WO2001066044A2 - Particule façonnee et composition pour carence osseuse, et procede de fabrication de ladite particule - Google Patents

Particule façonnee et composition pour carence osseuse, et procede de fabrication de ladite particule Download PDF

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Publication number
WO2001066044A2
WO2001066044A2 PCT/US2001/006043 US0106043W WO0166044A2 WO 2001066044 A2 WO2001066044 A2 WO 2001066044A2 US 0106043 W US0106043 W US 0106043W WO 0166044 A2 WO0166044 A2 WO 0166044A2
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WO
WIPO (PCT)
Prior art keywords
particle
particles
bone
adjacent
shaped
Prior art date
Application number
PCT/US2001/006043
Other languages
English (en)
Other versions
WO2001066044A3 (fr
Inventor
Julie Bearcroft
Michael B. Cooper
William B. Kaiser
Keith M. Kinnane
Jeff Schryver
Original Assignee
Smith & Nephew, 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 Smith & Nephew, Inc. filed Critical Smith & Nephew, Inc.
Priority to AU2001239874A priority Critical patent/AU2001239874A1/en
Priority to EP01914491A priority patent/EP1259196A2/fr
Priority to CA002401421A priority patent/CA2401421A1/fr
Priority to KR1020027011507A priority patent/KR20020082231A/ko
Priority to JP2001564698A priority patent/JP2003525696A/ja
Publication of WO2001066044A2 publication Critical patent/WO2001066044A2/fr
Publication of WO2001066044A3 publication Critical patent/WO2001066044A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS 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
    • A61F2/00—Filters 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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/10—Ceramics or glasses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61F2/02—Prostheses implantable into the body
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    • A—HUMAN NECESSITIES
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    • A61F2/00—Filters 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
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    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006—Properties of materials and coating materials
    • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
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    • A61F2/00—Filters 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
    • A61F2/02—Prostheses implantable into the body
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    • A61F2/00—Filters 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
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    • A61F2/00—Filters 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
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Definitions

  • the present invention generally relates to a shaped particle as a bone graft substitute and the use of such a substitute to repair, replace, augment or improve a bone deficiency.
  • the invention also relates to a composition having such a particle in a suspension material to enhance the utility of the particle as a bone graft substitute. Furthermore, a method of making an improved hardened calcium sulfate material for a shaped particle is provided.
  • Bone graft is used to fill spaces in bone tissue that are the result of trauma, disease degeneration or other loss of tissue.
  • Clinicians perform bone graft procedures for a variety of reasons, often to fill a bone void created by a loss of bone or compaction of cancellous bone.
  • the clinician also must rely on the bone graft material to provide some mechanical support, as in the case of subchondral bone replacement or compaction grafting around total joint replacement devices.
  • clinicians pack the material into the defect to create a stable platform to support the surrounding tissue and hardware.
  • the source of the graft material is either the patient (autograft) or a donor (allograft).
  • autograft In autograft and, to a lesser extent, in allograft there are biological factors such as proteins or cells that are present that can assist in the fracture healing process.
  • Xenografts and bone graft substitutes are other options.
  • Autograft is taken from the patient's own body and is the most commonly used graft material.
  • the graft which can come in the form of chips or blocks, is harvested from an ectopic bone site within the body, such as the iliac crest, and used in the deficient site.
  • Autograft has the potential draw back of increased pain and morbidity associated with a second surgical procedure, in addition to having a limited supply of the bone.
  • Allograft is another form of graft which comes from human bone tissue donated to tissue banks, such as from a cadaver. Allograft is available in a number of forms: granules or chips, blocks or sti uts, and processed forms such as gels or putties. In addition to having a limited supply, a serious drawback of allograft is the risk of disease transmission.
  • Xenografts are one such choice which come from non-human bone-tissue donors and are often processed and mixed with other components such as hydroxyapatite or other calcium salts. Again, xenografts are not favored for human use because of concerns over disease transmission and immunogenicity.
  • Bone graft substitutes are materials other than human or non-human bone tissue.
  • the advantages of a synthetically derived substitute material over human derived bone graft and naturally derived substitutes are: 1) more control over product consistency; 2) less risk for infection and disease; 3) no morbidity or pain caused by harvesting of the patient's own bone for graft; and 4) availability of the substitute in many different volumes (that is, it is not limited by harvest site of the patient).
  • the biological and physical demands placed on a bone graft material vary in response to the treatment indication. For instance, clinicians prefer different physical forms of the materials (granules, blocks, dense, porous, putty/paste, cement) depending on the difficulty filling a bone void sufficiently with graft.
  • Craniomaxillofacial defects typically pose relatively low loadbearing requirements on the graft material. The size of the defect may influence whether a conductive graft is sufficient or if an inductive graft is required.
  • a graft's ability to withstand high load and maintain structural support over a long period of time is more important than the graft's ability to accelerate bone healing or bridge a gap (such as in the case of grafting to achieve spine fusion).
  • Synthetic bone graft granules are commonly supplied in a simple glass vial, and very little has been done to improve the handling characteristics or ease the surgical procedure. There are a few exceptions. Although a syringe-like device is available on the market to assist in delivery of granules to the graft site, this does not address the issue of preferential sticking of the granules to soft tissue in the wound. Alternatively, demineralizing allograft products are commercially available which come premixed in a gel or putty for improved handling. Other bone graft substitutes are known in the art. US Patent No.
  • 5,676,700 is directed to interlocking structural elements for augmentation or replacement of bone in which at least four posts of the element project from a hub such that no more than two of the directions of any of the posts lie in a common plane.
  • the elements have posts with oval cross-sections and in a preferred embodiment have an angle of 109.47 degrees between each post.
  • US Patent No. 5,178,201 is directed to an implant method, as opposed to a graft method, in which particles with from four to eight pins which extend radially from a center have at least three pins which adhere to a basic pattern.
  • the body diameter of the particle is a maximum of 3 mm, and the specification does not teach tapering of the pins.
  • US Patent No. 5,458,970 teaches shaped particles comprising deformed fibers in which the fiber is a zinc oxide whisker having a plurality of needle-like portions being maximally 0.1mm in length and extending from its nucleus portion.
  • US Patent No. 5,258,028 is directed to an injectable micro- implantation system utilizing textured micro particles maximally 3mm in diameter and having a number of outwardly projecting pillar members.
  • WO 94/08912 teaches an aggregate having six arms in which the arms are generally obelisk-shaped and have four sides each.
  • the method of making a product from a form of hydrated calcium sulfate is known. Conversion of gypsum powders to plaster of Paris powders (calcination) is well established, and the rehydration of the plaster of Paris powder to convert to gypsum is also well known.
  • US Patent No. 5,320,677 describes the formation of a composite material of gypsum and a stronger component, such as wood fibers. The technique then dehydrates the mix and rehydrates it. The method is a way of mixing in and setting the wood fibers within calcium sulfate. A target application for such a method is the preparation of wallboard.
  • German Patentschrift DE 3732281 C2 relates to the process of compaction of gypsum, and the subsequent dehydration/rehydration at an elevated temperature and pressure for the purpose of forming a consolidation solid to create a more compact form of waste material for easier disposal.
  • Typical forming procedures for calcium sulfate are dry powder pressing (as in pharmaceutical tableting) or casting of a plaster of Paris slurry.
  • the wall board industry uses various wet forming processes to compact slurries of plaster of Paris into large sheets.
  • UK Patent 2 205 089 A is directed to a process for the production of calcium sulphate alpha-hemihydrate.
  • the calcium sulphate dihydrate is molded, introduced to an autoclave, and in the presence of an adequate amount of water in the pores, the crystal growth and crystal form of the calcium sulphate alpha-hemihydrate is controlled by maintaining a temperature between 110°C and 180°C and regulating the atmospheric pressure inside the autoclave.
  • the particle has at least three in a plane and the particle has six extremities.
  • the particle of is comprised of a material selected from the group consisting of ceramic, bioactive glass, polymer, polymer/ceramic composite, and polymer/glass composite.
  • the particle is comprised of ceramic and more preferred is comprised of a calcium salt such as calcium sulfate, calcium carbonate, calcium phosphate and calcium tartarate, but most preferable is of calcium sulfate, or gypsum.
  • the particle is comprised of a polymer such as polypropylene, polylactic acid, polyglycolic acid and polycaprolactone.
  • the particle has a diameter of about 3-10 millimeters, more preferred is 4-8 millimeters, and most perferred is 6 millimeters.
  • the different materials are selected from the group consisting of ceramic, such as a calcium salt, bioactive glass, polymer, polymer/ceramic composite, and polymer/glass composite.
  • a shaped particle for the treatment of a bone deficiency wherein said treatment is selected from the group consisting of augmentation of bone, repair of bone, replacement of bone, improvement of bone, strengthening of bone and healing of bone.
  • the bone deficiency is selected from the group consisting of a fracture, break, loss of bone, weak bone, brittle bone, hole in bone, void in bone, disease of bone and degeneration of bone.
  • the disease is selected from the group consisting of osteoporosis, Paget's disease, fibrous dysplasia, osteodystrophia, periodontal disease, osteopenia, osteopetrosis, primary hyperparathyroidism, hypophosphatasia, fibrous dysplasia, osteogenesis imperfecta, myeloma bone disease and bone malignancy.
  • the array of the present invention has interlocking of adjacent particles which provides adequate porosity to allow ingrowth from a host bone.
  • the porosity is between 40-80%. in a more preferred embodiment the porisity is between 60 and 80%.
  • said array comprises a plurality of shaped particles comprising one or more shaped particles from the group consisting of a first shaped particle comprising a center portion and at least four tapered extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a circular transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least one extremity of an adjacent said particle to facilitate interlocking of adjacent particles in said array of shaped particles; a second shaped particle comprising a center portion, at least two noncurved extremities, and at least three curved extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point
  • a shaped particle for use in treating a bone deficiency wherein said particle is shaped for use in an array of particles interlocked with one another, comprising a multi- ring structure having at least four curved projections wherein said projections provide for interstitial spaces between adjacent said projections, and wherein said projections facilitate interlocking of adjacent particles in said array.
  • the angles between the curved projections are equal.
  • the shaped particle is composed of a polymer such as polypropylene, polylactic acid, polyglycolic acid and polycaprolactone or a polymer/ceramic composite or polymer/glass composite.
  • a composition for use in treating a bone deficiency comprising a suspension material; and a shaped particle from the group consisting of a first shaped particle comprising a center portion and at least four tapered extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a circular transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least one extremity of an adjacent said particle to facilitate interlocking of adjacent particles in said array of shaped particles; a second shaped particle comprising a center portion, at least two noncurved extremities, and at least three curved extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least
  • the suspension material is selected from the group consisting of starch, sugar, glycerin, blood, bone marrow, autrograft material, allograft material, fibrin clot and fibrin matrix or the suspension material is a binder capable of forming a gel such as collagen derivative, cellulose derivative, methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, fibrin, and a biological adhesive such as cryoprecipitate.
  • the suspension material further comprises a biological agent, such as a growth factor, an antibiotic, a strontium salt, a fluoride salt, a magnesium salt, a sodium salt, a bone morphogenetic factor, a chemotherapeutic agent, a pain killer, a bisphosphonate and a bone growth agent.
  • a biological agent such as a growth factor, an antibiotic, a strontium salt, a fluoride salt, a magnesium salt, a sodium salt, a bone morphogenetic factor, a chemotherapeutic agent, a pain killer, a bisphosphonate and a bone growth agent.
  • the growth factor is selected from the group consisting of platelet derived growth factor (PDGF), transforming growth factor ⁇ (TGF- ⁇ ), insulin- related growth factor-l (IGF-I), insulin-related growth factor-ll (IGF-II), fibroblast growth factor (FGF), beta-2- microglobulin (BDGF II) and bone morphogenetic protein (BMP).
  • the bone morphogenetic factor is selected from the group consisting of proteins of demineralized bone, demineralized bone matrix (DBM), bone protein (BP), bone morphogenetic protein (BMP), osteonectin, osteocalcin and osteogenin.
  • the chemotherapeutic agent is selected from the group consisting of cis-platinum, ifosfamide, methotrexate and doxorubicin hydrochloride.
  • the pain killer is selected from the group consisting of lidocaine hydrochloride, bipivacaine hydrochloride, and non-steroidal anti-inflammatory drugs such as ketorolac tromethamine.
  • the composition further includes a clotting factor composition.
  • the clotting factor composition comprises fibrinogen, thrombin and Factor XIII.
  • there is a method to treat a bone deficiency comprising the step of applying a shaped particle to a bone deficiency wherein said shaped particle is selected from the group consisting of a first shaped particle comprising a center portion and at least four tapered extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a circular transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least one extremity of an adjacent said particle to facilitate interlocking of adjacent particles in said array of shaped particles; a second shaped particle comprising a center portion, at least two noncurved extremities, and at least three curved extremities projecting from said center portion wherein said projections
  • a method to treat a bone deficiency comprising the steps of combining a shaped particle with a suspension material wherein said particle is selected from the group consisting of a first shaped particle comprising a center portion and at least four tapered extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a circular transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least one extremity of an adjacent said particle to facilitate interlocking of adjacent particles in said array of shaped particles a second shaped particle comprising a center portion, at least two noncurved extremities, and at least three curved extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a transverse cross- sectional configuration, wherein said interstitial spaces of one
  • kits for the treatment of a bone deficiency comprising a suspension material; and multiple first shaped particles and multiple second shaped particles wherein said first and second particles are shaped for use in an array of particles interlocked with one another and wherein said particles are selected from the group consisting of a first shaped particle comprising a center portion and at least four tapered extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a circular transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least one extremity of an adjacent said particle to facilitate interlocking of adjacent particles in said array of shaped particles; a second shaped particle comprising a center portion, at least two noncurved extremities, and at least three curved extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion,
  • the kit further comprises a biological agent.
  • the kit further includes a clotting factor composition, such as a composition comprising fibrinogen, thrombin and Factor XIII.
  • the kit further comprises a bowl container for said multiple first and multiple second particles and a delivery tool.
  • the delivery tool is selected from the group consisting of a spoon, a spatula, a scoop, a tweezer, forceps, a knife, a hemostat, a syringe, a pipette, a cup and a ladle.
  • the bowl container is used for mixing said multiple first and multiple second particles and a suspension material.
  • the bowl container is used for mixing said multiple first and multiple second particles, said suspension material, and a biological agent.
  • a shaped particle for use in treating a bone deficiency wherein said particle is shaped for use in an array of particles interlocked with one another, comprising a center portion; at least two noncurved extremities; and at least three curved extremities projecting from said center portion wherein said projections provide for interstitial spaces between adjacent extremities, each extremity having a base attached at said center portion, an opposite point, a length, and a transverse cross-sectional configuration, wherein said interstitial spaces of one said particle will accept at least one extremity of an adjacent said particle to facilitate interlocking of adjacent particles in said array.
  • a method for manufacturing a shaped particle of calcium sulphate dihydrate comprising the steps of making a shaped particle of calcium sulphate dihydrate; heating said particle; and applying water to said particle.
  • a method for manufacturing a shaped particle of calcium sulphate dihydrate comprising the steps ofmaking a shaped particle of calcium sulphate dihydrate; heating in the presence of pressure and moisture said particle of calcium sulphate dihydrate to convert said particle to ⁇ -calcium sulphate hemihydrate partially or in full; and applying water to said particle to convert said ⁇ - calcium sulphate hemihydrate to said calcium sulphate dihydrate.
  • Figure 1 is a drawing of a preferred six-armed shaped particle of the invention.
  • Figure 2 is a drawing of an array of interlocked six-armed shaped particles of the invention.
  • Figure 3A through Figure 3D are drawings of a five-armed shaped particle of the invention.
  • Figure 3A is a top view of the particle.
  • Figure 3B is a view of the particle from an elevated side reference.
  • Figure 3C is a front view of the particle.
  • Figure 3D is a right view of the particle.
  • Figure 4A through 4D are drawings of a six-armed shaped particle of the invention having flat tips.
  • Figure 4A is a top view of the particle.
  • Figure 4B is a view of the particle from an elevated side reference.
  • Figure 4C is a front view of the particle.
  • Figure 4D is a right view of the particle.
  • Figure 5A through 5D are drawings of a six-armed shaped particle of the invention having rounded tips.
  • Figure 5A is a top view of the particle.
  • Figure 5B is a view of the particle from an elevated side reference.
  • Figure 5C is a front view of the particle.
  • Figure 5D is a right view of the particle.
  • Figures 6A through 6D are drawings of a shaped particle of the invention having an interlocked ring structure.
  • Figure 6A is a top view of the particle.
  • Figure 6B is a view of the particle from an elevated side reference.
  • Figure 6C is a front view of the particle.
  • Figure 6D is a right view of the particle.
  • Figures 7A through 7D are drawings of different views of a six-armed shaped particle of the invention having a propeller-like structure.
  • Figure 8A through Figure 8D are drawings of a six-armed shaped particle of the invention.
  • Figure 8A is a top view of the particle.
  • Figure 8B is a view of the particle from an elevated side reference.
  • Figure 8C is a front view of the particle.
  • Figure 8D is a right view of the particle.
  • bone deficiency as used herein is defined as a bone defect such as a break, fracture, void, diseased bone, loss of bone, brittle bone or weak bone, injury, disease or degeneration.
  • a defect may be the result of disease, surgical intervention, deformity or trauma.
  • the degeneration may be as a result of progressive aging.
  • Diseased bone could be the result of bone diseases such as osteoporosis, Paget's disease, fibrous dysplasia, osteodystrophia, periodontal disease, osteopenia, osteopetrosis, primary hyperparathyroidism, hypophosphatasia, fibrous dysplasia, osteogenesis imperfecta, myeloma bone disease and bone malignancy.
  • the bone deficiency may be due to a disease or condition, such as a disease which indirectly adversely affects bone.
  • the bone malignancy being treated may be of a primary bone malignancy or may be metastatic, originating from another tissue or part of the body.
  • ceramic as used herein is defined as any non-metallic, non-organic engineering material.
  • An example of such a material is hydroxylapatite, calcium sulphate, alumina or silica.
  • gypsum as used herein is defined as calcium sulfate in the stable dihydrate state (CaSO C2H 2 O) and includes the naturally occurring mineral, the synthetically derived equivalents, and the dihydrate material formed by the hydration of calcium sulfate hemihydrate (CaSO D! H 2 O)(Plaster of Paris) or anhydrite calcium sulphate.
  • the gypsum may be obtained from commercially available sources.
  • tapered as used herein is defined as referring to an extremity of a shaped particle wherein the width of one end of the extremity is different in size from the width of another end of the extremity. That is, the tapering of the extremity may be outward away from the center of the particle or may be inward toward the center of the particle.
  • An object of the present invention is a shaped particle as part of three-dimensional interlocking array of particles to be utilized in bone graft.
  • the particles may be utilized with inductive graft in which the graft actively facilitates, either directly or indirectly, bone growth.
  • the particles may be utilized for a conductive graft in which the graft is conducive to bone growth but does not actively or directly facilitate it.
  • conductive graft utilizes shaped particles made from a ceramic, polymeric, glass material, a polymeric/glass, or a polymeric/ceramic material.
  • the particles for conductive graft are augmented with a biological agent.
  • the material of the particle will be a biocompatible ceramic or glass that may or may not eventually resorb or degrade within the body as the bone heals and fills the bone void or improves the bone deficiency.
  • the particles will be of an appropriate size such that several individual granules will be used to fill a small void while many can be used to fill larger voids.
  • the three-dimensional structure will allow the granules to fill a volume and interlock with each other.
  • the particles will be able to interlock with bone.
  • the interlocking will enable the particles to support some mechanical forces while maintaining stability and assist in bone healing.
  • the interlocking feature makes it possible for the particles to resist some shear forces, unlike commercially available products. It will also help to resist migration away from the implant site.
  • the particles will be able to fill odd bone defect shapes and sizes without necessarily needing to carve a larger block to the approximate shape/size.
  • the interlocked particles also provide the ability for the entire implant to behave mechanically more like a single block as compared to current granular products.
  • the shapes would be such that a collection of these particles do not aggregate into a solid, packed volume but instead leave an open, interconnected porosity that is beneficial for bone healing. It is preferred that the shape of the particles and/or the array of the shaped particles allow the engineering or prediction of a specific porosity.
  • the particles can be shaped to have such a design as to allow 40-80% porosity upon agglomeration.
  • the purpose of having shaped particles is two-fold.
  • First, the capability to interlock provides resistance to shear forces and helps to increase the stability when the graft is packed into a defect.
  • the tapering of the extremities of the shaped particles improves manufacturability, maximizes the open space between the extremities, and provides greater mechanical stability in, for instance, the preferred shaped particle of Figure 1 because the arms are thicker as you get closer to the central body, which distributes loads over more mass of material.
  • Figure 1 shows a shaped particle (10) having an extremity (20), and in a preferred embodiment the particle has six extremities. In a preferred embodiment at least three of the extremities are in a common plane. The extremities are tapered outwardly along the length (30) of the extremity so that the base (40) of the extremity is wider than the tip (50) of the extremity. In a preferred embodiment the tip (50) of the extremities are rounded.
  • the particle has an interstitial space (60) between the adjacent extremities (20).
  • the radius of curvature of the tip (50) of an extremity (20) is about 0.5mm and the radius of curvature of the interstitial space (60) between adjacent extremities is about 0.5mm.
  • the preferred width of the entire particle is about 3-10 mm, and more preferred 4-8mm, and most preferred is 6mm.
  • the preferred width of a base (40) of an extremity (20) is about 1.85mm
  • the preferred width of a tip (50) of an extremity is about 1.19mm
  • the preferred length (30) of an extremity (20) is about 3mm.
  • the angles between any of the adjacent extremities (20) are approximately equal.
  • shaped particles may be used which are greater in size than these measurements or smaller in size than these measurements depending on the relevant application and bone deficiency. It is preferred to keep the size of the particle small relative to the wound site so that it will take many particles to fill the defect rather than one.
  • Figure 2 illustrates an array of shaped particles of the invention wherein the extremities (20) of adjacent particles (10) are interlocked.
  • Figures 3A through 3D illustrate different views of a specific embodiment wherein a five-armed shaped particle (100) is an object of the invention.
  • a five-armed shaped particle 100
  • at least three extremities lie in a plane.
  • An extremity (110) is tapered inwardly along its length (120) wherein the base (130) of the extremity (110) is more narrow in width than the tip (141) of the extremity (110).
  • An interstitial space (150) is present between adjacent extremities.
  • the tips (141) of the extremities (110) are rounded in a specific embodiment.
  • FIGS 3B through 3D illustrate that in a specific embodiment the tips (158 and 159) of two extremities (160 and 170, respectively) which are situated about 180 degrees from one another are generally more conical in shape than the tips (141) of the extremities (110).
  • the extremities (160 and 170) taper outwardly where the base (161 and 171 , respectively) is wider than the tips (158 and 159).
  • Figures 4A through 4D illustrate different views of a specific embodiment wherein a six-armed shaped particle (300) is an object of the invention.
  • at least three extremities lie in a plane.
  • An extremity (310) is tapered inwardly along its length (320) wherein the base (330) of an extremity (310) is more narrow in width than the tip (340) of the extremity (310).
  • An interstitial space (350) is present between adjacent extremities.
  • the tips (340) have a generally flat surface.
  • Figures 4B through 4D show the tips (360 and 361) of two extremities (370 and 380, respectively) are generally more conical in shape than the tips (340) of the extremities (310) and are situated about 180 degrees from one another in the particle (300).
  • FIGs 5A through 5D illustrate different views of a specific embodiment wherein a six-armed shaped particle (400) is an object of the invention.
  • at least three extremities lie in a plane.
  • An extremity (410) is tapered inwardly along its length (420) wherein the base (430) of an extremity (410) is more narrow in width than the tip (440) of the extremity (410).
  • An interstitial space (450) is present between adjacent extremities.
  • the tips (440) of the extremities (410) have a generally rounded surface.
  • Figures 5B through 5D show the tips (460 and 461) of two extremities (470 and 480, respectively) are generally more conical in shape than the tips (440) and are situated 180 degrees from one another in the particle (400).
  • the shaped particles represented in Figures 4 and 5 are made from a polymer, polymer/ceramic composite, or polymer/glass composite.
  • the tapering inwardly of the extremities (310 and 410) allows these shaped particles to "snap-fit" into an adjacent particle.
  • Figures 6A through 6D illustrate different views of a specific embodiment of the present invention wherein a shaped particle (500) is similar to two interlocked rings positioned at about 90 degrees from one another. Interstitial spaces (510) allow interlocking of the rings (520), or curved projections, of an adjacent particle.
  • the preferred composition material of this structure is a polymer, a polymer/glass composite or a polymer/ceramic composite. In a preferred embodiment the structure is relatively compliant in comparison to a ceramic-based structure.
  • a preferred diameter of the entire particle (500) is about 6 mm, and a preferred diameter of the ring (520) component of the structure is about 1mm.
  • the maximum number of rings would be such that the surface area of the rings should not be more than 50% of the surface area of the encompassed sphere - otherwise the parts would not interlock or nest with each other. Using this as a starting point, then the diameter of the solid structure of the ring (as an example at about 1 mm) becomes a factor. As that diameter decreases the number of possible rings increases.
  • a surface area of a sphere is 4- ⁇ 2 and a surface area of the interlocking rings is 2 ⁇ rdn.
  • the objective is that the surface area of the rings is less than or equal to 50% of the surface area of a sphere.
  • the mathematical relationship can be described as 2 ⁇ rrdn ⁇ 0.50 (4- ⁇ 2 ), or 2 ⁇ rdn ⁇ 2 ⁇ r 2 , or dn ⁇ r
  • Figures 7A through 7D illustrate a specific embodiment of the present invention wherein a shaped particle (600) is similar to a propeller. Interstitial spaces (610) allow interlocking of the extremities (620) of the particle.
  • the length (615) of an extremity (620) is curved generally as in a propeller arm.
  • the composition material of this structure is a ceramic, polymer, bioglass, polymer/ceramic composite, or polymer/glass composite.
  • the structure is relatively compliant in comparison to a ceramic-based structure.
  • a preferred diameter of the entire particle (600) is about 6 mm, and a preferred diameter of the extremities (620) component of the structure is about 1mm.
  • the extremities (630 and 631), particularly as shown in Figure 7D, are generally conical in shape, having a wider base (640 and 641 , respectively) tapering along the length (650 and 651 , respectively) of the extremity to a narrower tip (660 and 661 , respectively).
  • the extremities (630 and 631) are positioned about 180 degrees relative to each other.
  • Figures 8A through 8D illustrate different views of a specific embodiment wherein a six-armed shaped particle (700) is an object of the invention. In a preferred embodiment of a six-armed shaped particle at least three extremities lie in a plane.
  • An extremity (710) is tapered inwardly along its length (720) wherein the base (730) of the extremity (710) is more narrow in width than the tip (741) of the extremity (710).
  • An interstitial space (750) is present between adjacent extremities.
  • the tips (741) are rounded in a specific embodiment.
  • Figures 8B through 8D illustrate that in a specific embodiment the tips (702 and 704) of two extremities (760 and 770, respectively) which are situated about 180 degrees from one another are generally more conical in shape than the tips (741) of the extremities (710).
  • the extremities (760 and 770) taper outwardly where the base (761 and 771 , respectively) is wider than the tips (702 and 704, respectively).
  • the surface to volume ratio of the shaped particle of the present invention has influence upon several factors, including the intended application of the bone graft, which dictates the size of the particle needed and the dissolution rates, strength and manufacturability.
  • the assessment of the shaped particles was based on two tests designed to address interlocking of the particles and application to a clinical-type case.
  • A) 'Slump' test measure the ability of a pile of bone graft granules to maintain its height before and after vibration.
  • Push-thru test measure the resistance to push-thru of an agglomeration of bone graft granules through a cylindrical defect in a porous foam block, which is a lab model used for human cancellous bone.
  • the goal was to determine which of the designs provided the most interlocking that was also an improvement over a design comparable to a commercially available tablet-shaped product.
  • Shaped particle designs 28ml_ of each Shaped particle designs, 50mL of each
  • Cuplike container half angle 12°, base Image pro Plus Software (Media diameter 1.125”) Cybernetics, V 3.0.1)
  • SLA Stereo lithographic models
  • Clay formula 50-dry (81.6% gypsum, 1.1% carboxymethyl cellulose, 4.1% glycerin, 13% water) was rolled into sheets (about 1 mm thick), big enough to cover the cavities in the molds.
  • Gypsum FG-200, from BPB, Newarks, United Kingdom
  • the mold halves were closed together and compacted using about 4000 lbs. of force. 6.
  • the molds were heated in a microwave oven to dry the water from the parts.
  • the slump test was conducted first since it was non-destructive. Equal volumes (28mL) of each shaped particle design and the tablet samples were measured using a 100mL graduated cylinder. These equal volumes were weighed to determine the mass of material present.
  • the test begins by pouring the entire volume of individual shaped particle designs into a starting container. Either a funnel (half angle 28°) or a cuplike container (half angle 12° with a 1.125 inch flat base) was used to contain the shaped bone graft particles and provide a starting shape for the pile. The container was then inverted and placed on a base through which a vibration was applied for five seconds using an electronic, vibrating pencil. The vibration was used to settle the shaped bone graft particles into the container of choice and pre-pack them to that shape. Following the vibration, the container was carefully removed. A height gage was used to measure the initial height of the pile. Vibration was then applied to the base plate, causing the pile to settle further. The height gage was used again to measure this new height.
  • Table 1 shows the mass data collected for the three shaped particle designs and the tablet geometry. The mass shown is for 28mL of particles, as measured in a 100mL graduated cylinder. One data point was collected for each design. Mass and mass per volume are important and related to the dissolution time and the porosity of the agglomerated granules. If all parameters were equal (material, density, surface-area-to-volume ratios, etc.) it would be expected that the more mass per volume, the lower would be the porosity of the agglomerate and the longer duration it would have before dissolution. The dissolution rate would determine how much material would disappear per unit of time and may also be influenced by the surface-area-to-volume ratio and the material.
  • Table 2 shows the summarized results for the slump tests performed on each of the different sample geometries using the funnel for a starting form. Each sample was measured ten times. It was proposed that maximizing the starting height and the height after vibration and minimizing the change in height and percent change in height were the ideal cases. The best value for the shaped particle designs tested for each parameter is in bold. The tablets did not form a pile (tablets fell to only one or two layers high) when the supporting container was removed, qualitatively indicating poor interlocking relative to other samples.
  • Table 3 shows the summarized results for the slump tests performed using the cuplike container for a starting form. As with the slump test using the funnel for a starting container, maximizing the start height and the height after vibration and minimizing the change in height and percent change in height were the ideal cases. The best value for the shaped particle designs tested in each column in bold.
  • the push-thru test was a mechanical test performed using a Tinius- Olsen (Willow Grove, PA) screw-driven mechanical test frame. Once tested using this procedure, the sample parts and the defects in the porous blocks were considered to be damaged and not valid for additional testing.
  • a polyethylene stopper was placed into the bottom of the pre-drilled, 0.750" hole (thru) in the porous foam block. Then, a volume (approximately 8mL) of shaped particle is added to the hole and the top plunger is inserted. The correct amount of shaped particles are added when the plunger sits such that the fill mark just shows above the level of the top of the porous foam block.
  • the test block with plunger, stopper and shaped particles are then transferred to the test frame. The part to be tested is situated such that the stopper is over a solid block to temporarily block the shaped particle and stopper from falling through. A pre-load of ten pounds of force is then applied at a rate of 0.1 inches/minute.
  • the pre-load is then removed and the stopper is positioned over an opening such that the plunger can press against the shaped particles and the majority of resistance comes from frictional forces between the shaped particle and the shaped particle and the walls. Additional resistance is expected between the stopper/plunger and the walls, but this should be small and consistent in all tests performed.
  • Load is reapplied at a rate of 0.1 inches/minute until the resisting load drops to zero and the granules are gone from the test block. Data is recorded using a load/displacement graph. This test was repeated five times for each of the three shaped particle designs and three times for the tablet geometry.
  • Table 4 shows the summarized results for the push-thru testing on each of the different geometries.
  • the tested granules can be listed in order of decreasing mass per 28mL volume: tablet geometry, six-armed shaped particle with tapered arms, five-armed shaped particle, and six-armed shaped particle flared to bulb at the end of arms in X-Y plane.
  • Push-thru testing showed that the six-armed shaped particle with tapered arms offered the most resistance to push the granules all the way through the porous foam test block.
  • the other shaped particle designs both required about 1/3 less energy to push the granules through the same block.
  • the tablets required only about 3% of the energy required to push-thru the six-armed shaped particle with tapered arms. All of the shaped particle designs were observed to resist push-thru until the plunger was nearly all of the way through the test block. The tablet geometries fell through after the plunger traveled only a short distance through the block.
  • a material for the ceramic component of a bone grafting system of the present invention is calcium sulfate.
  • Other materials that could be used include: a calcium salt; hydroxylapatite, a calcium phosphate; bioactive glass, a vitreous based glass (such as may be used for maxio-cranio applications); calcium carbonate, a calcium based mineral; various calcium phosphates, and calcium-rich minerals, including tricalcium phosphate and orthophosphate; apatite/ wollastonite glass ceramic, a calcium silicate often used in bone spacer applications; resorbable polymers such as polysaccharides, polyglycolates, polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone, polypropylene fumarate (all of which can be blended or made to co-polymers to control the desired properties of the product); and composites of resorbable polymers and glass or ceramic fillers.
  • Bioactive glass is a material whose major components are CaO
  • the shaped particle of the present invention is colored to make it more visible.
  • differently shaped particles of the present invention are denoted with different colors for better differentiation of the particles.
  • the particles are coated or have contained within them an agent such as green fluorescent protein or blue fluorescent protein to make them fluorescent and therefore more visible.
  • the circular cross-section of the extremities, or arms, of the shaped particle of the invention is beneficial for strength purposes, because an equivalent response to loading will occur regardless of the application of the load around the circumference.
  • an oval shape as is utilized in commercially available products and in US Patent No. 5,676,700 has reduced resistance to loading when the loading is applied in the direction of the axis of the shorter width of the oval compared to the axis of the longer width of the oval.
  • a suspension material may be used as an additional component of a system for a bone graft substitute to treat bone deficiency.
  • the suspension material may be a liquid, putty, dough or gel phase component and may be mixed with the shaped particles described above at the time of use or come as a pre-packaged system.
  • the suspension material could serve two potential functions: 1) to act as a binder to improve handling by forming a putty-like material which is shapeable, and/or 2) to act as a biological tool to assist in the healing through the addition of infection control, bone growth, or other healing or biological agents.
  • the suspension material can provide standard suspension of particles within a material or it may provide adhering of particles or connecting of particles in a manner wherein the material is smaller in volume in an array than the volume of the particles themselves.
  • the suspension material can either be setting or non-setting in response to time, temperature, presence of body fluid or other external stimuli which might supply energy, such as ultraviolet radiation, magnetic radiation, electromotive force (EMF), radiowaves, or ultrasound.
  • EMF electromotive force
  • the suspension material will degrade once implanted. Ideally, it would be derived from naturally occurring substances such as carbohydrates, starches or glycerin. It should have a sufficient viscosity as to help the granules adhere to each other to improve intraoperative handling.
  • Coating calcium salts of the preferred embodiment of the shaped particles of the invention with this type of substance may also decrease their affinity to stick to soft tissue, making it easier to remove unwanted pieces from the application site.
  • Fibrinogen/thrombin/Factor XIII combinations may also provide a liquid or gel of appropriate viscosity to use as a binder.
  • the liquid may also be a synthetic material such as calcium sulfate (plaster of Paris) that would set in situ.
  • this binder could act as a carrier for a variety of agents including but not limited to growth factors, bone morphogenic proteins, fibrinogen/thrombin, antibiotics or some other therapeutic agent (see Example 6).
  • the suspension material is blood, bone marrow, autograft material, or allograft material. These materials are preferentially derived from the patient with the bone deficiency being treated. Alternatively, they are derived from a donor and preferable are free from being the source of disease transmission.
  • a suspension material which is compatible with all synthetics (calcium phosphates, calcium sulfates, bioactive glasses, and resorbable polymers).
  • An example of a suspension material is a mixing gel which can be mixed with the synthetic or natural products (autograft or allograft) of choice by the clinician to produce a 'paste' for application to a bone deficiency such as bone void filling.
  • the suspension material must have the appropriate viscosity and tackiness to agglomerate the particles for easy application to the graft site. Once agglomerated, the paste could be manipulated by hand or be transported by use of a tool such as a scoop, spoon or syringe to the defect site.
  • the suspension material can also reduce the preferential sticking to soft tissue. This adhesion to soft tissue may be caused by a number of factors. Calcium phosphates are known for their affinity for many proteins, as demonstrated by their use in chromatography columns for protein isolation. Thus, their surface chemistry contributes to their preferential sticking to soft tissues of the surgical site which is often covered in blood and protein-containing body fluids. Secondly, many of these commercially available products have rough surfaces that may mechanically adhere to soft tissues such as coral-derived products which contain many interconnected tubules that when fractured create a very rough surface. A suspension material can minimize both effects. In the first case, the suspension material alters the surface chemistry, thus reducing the particles' affinity for proteins. In the second, the suspension material fills in rough features, thereby reducing the particles' ability to mechanically adhere to the tissue.
  • the suspension material of the present invention may be comprised of biocompatible polymers, and in a specific embodiment the polymers are bioresorbable.
  • the polymers must be graftable into an animal without causing unacceptable side effects.
  • the polymers may be homopolymers or copolymers and are preferably amorphous.
  • a specific example is polymers in which the units are derived from hydroxy carboxylic acids, which are polyesters.
  • poly(lactic acids) which may originate from the polymerization of mixtures of L- and D-lactides in proportions such that the poly(lactic acids) are amorphous.
  • Another example is copolymers consisting of units derived from lactic and glycolic acids.
  • a biocompatible polymer may or may not be degradable, depending on the proposed use.
  • Degradable polymers which are nontoxic and implantable into organisms such as humans are preferable, and examples include polyglycolic acid or polylactic acid.
  • Other materials which may be useful based on their biocompatibility and the ability to alter their viscosity and tackiness to prove useful in this invention include: polyvinylpyrolidone, chitosin, glycerol, carboxymethylcellulose, methylcellulose, carrageenan, hyaluronic acid, collagen-hydroxyapatite-hyaluronic acid composite, alginate, dextrose, starches, cellulose gums or combinations of any of the above listed items.
  • a skilled artisan is aware that collagen or a derivative of collagen is preferably treated prior to use in the invention so as not to be immunoreactive, or alternatively a recombinant form of collagen may be used.
  • a binder is a material that aids in the agglomeration of the particles due to the tackiness of the binder both in a cohesive (with itself) and adhesive (with the particles) nature.
  • the final construct still has flexibility and pliability so that it can fill a defect completely. It is possible that plaster of Paris or a settable calcium phosphate cement system may be used as a binder which will still ultimately set to a firm construct. This would provide an improvement in the immediate structural strength under a loading pattern that is predominately compression. So, therefore, a binder may or may not harden. In a preferred embodiment the binder hardens.
  • physiological materials examples include saline, various starches, hydrogels, polyvinylpyrrolidines, other polymeric materials, polysaccharides, organic oils or fluids, all of which are well known and utilized in the art.
  • Biologically compatible saccharides such as glucose or aqueous solutions of starch may be used.
  • Certain fats may also be used.
  • highly compatible materials include esters of hyaluronic acids such as ethyl hyaluronate and polyvinylpyrrolidone (PVP).
  • PVP normally has the general empirical formula [CHCH 2 ) 2 N(CH 2 ) 3 CO] n wherein n equal 25-500, a form otherwise known as Plasdone ® (trademark of GAF Corporation, New York, NY).
  • Another biocompatible material is a patient's own plasma. Blood may be withdrawn from the patient, centrifuged to remove cells (or not) and mixed with appropriate volume of particles and the mixture applied in the desired locations.
  • the suspension material is comprised of the following: carboxymethylcellulose (maximum of 3 weight percent); glycerol USP (maximum of 20 weight percent); and purified water USP (maximum of 88.75 weight percent).
  • carboxymethylcellulose maximum of 3 weight percent
  • glycerol USP maximum of 20 weight percent
  • purified water USP maximum of 88.75 weight percent.
  • the shaped particles of the invention are of a polymeric phase.
  • the material could be derived from a wide variety of bioabsorbable, biocompatible polymers that will resorb or degrade over time. These polymers could also be ceramic or glass filled in order to boost the osteoconductivity of the polymer alone.
  • the polymers, or composites also allow control of mechanical properties, such as strength and stiffness, and control of degradation rates.
  • the function of this component is to offer compliance to a bone graft system comprised of this material and the ceramic and suspension material phases described above.
  • the polymeric shaped particles will interlock with a ceramic-based particle, still maintaining a certain volume of the combination that is open and has an interconnected porosity.
  • the polymeric granule also protects the ceramic components from brittle fracture under compaction, acting as a buffer while the system is compressed to fill a bone deficiency.
  • the polymeric shaped particles will be mostly plastic in their behavior with a small portion of elastic response. This will insure that the polymeric shaped particles will compress without too much rebound, but that they will also serve as buffers between the ceramic granules.
  • the polymeric/composite granules may be used without the ceramic granules in some indications where the ability to compact the material is very important, such as in the compaction grafting technique commonly used today in total joint revisions. No current ceramic shaped particle system is suitable for compaction since they would be pulverized by this technique.
  • the shaped particle of polymer has as the ends of its extremities a bubble shape which may provide a "snap-fit" for adjacent interlocking polymeric shaped particles, such as the particles illustrated in Figures 4 and 5.
  • the three components of the invention which provide a bone graft substitute system, including a ceramic shaped particle, a suspension material, and a polymeric shaped particle, will offer the clinician several options when approaching a grafting procedure.
  • the most basic option would be to use the ceramic granules alone when the defect is contained and does not have to provide a lot of mechanical or structural support.
  • the suspension material When the suspension material is added the clinician will be able to work with the granules outside of the bone deficiency site to shape the aggregate.
  • the suspension material may also offer the possibility to introduce infection control or active agents to promote bone healing and growth.
  • the addition of the polymeric shaped particles to the ceramic shaped particles offers the clinician the ability to compress the graft into a deficient site. This would be beneficial when more structural support and stability was required of the implant and might also be more suited to larger volume defects.
  • the system may also include allograft material, such as chips, blocks, putties and gels) or in addition or alternatively may include autograft
  • the system will include multiple shaped particles wherein the particles are of different shapes.
  • the different shapes which may be included are illustrated in the figures herein or may have variations of these shapes.
  • these multiple particles may be comprised of different materials.
  • the typical approach to address the breadth of properties required from bone graft materials is to provide multiple bone graft materials with the intention to apply each to a specific class of indications. If the clinician requires a mixture of properties or attributes, the clinician must mix the currently available products from different manufacturers to obtain a desirable set of attributes or move on to another product already designed with the right set of attributes.
  • a system of products that may be used either independently or mixed with any of the other constituents in the system is provided.
  • a list of the constituents envisioned include: a bioceramic component with osteoconductive properties that is available as a shaped particle; suspension material that aids primarily in the delivery of the shaped particles; a compliant shaped particle with improved mechanical properties that mimics the compliance of allograft cancellous bone; a fibrin matrix (see Example 7) that can act as a carrier as with the suspension material but can provide some enhancement to bone healing, as well as act as a carrier for the following items; antibiotics, cancer therapy, osteoporosis therapies, or therapies for other bone mineralization disorders that can affect the overall efficacy of a bone graft material depending on the complications associated with the graft procedure; growth factors, bone morphogentic proteins, or protein fragments that can further enhance bone healing and/or have a specific high affinity for the fibrin matrix (these factors may utilize wide variety of pathways to meet the end results such as influencing the development of mesenchymal stem cells, growth and reproduction of osteoblast/osteoclast/osteocytes, chemotoxic agents that encourage
  • these components are compatible with autograft. It is generally known that clinicians prefer to use autograft over existing synthetics since it is the tissue which is trying to be emulated. Clinicians will mix in autograft and/or blood to fill in the missing aspects or properties (primarily to capture the bioactive aspects) of the currently available products in an object of the present invention.
  • the present bone graft system invention offers several improvements over current bone graft substitutes: all components may be resorbable/degradable in-vivo (current products offered include both resorbable/degradable and permanent structure); interlocking structure increases mechanical strength and stability of the granular structure (particularly under shear forces) relative to the current designs of random and regular, non-interlocking structures; interlocking structure that also maintains open, interconnected porosity which allows the individual shaped particles (especially ceramic) to be dense and therefore less likely to chip and break than current porous (ceramic) structures which are friable and weak; dense shaped particles will not adhere to soft tissues as will the currently available porous ceramic structures; offering product as a shaped particle allows the clinician to fill a large range of defect sizes, whereas current products offer granule and block forms; a multi- component system allows the clinician to tailor the bone graft to the needs of the patient without having to utilize many different product offerings (current products do not offer this flexible, systematic approach); the addition of antibiotics to the system allows the clinician
  • the integral advantage of a system of the invention is that it eliminates the need to develop a specific product for each specific indication.
  • the clinician can now mix/match the components of the system as needed to provide the desirable mixture of attributes, thus having the ability to tailor or design a bone graft product for each patient to suit his or her unique needs and specific complications. This results in a lower cost to the patient who will be charged only for the products used.
  • the product may be limited in its use to treat larger defects for fear of over dosing. Similar issues are encountered in treating small defects where the dose may be too small to have a beneficial outcome. Giving the clinician the ability to set the dose allows that the proper dose will be used in all cases.
  • a biological agent is included in the suspension material.
  • examples include antibiotics, growth factors, fibrin (see Example 7), bone morphogenetic factors, bone growth agents, chemotherapeutics, pain killers, bisphosphonates, strontium salt, fluoride salt, magnesium salt, and sodium salt.
  • the present invention allows antibiotics to be included within the suspension material of the composition for a local administration. This reduces the amount of antibiotic required for treatment of or prophalaxis for an infection. Administration of the antibiotic by the suspension material in a composition would also allow less diffusing of the antibiotic, particularly if the antibiotic is contained within a fibrin matrix (see Example 7).
  • the particles of the present invention may be coated with the antibiotic and/or contained within the particle or the suspension material. Examples of antibiotics are tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycocides such as tobramycin and gentamicin. Growth factors may be included in the suspension material for a local application to encourage bone growth.
  • growth factors examples include platelet derived growth factor (PDGF), transforming growth factor ⁇ (TGF- ⁇ ), insulin-related growth factor-l (IGF-I), insulin- related growth factor-ll (IGF-II), fibroblast growth factor (FGF), beta-2- microglobulin (BDGF II) and bone morphogenetic protein (BMP).
  • PDGF platelet derived growth factor
  • TGF- ⁇ transforming growth factor ⁇
  • IGF-I insulin-related growth factor-l
  • IGF-II insulin-related growth factor-ll
  • FGF fibroblast growth factor
  • BMP bone morphogenetic protein
  • the particles of the present invention may be coated with a growth factor and/or contained within the particle or the suspension material.
  • Bone morphogenetic factors may include growth factors whose activity is specific to osseous tissue including proteins of demineralized bone, or DBM (demineralized bone matrix), and in particular the proteins called BP (bone protein) or BMP (bone morphogenetic protein), which actually contains a plurality of constituents such as osteonectin, osteocalcin and osteogenin.
  • the factors may coat the shaped particles of the present invention and/or may be contained within the particles or the suspension material.
  • Bone growth agents may be included within the suspension material of the composition of the invention in a specific embodiment.
  • nucleic acid sequences which encode an amino acid sequence, or an amino acid sequence itself may be included in the suspension material of the present invention wherein the amino acid sequence facilitates bone growth or bone healing.
  • leptin is known to inhibit bone formation (Ducy et al., 2000). Any nucleic acid or amino acid sequence which negatively impacts leptin, a leptin ortholog, or a leptin receptor may be included in the composition.
  • antisense leptin nucleic acid may be transferred within the composition of the invention to the site of a bone deficiency to inhibit leptin amino acid formation, thereby avoiding any inhibitory effects leptin may have on bone regeneration or growth.
  • Another example is a leptin antagonist or leptin receptor antagonist.
  • the nucleic acid sequence may be delivered within a nucleic acid vector wherein the vector is contained within a delivery vehicle.
  • a delivery vehicle is a liposome, a lipid or a cell.
  • the nucleic acid is transferred by carrier-assisted lipofection (Subramanian et al., 1999) to facilitate delivery.
  • a cationic peptide is attached to an M9 amino acid sequence and the cation binds the negatively charged nucleic acid.
  • M9 binds to a nuclear transport protein, such as transportin, and the entire DNA/protein complex can cross a membrane of a cell.
  • An amino acid sequence may be delivered within a delivery vehicle.
  • a delivery vehicle is a liposome.
  • Delivery of an amino acid sequence may utilize a protein transduction domain, an example being the HIV virus TAT protein (Schwarze et al., 1999).
  • the biological agent of the present invention has high affinity for a fibrin matrix (see Example 7).
  • the particle of the present invention may contain within it or on it a biological agent which would either elute from the particle as it degrades or through diffusion.
  • the biological agent may be a pain killer.
  • a pain killer examples include lidocaine hydrochloride, bipivacaine hydrochloride, and non- steroidal anti-inflammatory drugs such as ketorolac tromethamine.
  • chemotherapeutics such as cis-platinum, ifosfamide, methotrexate and doxorubicin hydrochloride.
  • chemotherapeutics would be suitable for a bone malignancy.
  • Another biological agent which may be included in the suspension material or contained on or in the particles of the present invention is a bisphosphonate.
  • bisphosphonates are alendronate, clodronate, etidronate, ibandronate,
  • the biological agent may be either in purified form, partially purified form, commercially available or in a preferred embodiment are recombinant in form. It is preferred to have the agent free of impurities or contaminants.
  • compositions of shaped particles and suspension material it is advantageous to include into the composition of shaped particles and suspension material any factor or agent which attracts, enhances, or augments bone growth.
  • the composition further includes fibrinogen which, upon cleaving by thrombin, gives fibrin.
  • Factor XIII is also included to crosslink fibrin, giving it more structural integrity.
  • Fibrin is known in the art to cause angiogenesis (growth of blood vessels) and in an embodiment of the present invention acts as an instigator of bone growth. It is preferred to mimic signals which are normally present upon, for instance, breaking of bone to encourage regrowth. It is known that fibrin tends to bind growth factors which facilitate this regrowth. In an object of the present invention the inclusion of fibrin into the composition is twofold: 1) to encourage bone growth; and 2) to act as a delivery vehicle.
  • the fibrin matrix is produced by reacting three clotting factors - fibrinogen, thrombin, and Factor XIII. These proteins may be manufactured using recombinant techniques to avoid issues associated with pooled-blood products and autologous products. Currently, the proteins are supplied in a frozen state ready for mixing upon thawing. However, lypholization process development allows that the final product will either be refrigerated or stored at room temperature and reconstituted immediately prior to use. In a preferred embodiment the clotting factors are recombinant in form.
  • Modifications can be made by altering the fibrin component.
  • One expected modification would be to use hyaluronic acid or a collagen gel instead of or in addition to a fibrin component.
  • Other variations may be inclusion of additional clotting factors in the fibrin matrix.
  • Additional examples of clotting factors are known in the art and may be used, but in a specific embodiment they are clotting factors relevant to a bone disorder.
  • the clotting factors may be purified, partially purified, commercially available, or in recombinant form.
  • thrombin alone is used with the patient's own blood or bone marrow aspirate to produce a fibrin matrix.
  • a biological agent as described above is contained within the fibrin matrix.
  • Example 8 Method of Making a Calcium Sulfate-based Shaped Particle
  • an improved method for making a calcium sulfate-based shaped particle is provided.
  • Calcium sulfate materials are typically not very strong when formed using conventional forming techniques. Plaster of Paris (CaSO »1 H 2 O; calcium sulfate hemihydrate) can be mixed with water and set through the following reaction to form gypsum (CaSO D2H 2 O; calcium sulfate dihydrate):
  • Another option is to utilize a gypsum material and form it into a shape through compaction of slurry casing. Since the gypsum is already fully hydrated the material will not set through a reaction as above. If water is used in the processing it is simply dried off, again leading to porosity in the final form.
  • This process invention allows the material to be formed using techniques that can provide the desired component geometry and reasonable density in the dried component.
  • a secondary process of heat treatment and hydration is then used to tailor the final material properties, namely for the purpose of increasing the strength and decreasing the dissolution rate. It should be possible to control these properties with the control of the forming process and the subsequent dehydration/rehydration.
  • the heating steps are performed at a pressure greater than ambient pressure, such as in an autoclave at 120-150 degrees Celsius or 25-50 PSI.
  • the calcium sulfate composition of the invention may be of the ⁇ or ⁇ form depending on the heat and pressure parameters utilized, and either form may be used or generated in the present invention.
  • a heat treatment and hydration process is applied to gypsum after it is formed into a shape (through pressing, casting, injection or other means known in the art).
  • the process could be done on a shaped component of plaster of Paris that was formed by some non-water based process (i.e.: die compaction).
  • die compaction some non-water based process
  • any calcium sulfate may be used which is capable of hydration reaction.
  • This includes gypsum formed in the exhaust gas desulfurization process, gypsum formed as a by-product by neutralization of waste sulfuric acid, gypsum formed as a by-product in the phosphoric acid reproduction process, and calcined gypsum (especially gypsum hemihydrate formed by refining such gypsum product by a known recrystallization method and calcining the refined gypsum).
  • the gypsum is commercially available.
  • a clay-gypsum powder is mixed with processing aids (such as binders and lubricants) and water to wet and make the clay plastic.
  • processing aids such as binders and lubricants
  • a forming operation such as pressing, rolling, extrusion or injection shapes the clay to the desired form.
  • the clay is set in the mold or is in contact with the mold to make a shape with enough green strength to be handled. Setting immediately following the forming should also be good for maintaining the particle geometry and tolerance. 4. The pieces can then be transported to the next processing step or to packaging.
  • the ceramic material for the shaped particle of the invention should not be too hard, sticky or dry.
  • binders there are many materials that may be suitable for use as binders, including carboxymethyl cellulose, hydroxypropylmethyl cellulose, or polyacrylate.
  • the shaping methods of the present invention can include pressing in a split mold, injection molding, rolling and extrusion.
  • the 'setting' action for the clay can be by simple dehydration or could be some more complex reaction that is mitigated by the combination of binders, water and gypsum and controlled by some external stimuli such as heat, radiation or chemical addition.
  • Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197-207.

Abstract

L'invention concerne une particule façonnée destinée à être utilisée dans un système de particules de verrouillage en vue de réparer, remplacer, améliorer ou contrecarrer une carence osseuse. Dans un mode de réalisation préféré, ladite particule a six extrémités, les extrémités d'une particule du système pouvant se loger dans les interstices situés entre les extrémités d'une particule adjacente. La particule est en suspension dans une matière qui facilite l'application de ladite particule sur l'os et qui peut contenir des facteurs biologiques de croissance osseuse ou de prévention d'infection. En outre, l'invention concerne un procédé de fabrication d'une particule façonnée grâce à la fabrication d'un matériau de sulphate de calcium durci.
PCT/US2001/006043 2000-03-03 2001-02-26 Particule façonnee et composition pour carence osseuse, et procede de fabrication de ladite particule WO2001066044A2 (fr)

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AU2001239874A AU2001239874A1 (en) 2000-03-03 2001-02-26 Shaped particle and composition for bone deficiency and method of making the particle
EP01914491A EP1259196A2 (fr) 2000-03-03 2001-02-26 Particule fa onnee et composition pour carence osseuse, et procede de fabrication de ladite particule
CA002401421A CA2401421A1 (fr) 2000-03-03 2001-02-26 Particule faconnee et composition pour carence osseuse, et procede de fabrication de ladite particule
KR1020027011507A KR20020082231A (ko) 2000-03-03 2001-02-26 뼈 결손을 위한 성형 입자 및 조성물과 상기 입자의 제조방법
JP2001564698A JP2003525696A (ja) 2000-03-03 2001-02-26 造形粒子および骨欠損用組成物および粒子を作る方法

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US09/517,981 2000-03-03

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