongate particles can be readily obtained by any one of several methods, e.g., by milling or shaving the surface of an entire bone or relatively large section of bone. Employing a milling technique, one can obtain a mass of elongate bone particles containing at least about 60 weight percent, preferably at least about 70 weight percent, and most preferably at least about 80 weight percent of elongate bone particles possessing a median length of from about 2 to about 200 mm or more and preferably from about 10 to about 100 mm, a median thickness of from about 0.05 to about 2 mm, and preferably from about 0.2 to about 1 mm and a median width of from about 1 mm to about 20 mm, and preferably from about 2 to about 5 mm. These elongate bone particles can possess a median length to median thickness ratio of at least about 50:1 up to about 500:1 or more, and preferably from about 50:1 to about 100:1, and a median length to median width ratio of from about 10:1 and about 200: 1 , and preferably from about 50: 1 to about 100: 1. Another procedure for obtaining elongate bone particles, particularly useful for pieces of bone of up to about 100 mm in length, is the bone processing mill described in commonly assigned U.S. Patent No. 5,607,269. Use of this bone mill results in the production of long, thin strips which quickly curl lengthwise to provide tubular-like bone particles. If desired, elongate bone particles can be graded into different sizes to reduce or eliminate any less desirable size(s) of particles which may be present. In overall appearance, elongate bone particles can be described as filaments, fibers, threads, slender or narrow strips, etc.
Preferably, at least about 60 weight percent, more preferably at least about 75 weight percent, and most preferably at least about 90 weight percent of the bone particles utilized in the preparation of the bone particle-containing composition herein are elongate. It has been observed that elongate bone particles provide an osteoimplant possessing particularly good compressive strength.
The bone particles are optionally demineralized in accordance with known and conventional procedures in order to reduce their inorganic mineral content. Demineralization methods remove the inorganic mineral component of bone by employing acid solutions. Such methods are well known in the art, see for example, Reddi et al., Proc. Nat. Acad. Sci. 69, ppl601-1605 (1972), incorporated herein by reference herein. The strength of the acid solution, the shape of the bone particles and the duration of the demineralization treatment will determine the extent of demineralization. Reference in this regard may be made to Lewandrowski et al., J. Biomed Materials Res,
31, pp 365-372 (1996), also incorporated herein by reference.
In a preferred demineralization procedure, the bone particles are subjected to a defatting/disinfecting step which is followed by an acid demineralization step. A preferred defatting/disinfectant solution is an aqueous solution of ethanol, the ethanol being a good solvent for lipids and the water being a good hydrophilic carrier to enable the solution to penetrate more deeply into the bone particles. The aqueous ethanol solution also disinfects the bone by killing vegetative microorganisms and viruses. Ordinarily, at least about 10 to about 40 percent by weight of water (i.e., about 60 to about 90 weight percent of defatting agent such as alcohol) should be present in the defatting disinfecting solution to produce optimal lipid removal and disinfection within the shortest period of time. The preferred concentration range of the defatting solution is from about 60 to about 85 weight percent alcohol and most preferably about 70 weight percent alcohol. Following defatting, the bone particles are immersed in acid over time to effect their demineralization. Acids which can be employed in this step include inorganic acids such as hydrochloric acid and organic acids such as peracetic acid. After acid treatment, the demineralized bone particles are rinsed with sterile water to remove residual amounts of acid and thereby raise the pH. Where elongate bone particles are employed, some entanglement of the wet demineralized bone particles will result. The wet demineralized bone particles can then be immediately shaped into any desired configuration or stored under aseptic conditions, advantageously in a lyophilized state, for processing at a later time. As an alternative to aseptic processing and storage, the particles can be shaped into a desired configuration and sterilized using known methods. As utilized herein, the phrase "superficially demineralized" as applied to the bone particles refers to bone particles possessing at least about 90 weight percent of their original inorganic mineral content. The phrase "partially demineralized" as applied to the bone particles refers to bone particles possessing from about 8 to about 90 weight percent of their original inorganic mineral content, and the phrase "fully demineralized" as applied to the bone particles refers to bone particles possessing less than about 8, preferably less than about 1 , weight percent of their original inorganic mineral content. The unmodified term "demineralized" as applied to the bone particles is intended to cover any one or combination of the foregoing types of demineralized bone particles. Mixtures or combinations of one or more of the foregoing types of bone particles can be employed. For example, one or more of the foregoing types of demineralized bone particles can be employed in combination with nondemineralized bone particles, i.e., bone particles that have not been subjected to a demineralization process.
Nondemineralized bone particles possess an initial and ongoing mechanical role, and later a biological role, in the osteoimplant of this invention. Nondemineralized bone particles act as a stiffener, providing strength to the osteoimplant and enhancing its ability to support load. These bone particles also play a biological role in bringing about new bone ingrowth by the process known as osteoconduction. Thus, these bone particles are gradually remodeled and replaced by new host bone as incorporation of the osteoimplant progresses over time. The use of nondemineralized bone particles is highly preferred, albeit not essential, in the fabrication of the osteoimplant of the present invention. Demineralized bone particles likewise possess an initial and ongoing mechanical role, and later a biological role, in the osteoimplant of this invention. Superficial or partial demineralization produces particles containing a mineralized core. Particles of this type actually can contribute to the strength of the osteoimplant, through their mineralized core. These particles also play a biological role in bringing about new bone ingrowth by the process known as osteoinduction. Full demineralization produces particles in which nearly all of the mineral content has been removed from the particles. Particles treated in this way do not directly contribute to the strength of the osteoimplant; however, they do contribute to the osteoinductivity of the osteoimplant and provide a coherency or binding effect.
When prepared from bone particles that are almost exclusively nondemineralized and/or superficially demineralized the osteoimplant herein will tend to possess a fairly high compressive strength, e.g., one approaching and even exceeding that of natural bone. Accordingly, when an osteoimplant exhibiting a wet compressive strength of on the order of from about 20 to about 200 MPa, is desired, a predominant amount of nondemineralized bone particles and/or superficially demineralized bone particles can be advantageously employed. In order to lower the compressive strength of the osteoimplant, a quantity of partially or fully demineralized bone particles can be employed in combination with nondemineralized bone particles or superficially demineralized bone particles. Thus, the use of various types of bone particles can be used to control the overall mechanical and biological properties, i.e., the strength, osteoconductivity and/or osteoinductivity, etc., of the osteoimplant. The differential in compressive strength, osteogenicity and other properties between partially and/or fully demineralized bone particles on the one hand and non-demineralized and/or superficially demineralized bone particles on the other hand can be exploited. For example, nondemineralized and/or superficially demineralized bone particles can be concentrated in that region of the osteoimplant which will be directly subjected to applied load upon implantation. In one embodiment, where the composition is compressed in a mold, e.g., a cylindrical press-mold, the walls of the mold can be coated with a slurry or paste containing partially and/or fully demineralized bone particles followed by addition of a slurry or paste containing nondemineralized and/or superficially demineralized bone particles (or vice versa) to provide an osteoimplant which contains at least one discrete region, e.g., an outer surface, composed of partially and/or fully demineralized bone particles and at least one discrete region, e.g., a core, composed of nondemineralized and/or superficially demineralized bone particles.
The amount of each individual type of bone particle employed can vary widely depending on the mechanical and biological properties desired. Thus, e.g., the weight ratio of nondemineralized to demineralized bone particles can broadly range from about 20:1 to about 1 :20 and the weight ratio of superficially and/or partially demineralized bone particles to fully demineralized bone particles can broadly range from about 20:1 to about 1 :20. Suitable amounts can be readily determined by those skilled in the art on a case-by-case basis by routine experimentation.
If desired, the bone particles can be modified in one or more ways, e.g., their protein content can be augmented or modified as described in U.S. Patent Nos. 4,743,259 and 4,902,296, the contents of which are incorporated by reference herein. The bone particle-containing composition fabricated in accordance with this disclosure will typically possess a bone particle content ranging from about 5 to about
100 weight percent, preferably from about 40 to about 99 weight percent, and more preferably from about 50 to about 95 weight percent, based on the weight of the entire composition calculated prior to compression of the composition.
The bone particles can be combined with one or more biocompatible components such as wetting agents, biocompatible binders, fillers, fibers, plasticizers, biostatic/biocidal agents, surface active agents, bioactive agents, and the like, prior to, during, or after compressing the bone particle-containing composition. One or more of such components can be combined with the bone particles by any suitable means, e.g., by soaking or immersing the bone particles in a solution or dispersion of the desired component, by physically admixing the bone particles and the desired component, and the like.
Suitable wetting agents include biocompatible liquids such as water, organic protic solvent, aqueous solution such as physiological saline, concentrated saline solutions, sugar solutions, ionic solutions of any kind, and liquid polyhydroxy compounds such as glycerol and glycerol esters, and mixtures thereof. The use of wetting agents in general is preferred in the practice of the present invention, as they improve handling of bone particles. When employed, wetting agents will typically represent from about 20 to about 80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition. Certain wetting agents such as water can be advantageously removed from the osteoimplant, e.g., by heating and lyophilizing the
osteoimplant. Suitable biocompatible binders include biological adhesives such as fibrin glue, fibrinogen, thrombin, mussel adhesive protein, silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin or chitosan; cyanoacrylates; epoxy-based compounds; dental resin sealants; bioactive glass ceramics (such as apatite-wollastonite), dental resin cements; glass ionomer cements (such as Ionocap® and Inocem® available from Ionos
Medizinische Produkte GmbH, Greisberg, Germany); gelatin-resorcinol-formaldehyde glues; collagen-based glues; cellulosics such as ethyl cellulose; bioabsorbable polymers such as starches, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters, polyamino acids, polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly (propylene glycol-co- fumaric acid), tyrosine-based polycarbonates, pharmaceutical tablet binders (such as Eudragit® binders available from Hϋls America, Inc.), polyvinylpyrrolidone, cellulose, ethyl cellulose, micro-crystalline cellulose and blends thereof; starch ethylenevinyl alcohols, polycyanoacrylates; polyphosphazenes; nonbioabsorbable polymers such as polyacrylate, polymethyl methacrylate, polytetrafluoroethylene, polyurethane and polyamide; etc. Preferred binders are polyhydroxybutyrate, polyhydroxyvalerate and tyrosine-based polycarbonates. When employed, binders will typically represent from about 5 to about 70 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
The use of biocompatible binder as biocompatible component is particularly preferred in the practice of the present invention. Biocompatible binder acts as a matrix which binds the bone particles, thus providing coherency in a fluid environment and also improving the mechanical strength of the osteoimplant. Suitable fillers include graphite, pyrolytic carbon, bioceramics, bone powder, demineralized bone powder, anorganic bone (i.e., bone mineral only, with the organic constituents removed), dentin tooth enamel, aragonite, calcite, nacre, amorphous calcium phosphate, hydroxyapatite, tricalcium phosphate, Bioglass® and other calcium phosphate materials, calcium salts, etc. Preferred fillers are demineralized bone powder and hydroxyapatite. When employed, filler will typically represent from about 5 to about
80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
Suitable fibers include carbon fibers, collagen fibers, tendon or ligament derived fibers, keratin, cellulose, hydroxyapatite and other calcium phosphate fibers. When employed, fiber will typically represent from about 5 to about 75 weight percent of the bone particle-containing composition, calculated prior to compression of the
composition.
Suitable plasticizers include liquid polyhydroxy compounds such as
glycerol, monoacetin, diacetin, etc. Glycerol and aqueous solutions of glycerol are preferred. When employed, plasticizer will typically represent from about 20 to about 80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition.
Suitable biostatic/biocidal agents include antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin, povidone, sugars, mucopolysaccharides, etc. Preferred biostatic/biocidal agents are antibiotics. When employed, biostatic/biocidal agent will typically represent from about 10 to about 95 weight percent of the bone particle-containing composition, calculated prior to compression of the composition. Suitable surface active agents include the biocompatible nonionic, cationic, anionic and amphoteric surfactants. Preferred surface active agents are the nonionic surfactants. When employed, surface active agent will typically represent from about 1 to about 80 weight percent of the bone particle-containing composition, calculated prior to compression of the composition. Any of a variety of bioactive substances can be incorporated in, or associated with, the bone particles. Thus, one or more bioactive substances can be combined with the bone particles by soaking or immersing the bone particles in a solution or dispersion of the desired bioactive substance(s). Bioactive substances include physiologically or pharmacologically active substances that act locally or systemically in the host. Bioactive substances which can be readily combined with the bone particles include, e.g., collagen, insoluble collagen derivatives, etc., and soluble solids and/or liquids dissolved therein; antiviricides, particularly those effective against HIV and hepatitis; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin, etc.; biocidal/biostatic sugars such as dextran, glucose, etc.; amino acids; peptides; vitamins; inorganic elements; co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.; polymer cell scaffolds with parenchymal cells; angiogenic agents and polymeric carriers containing such agents; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, genetically engineered living cells or otherwise modified living cells; DNA delivered by plasmid or viral vectors; tissue transplants; demineralized bone powder; autogenous tissues such as blood, serum, soft tissue, bone marrow, etc.; bioadhesives, bone morphogenic proteins (BMPs); osteoinductive factor; fibronectin (FN); endothelial cell growth factor (ECGF); cementum attachment extracts (CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal growth factor (EGF); interleukin-1 (IL-1); human alpha thrombin; transforming growth factor (TGF-beta); insulin-like growth factor (IGF-1); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, bFGF, etc.); periodontal ligament chemotactic factor (PDLGF); somatotropin; bone digestors; antitumor agents; immuno-suppressants; permeation enhancers, e.g., fatty acid esters such as laureate, myristate and stearate monoesters of polyethylene glycol, enamine derivatives, alpha-keto aldehydes, etc.; and nucleic acids. Preferred bioactive substances are currently bone morphogenic proteins and DNA delivered by plasmid or viral vector. When employed, bioactive substance will typically represent from about 0.1 to about 20 weight percent of the bone particle- containing composition, calculated prior to compression of the composition.
It will be understood by those skilled in the art that the foregoing biocompatible components are not intended to be exhaustive and that other biocompatible components may be admixed with bone particles within the practice of the present invention.
The total amount of such optionally added biocompatible substances will typically range from about 0 to about 95, preferably from about 1 to about 60, more preferably from about 5 to about 50, weight percent of the bone particle-containing composition, based on the weight of the entire composition prior to compression of the composition, with optimum levels being readily determined in a specific case by routine experimentation.
One method of fabricating the bone particle-containing composition which can be advantageously utilized herein involves wetting a quantity of bone particles, of which at least about 60 weight percent preferably constitute elongate bone particles, with a wetting agent as described above to form a composition having the consistency of a slurry or paste. Optionally, the wetting agent can comprise dissolved or admixed therein one or more biocompatible substances such as biocompatible binders, fillers, plasticizers, biostatic/biocidal agents, surface active agents, bioactive substances, etc., as previously described. Preferred wetting agents for forming the slurry or paste of bone particles include water, liquid polyhydroxy compounds and their esters, and polyhydroxy compounds in combination with water and/or surface active agents, e.g., the Pluronics® series of nonionic surfactants. Water is the most preferred wetting agent for utilization herein. The preferred polyhydroxy compounds possess up to about 12 carbon atoms and, where their esters are concerned, are preferably the monoesters and diesters. Specific polyhydroxy compounds of the foregoing type include glycerol and its monoesters and diesters derived from low molecular weight carboxylic acids, e.g., monoacetin and diacetin (respectively, glycerol monoacetate and glycerol diacetate), ethylene glycol, diethylene glycol, triethylene glycol, 1 ,2-propanediol, trimethylolethane, trimethylolpropane, pentaerythritol, sorbitol, and the like. Of these, glycerol is especially preferred as it improves the handling characteristics of the bone particles wetted therewith and is biocompatible and easily metabolized. Mixtures of polyhydroxy compounds or esters, e.g., sorbitol dissolved in glycerol, glycerol combined with monoacetin and/or diacetin, etc., are also useful. Where elongate bone particles are employed, some entanglement of the wet bone particles will result. Preferably, excess liquid can be removed from the slurry or paste, e.g., by applying the slurry or paste to a form such as a flat sheet, mesh screen or three-dimensional mold and draining away excess liquid.
Where, in a particular composition, the bone particles have a tendency to quickly or prematurely separate or to otherwise settle out from the slurry or paste such
that application of a fairly homogeneous composition is rendered difficult or inconvenient, it can be advantageous to include within the composition a substance whose thixotropic characteristics prevent or reduce this tendency. Thus, e.g., where the wetting agent is water and/or glycerol and separation of bone particles occurs to an excessive extent where a particular application is concerned, a thickener such as a solution of polyvinyl alcohol, polyvinylpyrrolidone, cellulosic ester such as hydroxypropyl methylcellulose, carboxy methylcellulose, pectin, xanthan gum, food- grade texturizing agent, gelatin, dextran, collagen, starch, hydrolyzed polyacrylonitrile, hydrolyzed polyacrylamide, polyelectrolyte such as polyacrylic acid salt, hydrogels, chitosan, other materials that can suspend particles, etc., can be combined with the wetting agent in an amount sufficient to significantly improve the suspension-keeping characteristics of the composition.
After production of the bone particle-containing composition, the composition is subjected to a compressive force of at least about 1,000 psi to produce the osteoimplant of this invention. Typically, compressive forces of from about 2,500 to about 60,000 psi can be employed with particularly good effect, with compressive forces of from about 2,500 to about 20,000 psi presently being preferred. The compression step will typically be conducted for a period of time ranging from about 0.1 to about 180 hours, preferably from about 4 to about 72 hours. The resulting osteoimplant possesses a bulk density (measured by dividing the weight of the osteoimplant by its volume) of at least about 0.7g/cm3, preferably at least about 1.0 g/cm3. After being immersed in physiological saline for 12-24 hours, the osteoimplant of this invention possesses a wet compressive strength (as measured by the method described hereinbelow) of at least about 3 MPa. Typically, the wet compressive strength of the osteoimplant substantially exceeds 3 MPa. In most cases (and especially where a predominant amount of nondemineralized elongate bone particles are utilized in the fabrication of the osteoimplant), the inventors have found that wet compressive strength normally exceeds about 15 MPa and typically ranges from about 15 to about 100 MPA. The wet compressive strength of the osteoimplant of this invention allows the osteoimplant to provide significant mechanical or structural support to a bone repair site in a body fluid environment over an extended period of time in vivo. To effect compression of the composition, the composition can be placed in a mold possessing any suitable or desired shape or configuration and compressed in a press, e.g., a Carver® manual press.
FIGS. 12a and 12b depict a cylindrical press-mold 10 which is suitable for use in the present invention. Mold 10 consists of three parts, a hollow cylinder 12, an end cap 14 and a plunger 16. Mold 10 is assembled by placing hollow cylinder 10 on top of end cap 12. The interior of hollow cylinder 12 is then filled with the bone particle- containing composition described herein, shown at 18. Thereafter, plunger 16 is placed on top of cylinder 10 which has been filled with bone particle-containing composition 18. As shown best in FIG. 12b, bone particle-containing composition 18 is filled to a height inside cylinder 12 which results in plunger 16 coming to a rest on composition 18 instead of cylinder 12. As shown in FIG. 13, mold 10 is placed inside a manual hydraulic press, generally depicted at 20. Press 20 is equipped with two plates 22 and 24. Plate 24 remains stationary while plate 22 moves in an upward direction as indicated by the arrow in FIG. 13. Movement of plate 22 is hydraulically controlled by means of a handle or other means (not shown) which is operated by the user. As plate 22 moves upward, plunger 16 is forced against plate 24 and moves downward to apply compressive force against composition 18 inside mold 10.
The osteoimplant produced by the method of this invention can be described as a hard, chalk-like material. The osteoimplant may possess tiny pores or cavities which permit the osteoimplant to be properly revascularized and incorporated by the host. It can be easily shaped or machined into any of a wide variety of configurations.
In accordance with a preferred embodiment, the osteoimplant is provided with macroporosity, i.e., holes, which enhance blood flow through the osteoimplant or can be filled with a medically useful substance (such as Grafton® putty available from Osteotech Inc., Eatontown, NJ). Such macroporosity can be provided, e.g., by drilling or by using a mold which possesses spikes therein. Before, during or after application of compressive force to the bone particle-containing composition, the composition can be subjected to an additional operation selected from heating, lyophilizing and cross-linking to further enhance the mechanical and/or biological properties of the osteoimplant. Incorporation of biocompatible component(s), if any, to the composition can precede or come after the step(s) of subjecting the composition to such additional operation(s).
In accordance with a preferred embodiment, the composition is heated during or after the compression step. The composition can be heated at a suitable temperature, e.g., one ranging from about 30° to about 70°C, preferably from about 40° to about 50°C, for 1 to 72 hours preferably 24 to 48 hours. A presently preferred mode of heating involves placing the bone particle-containing composition in a mold and immersing the mold in a heated biocompatible liquid, e.g., water, glycerol, solution of glycerol and water, ionic solutions of any kind, saline, concentrated saline, etc., such that the liquid can communicate with the composition being compressed. Concentrated saline is preferred. The composition inside the mold is compressed to provide an osteoimplant in accordance with the present invention. As shown in FIG. 13, mold 10 is placed in container 30 which is filled with biocompatible liquid 32. Surrounding container 30 is a heat tape 34 which contains electric heating elements (not shown) which are controlled by an electrostat (not shown). By raising the temperature of biocompatible liquid 32, heat is transferred to the composition (not shown) inside mold 10. As plate 22 moves upward, plunger 16 is compressed against plate 24 and exerts downward compressive force against the composition. While not wishing to be bound by theory, it is believed that biocompatible liquid 32 actually enters mold 10 through seams formed by the connection between end cap 14 and cylinder 12 and contacts the composition. It has been discovered that this mode of heating provides osteoimplants possessing particularly good strength characteristics.
The osteoimplant can be lyophilized, advantageously after the bone particle-containing composition has been compressed in accordance with this disclosure, under conditions that are well known in the art, e.g., a shelf temperature of from about - 20° to about -55 °C, a vacuum of from about 150 to about 100 mTorr for a period of time ranging from about 4 to about 48 hours.
Crosslinking can be performed in order to improve the strength of the osteoimplant. Crosslinking of the bone particle-containing composition can be effected by a variety of known methods including chemical reaction, the application of energy such as radiant energy, which includes irradiation by UV light or microwave energy, drying and/or heating and dye-mediated photo-oxidation; dehydrothermal treatment in which water is slowly removed while the bone particles are subjected to a vacuum; and, enzymatic treatment to form chemical linkages at any collagen-collagen interface. The preferred method of forming chemical linkages is by chemical reaction.
Chemical crosslinking agents include those that contain bifunctional or multifunctional reactive groups, and which react with surface-exposed collagen of adjacent bone particles within the bone particle-containing composition. By reacting with multiple functional groups on the same or different collagen molecules, the chemical crosslinking agent increases the mechanical strength of the osteoimplant.
Chemical crosslinking involves exposing the bone particles presenting surface-exposed collagen to the chemical crosslinking agent, either by contacting bone particles with a solution of the chemical crosslinking agent, or by exposing bone particles to the vapors of the chemical crosslinking agent under conditions appropriate for the particular type of crosslinking reaction. For example, the osteoimplant of this invention can be immersed in a solution of cross-linking agent for a period of time sufficient to allow complete penetration of the solution into the osteoimplant. Crosslinking conditions include an appropriate pH and temperature, and times ranging from minutes to days, depending upon the level of crosslinking desired, and the activity of the chemical crosslinking agent. The resulting osteoimplant is then washed to remove all leachable traces of the chemical.
Suitable chemical crosslinking agents include mono- and dialdehydes, including glutaraldehyde and formaldehyde; polyepoxy compounds such as glycerol polyglycidyl ethers, polyethylene glycol diglycidyl ethers and other polyepoxy and diepoxy glycidyl ethers; tanning agents including polyvalent metallic oxides such as titanium dioxide, chromium dioxide, aluminum dioxide, zirconium salt, as well as organic tannins and other phenolic oxides derived from plants; chemicals for esterification or carboxyl groups followed by reaction with hydrazide to form activated acyl azide functionalities in the collagen; dicyclohexyl carbodiimide and its derivatives as well as other heterobifunctional crosslinking agents; hexamethylene diisocyante; sugars, including glucose, will also crosslink collagen.
Glutaraldehyde crosslinked biomaterials have a tendency to over-calcify in the body. In this situation, should it be deemed necessary, calcification-controlling agents can be used with aldehyde crosslinking agents. These calcification-controlling agents include dimethyl sulfoxide (DMSO), surfactants, diphosphonates, aminooleic acid, and metallic ions, for example ions of iron and aluminum. The concentrations of these calcification-controlling agents can be determined by routine experimentation by those skilled in the art. When enzymatic treatment is employed, useful enzymes include those known in the art which are capable of catalyzing crosslinking reactions on proteins or peptides, preferably collagen molecules, e.g., transglutaminase as described in Jurgensen et al., The Journal of Bone and Joint Surgery, 79-a (2), 185-193 (1997), herein incorporated by reference. Formation of chemical linkages can also be accomplished by the application of energy. One way to form chemical linkages by application of energy is to use methods known to form highly reactive oxygen ions generated from atmospheric gas, which in turn, promote oxygen crosslinks between surface-exposed collagen. Such methods include using energy in the form of ultraviolet light, microwave energy and the like. Another method utilizing the application of energy is a process known as dye- mediated photo-oxidation in which a chemical dye under the action of visible light is used to crosslink surface-exposed collagen.
Another method for the formation of chemical linkages is by dehydrothermal treatment which uses combined heat and the slow removal of water, preferably under vacuum, to achieve crosslinking of bone particles. The process involves chemically combining a hydroxy group from a functional group of one collagen molecule and a hydrogen ion from a functional group of another collagen molecule reacting to form water which is then removed resulting in the formation of a bond between the collagen molecules. The resulting osteoimplant can assume a determined or regular form or configuration such as a sheet, plate, disk, cone, pin, screw, tube, tooth, tooth root, bone or portion of bone, wedge or portion of wedge, cylinder, threaded cylinder (dowel), to name but a few. Of course, the osteoimplant can be machined or shaped by any suitable mechanical shaping means. Computerized modeling can, for example, be employed to provide an intricately-shaped osteoimplant which is custom-fitted to the bone repair site with great precision. In a preferred embodiment, the osteoimplant possesses the configuration of a threaded cylinder (dowel).
It will be understood that combinations of one or more of the foregoing operations can be employed, e.g., heating followed by lyophilizing; cross-linking
followed by heating, etc. The osteoimplant herein is applied at a bone repair site, e.g., one resulting from injury, defect brought about during the course of surgery, infection, malignancy or developmental malformation, which requires mechanical support. The osteoimplant can be utilized in a wide variety of orthopaedic, periodontal, neurosurgical and oral and maxillofacial surgical procedures such as 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 filling, 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 replacement, alveolar ridge augmentation and reconstruction, onlay bone grafts, implant placement and revision, sinus lifts, etc. Specific bones which can be repaired or replaced with the bone- derived implant herein include 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 osteoimplant can be implanted at the bone repair site, if desired, using any suitable affixation means, e.g., sutures, staples, bioadhesives, and the like. Referring now to the drawings, FIGS, la-h depict various embodiments of an osteoimplant according to the present invention configured and dimensioned in the shape of a cylinder 40, wedge 50, plate 60, threaded cylinder (dowel) 70, fibular wedge 62, femoral struts 64, 66 and tibial strut 68. In accordance with a preferred embodiment, cylinder 20 and wedge 30 are provided with macroporosity, namely holes 42 and 52, respectively, which have been drilled into cylinder 40 and wedge 50. Macroporosity promotes blood flow through the osteoimplant and enhances and accelerates the incorporation of the osteoimplant by the host. Furthermore, macroporous holes 42 and 52 can be advantageously filled with an osteogenic material, e.g., Grafton® putty available from Osteotech, Inc., Eastontown, NJ.
In FIG. 2a, osteoimplant 80 is configured and dimensioned as a disk to be inserted into the intervertebral fibrocartilage site 82 on the anterior side of vertebral column 84. In FIG. 2b, osteoimplant 70 is configured and dimensioned as a threaded cylinder (as depicted in FIG. Id) to be inserted into the intervertebral site 72 on the anterior side of vertebral column 84.
In FIG. 3, the osteoimplant of the invention is configured and dimensioned as a cervical plate 90 and is shown affixed to cervical vertebrae 94, 96 by bone screws 92. In accordance with a preferred embodiment, bone screws 92 form yet another embodiment of the osteoimplant of the present invention. In FIG. 4, the osteoimplant 100 of the invention is sized and shaped to form the mandible of skull 102. In FIG. 5, the osteoimplant 110 of the invention is sized and shaped as a femoral implant. Osteoimplant 110 comprises head 112 which is attached to ball 114. Ball 114 is fabricated from plastic or metal and is affixed to osteoimplant 110 by any suitable means, e.g, screw 116. Osteoimplant is inserted into intramedullary canal 118 of femur 120.
In FIG. 6a and b, the osteoimplant 130 of the invention is sized and shaped as an acetabular cup which is configured and dimensioned to receive plastic or metallic liner 132.
In FIG. 7, a total hip replacement with the osteoimplant 110 depicted in FIG. 5 and the osteoimplant 130 of FIGS. 6a and 6b is depicted.
In FIG. 8a, the osteoimplant 140 of the invention is sized and shaped as a diaphyseal implant and is shown being implanted via bone screws 142 on a fracture 144 along the diaphyseal segment of a human radius 146. Optionally, and preferably, screws 142 can be fabricated from compressed bone particles in accordance with this disclosure. In FIG 8b, osteoimplant 180 of the invention is sized and shaped as an intercalary implant and is shown already implanted at a diaphyseal segment of human radius 146 that is missing due to trauma or tumor.
In FIG. 9, the osteoimplant 150 of the invention is sized and shaped as an intramedullary rod for insertion into the medullary canal 154 of femur 152.
In FIG. 10, osteoimplant 186 is sized and shaped as a reinforcement rod for insertion into a core decompression site 184 formed by drilling a hole into femoral head 182.
In FIG. 11, osteoimplant 160 is sized and shaped to form part of the parietal bone 162 for skull 164. Osteoimplant 160 promotes fusion with parietal bone 88.
The present invention is intended to embrace all such devices which are constructed as the osteoimplant of the present invention and the attendant uses of such devices.
It will also be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.
The following examples illustrate the practice of this invention. Wet Compressive Strength
Wet compressive strength of the osteoimplant of this invention is measured using the following method:
Initial density is determined by measuring specimen dimensions with a caliper to determine volume, and then weighing the specimen on a laboratory balance. The specimen is then placed in a container with 0.9% NaCl solution at room temperature for 12-24 hours. After the hydration period, the specimen is measured again to determine dimensions, and dimensions are recorded. The specimen is then centered on a compression platen (MTS 643.10A-01) in a servohydraulic testing system (MTS 858 Bionix). The top platen is lowered onto the specimen until a compressive preload of 0.1 kN is achieved. The system displacement transducer is then zeroed (MTS 358.10), defining zero displacement as the displacement associated initially with 0.1 kN preload.
Using system software (MTS 790.90 Testworks for Teststar), the specimen is loaded in the displacement mode, using a ramp compressive load of 0.5 mm/s, until an endpoint of 4 mm displacement is achieved. After the 4 mm displacement is achieved, the loading is stopped automatically, and the specimen is unloaded. During testing, load (from the system load cell MTS 661.20E-03) and displacement data are collected every 0.05 sec.
EXAMPLE 1
Elongate bone particles were prepared using a milling machine. Half of the volume of the particles was fully demineralized using two charges of 0.6N HC1 acid. The nondemineralized and the fully demineralized particles were then combined together in an aqueous solution containing glycerol and allowed to soak for 4-12 hours at room temperature. The particles were then removed from the solution by straining, and placed into a 28 mm diameter cylindrical press-mold while still moist. The particles were pressed to 10,000 psi for 15 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45 °C. The osteoimplant was then frozen in a -70°C freezer (1.5 hours), and freeze-dried overnight, after which it was removed from the mold. The bulk density of the osteoimplant produced was 1.34 g/cm3. The height of the osteoimplant was 29 mm. The wet compressive strength of the osteoimplant exceeded 3 MPa.
EXAMPLE 2
The procedure of Example 1 was used except the ratio of fully demineralized to nondemineralized bone particles was 2:1, the pellet was heated in situ in an oven for 4 hours at 40°C and the pressure was 2,500 psi. The resulting compressed pellet was cut into two portions and each portion was treated with crosslinking agent: 10% neutral buffered formalin (both dipped and in vapor phase) and 4% Denacol EX313
(a polyepoxy-ether compound available from Nagase America Corp., New York, NY), respectively. In each case, the resulting osteoimplant swelled a little and became stiff, and resistant to manual pressure. The bulk density of the osteoimplant produced was 1.2 g/cm3. The wet compressive strength of the osteoimplant exceeded 3 MPa.
EXAMPLE 3 The procedure of Example 1 was followed except that all of the particles were partially demineralized by using 225 ml of 0.6N HC1 and allowing the acid to react to depletion. Additionally, the mold was hexagonal in configuration (with each side of the hexagon measuring 18 mm). After completing the freeze-drying step, the resulting osteoimplant was placed in a bath of 10% neutral buffered formalin and the exposed collagen of the partially demineralized bone particles was allowed to cross-link for 48 hours. The resulting dry osteoimplant was tested mechanically and was found to possess a dry compressive strength of about 85 MPa. The bulk density of the osteoimplant was 1.05 g/cm3.
EXAMPLE 4
The procedure of Example 3 was repeated and the resulting osteoimplant was immersed in physiological saline for 12-24 hours and was found to possess an ultimate wet compressive strength of about 45 MPa. The bulk density of the osteoimplant was 1.05 g/cm3.
EXAMPLE 5
Elongate bone particles were prepared using a milling machine. The nondemineralized particles were then combined with ethyl cellulose (3:2 ratio by weight), and covered with 70% ethanol for 30 minutes, with stirring. The elongate bone particles were then removed from the solution by straining, and placed into a press-mold while still moist. The elongate bone particles were pressed to 10,000 psi for 15 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45 °C. The implant was then frozen in a -70 °C freezer (overnight), and freeze-dried, after which it was removed from the mold. The osteoimplant was immersed in physiological saline overnight and was found to possess a wet compressive strength of 20 MPa. EXAMPLE 6
Bone particles were prepared by using a block plane on the periosteal surface of cortical bone. Half of the volume of the bone particles was fully demineralized using two changes of 0.6N HC1 acid. The mineralized (25 g) and the demineralized particles (25 g based on original weight) were then combined together in a 70% ethanol solution with 20 g ethyl cellulose. This mixture was stirred for 30 minutes at room temperature. The particles were then removed form the solution by straining, and placed into a cylindrical press-mold while still moist. The particles were pressed to 18,000 psi for 10 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45°C. The implant was then frozen in a -70°C freezer (1.5 hours), and freeze-dried overnight, after which it was removed from the mold. The dry compressive strength of the osteoimplant was 6.5 MPa and the wet compressive strength of the osteoimplant was 4.0 MPa.
EXAMPLE 7
Elongate bone particles were prepared using a milling machine (30g). An equivalent amount by weight of cortical bone chips were also prepared by grinding in a bone mill. Chips were sieved between screens having dimensions between 4.0 mm and 1.8 mm. The elongate particles and the chips were then combined together in a container with 70% Ethanol (1 liter) and ethyl cellulose (20g). The components were mixed together thoroughly and allowed to soak for 30 minutes at room temperature. The mixture was then removed from the excess solution by straining, and placed into a press- mold while still moist. The particles were pressed to 10,000 psi for 10 minutes. The resulting compressed pellet was heated in situ in an oven for 4 hours at 45 °C. The implant was then frozen in a -70 °C freezer (1.5 hours), and freeze-dried overnight, after which it was removed from the mold. The wet compressive strength of the osteoimplant exceeded 3 MPa.
EXAMPLE 8
Twenty grams of elongate bone particles were produced by milling from diaphyseal bone. The nondemineralized elongate bone particles were mixed with 10 grams dry ethyl cellulose. To this mixture, 150 ml of 95% ethanol was added, and the mixture was stirred for 30 minutes. The fluid was then drained off, and 20 ml of elongate bone particles was measured out and placed in a cylindrical press-mold. The elongate bone particles were pressed for 10 minutes at 56,000 psi. After pressing, the pellet, still in its mold, was placed in an oven at 45 °C for 4 hours, and then in a -70 °C freezer overnight. The pellet was freeze-dried for about 3 days. The resulting osteoimplant (10 mm dia. by 9.1 mm high cylinder) was then re-hydrated overnight in physiological saline (water containing 0.9g NaCl/100 ml water). The wet compressive strength of the osteoimplant was 31.9 MPa.
EXAMPLE 9
Elongate bone particles were produced by milling from diaphyseal bone. These elongate bone particles were then partially demineralized using 14 ml of 0.6 HCl acid solution. The acid was allowed to react to exhaustion (pH=7). The partially demineralized elongate bone particles were then washed in water, and placed into a 13 mm cylindrical press-mold. The filled mold was placed in a heated water bath made by surrounding an open-topped metal flask with a heating strip. The water was heated continuously to 70 °C during the pressing process. The bone particles were pressed at 120,000 psi for 3 days. The pellet produced was placed in a -70°C freezer for 1 hour, then freeze-dried for 24 hours. The resulting osteoimplant had a bulk density of 1.9 g/cm3. This osteoimplant was rehydrated overnight in physiological saline, and then tested for wet compressive strength. The resulting wet compressive strength was 56.4
MPa.
EXAMPLE 10
An osteoimplant was prepared as in Example 9, except that the bone particles used were 100-500 μm powder, superficially demineralized with 0.6N HCl. The mold size was 10 mm diameter for this example. The resulting osteoimplant had a bulk density of 1.9 g/cm3 and a wet compressive strength of 17.6 MPa.
EXAMPLE 11
An osteoimplant was prepared as in Example 9, except that the elongate bone particles were pressed in a 10 mm diameter mold for 24 hours at 40°C. The resulting osteoimplant had a bulk density of 1.8 g/cm3, and a wet compressive strength of 41.6 MPa.
EXAMPLE 12
An osteoimplant was prepared as in Example 9, except that the elongate bone particles were placed in a 50% aqueous solution of glycerol and were pressed in a 10mm diameter mold surrounded by heated 50% aqueous solution of glycerol at 40 °C.
The implant was pressed to 40,000 psi for 24 hours. The resulting osteoimplant had a bulk density of 1.6 g/cm3, and a wet compressive strength of 12.5 MPa.

Claims

WHAT IS CLAIMED IS:
1. A method of fabricating a load-bearing osteoimplant which comprises: providing a composition comprising bone particles optionally in combination with one or more biocompatible components; and, applying a compressive force of greater than about 1000 psi to the composition to provide an osteoimplant, said osteoimplant possessing a bulk density of greater than about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa.
2. The method of Claim 1 wherein the biocompatible component is selected from the group consisting of wetting agent, biocompatible binder, filler, fiber, plasticizer, biostatic/biocidal agent, surface active agent, and bioactive substance.
3. The method of Claim 2 wherein the wetting agent is selected from the group consisting of water, organic pro tic solvent, physiological saline, concentrated saline, sugar solution, ionic solution, liquid polyhydroxy compound and mixtures thereof.
4. The method of Claim 3 wherein the polyhydroxy compound is selected from the group consisting of glycerol and glycerol esters.
5. The method of Claim 2 wherein the binder is a biological adhesive.
6. The method of Claim 5 wherein the biological adhesive is selected from the group consisting of fibrin glue, fibrinogen, thrombin, mussel adhesive protein, silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin and chitosan.
7. The method of Claim 2 wherein the binder is a bioabsorbable polymer.
8. The method of Claim 7 wherein the bioabsorbable polymer is selected from the group consisting of starches, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters, polyamino acids, polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly (propylene glycol-co-fumaric acid), tyrosine-based polycarbonates, pharmaceutical tablet binders, polyvinylpyroUidone, cellulose, ethyl cellulose, micro-crystalline cellulose, and blends thereof.
9. The method of Claim 2 wherein the binder is a nonbioabsorbable
polymer.
10. The method of Claim 9 wherein the nonbioabsorbable polymer is selected from the group consisting of poly aery late, polymethyl methacrylate, polytetrafluoroethylene, polyurethane, and polyamide.
11. The method of Claim 2 wherein the filler is selected from the group consisting calcium phosphates, tricalcium phosphate, hydroxyapatite calcium salts, bone powder, demineralized bone powder, anorganic bone, dental tooth enamel, aragonite, calcite, nacre, graphite, pyrolytic carbon, Bioglass®, bioceramic, and mixtures thereof.
12. The method of Claim 2 wherein the surface active agent is selected from the group consisting of nonionic, cationic, anionic, amphoteric surfactants, and mixtures thereof.
13. The method of Claim 2 wherein the bioactive substance is selected from the group consisting of collagen, insoluble collagen derivatives, and soluble solids and or liquids dissolved therein; antiviricides, antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin; biocidal/biostatic sugars such as dextran, glucose, amino acids, peptides; vitamins; inorganic elements; co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes such as collagenase, peptidases, oxidases; polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells such as chondrocytes; bone marrow cells; mesenchymal stem cells; natural extracts; genetically engineered living cells or otherwise modified living cells; DNA delivered by plasmid or viral vectors; tissue transplants; demineralized bone powder; autogenous tissues such as blood, serum, soft tissue, bone marrow; bioadhesives, bone morphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin (FN); endothelial cell growth factor (ECGF); cementum attachment extracts (CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal growth factor (EGF); interleukin-1 (IL-1); human alpha thrombin; fransfoπning growth factor (TGF- beta); insulin-like growth factor (IGF-1); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, bFGF, etc.); periodontal ligament chemotactic factor (PDLGF); somatotropin; bone digestors; antitumor agents; immuno-suppressants; permeation enhancers; enamine derivatives; alpha-keto aldehydes; and nucleic acids.
14. The method of Claim 12 wherein the bioactive substance is a growth factor selected from the group consisting of transforming growth factor (TGF- beta), insulin-like growth factor (IGF-1), somatotropin, basic fibroblast growth factor
(BFGF) and mixtures thereof.
15. The method of Claim 2 wherein the bioactive substance is bone
morphogenetic protein (BMP).
16. The method of Claim 2 wherein the biostatic/biocidal agent is selected from the group consisting of antibiotics, povidone, sugars and mixtures thereof.
17. The method of Claim 1 wherein the composition comprises from about 5 to about 100 weight percent bone particles and from about 0 to about 95 weight percent of at least one biocompatible component.
18. The method of Claim 1 wherein at least about 60 weight percent of the bone particles are elongate.
19. The method of Claim 1 wherein the bone particles are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and mixtures thereof.
20. The method of Claim 19 wherein the demineralized bone particles are selected from the group consisting of superficially demineralized, partially demineralized and fully demineralized bone particles.
21. The method of Claim 19 wherein the demineralized bone particles are fully demineralized bone particles.
22. The method of Claim 1 wherein the bone particles are obtained from cortical, cancellous or cortico-cancellous bone of autogenous, allogenic or xenogeneic origin.
23. The method of Claim 1 wherein the bone particles are obtained from porcine or bovine bone.
24. The method of Claim 1 wherein the bone particles comprise a mixture of nondemineralized bone particles and demineralized bone particles.
25. The method of Claim 24 wherein at least about 60 weight percent of the nondemineralized bone particles are elongate and at least about 60 weight percent of the demineralized bone particles are elongate.
26. The method of Claim 24 wherein the weight ratio of nondemineralized to demineralized bone particles ranges from about 20:1 to about 1:20.
27. The method of Claim 24 wherein the mixture comprises from about 5 to about 100 weight percent of the composition.
28. The method of Claim 24 wherein the biocompatible component comprises a wetting agent.
29. The method of Claim 24 wherein the biocompatible component comprises a binder.
30. The method of Claim 1 which further comprises applying heat to the composition before, during or after the application of compressive force to the composition.
31. The method of Claim 1 which further comprises cross-linking bone particles within the composition before, during or after the application of compressive force to the composition.
32. The method of Claim 1 which further comprises freeze-drying the composition before, during or after the application of compressive force to the composition.
33. The method of Claim 1 which further comprises applying heat to the composition before, during or after the application of compressive force to the composition followed by freeze-drying the heated, compressed composition.
34. The load-bearing osteoimplant produced by the method of Claim 1.
35. A load-bearing osteoimplant comprising a shaped, compressed composition of bone particles, wherein the osteoimplant possesses a bulk density of greater than about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa.
36. The osteoimplant of Claim 35 wherein the bone particles are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and mixtures thereof.
37. The osteoimplant of Claim 36 wherein the demineralized bone particles are selected from the group consisting of superficially demineralized, partially demineralized and fully demineralized bone particles.
38. The osteoimplant of Claim 36 wherein the demineralized bone particles are fully demineralized.
39. The osteoimplant of Claim 35 wherein the bone particles are obtained from cortical, cancellous or cortico-cancellous bone of autogenous, allogenic or
xenogeneic origin.
40. The osteoimplant of Claim 35 wherein the bone particles are obtained from porcine or bovine bone.
41. The osteoimplant of Claim 35 wherein the bone particles comprise a mixture of nondemineralized bone particles and demineralized bone particles.
42. The osteoimplant of Claim 35 wherein the bone particles comprise a mixture of partially demineralized bone particles and fully demineralized bone particles.
43. The osteoimplant of Claim 42 wherein the bone particles further comprise nondemineralized bone particles.
44. The osteoimplant of Claim 35 wherein at least about 60 weight percent of the bone particles are elongate.
45. The osteoimplant of Claim 35 wherein at least about 90 weight percent of the bone particles are elongate.
46. The osteoimplant of Claim 35 further comprising at least one biocompatible component.
47. The osteoimplant of Claim 46 wherein the biocompatible component is selected from the group consisting of wetting agent, biocompatible binder, filler, fiber, surface active agent, bioactive substance and biostatic/biocidal agent.
48. The osteoimplant of Claim 47 wherein the wetting agent is selected from the group consisting of water, organic protic solvent, physiological saline liquid polyhydroxy compound and mixture of water and liquid polyhydroxy compound.
49. The osteoimplant of Claim 48 wherein the polyhydroxy compound is selected from the group consisting of glycerol and glycerol esters.
50. The osteoimplant of Claim 47 wherein the biocompatible binder is a biological adhesive.
51. The osteoimplant of Claim 50 wherein the biological adhesive is fibrin glue, fibrinogen thrombin, mussel adhesive protein, silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin or chitosan.
52. The osteoimplant of Claim 47 wherein the biocompatible binder is a bioabsorbable polymer.
53. The osteoimplant of Claim 52 wherein the bioabsorbable polymer is selected from the group consisting of starches, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters, polyamino acids, polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly (propylene glycol-co-fumaric acid), tyrosine-based polycarbonates, tablet binders, polyvinylpyroUidone, cellulose, ethyl cellulose, micro- crystalline cellulose, and blends thereof.
54. The osteoimplant of Claim 47 wherein the biocompatible binder is a nonbioabsorbable polymer.
55. The osteoimplant of Claim 54 wherein the nonbioabsorbable polymer is selected from the group consisting of polyacrylate, polymethyl methacrylate polytetrafluoroethylene, polyurethane, and polyamide.
56. The osteoimplant of Claim 47 wherein the filler is selected from the group consisting calcium phosphates, calcium salts, bone powder, graphite, pyrolytic carbon, bioglass, bioceramic, and mixtures thereof.
57. The osteoimplant of Claim 47 wherein the surface active agent is selected from the group consisting of nonionic, cationic, anionic, amphoteric surfactants, and mixtures thereof.
58. The osteoimplant of Claim 47 wherein the bioactive substance is selected from the group consisting of collagen, insoluble collagen derivatives, and soluble solids and/or liquids dissolved therein; antiviricides, antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin; biocidal/biostatic sugars such as dextran, glucose, amino acids, peptides; vitamins; inorganic elements; co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes such as collagenase, peptidases, oxidases; polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells such as chondrocytes; bone marrow cells; mesenchymal stem cells; natural extracts; genetically engineered living cells or otherwise modified living cells; DNA delivered by plasmid or viral vectors; tissue transplants; demineralized bone powder; autogenous tissues such as blood, serum, soft tissue, bone marrow; bioadhesives, bone morphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin (FN); endothelial cell growth factor (ECGF); cementum attachment extracts
(CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal • growth factor (EGF); interleukin-1 (IL-1); human alpha thrombin; fransforrning growth factor (TGF-beta); insulin-like growth factor (IGF-1); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, bFGF, etc.); periodontal ligament chemotactic factor (PDLGF); somatotropin; bone digestors; antitumor agents; immuno-suppressants; permeation enhancers; enamine derivatives; alpha-keto aldehydes; and nucleic acids.
59. The osteoimplant of Claim 47 wherein the bioactive substance is a growth factor selected from the group consisting of transforming growth factor (TGF- beta), insulin-like growth factor (IGF-1), somatotropin, basic fibroblast growth factor (BFGF) and mixtures thereof.
60. The osteoimplant of Claim 47 wherein the bioactive substance is bone morphogenetic protein (BMP).
61. The osteoimplant of Claim 47 wherein the biostatic/biocidal agent is selected from the group consisting of antibiotics, povidone, sugars and mixtures
thereof.
62. The osteoimplant of Claim 47 wherein the bone particles represent from about 5 to about 100 and the biocompatible component represents from about 0 to about 95 weight percent of the osteoimplant.
63. The osteoimplant of Claim 41 wherein the weight ratio of nondemineralized bone particles to demineralized bone particles ranges from about 20:1 to about 1 :20.
64. The osteoimplant of Claim 42 wherein the weight ratio of partially demineralized bone particles to fully demineralized bone particles ranges from about 20:1 to about 1:20.
65. An osteoimplant comprising a shaped, compressed composition of elongate bone particles selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and combinations thereof, wherein the osteoimplant possesses a bulk density of greater than about 1.0 g/cm3 and a wet compressive strength of at least about 15 MPa.
66. The osteoimplant of Claim 65 further comprising at least one biocompatible component.
67. The osteoimplant of Claim 66 wherein the biocompatible component is selected from the group consisting of wetting agent, binder, filler, fiber, surface active agent, bioactive substance and biostatic/biocidal agent.
68. A method of repairing bone comprising implanting at a bone repair site a load-bearing osteoimplant comprising a shaped, compressed composition of bone particles, said osteoimplant possessing a bulk density of greater than about 0.7 g/cm3 and a wet compressive strength of at least about 3 MPa.
69. The method of Claim 68 wherein the bone particles are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and mixtures thereof.
70. The method of Claim 68 wherein the bone particles are obtained from cortical, cancellous or cortico-cancellous bone of autogenous, allogenic or xenogeneic origin.
71. The method of Claim 68 wherein at least about 60 weight percent of the bone particles are elongate.
72. The method of Claim 68 wherein the osteoimplant further comprises at least one biocompatible component.
73. The method of Claim 72 wherein the biocompatible component is selected from the group consisting of wetting agent, biocompatible binder, filler, fiber, surface active agent, bioactive substance and biostatic/biocidal agent.
74. The method of Claim 68 wherein the bone particles represent from about 5 to about 100 weight percent of the osteoimplant.
75. The method of Claim 72 wherein the biocompatible component represents from about 0 to about 95 weight percent of the osteoimplant.
76. The method of Claim 30 wherein heat is applied to the composition by contacting the composition with a heated biocompatible liquid.
PCT/US2000/004408 1999-02-23 2000-02-22 Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same WO2000050102A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000600712A JP4658331B2 (en) 1999-02-23 2000-02-22 Load-bearing implant, method for producing the same, and method for preparing bone using the same
EP00915821A EP1152777B1 (en) 1999-02-23 2000-02-22 Load-bearing osteoimplant and method for its manufacture
AU37033/00A AU758828B2 (en) 1999-02-23 2000-02-22 Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
CA2363153A CA2363153C (en) 1999-02-23 2000-02-22 Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
DE60027698T DE60027698T2 (en) 1999-02-23 2000-02-22 LOAD-LOADING OSTEOIMPLANTATE AND METHOD FOR THE PRODUCTION THEREOF

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/256,447 US6294187B1 (en) 1999-02-23 1999-02-23 Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
US09/256,447 1999-02-23

Publications (1)

Publication Number Publication Date
WO2000050102A1 true WO2000050102A1 (en) 2000-08-31

Family

ID=22972272

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/004408 WO2000050102A1 (en) 1999-02-23 2000-02-22 Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same

Country Status (10)

Country Link
US (2) US6294187B1 (en)
EP (1) EP1152777B1 (en)
JP (1) JP4658331B2 (en)
KR (1) KR100754814B1 (en)
AU (1) AU758828B2 (en)
CA (1) CA2363153C (en)
DE (1) DE60027698T2 (en)
ES (1) ES2261191T3 (en)
TR (1) TR200102480T2 (en)
WO (1) WO2000050102A1 (en)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001082993A2 (en) * 1999-03-16 2001-11-08 Regeneration Technologies, Inc. Implants for orthopedic applications
WO2002002156A2 (en) * 2000-07-03 2002-01-10 Osteotech, Inc. Osteogenic implants derived from bone
WO2002005750A2 (en) * 2000-07-19 2002-01-24 Osteotech, Inc. Osteoimplant and method of making same
WO2002024243A1 (en) * 2000-09-19 2002-03-28 Eduardo Anitua Aldecoa Method for surface treatment of implants or prosthesis made of titanium or other materials
WO2002032348A1 (en) * 2000-10-13 2002-04-25 Osteotech, Inc. Volume maintaining osteoinductive/oesteoconductive compositions
WO2002064181A1 (en) * 2001-02-14 2002-08-22 Osteotech, Inc. Implant derived from bone
WO2003013623A1 (en) * 2001-08-10 2003-02-20 Osteotech, Inc. Bone plating system and method of use
EP1369095A2 (en) * 2002-06-04 2003-12-10 MTF MediTech Franken GmbH Method and device for moistening a medical implant or graft
JP2004501682A (en) * 2000-06-29 2004-01-22 バイオシンテック カナダ インコーポレーティッド Compositions and methods for cartilage and other tissue repair and regeneration
US6863694B1 (en) 2000-07-03 2005-03-08 Osteotech, Inc. Osteogenic implants derived from bone
EP1534353A1 (en) * 2002-06-10 2005-06-01 Keratec Limited Orthopaedic materials derived from keratin
EP1578957A1 (en) * 2002-12-12 2005-09-28 Osteotech, Inc. Formable and settable polymer bone composite and method of production thereof
KR100750190B1 (en) 2004-06-16 2007-08-31 요업기술원 Effective bone filler and manufacturing methods thereof
AU2005203606B2 (en) * 2000-10-24 2009-01-08 Warsaw Orthopedic, Inc. Spinal fusion methods and devices
SG151097A1 (en) * 2002-08-12 2009-04-30 Osteotech Inc Synthesis of a bone-polymer composite material
US7594577B2 (en) 2002-06-04 2009-09-29 Mtf Meditech Franken Gmbh Method and device for moistening non-biological medical implant material
EP2231210A1 (en) * 2007-12-12 2010-09-29 Osteotech, Inc., Bone/collagen composites and uses thereof
EP2295088A1 (en) * 2001-10-12 2011-03-16 Osteotech, Inc., Improved bone graft
AU2006242649B2 (en) * 2005-04-29 2011-08-04 Warsaw Orthopedic, Inc. Synthetic loadbearing collagen-mineral composites for spinal implants
US8002843B2 (en) 2003-02-04 2011-08-23 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US8663672B2 (en) 2000-07-19 2014-03-04 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
US8758438B2 (en) 2000-12-08 2014-06-24 Warsaw Orthopedic, Inc. Implant for orthopedic applications
US9107751B2 (en) 2002-12-12 2015-08-18 Warsaw Orthopedic, Inc. Injectable and moldable bone substitute materials
US9393116B2 (en) 2003-06-11 2016-07-19 Warsaw Orthopedic, Inc. Osteoimplants and methods for their manufacture
EP3054870A4 (en) * 2013-10-09 2017-07-19 Lifenet Health Compressed bone composition and methods of use thereof
US10383974B2 (en) 2008-12-13 2019-08-20 Bioventus Llc Bioactive grafts and composites

Families Citing this family (382)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7019192B2 (en) * 1998-02-27 2006-03-28 Musculoskeletal Transplant Foundation Composition for filling bone defects
US6998135B1 (en) * 1998-02-27 2006-02-14 Musculoskeletal Transplant Foundation Demineralized corticocancellous bone sheet
US7045141B2 (en) 1998-02-27 2006-05-16 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
US20080077251A1 (en) * 1999-06-07 2008-03-27 Chen Silvia S Cleaning and devitalization of cartilage
US6293970B1 (en) 1998-06-30 2001-09-25 Lifenet Plasticized bone and soft tissue grafts and methods of making and using same
US20100030340A1 (en) * 1998-06-30 2010-02-04 Wolfinbarger Jr Lloyd Plasticized Grafts and Methods of Making and Using Same
US8563232B2 (en) 2000-09-12 2013-10-22 Lifenet Health Process for devitalizing soft-tissue engineered medical implants, and devitalized soft-tissue medical implants produced
US20030114936A1 (en) * 1998-10-12 2003-06-19 Therics, Inc. Complex three-dimensional composite scaffold resistant to delimination
US6025538A (en) * 1998-11-20 2000-02-15 Musculoskeletal Transplant Foundation Compound bone structure fabricated from allograft tissue
US6383519B1 (en) * 1999-01-26 2002-05-07 Vita Special Purpose Corporation Inorganic shaped bodies and methods for their production and use
US8133421B2 (en) * 1999-02-23 2012-03-13 Warsaw Orthopedic, Inc. Methods of making shaped load-bearing osteoimplant
US6294187B1 (en) * 1999-02-23 2001-09-25 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
US20070233272A1 (en) * 1999-02-23 2007-10-04 Boyce Todd M Shaped load-bearing osteoimplant and methods of making same
US6241770B1 (en) * 1999-03-05 2001-06-05 Gary K. Michelson Interbody spinal fusion implant having an anatomically conformed trailing end
US6767928B1 (en) * 1999-03-19 2004-07-27 The Regents Of The University Of Michigan Mineralization and biological modification of biomaterial surfaces
US6558422B1 (en) * 1999-03-26 2003-05-06 University Of Washington Structures having coated indentations
CA2363562C (en) 1999-05-05 2010-08-03 Gary Karlin Michelson Nested interbody spinal fusion implants
US6258124B1 (en) * 1999-05-10 2001-07-10 C. R. Bard, Inc. Prosthetic repair fabric
US7270705B2 (en) * 1999-07-14 2007-09-18 Jiin-Huey Chern Lin Method of increasing working time of tetracalcium phosphate cement paste
US7094282B2 (en) * 2000-07-13 2006-08-22 Calcitec, Inc. Calcium phosphate cement, use and preparation thereof
US6840995B2 (en) * 1999-07-14 2005-01-11 Calcitec, Inc. Process for producing fast-setting, bioresorbable calcium phosphate cements
US7169373B2 (en) * 1999-07-14 2007-01-30 Calcitec, Inc. Tetracalcium phosphate (TTCP) having calcium phosphate whisker on surface and process for preparing the same
US6960249B2 (en) * 1999-07-14 2005-11-01 Calcitec, Inc. Tetracalcium phosphate (TTCP) having calcium phosphate whisker on surface
US6458162B1 (en) 1999-08-13 2002-10-01 Vita Special Purpose Corporation Composite shaped bodies and methods for their production and use
AU7403100A (en) 1999-08-20 2001-03-19 Peter Metz-Stavenhagen Vertebral column segment
US20050059953A1 (en) 1999-09-03 2005-03-17 Lifenet Apparatus for demineralizing osteoinductive bone
US6830763B2 (en) * 1999-09-03 2004-12-14 Lifenet Continuous acidification demineralization process for producing osteoinductive bone; and osteoinductive bone produced thereby
KR100689250B1 (en) * 1999-09-30 2007-03-08 가켄 세야쿠 가부시키가이샤 Method to enhance healing of sternum after sternotomy
US20030228288A1 (en) 1999-10-15 2003-12-11 Scarborough Nelson L. Volume maintaining osteoinductive/osteoconductive compositions
US20010032017A1 (en) 1999-12-30 2001-10-18 Alfaro Arthur A. Intervertebral implants
US7635390B1 (en) 2000-01-14 2009-12-22 Marctec, Llc Joint replacement component having a modular articulating surface
US6702821B2 (en) 2000-01-14 2004-03-09 The Bonutti 2003 Trust A Instrumentation for minimally invasive joint replacement and methods for using same
WO2001068004A2 (en) * 2000-03-10 2001-09-20 Sdgi Holdings, Inc. Synthetic reinforced interbody fusion implants
AR027685A1 (en) 2000-03-22 2003-04-09 Synthes Ag METHOD AND METHOD FOR CARRYING OUT
US6350283B1 (en) 2000-04-19 2002-02-26 Gary K. Michelson Bone hemi-lumbar interbody spinal implant having an asymmetrical leading end and method of installation thereof
US7462195B1 (en) 2000-04-19 2008-12-09 Warsaw Orthopedic, Inc. Artificial lumbar interbody spinal implant having an asymmetrical leading end
AU2001274821A1 (en) * 2000-06-13 2001-12-24 Gary K. Michelson Manufactured major long bone ring implant shaped to conform to a prepared intervertebral implantation space
US20020111680A1 (en) * 2000-06-13 2002-08-15 Michelson Gary K. Ratcheted bone dowel
US6332779B1 (en) 2000-07-03 2001-12-25 Osteotech, Inc. Method of hard tissue repair
US7182928B2 (en) * 2000-07-13 2007-02-27 Calcitec, Inc. Calcium phosphate cements made from (TTCP) with surface whiskers and process for preparing same
US7001551B2 (en) * 2000-07-13 2006-02-21 Allograft Research Technologies, Inc. Method of forming a composite bone material implant
US7156915B2 (en) * 2000-07-13 2007-01-02 Calcitec, Inc. Tetracalcium phosphate (TTCP) with surface whiskers and method of making same
US6638312B2 (en) * 2000-08-04 2003-10-28 Depuy Orthopaedics, Inc. Reinforced small intestinal submucosa (SIS)
US8366787B2 (en) * 2000-08-04 2013-02-05 Depuy Products, Inc. Hybrid biologic-synthetic bioabsorbable scaffolds
US6739112B1 (en) * 2000-08-21 2004-05-25 Nu Vasive, Inc. Bone allograft packaging system
US20050064041A1 (en) * 2000-09-05 2005-03-24 Lifenet Continuous acidification demineralization process for producing osteoinductive bone; and osteoinductive bone produced thereby
EP1576938B1 (en) 2000-10-11 2006-08-02 Michael D. Mason Spinal fusion device
US20030120274A1 (en) * 2000-10-20 2003-06-26 Morris John W. Implant retaining device
WO2002036049A2 (en) 2000-11-03 2002-05-10 Osteotech, Inc. Spinal intervertebral implant and method of making
US6692498B1 (en) * 2000-11-27 2004-02-17 Linvatec Corporation Bioabsorbable, osteopromoting fixation plate
US7323193B2 (en) 2001-12-14 2008-01-29 Osteotech, Inc. Method of making demineralized bone particles
US20020114795A1 (en) 2000-12-22 2002-08-22 Thorne Kevin J. Composition and process for bone growth and repair
US20030045935A1 (en) * 2001-02-28 2003-03-06 Angelucci Christopher M. Laminoplasty implants and methods of use
US6855169B2 (en) * 2001-02-28 2005-02-15 Synthes (Usa) Demineralized bone-derived implants
IL141813A (en) * 2001-03-05 2010-04-15 Hadasit Med Res Service Mixture comprising bone marrow cells together with demineralized and/or mineralized bone matrix and uses thereof in the preparation of compositions for the treatment of hematopoietic dusirders
US6890355B2 (en) 2001-04-02 2005-05-10 Gary K. Michelson Artificial contoured spinal fusion implants made of a material other than bone
US6989031B2 (en) 2001-04-02 2006-01-24 Sdgi Holdings, Inc. Hemi-interbody spinal implant manufactured from a major long bone ring or a bone composite
US6749636B2 (en) * 2001-04-02 2004-06-15 Gary K. Michelson Contoured spinal fusion implants made of bone or a bone composite material
CA2442855A1 (en) * 2001-04-12 2002-10-24 Therics, Inc. Method and apparatus for engineered regenerative biostructures
DE10126085A1 (en) * 2001-05-29 2002-12-05 Tutogen Medical Gmbh bone implant
US7819918B2 (en) * 2001-07-16 2010-10-26 Depuy Products, Inc. Implantable tissue repair device
AU2002316696B2 (en) * 2001-07-16 2007-08-30 Depuy Products, Inc. Cartilage repair and regeneration scaffold and method
WO2003007790A2 (en) 2001-07-16 2003-01-30 Depuy Products, Inc. Hybrid biologic/synthetic porous extracellular matrix scaffolds
WO2003007839A2 (en) * 2001-07-16 2003-01-30 Depuy Products, Inc. Devices form naturally occurring biologically derived
EP1416888A4 (en) 2001-07-16 2007-04-25 Depuy Products Inc Meniscus regeneration device and method
US8025896B2 (en) 2001-07-16 2011-09-27 Depuy Products, Inc. Porous extracellular matrix scaffold and method
US7618937B2 (en) * 2001-07-20 2009-11-17 Northwestern University Peptidomimetic polymers for antifouling surfaces
US8815793B2 (en) * 2001-07-20 2014-08-26 Northwestern University Polymeric compositions and related methods of use
US7858679B2 (en) * 2001-07-20 2010-12-28 Northwestern University Polymeric compositions and related methods of use
US7892288B2 (en) 2001-08-27 2011-02-22 Zimmer Technology, Inc. Femoral augments for use with knee joint prosthesis
US20030065397A1 (en) 2001-08-27 2003-04-03 Hanssen Arlen D. Prosthetic implant support structure
US20040162619A1 (en) 2001-08-27 2004-08-19 Zimmer Technology, Inc. Tibial augments for use with knee joint prostheses, method of implanting the tibial augment, and associated tools
US7708741B1 (en) 2001-08-28 2010-05-04 Marctec, Llc Method of preparing bones for knee replacement surgery
US6635087B2 (en) 2001-08-29 2003-10-21 Christopher M. Angelucci Laminoplasty implants and methods of use
US20030139812A1 (en) * 2001-11-09 2003-07-24 Javier Garcia Spinal implant
US6855167B2 (en) 2001-12-05 2005-02-15 Osteotech, Inc. Spinal intervertebral implant, interconnections for such implant and processes for making
WO2003055933A1 (en) * 2001-12-21 2003-07-10 Isotis Orthobiologics, Inc. End-capped polyalkylene glycols and compositions containing such compounds
US7205337B2 (en) * 2001-12-21 2007-04-17 Isotis Orthobiologics, Inc. End-capped polymers and compositions containing such compounds
JP2005516972A (en) * 2002-01-22 2005-06-09 ファイザー・インク 3- (imidazolyl) -2-aminopropionic acid used as TAFI-A inhibitor for the treatment of thrombotic diseases
EP1344538A1 (en) * 2002-03-14 2003-09-17 Degradable Solutions AG Porous biodegradable implant material and method for its fabrication
US20040137032A1 (en) * 2002-03-15 2004-07-15 Wang Francis W. Combinations of calcium phosphates, bone growth factors, and pore-forming additives as osteoconductive and osteoinductive composite bone grafts
US7832566B2 (en) 2002-05-24 2010-11-16 Biomet Biologics, Llc Method and apparatus for separating and concentrating a component from a multi-component material including macroparticles
US20030205538A1 (en) 2002-05-03 2003-11-06 Randel Dorian Methods and apparatus for isolating platelets from blood
US7992725B2 (en) 2002-05-03 2011-08-09 Biomet Biologics, Llc Buoy suspension fractionation system
US20030216777A1 (en) * 2002-05-16 2003-11-20 Yin-Chun Tien Method of enhancing healing of interfacial gap between bone and tendon or ligament
US20060204544A1 (en) * 2002-05-20 2006-09-14 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
US20060278588A1 (en) 2002-05-24 2006-12-14 Woodell-May Jennifer E Apparatus and method for separating and concentrating fluids containing multiple components
WO2003099412A1 (en) 2002-05-24 2003-12-04 Biomet Manufacturing Corp. Apparatus and method for separating and concentrating fluids containing multiple components
US7845499B2 (en) 2002-05-24 2010-12-07 Biomet Biologics, Llc Apparatus and method for separating and concentrating fluids containing multiple components
AU2003238805A1 (en) * 2002-05-30 2003-12-19 Osteotech, Inc. Method and apparatus for machining a surgical implant
JP4179495B2 (en) * 2002-06-12 2008-11-12 松崎 浩巳 Bone filling material
US7166133B2 (en) * 2002-06-13 2007-01-23 Kensey Nash Corporation Devices and methods for treating defects in the tissue of a living being
US8911831B2 (en) * 2002-07-19 2014-12-16 Northwestern University Surface independent, surface-modifying, multifunctional coatings and applications thereof
US20080171012A1 (en) * 2007-01-11 2008-07-17 Phillip Messersmith Fouling Resistant Coatings and Methods of Making Same
AU2002950443A0 (en) * 2002-07-26 2002-09-12 Graeme Brazenor Pty Limited Spinal implant
US7270813B2 (en) * 2002-10-08 2007-09-18 Osteotech, Inc. Coupling agents for orthopedic biomaterials
US7323011B2 (en) 2002-10-18 2008-01-29 Musculoskeletal Transplant Foundation Cortical and cancellous allograft cervical fusion block
US7682392B2 (en) * 2002-10-30 2010-03-23 Depuy Spine, Inc. Regenerative implants for stabilizing the spine and devices for attachment of said implants
US7582309B2 (en) * 2002-11-15 2009-09-01 Etex Corporation Cohesive demineralized bone compositions
US6761739B2 (en) 2002-11-25 2004-07-13 Musculoskeletal Transplant Foundation Cortical and cancellous allograft spacer
US20060216494A1 (en) * 2002-11-25 2006-09-28 Helga Furedi-Milhofer Organic-inorganic nanocomposite coatings for implant materials and methods of preparation thereof
US20050251267A1 (en) * 2004-05-04 2005-11-10 John Winterbottom Cell permeable structural implant
US7192447B2 (en) 2002-12-19 2007-03-20 Synthes (Usa) Intervertebral implant
US7985414B2 (en) * 2003-02-04 2011-07-26 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US7648509B2 (en) 2003-03-10 2010-01-19 Ilion Medical Llc Sacroiliac joint immobilization
US20050064042A1 (en) * 2003-04-29 2005-03-24 Musculoskeletal Transplant Foundation Cartilage implant plug with fibrin glue and method for implantation
US7067123B2 (en) * 2003-04-29 2006-06-27 Musculoskeletal Transplant Foundation Glue for cartilage repair
WO2004098457A1 (en) * 2003-04-30 2004-11-18 Therics, Inc. Bone void filler and method of manufacture
US7901457B2 (en) 2003-05-16 2011-03-08 Musculoskeletal Transplant Foundation Cartilage allograft plug
US7488348B2 (en) 2003-05-16 2009-02-10 Musculoskeletal Transplant Foundation Cartilage allograft plug
US20050020506A1 (en) * 2003-07-25 2005-01-27 Drapeau Susan J. Crosslinked compositions comprising collagen and demineralized bone matrix, methods of making and methods of use
US7806932B2 (en) * 2003-08-01 2010-10-05 Zimmer Spine, Inc. Spinal implant
US20060229627A1 (en) 2004-10-29 2006-10-12 Hunt Margaret M Variable angle spinal surgery instrument
US7163651B2 (en) * 2004-02-19 2007-01-16 Calcitec, Inc. Method for making a porous calcium phosphate article
US6994726B2 (en) * 2004-05-25 2006-02-07 Calcitec, Inc. Dual function prosthetic bone implant and method for preparing the same
US7118705B2 (en) 2003-08-05 2006-10-10 Calcitec, Inc. Method for making a molded calcium phosphate article
US7169405B2 (en) * 2003-08-06 2007-01-30 Warsaw Orthopedic, Inc. Methods and devices for the treatment of intervertebral discs
WO2005032612A2 (en) * 2003-10-02 2005-04-14 Lostec, Inc. A transplantable particulate bone composition and methods for making and using same
US20050085922A1 (en) * 2003-10-17 2005-04-21 Shappley Ben R. Shaped filler for implantation into a bone void and methods of manufacture and use thereof
WO2005046440A2 (en) * 2003-11-07 2005-05-26 Calcitec, Inc. Spinal fusion procedure using an injectable bone substitute
EP1701672A4 (en) * 2003-12-19 2011-04-27 Osteotech Inc Tissue-derived mesh for orthopedic regeneration
US8734525B2 (en) 2003-12-31 2014-05-27 Warsaw Orthopedic, Inc. Osteoinductive demineralized cancellous bone
CA2535169A1 (en) 2003-12-31 2005-07-21 Osteotech, Inc. Improved bone matrix compositions and methods
US8012210B2 (en) 2004-01-16 2011-09-06 Warsaw Orthopedic, Inc. Implant frames for use with settable materials and related methods of use
JP2007519496A (en) 2004-01-27 2007-07-19 オステオテック,インコーポレイテッド Stabilized bone graft
US20060015184A1 (en) * 2004-01-30 2006-01-19 John Winterbottom Stacking implants for spinal fusion
US7189263B2 (en) 2004-02-03 2007-03-13 Vita Special Purpose Corporation Biocompatible bone graft material
US20050177245A1 (en) * 2004-02-05 2005-08-11 Leatherbury Neil C. Absorbable orthopedic implants
CA2575740A1 (en) 2004-03-24 2005-10-13 Doctor's Research Group, Inc. Methods of performing medical procedures that promote bone growth, methods of making compositions that promote bone growth, and apparatus for use in such methods
US20070190101A1 (en) * 2004-03-31 2007-08-16 Chunlin Yang Flowable bone grafts
US7942913B2 (en) 2004-04-08 2011-05-17 Ebi, Llc Bone fixation device
US20060228252A1 (en) * 2004-04-20 2006-10-12 Mills C R Process and apparatus for treating implants comprising soft tissue
US7648676B2 (en) * 2004-04-20 2010-01-19 Rti Biologics, Inc. Process and apparatus for treating implants comprising soft tissue
US20050244450A1 (en) * 2004-04-28 2005-11-03 Reddi A H Heat-treated implantable bone material
US7678385B2 (en) * 2004-04-28 2010-03-16 Biomet Manufacturing Corp. Irradiated implantable bone material
US8163030B2 (en) * 2004-05-06 2012-04-24 Degradable Solutions Ag Biocompatible bone implant compositions and methods for repairing a bone defect
WO2005110437A2 (en) * 2004-05-10 2005-11-24 Therics, Inc. Implantable biostructure comprising an osteoconductive member and an osteoinductive material
CA2564605A1 (en) 2004-05-12 2005-12-01 Massachusetts Institute Of Technology Manufacturing process, such as three-dimensional printing, including solvent vapor filming and the like
US7887587B2 (en) 2004-06-04 2011-02-15 Synthes Usa, Llc Soft tissue spacer
US9220595B2 (en) 2004-06-23 2015-12-29 Orthovita, Inc. Shapeable bone graft substitute and instruments for delivery thereof
US20060039949A1 (en) * 2004-08-20 2006-02-23 Nycz Jeffrey H Acetabular cup with controlled release of an osteoinductive formulation
CA2579041A1 (en) * 2004-09-07 2006-03-16 Smith & Nephew, Inc. Methods and devices for sterile field transfer
US8697139B2 (en) 2004-09-21 2014-04-15 Frank M. Phillips Method of intervertebral disc treatment using articular chondrocyte cells
US20090088846A1 (en) 2007-04-17 2009-04-02 David Myung Hydrogel arthroplasty device
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US7670384B2 (en) * 2004-10-14 2010-03-02 Biomet Manufacturing Corp. Bone graft composition comprising a bone material and a carrier comprising denatured demineralized bone
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US20060083769A1 (en) * 2004-10-14 2006-04-20 Mukesh Kumar Method and apparatus for preparing bone
US20060111779A1 (en) 2004-11-22 2006-05-25 Orthopedic Development Corporation, A Florida Corporation Minimally invasive facet joint fusion
US20060111786A1 (en) * 2004-11-22 2006-05-25 Orthopedic Development Corporation Metallic prosthetic implant for use in minimally invasive acromio-clavicular shoulder joint hemi-arthroplasty
US20060111780A1 (en) 2004-11-22 2006-05-25 Orthopedic Development Corporation Minimally invasive facet joint hemi-arthroplasty
US8021392B2 (en) 2004-11-22 2011-09-20 Minsurg International, Inc. Methods and surgical kits for minimally-invasive facet joint fusion
US8308340B2 (en) 2004-11-23 2012-11-13 Smith & Nephew, Inc. Composite mixer
WO2006060416A2 (en) * 2004-11-30 2006-06-08 Osteobiologics, Inc. Implants and delivery system for treating defects in articulating surfaces
US7527640B2 (en) 2004-12-22 2009-05-05 Ebi, Llc Bone fixation system
MX2007008561A (en) * 2005-01-14 2008-02-21 Osteotech Inc Expandable osteoimplant.
US20060216321A1 (en) * 2005-03-24 2006-09-28 Sdgi Holdings, Inc. Solvent based processing technologies for making tissue/polymer composites
US20060229723A1 (en) * 2005-04-08 2006-10-12 Sdgi Holdings, Inc. Intervertebral fusion device and method
US7621963B2 (en) * 2005-04-13 2009-11-24 Ebi, Llc Composite bone graft material
US20060233849A1 (en) * 2005-04-13 2006-10-19 Simon Bruce J Composite bone graft material
US7879103B2 (en) 2005-04-15 2011-02-01 Musculoskeletal Transplant Foundation Vertebral disc repair
US20060258578A1 (en) * 2005-05-10 2006-11-16 The University Of Zurich Pharmaceutical composition
US8070749B2 (en) 2005-05-12 2011-12-06 Stern Joseph D Revisable anterior cervical plating system
WO2006124273A2 (en) * 2005-05-12 2006-11-23 Stern Joseph D Revisable anterior cervical plating system
US7815926B2 (en) 2005-07-11 2010-10-19 Musculoskeletal Transplant Foundation Implant for articular cartilage repair
US7771590B2 (en) * 2005-08-23 2010-08-10 Biomet Manufacturing Corp. Method and apparatus for collecting biological materials
US8048297B2 (en) * 2005-08-23 2011-11-01 Biomet Biologics, Llc Method and apparatus for collecting biological materials
US20070074980A1 (en) * 2005-09-02 2007-04-05 Bankoski Brian R Implant rehydration packages and methods of use
WO2007035778A2 (en) 2005-09-19 2007-03-29 Histogenics Corporation Cell-support matrix and a method for preparation thereof
US7955364B2 (en) 2005-09-21 2011-06-07 Ebi, Llc Variable angle bone fixation assembly
US7691105B2 (en) * 2005-09-26 2010-04-06 Depuy Spine, Inc. Tissue augmentation, stabilization and regeneration technique
US8911759B2 (en) 2005-11-01 2014-12-16 Warsaw Orthopedic, Inc. Bone matrix compositions and methods
WO2007056671A1 (en) 2005-11-02 2007-05-18 Osteotech, Inc. Hemostatic bone graft
WO2007061889A2 (en) * 2005-11-17 2007-05-31 Biomimetic Therapeutics, Inc. Maxillofacial bone augmentation using rhpdgf-bb and a biocompatible matrix
US7901458B2 (en) * 2005-12-16 2011-03-08 Warsaw Orthopedic, Inc. Intervertebral spacer and insertion tool
US8287914B2 (en) * 2006-01-12 2012-10-16 Rutgers, The State University Of New Jersey Biomimetic hydroxyapatite synthesis
US20100040668A1 (en) * 2006-01-12 2010-02-18 Rutgers, The State University Of New Jersey Biomimetic Hydroxyapatite Composite Materials and Methods for the Preparation Thereof
EP1976459A4 (en) 2006-01-19 2012-06-20 Warsaw Orthopedic Inc Porous osteoimplant
US7749555B2 (en) * 2006-01-25 2010-07-06 Medtronic, Inc Modification of chemical forces of bone constructs
US7824703B2 (en) * 2006-02-01 2010-11-02 Warsaw Orthopedics, Inc. Medical implants with reservoir(s), and materials preparable from same
EP2311505B1 (en) 2006-02-09 2013-11-06 BioMimetic Therapeutics, LLC Compositions and methods for treating bone
US7732539B2 (en) * 2006-02-16 2010-06-08 National Science Foundation Modified acrylic block copolymers for hydrogels and pressure sensitive wet adhesives
US20070270971A1 (en) * 2006-03-14 2007-11-22 Sdgi Holdings, Inc. Intervertebral prosthetic disc with improved wear resistance
US20070233246A1 (en) * 2006-03-31 2007-10-04 Sdgi Holdings, Inc. Spinal implants with improved mechanical response
US8673019B2 (en) * 2006-04-13 2014-03-18 Warsaw Orthopedic, Inc. Use of anti-inflammatory compounds with allograft tissue implantation
US7771414B2 (en) * 2006-04-24 2010-08-10 Warsaw Orthopedic, Inc. Controlled release devices for therapeutic treatments of spinal discs
US8642060B2 (en) * 2006-04-24 2014-02-04 Warsaw Orthopedic, Inc. Controlled release systems and methods for osteal growth
US7879027B2 (en) * 2006-04-24 2011-02-01 Warsaw Orthopedic, Inc. Controlled release devices for fusion of osteal structures
US8642059B2 (en) * 2006-04-24 2014-02-04 Warsaw Orthopedic, Inc. Controlled release systems and methods for intervertebral discs
AU2007243353B2 (en) 2006-04-26 2012-05-31 Illuminoss Medical, Inc. Apparatus and methods for reinforcing bone
US7806900B2 (en) 2006-04-26 2010-10-05 Illuminoss Medical, Inc. Apparatus and methods for delivery of reinforcing materials to bone
US20100209470A1 (en) * 2006-05-01 2010-08-19 Warsaw Orthopedic, Inc. An Indiana Corporation Demineralized bone matrix devices
US7838022B2 (en) 2006-05-01 2010-11-23 Warsaw Orthopedic, Inc Malleable implants containing demineralized bone matrix
US7771741B2 (en) 2006-05-01 2010-08-10 Warsaw Orthopedic, Inc Demineralized bone matrix devices
US8506983B2 (en) * 2006-05-01 2013-08-13 Warsaw Orthopedic, Inc. Bone filler material
US20080262633A1 (en) 2006-05-08 2008-10-23 Williams Michelle Leroux Cancellous bone treated with collagenase and essentially free of blood cells
AU2007250080B2 (en) 2006-05-08 2011-08-18 Nuvasive, Inc. Cancellous bone treated with collagenase and essentially free of blood cells
US8567609B2 (en) 2006-05-25 2013-10-29 Biomet Biologics, Llc Apparatus and method for separating and concentrating fluids containing multiple components
WO2008002682A2 (en) * 2006-06-29 2008-01-03 Orthovita, Inc. Bioactive bone graft substitute
AU2007269712B2 (en) 2006-06-30 2013-02-07 Biomimetic Therapeutics, Llc PDGF-biomatrix compositions and methods for treating rotator cuff injuries
US9161967B2 (en) 2006-06-30 2015-10-20 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US20080021462A1 (en) * 2006-07-24 2008-01-24 Warsaw Orthopedic Inc. Spinal stabilization implants
US20080021557A1 (en) * 2006-07-24 2008-01-24 Warsaw Orthopedic, Inc. Spinal motion-preserving implants
EP2076220A2 (en) 2006-07-25 2009-07-08 Musculoskeletal Transplant Foundation Packed demineralized cancellous tissue forms for disc nucleus augmentation, restoration, or replacement and methods of implantation
US20080033572A1 (en) * 2006-08-03 2008-02-07 Ebi L.P. Bone graft composites and methods of treating bone defects
WO2008091386A2 (en) * 2006-08-04 2008-07-31 Northwestern University Biomimetic modular adhesive complex: material, methods and applications therefore
JP5597836B2 (en) 2006-08-04 2014-10-01 ケンジー ナッシュ コーポレイション Biomimetic compound and synthesis method thereof
US9066994B2 (en) * 2006-08-31 2015-06-30 Warsaw Orthopedic, Inc. Demineralized cancellous strip DBM graft
CA2667000A1 (en) * 2006-09-25 2008-04-03 James P. Murphy Bioactive load-bearing composites comprising peek and bioglass particles
EP2086598B1 (en) 2006-11-03 2015-05-27 BioMimetic Therapeutics, LLC Compositions and methods for arthrodetic procedures
US8388626B2 (en) * 2006-11-08 2013-03-05 Warsaw Orthopedic, Inc. Methods of employing calcium phosphate cement compositions and osteoinductive proteins to effect vertebrae interbody fusion absent an interbody device
WO2008063265A1 (en) 2006-11-10 2008-05-29 Illuminoss Medical, Inc. Systems and methods for internal bone fixation
US7879041B2 (en) 2006-11-10 2011-02-01 Illuminoss Medical, Inc. Systems and methods for internal bone fixation
US7871440B2 (en) 2006-12-11 2011-01-18 Depuy Products, Inc. Unitary surgical device and method
US7718616B2 (en) 2006-12-21 2010-05-18 Zimmer Orthobiologics, Inc. Bone growth particles and osteoinductive composition thereof
US20080195476A1 (en) * 2007-02-09 2008-08-14 Marchese Michael A Abandonment remarketing system
AU2008216371B2 (en) 2007-02-12 2014-04-10 Warsaw Orthopedic, Inc. Joint revision implant
US8673286B2 (en) 2007-04-09 2014-03-18 Northwestern University DOPA-functionalized, branched, poly(aklylene oxide) adhesives
US8383092B2 (en) * 2007-02-16 2013-02-26 Knc Ner Acquisition Sub, Inc. Bioadhesive constructs
US20080206299A1 (en) * 2007-02-27 2008-08-28 Shimp Lawrence A Method for Recovering Minerals From Bone and Use of Same
US8435551B2 (en) 2007-03-06 2013-05-07 Musculoskeletal Transplant Foundation Cancellous construct with support ring for repair of osteochondral defects
JP2010522046A (en) 2007-03-22 2010-07-01 ノヴァリン・オルソペディクス・インコーポレーテッド Segmented intramedullary structure
US20080230094A1 (en) * 2007-03-23 2008-09-25 Buckman Laboratories International, Inc. Method to inhibit growth of microorganisms in aqueous systems and on substrates using persulfate and a bromide
US7658940B2 (en) * 2007-03-30 2010-02-09 Skeletal Kinetics, Llc Calcium phosphate cements comprising autologous bone
JP5479319B2 (en) 2007-04-12 2014-04-23 バイオメット・バイオロジックス・リミテッド・ライアビリティ・カンパニー Buoy suspension fractionation system
US8328024B2 (en) 2007-04-12 2012-12-11 Hanuman, Llc Buoy suspension fractionation system
US9554920B2 (en) 2007-06-15 2017-01-31 Warsaw Orthopedic, Inc. Bone matrix compositions having nanoscale textured surfaces
CA2690457C (en) * 2007-06-15 2018-02-20 Osteotech, Inc. Bone matrix compositions and methods
WO2008157497A2 (en) 2007-06-15 2008-12-24 Osteotech, Inc. Method of treating tissue
US20100268339A1 (en) * 2007-07-10 2010-10-21 Malinin Theodore I Intervertebral Spinal Implant and Method of Making the Same
US20090018659A1 (en) * 2007-07-10 2009-01-15 Malinin Theodore I Invertebral spinal implant and method of making the same
US9492278B2 (en) 2007-07-10 2016-11-15 Warsaw Orthopedic, Inc. Delivery system
US9125743B2 (en) * 2007-07-16 2015-09-08 Lifenet Health Devitalization and recellularization of cartilage
US9744043B2 (en) * 2007-07-16 2017-08-29 Lifenet Health Crafting of cartilage
US20090024174A1 (en) 2007-07-17 2009-01-22 Stark John G Bone screws and particular applications to sacroiliac joint fusion
US8512342B2 (en) * 2007-08-11 2013-08-20 Thomas L. Meredith Portable bone grinder
US20090130174A1 (en) * 2007-08-20 2009-05-21 Vanderbilt University Poly (ester urethane) urea foams with enhanced mechanical and biological properties
US9138509B2 (en) * 2007-09-14 2015-09-22 Musculoskeletal Transplant Foundation Composition for filling bone defects
KR100916722B1 (en) * 2007-10-13 2009-09-14 민병호 Artificial tooth operating method using mussel bond
JP2011504409A (en) * 2007-10-16 2011-02-10 エイチケーピービー サイエンティフィック リミテッド Surface coating method and use thereof
WO2009052492A2 (en) 2007-10-19 2009-04-23 Osteotech, Inc. Demineralized bone matrix compositions and methods
WO2009059090A1 (en) 2007-10-31 2009-05-07 Illuminoss Medical, Inc. Light source
WO2009082554A2 (en) 2007-11-09 2009-07-02 Osteotech, Inc. Bone matrix compositions having nanoscale textured surfaces
US9056150B2 (en) 2007-12-04 2015-06-16 Warsaw Orthopedic, Inc. Compositions for treating bone defects
US8403968B2 (en) 2007-12-26 2013-03-26 Illuminoss Medical, Inc. Apparatus and methods for repairing craniomaxillofacial bones using customized bone plates
JP5864106B2 (en) 2008-02-07 2016-02-17 バイオミメティック セラピューティクス, エルエルシー Compositions and methods for callus extension
US8740912B2 (en) 2008-02-27 2014-06-03 Ilion Medical Llc Tools for performing less invasive orthopedic joint procedures
EP2620139B1 (en) 2008-02-27 2016-07-20 Biomet Biologics, LLC Interleukin-1 receptor antagonist rich solutions
US8337711B2 (en) 2008-02-29 2012-12-25 Biomet Biologics, Llc System and process for separating a material
WO2009111069A1 (en) 2008-03-05 2009-09-11 Musculoskeletal Transplant Foundation Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US8840913B2 (en) 2008-03-27 2014-09-23 Warsaw Orthopedic, Inc. Malleable multi-component implants and materials therefor
CN102046237A (en) 2008-03-28 2011-05-04 骨骼技术股份有限公司 Delivery system attachment
US20100082072A1 (en) * 2008-03-28 2010-04-01 Sybert Daryl R Bone anchors for orthopedic applications
US20100068171A1 (en) * 2008-05-27 2010-03-18 Vanderbilt University Injectable bone/polymer composite bone void fillers
US20120209396A1 (en) 2008-07-07 2012-08-16 David Myung Orthopedic implants having gradient polymer alloys
US8883915B2 (en) 2008-07-07 2014-11-11 Biomimedica, Inc. Hydrophobic and hydrophilic interpenetrating polymer networks derived from hydrophobic polymers and methods of preparing the same
WO2010004057A1 (en) * 2008-07-08 2010-01-14 Histocell, S.L Three-dimensional matrices of structured porous monetite for tissue engineering and osseous regeneration, and method for the preparation thereof
JP5722773B2 (en) 2008-08-05 2015-05-27 バイオミメディカ インコーポレイテッド Polyurethane grafted hydrogel
JP5816553B2 (en) 2008-09-09 2015-11-18 バイオミメティック セラピューティクス, エルエルシー Platelet-derived growth factor compositions and methods for treating tendon or ligament injury
WO2010048610A2 (en) 2008-10-24 2010-04-29 Osteotech, Inc. Compositions and methods for promoting bone formation
CA2745038A1 (en) * 2008-10-30 2010-05-27 Osteotech, Inc. Bone/polyurethane composites and methods thereof
WO2012134540A2 (en) 2010-10-22 2012-10-04 Vanderbilt University Injectable synthetic pur composite
US9192695B2 (en) 2008-11-20 2015-11-24 Allosource Allografts combined with tissue derived stem cells for bone healing
PT2389205T (en) * 2008-12-13 2021-03-29 Bioventus Llc Bioactive grafts and composites
US20100151114A1 (en) * 2008-12-17 2010-06-17 Zimmer, Inc. In-line treatment of yarn prior to creating a fabric
US20100168798A1 (en) 2008-12-30 2010-07-01 Clineff Theodore D Bioactive composites of polymer and glass and method for making same
WO2010093950A1 (en) 2009-02-12 2010-08-19 Osteotech, Inc. Delivery system cartridge
US9821033B2 (en) * 2009-02-27 2017-11-21 Kieran Murphy Llc Modulating bone growth in treating scoliosis
US8187475B2 (en) 2009-03-06 2012-05-29 Biomet Biologics, Llc Method and apparatus for producing autologous thrombin
US9241798B2 (en) * 2009-03-20 2016-01-26 David A. Petersen Surgical methods and tools
US8313954B2 (en) 2009-04-03 2012-11-20 Biomet Biologics, Llc All-in-one means of separating blood components
US8210729B2 (en) 2009-04-06 2012-07-03 Illuminoss Medical, Inc. Attachment system for light-conducting fibers
US8512338B2 (en) 2009-04-07 2013-08-20 Illuminoss Medical, Inc. Photodynamic bone stabilization systems and methods for reinforcing bone
US20100297082A1 (en) * 2009-05-19 2010-11-25 Osteotech, Inc. Weight-bearing polyurethane composites and methods thereof
US9011800B2 (en) 2009-07-16 2015-04-21 Biomet Biologics, Llc Method and apparatus for separating biological materials
USD773047S1 (en) * 2009-07-20 2016-11-29 Teknimed S.A. Bone filler particle
WO2011017284A2 (en) 2009-08-03 2011-02-10 Osteotech, Inc. Bone matrix compositions and methods
US9173748B2 (en) * 2009-08-07 2015-11-03 Ebi, Llc Toroid-shaped spinal disc
US20110035010A1 (en) * 2009-08-07 2011-02-10 Ebi, Llc Toroid-shaped spinal disc
US8926552B2 (en) * 2009-08-12 2015-01-06 Medtronic, Inc. Particle delivery
US8870965B2 (en) 2009-08-19 2014-10-28 Illuminoss Medical, Inc. Devices and methods for bone alignment, stabilization and distraction
WO2011063250A1 (en) * 2009-11-20 2011-05-26 Knee Creations, Llc Implantable devices for subchondral treatment of joint pain
CN102781348B (en) 2009-11-20 2015-07-15 膝部创造物有限责任公司 Navigation and positioning instruments for joint repair
US8801800B2 (en) 2009-11-20 2014-08-12 Zimmer Knee Creations, Inc. Bone-derived implantable devices and tool for subchondral treatment of joint pain
WO2011063257A1 (en) 2009-11-20 2011-05-26 Knee Creations, Llc Instruments for targeting a joint defect
US8906032B2 (en) 2009-11-20 2014-12-09 Zimmer Knee Creations, Inc. Instruments for a variable angle approach to a joint
CN102770067A (en) 2009-11-20 2012-11-07 膝部创造物有限责任公司 Coordinate mapping system for joint treatment
US8821504B2 (en) 2009-11-20 2014-09-02 Zimmer Knee Creations, Inc. Method for treating joint pain and associated instruments
US8608802B2 (en) 2009-11-20 2013-12-17 Zimmer Knee Creations, Inc. Implantable devices for subchondral treatment of joint pain
US8951261B2 (en) 2009-11-20 2015-02-10 Zimmer Knee Creations, Inc. Subchondral treatment of joint pain
US20110130465A1 (en) * 2009-12-01 2011-06-02 Nerites Corporation Coatings for prevention of biofilms
US8778378B2 (en) * 2009-12-21 2014-07-15 Orthovita, Inc. Bioactive antibacterial bone graft materials
US9125902B2 (en) 2010-01-28 2015-09-08 Warsaw Orthopedic, Inc. Methods for treating an intervertebral disc using local analgesics
US9486500B2 (en) 2010-01-28 2016-11-08 Warsaw Orthopedic, Inc. Osteoimplant and methods for making
US9050274B2 (en) * 2010-01-28 2015-06-09 Warsaw Orthopedic, Inc. Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents
US20110189253A1 (en) * 2010-01-29 2011-08-04 Warsaw Orthopedic, Inc. Biomaterial composition and method
MX2012009687A (en) 2010-02-22 2012-11-29 Biomimetic Therapeutics Inc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies.
US8591391B2 (en) 2010-04-12 2013-11-26 Biomet Biologics, Llc Method and apparatus for separating a material
US9352003B1 (en) 2010-05-14 2016-05-31 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US10130736B1 (en) 2010-05-14 2018-11-20 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US8684965B2 (en) 2010-06-21 2014-04-01 Illuminoss Medical, Inc. Photodynamic bone stabilization and drug delivery systems
EP2608778B1 (en) * 2010-08-26 2017-11-01 University of Louisville Research Foundation, Inc. Compositions and methods for treating bone defects
EP2637707A4 (en) 2010-11-09 2014-10-01 Kensey Nash Corp Adhesive compounds and methods use for hernia repair
AU2011329054B2 (en) 2010-11-15 2015-05-28 Zimmer Orthobiologics, Inc. Bone void fillers
WO2012088432A1 (en) 2010-12-22 2012-06-28 Illuminoss Medical, Inc. Systems and methods for treating conditions and diseases of the spine
US8551525B2 (en) 2010-12-23 2013-10-08 Biostructures, Llc Bone graft materials and methods
EP3733099B1 (en) * 2011-02-28 2022-08-31 DePuy Synthes Products, Inc. Modular tissue scaffolds
US8673014B2 (en) 2011-04-01 2014-03-18 Kls-Martin, L.P. Method of cranial repair and cranial repair implant molding device
US20140236312A1 (en) * 2011-05-10 2014-08-21 Mark R. Appleford Cortical bone scaffold for guided osteon regeneration in load-bearing orthopaedic applications
US8936644B2 (en) 2011-07-19 2015-01-20 Illuminoss Medical, Inc. Systems and methods for joint stabilization
US9775661B2 (en) 2011-07-19 2017-10-03 Illuminoss Medical, Inc. Devices and methods for bone restructure and stabilization
DE102011112249A1 (en) * 2011-09-01 2013-03-07 Heinrich-Heine-Universität Düsseldorf Dental filler mix for filling root canals
US10881526B2 (en) 2011-09-16 2021-01-05 Globus Medical, Inc. Low profile plate
US9237957B2 (en) 2011-09-16 2016-01-19 Globus Medical, Inc. Low profile plate
US10245155B2 (en) 2011-09-16 2019-04-02 Globus Medical, Inc. Low profile plate
US9204975B2 (en) 2011-09-16 2015-12-08 Globus Medical, Inc. Multi-piece intervertebral implants
US8961606B2 (en) 2011-09-16 2015-02-24 Globus Medical, Inc. Multi-piece intervertebral implants
US9848994B2 (en) 2011-09-16 2017-12-26 Globus Medical, Inc. Low profile plate
US9149365B2 (en) 2013-03-05 2015-10-06 Globus Medical, Inc. Low profile plate
US9398960B2 (en) 2011-09-16 2016-07-26 Globus Medical, Inc. Multi-piece intervertebral implants
US9770340B2 (en) 2011-09-16 2017-09-26 Globus Medical, Inc. Multi-piece intervertebral implants
US9681959B2 (en) 2011-09-16 2017-06-20 Globus Medical, Inc. Low profile plate
US9539109B2 (en) 2011-09-16 2017-01-10 Globus Medical, Inc. Low profile plate
EP3357518B1 (en) 2011-10-03 2020-12-02 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
US20140370094A1 (en) 2011-11-08 2014-12-18 Tufts University Silk-based scaffold platform for engineering tissue constructs
US8920511B2 (en) 2011-11-17 2014-12-30 Allosource Multi-piece machine graft systems and methods
WO2013078284A1 (en) 2011-11-21 2013-05-30 Biomimedica, Inc. Systems, devices, and methods for anchoring orthopaedic implants to bone
US9554914B2 (en) 2011-12-12 2017-01-31 Wright Medical Technology, Inc. Fusion implant
US8992628B2 (en) 2012-01-20 2015-03-31 Warsaw Orthopedic, Inc. Bone delivery system
US9198758B2 (en) 2012-01-26 2015-12-01 Warsaw Orthopedic, Inc. Delivery systems
US9775862B2 (en) 2012-01-30 2017-10-03 Warsaw Orthopedic, Inc. Modification of reactivity of bone constructs
US8926622B2 (en) 2012-04-03 2015-01-06 Warsaw Orthopedic, Inc. Bone delivery systems including holding and filling devices and methods
KR20150035588A (en) 2012-05-11 2015-04-06 알티아이 서지칼, 인크. Xenograft soft tissue implants and methods of making and using
US8939977B2 (en) 2012-07-10 2015-01-27 Illuminoss Medical, Inc. Systems and methods for separating bone fixation devices from introducer
US9655994B2 (en) 2012-07-25 2017-05-23 William F. McKay Delivery systems
US9642956B2 (en) 2012-08-27 2017-05-09 Biomet Biologics, Llc Apparatus and method for separating and concentrating fluids containing multiple components
US10172651B2 (en) * 2012-10-25 2019-01-08 Warsaw Orthopedic, Inc. Cortical bone implant
US10780197B1 (en) 2012-10-29 2020-09-22 Nuvasive, Inc. Malleable, cryopreserved osteogenic compositions with viable cells
US9687281B2 (en) 2012-12-20 2017-06-27 Illuminoss Medical, Inc. Distal tip for bone fixation devices
US9265609B2 (en) 2013-01-08 2016-02-23 Warsaw Orthopedic, Inc. Osteograft implant
US9034052B2 (en) 2013-01-14 2015-05-19 Warsaw Orthopedic, Inc. Delivery systems containing bioactive materials
KR102215401B1 (en) 2013-02-22 2021-02-10 알로소스 Cartilage mosaic compositions and methods
US9283013B2 (en) 2013-03-14 2016-03-15 Warsaw Orthopedic, Inc. Filling systems for bone delivery devices
US10208095B2 (en) 2013-03-15 2019-02-19 Biomet Manufacturing, Llc Methods for making cytokine compositions from tissues using non-centrifugal methods
US9119732B2 (en) 2013-03-15 2015-09-01 Orthocision, Inc. Method and implant system for sacroiliac joint fixation and fusion
US9168140B2 (en) 2013-03-15 2015-10-27 Allosource Perforated osteochondral allograft compositions
US9950035B2 (en) 2013-03-15 2018-04-24 Biomet Biologics, Llc Methods and non-immunogenic compositions for treating inflammatory disorders
US9895418B2 (en) 2013-03-15 2018-02-20 Biomet Biologics, Llc Treatment of peripheral vascular disease using protein solutions
US20140271589A1 (en) 2013-03-15 2014-09-18 Biomet Biologics, Llc Treatment of collagen defects using protein solutions
CA2899713C (en) 2013-03-15 2022-07-19 Allosource Cell repopulated collagen matrix for soft tissue repair and regeneration
US10143725B2 (en) 2013-03-15 2018-12-04 Biomet Biologics, Llc Treatment of pain using protein solutions
RU2557893C1 (en) * 2014-04-10 2015-07-27 Федеральное государственное бюджетное учреждение "Центральный научно-исследовательский институт травматологии и ортопедии имени Н.Н. Приорова" Министерства здравоохранения Российской Федерации (ФГБУ "ЦИТО им. Н.Н. Приорова" Минздрава России) Method for two-staged surgical treatment of spinal deformity with using autopreserved resected rib autograft and dry vertical halotraction
US9364583B2 (en) 2014-04-25 2016-06-14 Warsaw Orthopedic, Inc. Osteoinductive demineralized bone implant
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
CN104606713B (en) * 2015-01-04 2017-04-19 浙江大学 Three-dimensional parallel collagenous fiber-silk bracket as well as preparation method and application thereof
US10238507B2 (en) 2015-01-12 2019-03-26 Surgentec, Llc Bone graft delivery system and method for using same
US10610366B2 (en) 2015-01-29 2020-04-07 Theracell, Inc. Demineralized bone fiber composition for use in minimally invasive surgery
US10006705B2 (en) 2015-02-09 2018-06-26 Warsaw Orthopedic, Inc. Methods for treating tissue materials
RU2597786C2 (en) * 2015-02-10 2016-09-20 Общество с ограниченной ответственностью "НекстГен" Method for creating personalized gene-activated implant for bone tissue regeneration
US10779960B2 (en) * 2015-02-27 2020-09-22 In2Bones Usa, Llc Engineered sterile cartilage allograft implant plug with sterile, specific instrument kit(s)
US10531957B2 (en) 2015-05-21 2020-01-14 Musculoskeletal Transplant Foundation Modified demineralized cortical bone fibers
US11077228B2 (en) 2015-08-10 2021-08-03 Hyalex Orthopaedics, Inc. Interpenetrating polymer networks
US11052175B2 (en) 2015-08-19 2021-07-06 Musculoskeletal Transplant Foundation Cartilage-derived implants and methods of making and using same
US10383731B2 (en) 2016-02-24 2019-08-20 Warsaw Orthopedic, Inc. Spinal implant system and method
ES2579305B1 (en) * 2016-04-29 2017-03-24 Optimus 3D S.L. PROCEDURE FOR OBTAINING AN ACTIVE IMPLANT FOR USE IN THE REGENERATION OF BONE MASS AND CORRESPONDING IMPLANT OBTAINED
WO2017201259A1 (en) 2016-05-18 2017-11-23 Rti Surgical, Inc. Osteoinductive nanofiber scaffold for bone regeneration
WO2018071053A1 (en) * 2016-10-14 2018-04-19 Allosource Consistent calcium content bone allograft systems and methods
US11141276B2 (en) 2017-01-20 2021-10-12 Biomet Manufacturing, Llc Modular augment component
US11452608B2 (en) 2017-04-05 2022-09-27 Globus Medical, Inc. Decoupled spacer and plate and method of installing the same
US10376385B2 (en) 2017-04-05 2019-08-13 Globus Medical, Inc. Decoupled spacer and plate and method of installing the same
US10064726B1 (en) 2017-04-18 2018-09-04 Warsaw Orthopedic, Inc. 3D printing of mesh implants for bone delivery
US11660196B2 (en) 2017-04-21 2023-05-30 Warsaw Orthopedic, Inc. 3-D printing of bone grafts
US11452796B2 (en) 2017-06-30 2022-09-27 Allosource Cellular bone grafts, and methods of manufacture and use
EP3656785A4 (en) * 2017-07-18 2020-07-15 Posco Antimicrobial adhesive protein, antimicrobial nanoparticle, antimicrobial composition comprising same nanoparticle, and preparation method for same composition
US10970789B2 (en) 2018-01-23 2021-04-06 Full Circle Innovation Llc Systems and methods for facilitating insurance coverage
US11147567B2 (en) 2018-02-28 2021-10-19 Joint Restoration Foundation, Inc. Methods and devices for restoration of a bone surface
US10687828B2 (en) 2018-04-13 2020-06-23 Surgentec, Llc Bone graft delivery system and method for using same
US11116647B2 (en) 2018-04-13 2021-09-14 Surgentec, Llc Bone graft delivery system and method for using same
WO2020006239A1 (en) 2018-06-27 2020-01-02 Illuminoss Medical, Inc. Systems and methods for bone stabilization and fixation
US10869950B2 (en) 2018-07-17 2020-12-22 Hyalex Orthopaedics, Inc. Ionic polymer compositions
CN111973797B (en) * 2020-09-04 2022-06-03 湖南奥星生物医药股份有限公司 Non-invasive implantation high-viscosity adhesive material for orthopedics department and preparation method and application thereof
USD993452S1 (en) * 2021-09-13 2023-07-25 Regenbiotech, Inc. Medical filler for scaffold for optimizing tissue regeneration

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4743259A (en) 1986-10-29 1988-05-10 The University Of Virginia Alumni Patents Foundation Use of demineralized bone matrix in the repair of segmental defects
US4902296A (en) 1986-10-29 1990-02-20 The University Of Virginia Alumni Patents Foundation Use of demineralized bone matrix in the repair of segmental defects
US5507813A (en) * 1993-12-09 1996-04-16 Osteotech, Inc. Shaped materials derived from elongate bone particles
WO1997025941A1 (en) * 1996-01-17 1997-07-24 Osteotech, Inc. Process and apparatus for producing flexible sheets from demineralized, elongate, bone particles
WO1999039757A1 (en) * 1998-02-06 1999-08-12 Osteotech, Inc. Osteoimplant and method for its manufacture

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030583B1 (en) 1979-12-18 1984-06-13 Oscobal Ag Bone replacement material and process for producing a bone replacement material
US4637931A (en) 1984-10-09 1987-01-20 The United States Of America As Represented By The Secretary Of The Army Polyactic-polyglycolic acid copolymer combined with decalcified freeze-dried bone for use as a bone repair material
CA1339083C (en) 1987-11-13 1997-07-29 Steven R. Jefferies Bone repair material and delayed drug delivery system
US5219576A (en) * 1988-06-30 1993-06-15 Collagen Corporation Collagen wound healing matrices and process for their production
US5207710A (en) 1988-09-29 1993-05-04 Collagen Corporation Method for improving implant fixation
US5061286A (en) * 1989-08-18 1991-10-29 Osteotech, Inc. Osteoprosthetic implant
US5290558A (en) 1989-09-21 1994-03-01 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
JPH03131263A (en) * 1989-10-16 1991-06-04 Nippon Electric Glass Co Ltd Cement for living body
US5314476A (en) * 1992-02-04 1994-05-24 Osteotech, Inc. Demineralized bone particles and flowable osteogenic composition containing same
JPH0753204A (en) * 1993-08-18 1995-02-28 S T K Ceramics Kenkyusho:Kk Calcium phosphate-based self-hardenable composition
US5709683A (en) 1995-12-19 1998-01-20 Spine-Tech, Inc. Interbody bone implant having conjoining stabilization features for bony fusion
US5814084A (en) 1996-01-16 1998-09-29 University Of Florida Tissue Bank, Inc. Diaphysial cortical dowel
US5824078A (en) * 1996-03-11 1998-10-20 The Board Of Trustees Of The University Of Arkansas Composite allograft, press, and methods
US5868749A (en) 1996-04-05 1999-02-09 Reed; Thomas M. Fixation devices
JP4014698B2 (en) * 1997-07-15 2007-11-28 ペンタックス株式会社 Method for producing porous calcium phosphate ceramics
US5899939A (en) * 1998-01-21 1999-05-04 Osteotech, Inc. Bone-derived implant for load-supporting applications
US6294187B1 (en) * 1999-02-23 2001-09-25 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4743259A (en) 1986-10-29 1988-05-10 The University Of Virginia Alumni Patents Foundation Use of demineralized bone matrix in the repair of segmental defects
US4902296A (en) 1986-10-29 1990-02-20 The University Of Virginia Alumni Patents Foundation Use of demineralized bone matrix in the repair of segmental defects
US5507813A (en) * 1993-12-09 1996-04-16 Osteotech, Inc. Shaped materials derived from elongate bone particles
WO1997025941A1 (en) * 1996-01-17 1997-07-24 Osteotech, Inc. Process and apparatus for producing flexible sheets from demineralized, elongate, bone particles
WO1999039757A1 (en) * 1998-02-06 1999-08-12 Osteotech, Inc. Osteoimplant and method for its manufacture

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001082993A2 (en) * 1999-03-16 2001-11-08 Regeneration Technologies, Inc. Implants for orthopedic applications
WO2001082993A3 (en) * 1999-03-16 2002-07-18 Regeneration Tech Inc Implants for orthopedic applications
JP2004501682A (en) * 2000-06-29 2004-01-22 バイオシンテック カナダ インコーポレーティッド Compositions and methods for cartilage and other tissue repair and regeneration
JP2004501719A (en) * 2000-07-03 2004-01-22 オステオテック インコーポレーテッド Osteogenic implants derived from bone
WO2002002156A2 (en) * 2000-07-03 2002-01-10 Osteotech, Inc. Osteogenic implants derived from bone
US6863694B1 (en) 2000-07-03 2005-03-08 Osteotech, Inc. Osteogenic implants derived from bone
US6808585B2 (en) 2000-07-03 2004-10-26 Osteotech, Inc. Osteogenic implants derived from bone
WO2002002156A3 (en) * 2000-07-03 2002-05-23 Osteotech Inc Osteogenic implants derived from bone
WO2002005750A3 (en) * 2000-07-19 2002-06-06 Osteotech Inc Osteoimplant and method of making same
US9999520B2 (en) 2000-07-19 2018-06-19 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
US9387094B2 (en) 2000-07-19 2016-07-12 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
WO2002005750A2 (en) * 2000-07-19 2002-01-24 Osteotech, Inc. Osteoimplant and method of making same
US8663672B2 (en) 2000-07-19 2014-03-04 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
US7144428B2 (en) 2000-09-19 2006-12-05 Eduardo Aldecoa Anitua Method for surface treatment of implants or prosthesis made of titanium or other materials
WO2002024243A1 (en) * 2000-09-19 2002-03-28 Eduardo Anitua Aldecoa Method for surface treatment of implants or prosthesis made of titanium or other materials
AU2006225230B2 (en) * 2000-10-13 2009-04-02 Warsaw Orthopedic, Inc. Volume maintaining osteoinductive/osteoconductive compositions
WO2002032348A1 (en) * 2000-10-13 2002-04-25 Osteotech, Inc. Volume maintaining osteoinductive/oesteoconductive compositions
JP2004512870A (en) * 2000-10-13 2004-04-30 オステオテック インコーポレーテッド Volume maintaining osteoinductive / osteoconductive composition
AU2001210862B2 (en) * 2000-10-13 2006-06-29 Warsaw Orthopedic, Inc. Volume maintaining osteoinductive/oesteoconductive compositions
AU2005203606B2 (en) * 2000-10-24 2009-01-08 Warsaw Orthopedic, Inc. Spinal fusion methods and devices
US8758438B2 (en) 2000-12-08 2014-06-24 Warsaw Orthopedic, Inc. Implant for orthopedic applications
US8608803B2 (en) 2001-02-14 2013-12-17 Warsaw Orthopedic, Inc. Implant derived from bone
US7931692B2 (en) 2001-02-14 2011-04-26 Osteotech, Inc. Implant derived from bone
WO2002064181A1 (en) * 2001-02-14 2002-08-22 Osteotech, Inc. Implant derived from bone
WO2003013623A1 (en) * 2001-08-10 2003-02-20 Osteotech, Inc. Bone plating system and method of use
EP2295088A1 (en) * 2001-10-12 2011-03-16 Osteotech, Inc., Improved bone graft
US7594577B2 (en) 2002-06-04 2009-09-29 Mtf Meditech Franken Gmbh Method and device for moistening non-biological medical implant material
US7506759B2 (en) 2002-06-04 2009-03-24 Mtf Meditech Franken Gmbh Method and device for wetting a medical implant or transplant
EP1369095A2 (en) * 2002-06-04 2003-12-10 MTF MediTech Franken GmbH Method and device for moistening a medical implant or graft
EP1369095A3 (en) * 2002-06-04 2004-01-14 MTF MediTech Franken GmbH Method and device for moistening a medical implant or graft
EP1534353A1 (en) * 2002-06-10 2005-06-01 Keratec Limited Orthopaedic materials derived from keratin
EP1534353A4 (en) * 2002-06-10 2010-10-13 Keratec Ltd Orthopaedic materials derived from keratin
SG151097A1 (en) * 2002-08-12 2009-04-30 Osteotech Inc Synthesis of a bone-polymer composite material
US10080661B2 (en) 2002-12-12 2018-09-25 Warsaw Orthopedic, Inc. Injectable and moldable bone substitute materials
EP1578957A4 (en) * 2002-12-12 2008-09-03 Osteotech Inc Formable and settable polymer bone composite and method of production thereof
US9308292B2 (en) 2002-12-12 2016-04-12 Warsaw Orthopedic, Inc. Formable and settable polymer bone composite and methods of production thereof
US9107751B2 (en) 2002-12-12 2015-08-18 Warsaw Orthopedic, Inc. Injectable and moldable bone substitute materials
EP1578957A1 (en) * 2002-12-12 2005-09-28 Osteotech, Inc. Formable and settable polymer bone composite and method of production thereof
US9327052B2 (en) 2003-02-04 2016-05-03 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US9993579B2 (en) 2003-02-04 2018-06-12 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US8425893B2 (en) 2003-02-04 2013-04-23 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US10322209B2 (en) 2003-02-04 2019-06-18 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US8002843B2 (en) 2003-02-04 2011-08-23 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US9789223B2 (en) 2003-02-04 2017-10-17 Warsaw Orthopedic, Inc. Polyurethanes for osteoimplants
US9393116B2 (en) 2003-06-11 2016-07-19 Warsaw Orthopedic, Inc. Osteoimplants and methods for their manufacture
KR100750190B1 (en) 2004-06-16 2007-08-31 요업기술원 Effective bone filler and manufacturing methods thereof
AU2006242649B2 (en) * 2005-04-29 2011-08-04 Warsaw Orthopedic, Inc. Synthetic loadbearing collagen-mineral composites for spinal implants
EP2231210A1 (en) * 2007-12-12 2010-09-29 Osteotech, Inc., Bone/collagen composites and uses thereof
EP2231210A4 (en) * 2007-12-12 2013-01-23 Warsaw Orthopedic Inc Bone/collagen composites and uses thereof
US10383974B2 (en) 2008-12-13 2019-08-20 Bioventus Llc Bioactive grafts and composites
US11491260B2 (en) 2008-12-13 2022-11-08 Bioventus, Llc Method of making osteoinductive bone implant
EP3054870A4 (en) * 2013-10-09 2017-07-19 Lifenet Health Compressed bone composition and methods of use thereof
AU2014331769B2 (en) * 2013-10-09 2019-01-24 Lifenet Health Compressed bone composition and methods of use thereof
US10780196B2 (en) 2013-10-09 2020-09-22 Lifenet Health Compressed bone composition and methods of use thereof
US11576999B2 (en) 2013-10-09 2023-02-14 Lifenet Health Compressed bone composition and methods of use thereof

Also Published As

Publication number Publication date
AU758828B2 (en) 2003-04-03
JP4658331B2 (en) 2011-03-23
JP2002537073A (en) 2002-11-05
KR100754814B1 (en) 2007-09-03
US6294187B1 (en) 2001-09-25
EP1152777B1 (en) 2006-05-03
KR20010104351A (en) 2001-11-24
ES2261191T3 (en) 2006-11-16
DE60027698T2 (en) 2007-04-26
EP1152777A1 (en) 2001-11-14
CA2363153A1 (en) 2000-08-31
CA2363153C (en) 2011-04-26
AU3703300A (en) 2000-09-14
US20010043940A1 (en) 2001-11-22
US6440444B2 (en) 2002-08-27
TR200102480T2 (en) 2001-12-21
DE60027698D1 (en) 2006-06-08

Similar Documents

Publication Publication Date Title
CA2363153C (en) Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
US6696073B2 (en) Shaped load-bearing osteoimplant and methods of making same
US8133421B2 (en) Methods of making shaped load-bearing osteoimplant
US7001551B2 (en) Method of forming a composite bone material implant
US6616698B2 (en) Bone graft and guided bone regeneration method
US20070233272A1 (en) Shaped load-bearing osteoimplant and methods of making same
US5507813A (en) Shaped materials derived from elongate bone particles
US6843807B1 (en) Osteoimplant
AU2001275999B2 (en) Osteoimplant and method of making same
CA2415061C (en) Osteogenic implants derived from bone
AU2001275999A1 (en) Osteoimplant and method of making same
US20120245703A1 (en) Composite bone material implant and method
US20090098092A1 (en) Composite Bone Material and Method of Making and Using Same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2363153

Country of ref document: CA

Ref document number: 2363153

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2000 600712

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020017010795

Country of ref document: KR

Ref document number: 2001/02480

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 37033/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2000915821

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2000915821

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020017010795

Country of ref document: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWG Wipo information: grant in national office

Ref document number: 37033/00

Country of ref document: AU

WWG Wipo information: grant in national office

Ref document number: 2000915821

Country of ref document: EP