US20020098222A1 - Bone paste - Google Patents

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Publication number
US20020098222A1
US20020098222A1 US08/816,079 US81607997A US2002098222A1 US 20020098222 A1 US20020098222 A1 US 20020098222A1 US 81607997 A US81607997 A US 81607997A US 2002098222 A1 US2002098222 A1 US 2002098222A1
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United States
Prior art keywords
composition
bone
gelatin
dbm
mixtures
Prior art date
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Abandoned
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US08/816,079
Inventor
John F. Wironen
Jamie M. Grooms
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University of Florida Research Foundation Inc
RTI Biologics Inc
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Individual
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.)
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Priority to US08/816,079 priority Critical patent/US20020098222A1/en
Assigned to UNIVERSITY OF FLORIDA TISSUE BANK, INC. reassignment UNIVERSITY OF FLORIDA TISSUE BANK, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GROOMS, JAMIE M., WIRONEN, JOHN F.
Assigned to WIRONEN, JOHN F. reassignment WIRONEN, JOHN F. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF FLORIDA TISSUE BANK, INC.
Assigned to FLORIDA, UNIVERSITY OF reassignment FLORIDA, UNIVERSITY OF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WIRONEN, JOHN F.
Assigned to UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. reassignment UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FLORIDA, UNIVERSITY OF
Priority to EP98911607A priority patent/EP0984797A1/en
Priority to AU65528/98A priority patent/AU6552898A/en
Priority to PL98335800A priority patent/PL335800A1/en
Priority to PCT/US1998/004904 priority patent/WO1998040113A1/en
Priority to JP53981998A priority patent/JP2001514565A/en
Priority to SK1257-99A priority patent/SK125799A3/en
Priority to HU0001811A priority patent/HUP0001811A3/en
Priority to CA002280745A priority patent/CA2280745A1/en
Publication of US20020098222A1 publication Critical patent/US20020098222A1/en
Assigned to REGENERATION TECHNOLOGIES, INC. reassignment REGENERATION TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SOUTHEAST TISSUE ALLIANCE, INC., UNIVERSITY OF FLORIDA ORTHOPAEDIC TISSUE BANK, INC., UNIVERSITY OF FLORIDA TISSUE BANK, INC.
Priority to US11/152,548 priority patent/US8652503B2/en
Assigned to RTI BIOLOGICS, INC. reassignment RTI BIOLOGICS, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: REGENERATION TECHNOLOGIES, INC., A DELAWARE CORPORATION
Abandoned legal-status Critical Current

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    • 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
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    • A61L24/0073Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0084Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
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    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
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    • 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
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    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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    • A61L27/48Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
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    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/02Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • This invention relates to a new osteogenic, osteoinductive composition for use in the field of orthopedic medicine to achieve bone fusions, fusion of implants to bone, filing of bone defects, or any other application in which an osteoinductive, osteogenic composition is desirable.
  • Osteogenic bone grafting materials may be separated into two classes, namely those which are osteoconductive, and those which are osteoinductive. While the exact definition of these terms remains a matter of debate, it can be said that osteoconductive implants “conduct” bone growth across defects when implanted into osseous tissue. (Einhorn). Osteoinductive implants, on the other hand, have the ability to “induce” cells in the area to generate bone of their own accord. (Einhorn). These osteoinductive implants will cause the generation of bone even when they are implanted into non-osseous tissue (e.g. subcutaneous or intramuscular implantation). (Einhorn; Benedict; Strates; Urist).
  • FIG. 1 provides a list of relevant properties of selected bone graft materials.
  • the other category of bone grafting materials currently available is encompassed by autograft or allograft bone. If not too harshly processed, these materials are generally osteoinductive. (Yazdi). Since they are tissue transplants, their use imposes certain risks. Autografts have been associated with harvest site morbidity in excess of 20%. (Younger). Frozen or freeze-dried allografts induce some immune response, and if not properly screened, can be associated with disease transmission. (Hordin). The last variety of allografts is demineralized bone matrix.
  • DBM Demineralized Bone Matrix
  • DBM has the ability to induce the formation of bone even in non-osseous tissues within 4 weeks.
  • the standard technique for determining the activity of DBM is to implant it subcutaneously or intramuscularly. (Nathan). It is believed that the major active factor in DBM is one or more bone morphogenetic proteins (BMP), (see U.S. Pat. No. 4,294,753, herein incorporated by reference).
  • BMP bone morphogenetic proteins
  • Other growth factors including but not limited to TGF-beta, (see U.S. Pat. No. 5,422,340, herein incorporated by reference), platelet derived growth factor (PDGF), and the like, may be important for this function also.
  • Bioglass® is a bone grafting material which is a SiO 2 , Na 2 O, CaO, P 2 O 5 glass which has the ability to produce a bio-active surface layer of hydroxylapatite carbonate within minutes of implantation. (Hench).
  • a bone paste would be osteoconductive (i.e. it conducts bone cells into a region) and osteoinductive (i.e. stem cells are induced to differentiate into bone forming cells which begin production of new bone).
  • osteoconductive i.e. it conducts bone cells into a region
  • osteoinductive i.e. stem cells are induced to differentiate into bone forming cells which begin production of new bone.
  • bone pastes known in the art are osteoconductive, with only weak osteoinductive effects. Accordingly, such known pastes are inadequate for filling of large voids and frequently do not effect proper bone formation even in small voids. All currently available bone pastes, including those that exhibit some osteoinductive activity, are difficult to handle, do not adequately remain at the site of implantation, or both.
  • one commercially available product GRAFTON®, (see U.S. Pat. No. 5,484,601) is a non-cross-linkable composition of demineralized bone powder suspended in a polyhydroxy compound (e.g. glycerol) or esters thereof, optionally including various other ingredients, including gelatin. It is considered likely that this material is rapidly washed away from the implant location as the carrier matrix is glycerol, which is water soluble.
  • glycerol e.g. glycerol
  • esters thereof optionally including various other ingredients, including gelatin. It is considered likely that this material is rapidly washed away from the implant location as the carrier matrix is glycerol, which is water soluble.
  • U.S. Pat. Nos. 5,236,456 and 5,405,390 outline an “osteogenic” gel composition which is made from demineralized bone matrix (DBM) by treating with concentrated acid (3 M HCl) and heating to between 40 and 50° C.
  • DBM demineralized bone matrix
  • the patent briefly describes mixing the gel with DBM and several other components.
  • the method of manufacturing the gel composition is such that it produces mostly collagen fibers (i.e. the temperature elevation is insufficient to produce gelatin). As a result, the collagen fibers are not soluble in neutral solutions.
  • the patent specifies that the collagen must be dissolved in acid of low pH (e.g. HCl or 1% acetic acid, at a pH of less than 4.0).
  • compositions of low pH are not typically very compatible with biological implantations. It is also noted that at column 5, line 20, and column 6, line 15, it is specified that the temperature at which the gel solidifies is 0-5° C., which precludes gellation in vivo.
  • U.S. Pat. No. 4,440,750 (Glowacki and Pharris) outlines a standard enzymatic technique for extracting collagen from tissue using Pepsin.
  • a highly refined collagen is obtained from animal sources, which is then reconstituted prior to forming the working composition.
  • the collagen will not readily cross-link without the addition of other chemicals (e.g. aldehydes, chondroitin sulfate), which they do not specify in the composition. There is no mention of a set temperature or any reference to cross-linking behavior.
  • a bone repair material having good structural strength was disclosed.
  • the material comprised a demineralized bone matrix which had been surface activated by treatment with glutaraldehyde or like cross-linking agent to increase the binding thereof to biocompatible matrices.
  • the resulting material has such a rigid structure that, prior to implantation into a biological recipient, the material may be machined.
  • the bone paste of the present invention meets the needs in the art by providing a material that is easy to handle and store, which adheres to the site of implantation, displays both osteoconductive and osteoinductive activities, is thermally cross-linkable, and is substantially bioabsorbable.
  • the composition is provided as a gel which contains mineral and protein components which have been clinically shown to induce rapid bone ingrowth.
  • the composition may be delivered to the surgeon in a pre-loaded syringe, ready for use.
  • the gel is easily formable into any shape, and is adhesive.
  • the gel desirably hardens as a rubbery solid, which does not wash away or migrate from the site of implantation.
  • the implant material becomes completely incorporated into the biological system.
  • the mode of making and using this composition is set forth in detail below.
  • a bone paste useful in the orthopaedic arts for example in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, implant fixation, arthrodesis of spinal or other joints, including spinal fusion procedures, or any other procedure in which generation of new bone is deemed necessary, is provided by a composition comprising gelatin and additional osteogenic components.
  • the gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from:
  • demineralized bone preferably derived from the species into which the bone paste is to be implanted.
  • bioactive glass ceramic BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or
  • Demineralized bone has been shown to be highly effective in inducing bone formation.
  • the gelatin provides a cross-linkable, adhesive and easily manipulated matrix in which the osteoconductive and osteoinductive elements of the composition are carried.
  • Other factors such as antibiotics, bone morphogenetic or other proteins, whether derived from natural or recombinant sources, wetting agents, glycerol, dextran, carboxymethyl cellulose (CMC), growth factors, steroids, non-steroidal anti-inflammatory compounds, or combinations thereof or any other material found to add to the desirable properties of the essential composition of this invention may be included.
  • the composition may be freeze-dried or pre-constituted, and may be provided in a convenient dispensing device, such as a pre-loaded syringe.
  • the gel is preferably in a liquid or highly malleable state at temperatures above about 40° C., but sets up as a hard gel at or preferably slightly above the body temperature of the organism into which it is implanted (e.g. at 38° C. in humans).
  • FIG. 1 is a chart of existing bone grafting materials.
  • FIG. 2 represents a bone demineralization process
  • FIG. 3 is a graph of the kinematic viscosity (centistokes) versus concentration (%) for human gelatin processed at various temperatures in phosphate buffered saline solution (PBS).
  • PBS phosphate buffered saline solution
  • FIG. 4A is a photomicrograph of a section of an implant comprising demineralized bone matrix (DBM) without any carrier after four weeks intramuscularly in a rat.
  • DBM demineralized bone matrix
  • FIG. 4B is a photomicrograph of a section of an implant comprising 33% DBM in gelatin (i.e. the paste of this invention) after four weeks intramuscularly in a rat.
  • composition of this invention its method of preparation and use are applicable to such compositions for use in any vertebrate species. Nonetheless, because human use is considered likely to be the principal orthopedic application of this new material, the following description concentrates on exemplying this material for human applications.
  • the composition of this invention comprises gelatin and additional osteogenic components.
  • the gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from:
  • demineralized bone preferably derived from the species into which the bone paste is to be implanted.
  • bioactive glass ceramic BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or
  • the composition is fluid at a first temperature (e.g., above 38° C.) and becomes thermally cross-linked at or just above a second temperature, corresponding to the normal body temperature of the organism into which the composition is to be implanted (e.g., at 38° C. in humans).
  • a first temperature e.g., above 38° C.
  • a second temperature corresponding to the normal body temperature of the organism into which the composition is to be implanted (e.g., at 38° C. in humans).
  • thermoally cross-linked or “thermally cross-linkable” are used herein to describe the property of a composition which contains molecules which, at or below a given temperature and concentration, associate in such a fashion as to result in gelation of a solution containing these molecules.
  • substantially bioabsorbable is used herein to describe the property of a material able to cooperate in and become incorporated with new bone formation. Accordingly, for example, demineralized bone matrix which has been chemically cross-linked with an agent such as glutaraldehyde, is not considered to be substantially bioabsorbable. However, demineralized bone matrix itself, bioactive glass or like ceramics, gelatin, and bone morphogenetic factors are all considered to be substantially bioabsorbable as they cooperate in new bone formation, rather than purely providing structural rigidity or support.
  • the gelatin acts as a carrier phase and has the ability to thermally cross-link over a very small temperature range. This thermal cross-linking reaction is largely controlled by physical entanglement and hydrogen bonding between chains, and so is dependant on concentration and temperature. (Sperling). Additionally, since gelatin has been used extensively in the medical market, its in vivo properties are thoroughly studied. (McDonald). The gel-foam sponge is the most familiar application of this biopolymer. Studies have indicated that gelatin is only mildly antigenic upon implantation, and is comparable in some of its properties to collagen, (McDonald). However, collagen does not exhibit the thermal cross-linking property so important to the composition of this invention.
  • the bioactive glass such as BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, calcined bone, tricalcium phosphate, or like material, is included to enhance the range of manipulable characteristics of strength and osteogenesis (osteoinduction and osteoconduction) exhibited by the composition.
  • gelatin The manufacture of gelatin is based on the partial hydrolysis of collagen.
  • Collagen is available from skin, bone, cartilage, tendon and other connective tissue. Skin and bone yield Type I and Type III collagen molecules, while tendon yields nearly pure Type I collagen, and cartilage yields a mixture of Type II and rarer types of collagen molecules.
  • Gelatin molecules resemble collagen triple helices, however, they are partially hydrolyzed. As a result, in solution they have little organization. But, as the solution cools, the gelatin molecules begin to form helical structures. As the solution cools further, the viscosity increases and a phase transformation from a solution to a gel occurs. This phase change is reversible when heat is added.
  • the set time and set temperature of a gelatin solution are dependent on the concentration of gelatin in solution, the molecular weight, or intrinsic viscosity, of the gelatin molecules, and the pH of the solution. At the isoelectric point, or the pH at which the gelatin molecules are electrically neutral, the set time is the shortest.
  • Collagen can be partially hydrolyzed by several methods.
  • the Type A process is the simplest and most rapid process, in which dilute acid (e.g. less than 1 M HCl) is used to partially hydrolyze the collagen.
  • Type A processing is generally used with porcine skin and demineralized bovine bone.
  • the Type B process uses an alkaline solution to partially hydrolyze the collagen.
  • Type B processing is generally used with bovine hide and demineralized bovine bone.
  • enzymes such as pepsin, may be used to partially hydrolyze collagen. Pepsin preferentially cleaves peptide bonds between aromatic amino acids. Pepsin also acts as an esterase, but amides of amino acids are not hydrolyzed.
  • the gelatin is prepared from the bones of the species into which the compositions are to be implanted, by crushing and defatting the bones followed by soaking for about 24 hours in approximately 300 mg/L pepsin in a 0.5 M acetic acid at 33° C.
  • the pH of the resulting solution is brought to 9.0 with sodium hydroxide to denature the pepsin, then it is returned to 7.0 with hydrochloric acid.
  • the temperature of the solution is raised to 60° C. for about 15 to 30 minutes and returned to 4° C. to effect denaturation of remaining collagen and complete conversion to gelatin.
  • the resulting solution is filtered to remove particulates and dialyzed against distilled water for 48 hours in a 50K-100K molecular weight cut-off (50K-100K MWCO) dialysis membrane.
  • 50K-100K MWCO 50K-100K molecular weight cut-off dialysis membrane.
  • the gelatin is redissolved in phosphate buffered saline (PBS) or water to an effective concentration of about 30-45 weight percent of gelatin in solution.
  • PBS phosphate buffered saline
  • the gelatin content of the composition is desirably between about 20-45% (w/w).
  • the gelatin may be derived from the same or different species than that into which the composition is to be implanted.
  • human, porcine, bovine, equine, or canine gelatin is derived from collagen sources such as bone, skin, tendons, or cartilage, and may then be mixed with DBM or other osteogenic materials.
  • the collagen is converted to gelatin via, liming, acidification or by enzymatic extraction, for example by pepsin or like enzymatic treatment, followed by denaturation by heat or other means.
  • the gelatin may be derived from tissue by mastication of the tissue, followed by an extended treatment capable of breaking cross-links in the long collagen chains.
  • the tissue is ground then soaked for about 24-72 hours at between about 2-40° C. in dilute acid, such as 0.1 normal acetic acid.
  • dilute acid such as 0.1 normal acetic acid.
  • an enzyme such as pepsin at a sufficiently high concentration is added.
  • Pepsin concentrations of between about 10-20,000 i.u./liter, 100-2,000 i.u/liter, or like concentrations are added to the dilute acid at the start of the treatment, with the period of treatment being adjusted according to the enzyme concentration used.
  • Solids are removed from the composition, for example by centrifugation, and the supernatant material in solution having a molecular weight of about 50,000 daltons or higher is retained.
  • This may be achieved by any of a number of methods known in the art including, but not limited to, dialyzing the supernatant in a 50,000 dalton molecular weight cut-off membrane against several changes of solution, ultrafiltration against a membrane having a like molecular weight cut-off, (MWCO) or gel permeation chromatography through a medium having a 50,000 dalton molecular mass cut-off.
  • MWCO molecular weight cut-off
  • the gelatin solution resulting from the foregoing extraction is preferably denatured, for example by heat-treatment to above about 50° C.
  • the denatured protein is then stored in a frozen state or it may be freeze-dried or precipitated, for example in a volatile organic solvent, and reconstituted in a solution, such as an isotonic saline solution, at a concentration of between about 30-45% (w/w) gelatin.
  • the demineralized bone is preferably in a powdered form, and is preferably composed of particles in the size range between about 80-850 ⁇ m in diameter.
  • Methods for producing demineralized bone powder are known in the art (see for example U.S. Pat. No. 5,405,390, herein incorporated by reference for this purpose), and are not, therefore, elaborated here.
  • Demineralized bone powder extracted by standard techniques, is mixed with the gelatin solution prepared as described above, to form a composition comprising about 0-40% (w/w) demineralized bone powder.
  • bone morphogenetic proteins reduce the percentage of DBM required in the composition.
  • the BMP is preferably present at a concentration of between about 0.0001 to 0.1 mg/ml, 0.001 mg/ml to 0.01 mg/ml, or like concentration, depending on the amount of DBM present (0-40% w/w).
  • the final composition preferably comprises gelatin having a viscosity of about 3600 centipoise at 44° C. (when measured in the linear range of a viscosity/sheer rate plot—0.87/s), or a kinematic viscosity of about 0.7 centistokes at 44° C.
  • concentration of the gelatin in the carrier phase i.e. absent added osteogenic components
  • the concentration of the gelatin in the carrier phase is preferably about 30-45% (w/w), (approximately 50-60% w/v), to ensure that gelation at 38° C. will occur in a reasonable amount of time.
  • different temperatures may be required. These needs are accommodated by altering the gelatin concentration, increasing the concentration if a higher gel temperature is desired, and lowering the concentration if a lower gel temperature is desired.
  • the DBM content of the composition is defined herein by the concentration required to obtain bone formation similar to that seen with DBM alone. We have found that about 5-40% (w/w) DBM in the composition is effective. Anything lower than about 5% seems to do very little by way of bone formation, unless added BMPs (component iii) are present in the composition, in which case the DBM concentration may be substantially reduced or eliminated altogether.
  • BMPs component iii
  • the weight percent of DBM in the composition may be manipulated up or down. In addition, it will be recognized that, depending on the species into which the composition is implanted, the DBM weight percent may need to be adjusted up or down.
  • composition according to this invention may act as a carrier for cortical, cancellous or cortical and cancerous bone chips. Such compositions are useful for fling larger bone voids.
  • these bone chips when they are not demineralized, they provide an added spectrum of biological properties not exhibited by the gelatin alone or the gelatin plus osteogenic components (i-iv). When present, it is preferred for such bone chips to be in the size range of about 80 ⁇ m to about 10 mm.
  • the composition of gelatin and osteogenic components (i-iv) is injection molded, vacuum molded, rotation molded, blow molded, extruded or otherwise formed into a solid form.
  • Such forms would desirably take the form of vertebral disks, acetabular hemispheres, tubes, ellipsoid shapes for void filling, and intramedullary plugs, which are useful to plug the intramedullary canal of various bones (i.e. the marrow containing portion of the bone) to prevent bone cement from entering healthy bone tissue.
  • These forms are produced, for example, by raising the temperature of the composition above its liquefaction temperature (e.g. about 45° C.), and allowing the composition to gel in a mold of appropriate shape.
  • the gelatin content is preferably made as high as possible to ensure that the form remains solid upon grafting into a vertebrate recipient.
  • the source of collagen was from demineralized human cortical bone powder in the size range of 250-850 ⁇ m.
  • the demineralized bone matrix powder (DBM), 0.5 M. acetic acid solution, and pepsin were added to a centrifuge tube.
  • the centrifuge tube was tumbled for 24 hours at the desired temperature: 4° C., 30° C., 33° C. or 37° C.
  • the pH was adjusted to 9.0 then down to 7.0 with 1 N NaOH and 1N HCl, respectively, deactivating the pepsin.
  • the solution was placed in a 60° C. water bath for 15 minutes, then quenched in ice water.
  • the solution was centrifuged and the supernatant was poured into dialysis membrane tubing with a 1000 Daltons molecular weight cut off. The supernatant was dialyzed to obtain a 1000:1 dilution factor, frozen and lyophilized until completely dry. This experiment was performed in quintuplicates for each temperature.
  • the kinematic viscosities (centistokes) were graphed versus concentration of human gelatin solution, FIG. 3.
  • the linear regression was extrapolated to zero to determine the kinematic viscosity at zero concentration.
  • the optimum processing temperature was determined by the temperature that yielded the highest solution viscosity at zero concentration, largest slope of the linear regression, greatest yield, and lastly, the gelatin that produced a solid bone composite at slightly above human body temperature.
  • the human gelatin processed at 30° C. had the highest slope on the kinematic viscosity versus concentration plot, 0.40 (centistokes/%), followed by the human gelatin processed at 4° C., 0.26 (centistokes/%), the human gelatin processed at 33° C., 0.21 (centistokes/%), and lastly the human gelatin processed at 37° C., 0.17 (centistokes/%), Table 1.
  • the set temperatures for various bone paste compositions were determined, Table 2. Human gelatin made from DBM via pepsin at 33° C., 35° C., and 37° C. was used in the bone paste compositions. Gelatin concentrations were varied from 19 w/w % of total composite to 25 w/w % of total composite (corresponding to 40 w/v % to 60 w/v % gelatin in the carrier matrix) in a pH 7.4 phosphate buffered saline solution (PBS). All bone paste composites tested contained DBM at a concentration of 33 w/w % of the total composite.
  • PBS pH 7.4 phosphate buffered saline solution
  • the critical concentration of gelatin in a bone paste composite that was solid at slightly above human body temperature, 38° C. to 39° C. was 25 w/w % of the total composite for human gelatin, processed at 33° C., and with 33 w/w % of the composite being DBM, the remainder being PBS.
  • the human gelatin processed at 33° C. had a zero concentration kinematic viscosity of 0.71 centistokes.
  • Human gelatin solutions of lower kinematic viscosities were found to have critical concentrations in excess of about 25 w/w %.
  • gelatins with viscosities higher than about 0.71 centistokes are expected to thermally cross-link at concentrations lower than about 25% (w/w).
  • This study demonstrates that the bone paste of this invention is osteoinductive.
  • this study demonstrates particle sizes for the DBM component of the composition which operate well in promoting new bone growth in an animal into which it is implanted.
  • the intra-muscular rat model is the standard model for testing the osteoinductivity of demineralized bone and other osteoinductive factors. Strates et al. have used this model for many years (Strates).
  • the femurs, tibiae, and fibulae were harvested from fresh-killed (within 24 hours, refrigerated at 4° C.) Sprague-Dawley rats.
  • the diaphyses were cut from the bones and the marrow removed from the mid-shaft with a dissecting probe and sterile water wash.
  • Mid-shaft segments were then demineralized in 0.6 M. HCl for 24 hours at 4° C. with the mass ratio of bone to acid maintained at ⁇ fraction (1/10) ⁇ or lower.
  • the bone segments were lyophilized and then mixed with dry ice and ground in a lab-scale bone mill. DBM powder was sieved and the fraction from 125-450 ⁇ m was retained.
  • a carrier matrix of 50% (w/v) gelatin was made by heating phosphate buffered saline (PBS) to 60° C. and then adding powdered porcine gelatin (Sigma, 300 bloom) and stirring vigorously. Carrier matrix was allowed to age for 15 minutes (to even out the distribution of gelatin in solution) and then it was allowed to cool to 50° C. DBM was added to the gelatin solution at this point in the following amounts: 0 (negative control), 15, 19, 24, and 33% w/w of the total composite. The composite was blended thoroughly by hand mixing.
  • PBS phosphate buffered saline
  • powdered porcine gelatin Sigma, 300 bloom
  • Implants were prepared by ejecting a thread of composite onto a petri dish. These threads were cut into short segments ( ⁇ 4 mm.), weighed, and placed into sterile petri dishes. Positive controls were prepared by pelletizing DBM mixed with PBS in a centrifuge. To maintain pellet integrity during the hazards of surgery, these pellets were frozen and implanted as such.
  • Each muscle was notched to mark the superior side of the animal and placed into a labeled petri dish.
  • the muscle was X-rayed with mammography equipment, using mammography film (DuPont).
  • Roentgenograms were analyzed using a digital camera attached to an Apple LCII equipped with NIH Image 4.1 software. Images were thresholded to highlight the implant shadow and then the area of the shadow was determined by pixel counting.
  • FIGS. 4A and 4B provide photomicrographs of sections of implants after four weeks in vivo in the rat intramuscular model. We found that 33% (w/w) DBM in gelatin carrier (FIG.
  • FIG. 4A DBM (FIG. 4A).
  • 10 is mature bone, as evidenced by red stain uptake from Masson's stain
  • 20 is new cartilage formation, as evidenced by uptake of blue stain from Masson's stain and the presence of cells
  • 30 is residual DBM, as evidenced by uptake of blue stain and the absence of cells, from which all cartilagenous and bone structures in the muscle cross section arose
  • 40 is immature bone, as evidenced by light blue staining and the presence of cells.
  • the cells seen are osteoclasts, degrading the newly formed cartilage, and osteoblasts, laying down new bone.
  • vascular infiltration in the mature bone is evident in the Masson's stained sections, from which the black and white prints were made.
  • GraftonTM contains only 8% DBM in a glycerol carrier.
  • This example provides one procedure for the manufacture of bone paste from gelatin and demineralized bone. As fractions of the total mass of composition desired, the following components are weighed (percentages given are of total composite weight): Dry demineralized bone: 0-40% (w/w) Lyophilized thermally 20-45% (w/w) cross-linkable gelatin: BIOGLASS ®: 0-40% (w/w) bone morphogenetic protein: 0.001 mg/ml
  • compositions are thoroughly blended while dry, and the balance of the composition mass is made up by addition of water, phosphate buffered saline, or any other physiologically acceptable liquid carrier.
  • the composition may be packaged in this form or lyophilized for later reconstruction with water.
  • the malleable properties of the composition are achieved by heating the composition to a temperature sufficient to exceed the liquefaction point of the gelatin, and then allowing the composition to cool to the temperature at which it gels.

Abstract

A bone paste useful in the orthopedic arts, for example in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, implant fixation, impaction grafting, or any other procedure in which generation of new bone is deemed necessary, is provided by a composition comprising a substantially bioabsorbable osteogenic compound in a gelatin matrix. In various embodiments, the osteogenic compound is selected from (i) demineralized bone matrix (DBM); (ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, or like material; (iii) bone morphogenetic protein, TGF-β, PDGF, or mixtures thereof, natural or recombinant; and (iv) mixtures of (i)-(iii).

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • This invention relates to a new osteogenic, osteoinductive composition for use in the field of orthopedic medicine to achieve bone fusions, fusion of implants to bone, filing of bone defects, or any other application in which an osteoinductive, osteogenic composition is desirable. [0002]
  • 2. Background [0003]
  • More than 100,000 bone grafting procedures are performed every year in the United States alone. (Cornell). In the majority of reconstruction procedures, the graft material is used as a filler between bone particles in the belief that continuous contact between particles of bone leads to more rapid and complete healing at the repair site (as well as greater mechanical integrity). (Bloebaum). In the cases of bone augmentation and spinal fusion, these bone grafts may make up the entire structure of the graft, since there are no bone fragments in the area. With the possible exception of one product (whose use guidelines do not allow this), all bone grafting materials require surgical placement with the requisite incisions. [0004]
  • Osteogenic bone grafting materials may be separated into two classes, namely those which are osteoconductive, and those which are osteoinductive. While the exact definition of these terms remains a matter of debate, it can be said that osteoconductive implants “conduct” bone growth across defects when implanted into osseous tissue. (Einhorn). Osteoinductive implants, on the other hand, have the ability to “induce” cells in the area to generate bone of their own accord. (Einhorn). These osteoinductive implants will cause the generation of bone even when they are implanted into non-osseous tissue (e.g. subcutaneous or intramuscular implantation). (Einhorn; Benedict; Strates; Urist). [0005]
  • All of the artificially produced bone-grafting materials available today fall in the osteoconductive category of grafts. Among these are Bioglass®, Norian®, Collagraft®, corraline hydroxyapatite, powdered hydroxyapatite, crystalline and amorphous hydroxyapatite (hydroxyl apatite), and a number of other products. All of these implants rely on their similarity to natural bone hydroxyapatite. A likely mechanism for bone conduction lies in the ability of these materials to enhance diffusion of trophic factors and cells over their very large surface areas and the mechanical support which they provide to growing tissues. FIG. 1 provides a list of relevant properties of selected bone graft materials. [0006]
  • The other category of bone grafting materials currently available is encompassed by autograft or allograft bone. If not too harshly processed, these materials are generally osteoinductive. (Yazdi). Since they are tissue transplants, their use imposes certain risks. Autografts have been associated with harvest site morbidity in excess of 20%. (Younger). Frozen or freeze-dried allografts induce some immune response, and if not properly screened, can be associated with disease transmission. (Hordin). The last variety of allografts is demineralized bone matrix. [0007]
  • Demineralized Bone Matrix (DBM) was first described by Senn in 1889. (Senn). It was rediscovered, largely by accident, and thoroughly studied by Urist and Strates in the late 1960's. (Strates; Urist). It has since become a major product of tissue banks around the world. As the name implies, it is bone which has been demineralized by treatment with acid. A detailed outline of the process for producing this product is provided in FIG. 2. [0008]
  • DBM has the ability to induce the formation of bone even in non-osseous tissues within 4 weeks. (Strates; Urist; Lasa). The standard technique for determining the activity of DBM is to implant it subcutaneously or intramuscularly. (Nathan). It is believed that the major active factor in DBM is one or more bone morphogenetic proteins (BMP), (see U.S. Pat. No. 4,294,753, herein incorporated by reference). Other growth factors, including but not limited to TGF-beta, (see U.S. Pat. No. 5,422,340, herein incorporated by reference), platelet derived growth factor (PDGF), and the like, may be important for this function also. [0009]
  • Bioglass® is a bone grafting material which is a SiO[0010] 2, Na2O, CaO, P2O5 glass which has the ability to produce a bio-active surface layer of hydroxylapatite carbonate within minutes of implantation. (Hench).
  • Two problems are associated with the use of DBM or Bioglass. Both of these materials are supplied as large particles, and do not always stay in the area into which they are implanted. (Scarborough; Frenkel). Also, due to their coarse nature, they are hard to mold and handle in the operating room. Accordingly, there is the need for a product which does not allow for particle migration, while also being easier to use in the operating environment. [0011]
  • As noted in table 1, in recent years, several bone-filling surgical pastes have become commercially available. These products range from simple mixtures of saline with a sand-like powder to a recently released gel, known as GRAFTON®, a glycerol-based, non-cross-linkable composition. All of these products are used in orthopedics to repair bone defects, such as voids, cavities, cracks etc. Such defects may be the result of trauma or may be congenital, and the known pastes may be used to patch or fill such defects, or build upon existing bony structures. The ultimate goal of such treatments is that the paste will induce bone formation to replace the paste while retaining the form created by the surgeon when applying the paste. [0012]
  • Desirably, a bone paste would be osteoconductive (i.e. it conducts bone cells into a region) and osteoinductive (i.e. stem cells are induced to differentiate into bone forming cells which begin production of new bone). In general, bone pastes known in the art are osteoconductive, with only weak osteoinductive effects. Accordingly, such known pastes are inadequate for filling of large voids and frequently do not effect proper bone formation even in small voids. All currently available bone pastes, including those that exhibit some osteoinductive activity, are difficult to handle, do not adequately remain at the site of implantation, or both. [0013]
  • Thus, one commercially available product, GRAFTON®, (see U.S. Pat. No. 5,484,601) is a non-cross-linkable composition of demineralized bone powder suspended in a polyhydroxy compound (e.g. glycerol) or esters thereof, optionally including various other ingredients, including gelatin. It is considered likely that this material is rapidly washed away from the implant location as the carrier matrix is glycerol, which is water soluble. [0014]
  • U.S. Pat. Nos. 5,236,456 and 5,405,390 (O'Leary and Prewett) outline an “osteogenic” gel composition which is made from demineralized bone matrix (DBM) by treating with concentrated acid (3 M HCl) and heating to between 40 and 50° C. The patent briefly describes mixing the gel with DBM and several other components. However, the method of manufacturing the gel composition is such that it produces mostly collagen fibers (i.e. the temperature elevation is insufficient to produce gelatin). As a result, the collagen fibers are not soluble in neutral solutions. To obtain a gel, the patent specifies that the collagen must be dissolved in acid of low pH (e.g. HCl or 1% acetic acid, at a pH of less than 4.0). However, compositions of low pH are not typically very compatible with biological implantations. It is also noted that at [0015] column 5, line 20, and column 6, line 15, it is specified that the temperature at which the gel solidifies is 0-5° C., which precludes gellation in vivo.
  • U.S. Pat. No. 4,440,750 (Glowacki and Pharris) outlines a standard enzymatic technique for extracting collagen from tissue using Pepsin. A highly refined collagen is obtained from animal sources, which is then reconstituted prior to forming the working composition. The collagen will not readily cross-link without the addition of other chemicals (e.g. aldehydes, chondroitin sulfate), which they do not specify in the composition. There is no mention of a set temperature or any reference to cross-linking behavior. [0016]
  • In U.S. Pat. Nos. 4,394,370 and 4,472,840, (Jefferies), complexes of reconstituted collagen with demineralized bone or solubilized bone morphogenetic protein, optionally cross-linked with glutaraldehyde, were reported to be osteogenic when implanted in vivo. The reconstituted collagen of these patents is pulverized, lyophilized, microcrystalline collagen which has been dialyzed to remove the hydrochloric acid used in collagen preparation. Accordingly, the composition of those patents does not involve the conversion of collagen to gelatin prior to formation of the composition. Hence, the composition would not exhibit the thermal cross-linking behaviour of the instant composition. [0017]
  • In U.S. Pat. No. 4,678,470 (Nashef et al.) disclosed a non-resorbable bone-grafting material comprising demineralized bone matrix that had been cross-linked by treatment with glutaraldehyde, or like cross-lining agent, suspended in a gelatinous or semi-solid carrier. Given that the demineralized bone of that patent is chemically cross-linked, its bone inductive properties are considered to be destroyed and the composition essentially forms a structural filler or matrix into which recipient bone may grow. [0018]
  • In WO 89/04646 (Jefferies), a bone repair material having good structural strength was disclosed. The material comprised a demineralized bone matrix which had been surface activated by treatment with glutaraldehyde or like cross-linking agent to increase the binding thereof to biocompatible matrices. The resulting material has such a rigid structure that, prior to implantation into a biological recipient, the material may be machined. [0019]
  • The bone paste of the present invention meets the needs in the art by providing a material that is easy to handle and store, which adheres to the site of implantation, displays both osteoconductive and osteoinductive activities, is thermally cross-linkable, and is substantially bioabsorbable. Preferably, the composition is provided as a gel which contains mineral and protein components which have been clinically shown to induce rapid bone ingrowth. The composition may be delivered to the surgeon in a pre-loaded syringe, ready for use. Preferably, at a first temperature, the gel is easily formable into any shape, and is adhesive. Once inside the biological milieu, or at a second lower temperature, the gel desirably hardens as a rubbery solid, which does not wash away or migrate from the site of implantation. Upon ingrowth of bone, the implant material becomes completely incorporated into the biological system. The mode of making and using this composition is set forth in detail below. [0020]
  • BRIEF SUMMARY OF THE INVENTION
  • A bone paste useful in the orthopaedic arts, for example in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, implant fixation, arthrodesis of spinal or other joints, including spinal fusion procedures, or any other procedure in which generation of new bone is deemed necessary, is provided by a composition comprising gelatin and additional osteogenic components. The gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from: [0021]
  • (i) demineralized bone, preferably derived from the species into which the bone paste is to be implanted; or [0022]
  • (ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or [0023]
  • (iii) bone morphogenetic protein, TGF-beta, PDGF, or mixtures thereof, natural or recombinant; or [0024]
  • (iv) mixtures of (i)-(iii). [0025]
  • Where present (ii) or like material is included to enhance the range of manipulable characteristics of strength and osteoinduction exhibited by the composition. Where present, (iii) reduces the need for demineralized bone, which otherwise provides a source of osteoinductive factors. [0026]
  • Demineralized bone has been shown to be highly effective in inducing bone formation. The gelatin provides a cross-linkable, adhesive and easily manipulated matrix in which the osteoconductive and osteoinductive elements of the composition are carried. Other factors, such as antibiotics, bone morphogenetic or other proteins, whether derived from natural or recombinant sources, wetting agents, glycerol, dextran, carboxymethyl cellulose (CMC), growth factors, steroids, non-steroidal anti-inflammatory compounds, or combinations thereof or any other material found to add to the desirable properties of the essential composition of this invention may be included. [0027]
  • The composition may be freeze-dried or pre-constituted, and may be provided in a convenient dispensing device, such as a pre-loaded syringe. The gel is preferably in a liquid or highly malleable state at temperatures above about 40° C., but sets up as a hard gel at or preferably slightly above the body temperature of the organism into which it is implanted (e.g. at 38° C. in humans).[0028]
  • BRIEF SUMMARY OF THE FIGURES
  • FIG. 1 is a chart of existing bone grafting materials. [0029]
  • FIG. 2 represents a bone demineralization process. [0030]
  • FIG. 3 is a graph of the kinematic viscosity (centistokes) versus concentration (%) for human gelatin processed at various temperatures in phosphate buffered saline solution (PBS). [0031]
  • FIG. 4A is a photomicrograph of a section of an implant comprising demineralized bone matrix (DBM) without any carrier after four weeks intramuscularly in a rat. [0032]
  • FIG. 4B is a photomicrograph of a section of an implant comprising 33% DBM in gelatin (i.e. the paste of this invention) after four weeks intramuscularly in a rat.[0033]
  • DETAILED DESCRIPTION OF THE INVENTION
  • It will be appreciated by those skilled in the art that the specifics of the composition of this invention, its method of preparation and use are applicable to such compositions for use in any vertebrate species. Nonetheless, because human use is considered likely to be the principal orthopedic application of this new material, the following description concentrates on exemplying this material for human applications. [0034]
  • The composition of this invention comprises gelatin and additional osteogenic components. The gelatin is preferably thermally cross-linkable, and the osteogenic components are selected from: [0035]
  • (i) demineralized bone, preferably derived from the species into which the bone paste is to be implanted; or [0036]
  • (ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, like material, or mixtures thereof; or [0037]
  • (iii) bone morphogenetic protein, TGF-beta, PDGF, or mixtures thereof, natural or recombinant; or [0038]
  • (iv) mixtures of (i)-(iii). [0039]
  • The composition is fluid at a first temperature (e.g., above 38° C.) and becomes thermally cross-linked at or just above a second temperature, corresponding to the normal body temperature of the organism into which the composition is to be implanted (e.g., at 38° C. in humans). [0040]
  • The terms “thermally cross-linked” or “thermally cross-linkable” are used herein to describe the property of a composition which contains molecules which, at or below a given temperature and concentration, associate in such a fashion as to result in gelation of a solution containing these molecules. [0041]
  • The term “substantially bioabsorbable” is used herein to describe the property of a material able to cooperate in and become incorporated with new bone formation. Accordingly, for example, demineralized bone matrix which has been chemically cross-linked with an agent such as glutaraldehyde, is not considered to be substantially bioabsorbable. However, demineralized bone matrix itself, bioactive glass or like ceramics, gelatin, and bone morphogenetic factors are all considered to be substantially bioabsorbable as they cooperate in new bone formation, rather than purely providing structural rigidity or support. [0042]
  • The gelatin acts as a carrier phase and has the ability to thermally cross-link over a very small temperature range. This thermal cross-linking reaction is largely controlled by physical entanglement and hydrogen bonding between chains, and so is dependant on concentration and temperature. (Sperling). Additionally, since gelatin has been used extensively in the medical market, its in vivo properties are thoroughly studied. (McDonald). The gel-foam sponge is the most familiar application of this biopolymer. Studies have indicated that gelatin is only mildly antigenic upon implantation, and is comparable in some of its properties to collagen, (McDonald). However, collagen does not exhibit the thermal cross-linking property so important to the composition of this invention. [0043]
  • Where present, the bioactive glass, such as BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, calcined bone, tricalcium phosphate, or like material, is included to enhance the range of manipulable characteristics of strength and osteogenesis (osteoinduction and osteoconduction) exhibited by the composition. [0044]
  • The manufacture of gelatin is based on the partial hydrolysis of collagen. Collagen is available from skin, bone, cartilage, tendon and other connective tissue. Skin and bone yield Type I and Type III collagen molecules, while tendon yields nearly pure Type I collagen, and cartilage yields a mixture of Type II and rarer types of collagen molecules. Gelatin molecules resemble collagen triple helices, however, they are partially hydrolyzed. As a result, in solution they have little organization. But, as the solution cools, the gelatin molecules begin to form helical structures. As the solution cools further, the viscosity increases and a phase transformation from a solution to a gel occurs. This phase change is reversible when heat is added. [0045]
  • The set time and set temperature of a gelatin solution are dependent on the concentration of gelatin in solution, the molecular weight, or intrinsic viscosity, of the gelatin molecules, and the pH of the solution. At the isoelectric point, or the pH at which the gelatin molecules are electrically neutral, the set time is the shortest. [0046]
  • Collagen can be partially hydrolyzed by several methods. The Type A process is the simplest and most rapid process, in which dilute acid (e.g. less than 1 M HCl) is used to partially hydrolyze the collagen. Type A processing is generally used with porcine skin and demineralized bovine bone. The Type B process uses an alkaline solution to partially hydrolyze the collagen. Type B processing is generally used with bovine hide and demineralized bovine bone. Finally, enzymes, such as pepsin, may be used to partially hydrolyze collagen. Pepsin preferentially cleaves peptide bonds between aromatic amino acids. Pepsin also acts as an esterase, but amides of amino acids are not hydrolyzed. [0047]
  • As one example of this method, the gelatin is prepared from the bones of the species into which the compositions are to be implanted, by crushing and defatting the bones followed by soaking for about 24 hours in approximately 300 mg/L pepsin in a 0.5 M acetic acid at 33° C. The pH of the resulting solution is brought to 9.0 with sodium hydroxide to denature the pepsin, then it is returned to 7.0 with hydrochloric acid. The temperature of the solution is raised to 60° C. for about 15 to 30 minutes and returned to 4° C. to effect denaturation of remaining collagen and complete conversion to gelatin. The resulting solution is filtered to remove particulates and dialyzed against distilled water for 48 hours in a 50K-100K molecular weight cut-off (50K-100K MWCO) dialysis membrane. After lyophilization, the gelatin is redissolved in phosphate buffered saline (PBS) or water to an effective concentration of about 30-45 weight percent of gelatin in solution. [0048]
  • The gelatin content of the composition is desirably between about 20-45% (w/w). The gelatin may be derived from the same or different species than that into which the composition is to be implanted. For example, human, porcine, bovine, equine, or canine gelatin is derived from collagen sources such as bone, skin, tendons, or cartilage, and may then be mixed with DBM or other osteogenic materials. As noted above, the collagen is converted to gelatin via, liming, acidification or by enzymatic extraction, for example by pepsin or like enzymatic treatment, followed by denaturation by heat or other means. The gelatin may be derived from tissue by mastication of the tissue, followed by an extended treatment capable of breaking cross-links in the long collagen chains. In one embodiment, the tissue is ground then soaked for about 24-72 hours at between about 2-40° C. in dilute acid, such as 0.1 normal acetic acid. Preferably, an enzyme such as pepsin at a sufficiently high concentration is added. Pepsin concentrations of between about 10-20,000 i.u./liter, 100-2,000 i.u/liter, or like concentrations are added to the dilute acid at the start of the treatment, with the period of treatment being adjusted according to the enzyme concentration used. Solids are removed from the composition, for example by centrifugation, and the supernatant material in solution having a molecular weight of about 50,000 daltons or higher is retained. This may be achieved by any of a number of methods known in the art including, but not limited to, dialyzing the supernatant in a 50,000 dalton molecular weight cut-off membrane against several changes of solution, ultrafiltration against a membrane having a like molecular weight cut-off, (MWCO) or gel permeation chromatography through a medium having a 50,000 dalton molecular mass cut-off. It will be recognized by those skilled in the art that the higher the MWCO of the gelatin, the lower the yield. Accordingly, lower MWCO gelatin preparations, down to abut 1000 dalton MWCO's could be used, recognizing that undesirable low molecular weight species might thereby be retained. [0049]
  • The gelatin solution resulting from the foregoing extraction is preferably denatured, for example by heat-treatment to above about 50° C. The denatured protein is then stored in a frozen state or it may be freeze-dried or precipitated, for example in a volatile organic solvent, and reconstituted in a solution, such as an isotonic saline solution, at a concentration of between about 30-45% (w/w) gelatin. [0050]
  • The demineralized bone is preferably in a powdered form, and is preferably composed of particles in the size range between about 80-850 μm in diameter. Methods for producing demineralized bone powder are known in the art (see for example U.S. Pat. No. 5,405,390, herein incorporated by reference for this purpose), and are not, therefore, elaborated here. Demineralized bone powder, extracted by standard techniques, is mixed with the gelatin solution prepared as described above, to form a composition comprising about 0-40% (w/w) demineralized bone powder. Where present, bone morphogenetic proteins (BMP) reduce the percentage of DBM required in the composition. The BMP is preferably present at a concentration of between about 0.0001 to 0.1 mg/ml, 0.001 mg/ml to 0.01 mg/ml, or like concentration, depending on the amount of DBM present (0-40% w/w). [0051]
  • The final composition preferably comprises gelatin having a viscosity of about 3600 centipoise at 44° C. (when measured in the linear range of a viscosity/sheer rate plot—0.87/s), or a kinematic viscosity of about 0.7 centistokes at 44° C. The concentration of the gelatin in the carrier phase (i.e. absent added osteogenic components) is preferably about 30-45% (w/w), (approximately 50-60% w/v), to ensure that gelation at 38° C. will occur in a reasonable amount of time. Naturally, those skilled in the art will recognize that, depending on the species of the organism into which the composition is to be implanted, different temperatures may be required. These needs are accommodated by altering the gelatin concentration, increasing the concentration if a higher gel temperature is desired, and lowering the concentration if a lower gel temperature is desired. [0052]
  • The DBM content of the composition is defined herein by the concentration required to obtain bone formation similar to that seen with DBM alone. We have found that about 5-40% (w/w) DBM in the composition is effective. Anything lower than about 5% seems to do very little by way of bone formation, unless added BMPs (component iii) are present in the composition, in which case the DBM concentration may be substantially reduced or eliminated altogether. Naturally, based on this disclosure, those skilled in the art will recognize that by addition of different concentrations and compositions of bone morphogenetic proteins or other osteogenic or osteoinductive factors, the weight percent of DBM in the composition may be manipulated up or down. In addition, it will be recognized that, depending on the species into which the composition is implanted, the DBM weight percent may need to be adjusted up or down. [0053]
  • We have found in in vivo studies that the compositions with DBM contents from 15 to 33% all produce calcified tissue. We have found that there is a good correlation between the amount of DBM in the composition and the level of bone induction, as long as the DBM concentration is greater than about 19% (w/w). About 38-40% (w/w) is the upper mass limit for DBM. Accordingly, 0-40% (w/w) DBM, and more preferably 5-30% (w/w), 7-33%(w/w) or 15-25% (w/w) is desirable for this component. [0054]
  • We have observed histologically that, subsequent to implantation into an animal, the gelatin phase is totally absorbed within about 2 weeks. Additionally, cartilage and mineralized bone formed within two weeks, with mature bone being evident by about the fourth week. The animals in these studies did not exhibit any gross health problems or any indications of irritation, hematoma, soreness, fever, or weight loss during the study. The composition according to this invention, whether it comprises gelatin and osteogenic components (i-iv) may act as a carrier for cortical, cancellous or cortical and cancerous bone chips. Such compositions are useful for fling larger bone voids. In addition, when these bone chips are not demineralized, they provide an added spectrum of biological properties not exhibited by the gelatin alone or the gelatin plus osteogenic components (i-iv). When present, it is preferred for such bone chips to be in the size range of about 80 μm to about 10 mm. [0055]
  • In a further embodiment of this invention, the composition of gelatin and osteogenic components (i-iv) is injection molded, vacuum molded, rotation molded, blow molded, extruded or otherwise formed into a solid form. Such forms would desirably take the form of vertebral disks, acetabular hemispheres, tubes, ellipsoid shapes for void filling, and intramedullary plugs, which are useful to plug the intramedullary canal of various bones (i.e. the marrow containing portion of the bone) to prevent bone cement from entering healthy bone tissue. These forms are produced, for example, by raising the temperature of the composition above its liquefaction temperature (e.g. about 45° C.), and allowing the composition to gel in a mold of appropriate shape. For such forms, the gelatin content is preferably made as high as possible to ensure that the form remains solid upon grafting into a vertebrate recipient. [0056]
  • Those skilled in the art will recognize the many orthopedic applications of the bone paste of this invention. However, by way of illustration rather than limitation, for purposes of arthrodesis of the spine, one particularly preferred mode of using this composition would be at an early stage of vertebral disk degeneration or subsequent to trauma. Diagnosis of trauma or degeneration is followed by formation of a small orifice, or a plurality of small orifices in the intervertebral cartilage at the site of degeneration. The bone paste is then injected into the intervertebral space to induce arthrodesis. A similar procedure could be used with other joints or bone damage. [0057]
  • Having generally described the invention, the following examples are provided to show specific features and applications of the invention. It should be recognized that this invention is in no way limited to the specifics of the examples as set forth below, and that the limits of this invention are defined by the claims which are appended hereto. [0058]
  • EXAMPLE 1 Gelatin Production, Kinematic Viscosity, and Critical Concentration for Gelation at 38° C.
  • In this experiment, the source of collagen was from demineralized human cortical bone powder in the size range of 250-850 μm. The demineralized bone matrix powder (DBM), 0.5 M. acetic acid solution, and pepsin were added to a centrifuge tube. The centrifuge tube was tumbled for 24 hours at the desired temperature: 4° C., 30° C., 33° C. or 37° C. The pH was adjusted to 9.0 then down to 7.0 with 1 N NaOH and 1N HCl, respectively, deactivating the pepsin. The solution was placed in a 60° C. water bath for 15 minutes, then quenched in ice water. The solution was centrifuged and the supernatant was poured into dialysis membrane tubing with a 1000 Daltons molecular weight cut off. The supernatant was dialyzed to obtain a 1000:1 dilution factor, frozen and lyophilized until completely dry. This experiment was performed in quintuplicates for each temperature. [0059]
  • The kinematic viscosities of dilute concentrations of gelatin, 0.0625 w/v %, 0.125 w/v %, 0.25 w/v %, and 0.5 w/v % in phosphate buffered saline solutions (pH 7.4 at 25° C.), were measured with an Ubbelhode viscometer at 44° C. The kinematic viscosities of human gelatin processed at 4° C., 30° C., 33° C., and 37° C., were measured in duplicates, except for 33° C. which was only measured once. The kinematic viscosities (centistokes) were graphed versus concentration of human gelatin solution, FIG. 3. The linear regression was extrapolated to zero to determine the kinematic viscosity at zero concentration. The optimum processing temperature was determined by the temperature that yielded the highest solution viscosity at zero concentration, largest slope of the linear regression, greatest yield, and lastly, the gelatin that produced a solid bone composite at slightly above human body temperature. [0060]
  • As the processing temperature increased, the yield of gelatin, normalized for the same pepsin to DBM ratio (0.03% (w/v) pepsin/1 g DBM), increased. The kinematic viscosity at zero concentration, or y-intercept, followed a reverse trend. As the processing temperatures increased, the extrapolated kinematic viscosities decreased, Table 1. [0061]
  • The human gelatin processed at 30° C. had the highest slope on the kinematic viscosity versus concentration plot, 0.40 (centistokes/%), followed by the human gelatin processed at 4° C., 0.26 (centistokes/%), the human gelatin processed at 33° C., 0.21 (centistokes/%), and lastly the human gelatin processed at 37° C., 0.17 (centistokes/%), Table 1. [0062]
  • In order to correlate the kinematic viscosities to molecular weight of gelatin, the kinematic viscosities must be translated into intrinsic viscosities. However, the intrinsic viscosities were undefined due to the polyelectrolytic nature of gelatin. As a result, a direct relationship between viscosity and molecular weight of human gelatin can not be made. [0063]
    TABLE 1
    Physical properties of human gelatin and human gelatin in phosphate
    buffered saline solution. Human gelatin was processed at 4° C., 30° C.,
    33° C., and 37° C., resulting from 1 g of DBM and 0.03 w/v % pepsin
    solution in 0.5 N acetic acid:
    Human Slope of
    Gelatin Linear
    Processed Average Yield Extrapolated Regression r2 Value of
    at Various Percent by y-intercept (centistokes/ Linear
    Temp. Weight (centistokes) %) Regression
     4° C.  6% (n = 5) 0.72 (trial 0.26 (trial 0.985 (trial
    1 & 2) 1 & 2) 1 & 2)
    30° C. 18% (n = 5) 0.71 (trial 0.40 (trial 0.993 (trial
    1 & 2) 1 & 2) 1 & 2)
    33° C. 30% (n = 4) 0.71 (trial 1) 0.21 (trial 1) 0.994 (trial 1)
    37° C. 60% (n = 5) 0.70 (trial 0.17 (trial 0.996 (trial
    1 & 2) 1 & 2) 1 & 2)
  • The set temperatures for various bone paste compositions were determined, Table 2. Human gelatin made from DBM via pepsin at 33° C., 35° C., and 37° C. was used in the bone paste compositions. Gelatin concentrations were varied from 19 w/w % of total composite to 25 w/w % of total composite (corresponding to 40 w/v % to 60 w/v % gelatin in the carrier matrix) in a pH 7.4 phosphate buffered saline solution (PBS). All bone paste composites tested contained DBM at a concentration of 33 w/w % of the total composite. Different ambient temperatures were used to test whether the bone paste was solid or liquid, 45° C., 43° C., 41° C., 40° C., 38° C., and 35.5° C. The set temperature was determined both by subsequent lowering of the ambient temperature and raising of the ambient temperature. [0064]
    TABLE 2
    Ambient temperatures corresponding to solidified (non-syringe-able) bone
    paste composites.
    Human Gelatin as a
    Percent of Total 37° C. Process 35° C. Process 33° C. Process
    Composite Weight Temp Temp Temp
    25 w/w % <35.5° C. <35.5° C. 40° C.
    24 w/w % <35.5° C. <35.5° C. <35.5° C.
    22 w/w % <35.5° C. <35.5° C. <35.5° C.
    21 w/w % <35.5° C. <35.5° C. <35.5° C.
    19 w/w % <35.5° C. <35.5° C. <35.5° C.
  • Accordingly, the critical concentration of gelatin in a bone paste composite that was solid at slightly above human body temperature, 38° C. to 39° C., was 25 w/w % of the total composite for human gelatin, processed at 33° C., and with 33 w/w % of the composite being DBM, the remainder being PBS. The human gelatin processed at 33° C. had a zero concentration kinematic viscosity of 0.71 centistokes. Human gelatin solutions of lower kinematic viscosities were found to have critical concentrations in excess of about 25 w/w %. Correspondingly, gelatins with viscosities higher than about 0.71 centistokes are expected to thermally cross-link at concentrations lower than about 25% (w/w). [0065]
  • EXAMPLE 2 In Vivo Bone Paste Composition and Activity
  • This study demonstrates that the bone paste of this invention is osteoinductive. In addition, this study demonstrates particle sizes for the DBM component of the composition which operate well in promoting new bone growth in an animal into which it is implanted. [0066]
  • The intra-muscular rat model is the standard model for testing the osteoinductivity of demineralized bone and other osteoinductive factors. Strates et al. have used this model for many years (Strates). [0067]
  • As noted in Example 1 above, we determined that for gelation at 38° C., a gelatin solution concentration of 40-60% w/v (30-45% w/w of the solution absent added osteogenic components) is required. At this concentration, gelatin acting as a carrier matrix thermally cross-links at 38° C. within approximately 8 minutes. In this study we addressed the question of how much DBM must be present in this fixed 40-60% gelatin carrier matrix to induce bone formation which favorably compares with positive controls. We compared 4 different compositions of a DBM/Gelatin composite with both positive and negative controls in a rat intra-muscular model. [0068]
  • A. Implant Preparation: [0069]
  • The femurs, tibiae, and fibulae were harvested from fresh-killed (within 24 hours, refrigerated at 4° C.) Sprague-Dawley rats. The diaphyses were cut from the bones and the marrow removed from the mid-shaft with a dissecting probe and sterile water wash. Mid-shaft segments were then demineralized in 0.6 M. HCl for 24 hours at 4° C. with the mass ratio of bone to acid maintained at {fraction (1/10)} or lower. The bone segments were lyophilized and then mixed with dry ice and ground in a lab-scale bone mill. DBM powder was sieved and the fraction from 125-450 μm was retained. [0070]
  • A carrier matrix of 50% (w/v) gelatin was made by heating phosphate buffered saline (PBS) to 60° C. and then adding powdered porcine gelatin (Sigma, 300 bloom) and stirring vigorously. Carrier matrix was allowed to age for 15 minutes (to even out the distribution of gelatin in solution) and then it was allowed to cool to 50° C. DBM was added to the gelatin solution at this point in the following amounts: 0 (negative control), 15, 19, 24, and 33% w/w of the total composite. The composite was blended thoroughly by hand mixing. [0071]
  • Implants were prepared by ejecting a thread of composite onto a petri dish. These threads were cut into short segments ([0072] ˜4 mm.), weighed, and placed into sterile petri dishes. Positive controls were prepared by pelletizing DBM mixed with PBS in a centrifuge. To maintain pellet integrity during the hazards of surgery, these pellets were frozen and implanted as such.
  • B. Rat Surgery: [0073]
  • Young Sprague-Dawley rats (200-410 g) were anesthetized with 86 mg/kg Ketamine, and 13 mg/kg Xylazine administered intramuscularly (in the thigh). A parallel-mid-line incision was made from the tip of the sternum to just above the groin. The lateral aspects of the rectus abdominus were accessed by blunt dissection to either side of the animal. Three short incisions were made in the muscle on each side and the implants inserted, followed by 1 to 2 stitches with Prolene¤ 3-0 suture (to mark the location and prevent the ejection of the implant mass). One positive or one negative control as well as two experimental compositions were inserted on each side. Implant locations were random except that each rat had one positive control on one side and one negative control on the contralateral side. [0074]
  • Animals were returned to their cages and provided food and water ad-lib. All members of the study group were kept for 4 weeks except one animal (R1) which was sacrificed after 2 weeks for histology. [0075]
  • After 4 weeks, animals were sacrificed with an overdose of Nembutal. The rectus abdominus was removed by sharp dissection, removing as much tissue as possible. [0076]
  • C. Explant Analysis: [0077]
  • Each muscle was notched to mark the superior side of the animal and placed into a labeled petri dish. The muscle was X-rayed with mammography equipment, using mammography film (DuPont). Roentgenograms were analyzed using a digital camera attached to an Apple LCII equipped with NIH Image 4.1 software. Images were thresholded to highlight the implant shadow and then the area of the shadow was determined by pixel counting. [0078]
  • Two of each variety of explant were removed from the muscle and fixed in 10% buffered formalin. Histological sections were taken and consecutive sections were stained with H&E and Masson's trichrome stain. These histological samples were examined by a qualified pathologist. [0079]
  • Remaining explants were cut from the muscle tissue and ashed in a muffle furnace for 4.5 hours at 700-750° C. Ash weight was determined and normalized to original implant weight. Ash was dissolved in 1.0N HCl and analyzed for calcium content by atomic absorption spectroscopy. [0080]
  • All analyses were conducted in a blinded manner with decoding done only after processing of the data was complete. [0081]
  • D. Histology: [0082]
  • Two week histology samples of 15% and 19% DBM composites indicated that bone formation was occurring, even at this early date. The route of bone formation is not readily apparent, but appears to be endochondral. Four week histology samples revealed that mature bone was formed at the site of implantation. The quality of bone formed was comparable to that of natural bone as shown by the ash and percent calcium analyses. All implants containing DBM were found to lead to the production of some bone. Those containing greater than about 20% DBM yielded the highest quality bone. FIGS. 4A and 4B provide photomicrographs of sections of implants after four weeks in vivo in the rat intramuscular model. We found that 33% (w/w) DBM in gelatin carrier (FIG. 4B) according to this invention produced as much new bone as pure, 100% DBM (FIG. 4A). In these figures, the following structures are evident: [0083] 10 is mature bone, as evidenced by red stain uptake from Masson's stain; 20 is new cartilage formation, as evidenced by uptake of blue stain from Masson's stain and the presence of cells; 30 is residual DBM, as evidenced by uptake of blue stain and the absence of cells, from which all cartilagenous and bone structures in the muscle cross section arose; and 40 is immature bone, as evidenced by light blue staining and the presence of cells. The cells seen are osteoclasts, degrading the newly formed cartilage, and osteoblasts, laying down new bone. In addition, vascular infiltration in the mature bone is evident in the Masson's stained sections, from which the black and white prints were made.
  • E. Compositional Analysis: [0084]
  • There was no statistically significant difference, using a 2σ test, in ash content between the negative control, the positive control, or compositions comprising 15% or 19% (w/w) DBM. This does not necessarily imply that these compositions do not work (examination of the Roentgenograms obviates this conclusion). Rather, it indicates that the sensitivity of the ash method does not allow the detection of the difference. Examination of the data for the 24% and 33% composites indicates that they are significantly better than 19%, 15%, and the negative controls, and are not significantly different from the (positive) control, see Table 3: [0085]
    TABLE 3
    Composition % Yield Ash/g
    (% DBM) Implant Standard Deviation
     0 {− control} 10.1   9 (n = 6)
     15  5.5 12.7 (n = 6)
     19 11.9 12.2 (n = 6)
     24 34.5 14.9 (n = 5)
     33 30.0  8.0 (n = 4)
    100 {+ control} 31.9  8.8 (n = 6)
  • F. Atomic Absorption Spectroscopy: [0086]
  • The atomic absorption spectroscopy of ashed compositions of DBMI/gelatin composites yielded the amount of calcium in the samples. The 15% and 19% compositions did not show a statistically significant difference from the negative controls. However, it is expected that with greater assay sensitivity, positive effects of DBM at concentrations as low as about 7% (w/w) in gelatin carrier would be measurable. The average calcium content produced by compositions greater than or equal to 24% appeared to be proportional to the amount of DBM, by weight, in the composition: [0087]
    TABLE 4
    Comparison between the atomic absorption spectroscopy results of ashed
    samples of six different DBM/gelatin composites explanted from rats after
    4 weeks in vivo.
    Composition Average Ca
    (% DBM w/w) Content/gram Standard Deviation (σ)
     0 {(−) control} 1.2 1.2 (n = 6)
     15 3.9 2.4 (n = 4)
     19 7.3 7.5 (n = 4)
     24 23.1 8.7 (n = 3)
     33 28.0 4.4 (n = 4)
    100 {(+) 81.3 30.0 (n = 5) 
    control}
  • G. X-Ray Digital Analysis: [0088]
  • Gross examination/comparison of the x-rays reveals that the 24% and 33% compositions are not significantly different from the (+) controls. The 15% and 19% compositions do not appear to generate significant bone. However, it is expected that with greater assay sensitivity, positive effects of DBM at concentrations as low as about 7% (w/w) in gelatin carrier would be measurable. No bone formation was apparent on the x-rays at the locations of the (−) controls. Accordingly, we conclude that DBM at a concentration of between about 24% to 33% (w/w) in gelatin is active in inducing bone formation. These same data indicate that concentrations of DBM below about 20% are less effective in generating significant bone in comparison to positive controls. It is noted that Grafton™ contains only 8% DBM in a glycerol carrier. [0089]
    TABLE 5
    Composition Normalized Area (% of
    (% DBM w/w) + ve control) Standard Deviation (σ)
     0 {(−) control} 0   0 (n = 10)
     15 2.8 1.9 (n = 7)
     19 4.1 4.2 (n = 7)
     24 33.0 15.2 (n = 10)
     33 36.7 14.9 (n = 10)
    100 {(+) 100 43.1 (n = 10)
    control}
  • EXAMPLE 3 Procedure for the Production Bone Paste of this Invention
  • This example provides one procedure for the manufacture of bone paste from gelatin and demineralized bone. As fractions of the total mass of composition desired, the following components are weighed (percentages given are of total composite weight): [0090]
    Dry demineralized bone: 0-40% (w/w)
    Lyophilized thermally 20-45% (w/w) 
    cross-linkable gelatin:
    BIOGLASS ®: 0-40% (w/w)
    bone morphogenetic protein: 0.001 mg/ml
  • These components are thoroughly blended while dry, and the balance of the composition mass is made up by addition of water, phosphate buffered saline, or any other physiologically acceptable liquid carrier. The composition may be packaged in this form or lyophilized for later reconstruction with water. The malleable properties of the composition are achieved by heating the composition to a temperature sufficient to exceed the liquefaction point of the gelatin, and then allowing the composition to cool to the temperature at which it gels. [0091]
  • REFERENCES
  • Cornell, C. [0092] Techniques in Orthopaedics 1992, 7, 55-63.
  • Bloebaum, R. D. [0093] Human Bone Ingrowth and Materials; Bloebaum, R. D., Ed.; Society for Biomaterials: Denver, Colo., 1996.
  • Einhorn, T. A. [0094] Enhancement of Bone Repair Using Biomaterials; Einhorn, T. A., Ed.; Society for Biomaterials: Denver, Colo., 1996.
  • Benedict, J. J. [0095] The Role of Carrier Matrices on Bone Induction In Vivo; Benedict, J. J., Ed.; Society for Biomaterials: Denver, Colo., 1996.
  • Strates, B.; Tiedeman, J. [0096] European Journal of Experimental Musculoskeletal Research 1993, 2, 61-67.
  • Urist, M. R. [0097] Bone Morphogenetic Protein; Urist, M. R., Ed.; W. B. Saunders Co.: Philadelphia, 1992, pp 70-83.
  • Yazdi, M.; Bernick, S.; Paule, W.; Nimni, M. [0098] Clinical Orthopaedics and Related Research 1991, 262, 281-285.
  • Younger, E.; Chapman, M. [0099] Journal of Orthopaedic Trauma 1989, 3, 192-195.
  • Hardin, C. K. [0100] Otolaringologic Clinics of North America 1994, 27, 911-925.
  • Senn, N. [0101] The American Journal of the Medical Sciences 1889, 98, 219-243.
  • Urist, M. R.; Huo, Y. K; Brownell, A. G.; Hohl, W. M.; Buyske, J.; Lietze, A.; Tempst, P.; Hunkapiller, M.; DeLange, R. J. [0102] Procedures of the National Acadamy of Sciences, USA 1984, 81, 371-375.
  • Urist, M. R.; Chang, J. J.; Lietze, A.; Huo, Y. K.; Brownell, A. G.; DeLang, R. J. [0103] Methods in Enzymology 1987, 146, 294-313.
  • Lasa, C.; Hollinger, J.; Droham, W.; MacPhee, M. [0104] Plastic and Reconstructive Surgery 1995, 96, 1409-1417.
  • Nathan, R.; Bentz, H.; Armstrong, R.; Piez, K; Smestad, T.; Ellingsworth, L.; McPherson, J.; Seyedin, S. [0105] Journal of Orthopaedic Research 1988, 6, 324-334.
  • Hench, L. L.; Andersson, O. H. [0106] Bioactive Glasses; Hench, L. L.; Andersson, O. H., Ed.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 1993, pp 41-63.
  • Scarborough, N. [0107] Bone Repair Using Allografts; Scarborough, N., Ed.; Society for Biomaterials, 1996.
  • Frenkel, S. R.; Moskovich, R.; Spivak, J.; Zhang, Z. H.; Prewett, A. B. [0108] Spine 1993, 18, 1634-1639.
  • Sperling, L. H. [0109] Introduction to Physical Polymer Science; John Wiley and Sons, Inc.: New York, 1992.
  • McDonald, T. O.; Britton, B.; Borgmann, A. R.; Robb, C. A. [0110] Toxicology 1977, 7, 37-44.
  • Culling, C. F. A.; Allison, R. T.; Barr, W. T. [0111] Cellular Pathology Technique; 4 ed.; Butterworths: London, 1985.
  • U.S. Pat. No. 5,481,601 [0112]
  • U.S. Pat. No. 5,236,456 [0113]
  • U.S. Pat. No. 5,405,390 [0114]
  • U.S. Pat. No. 4,440,750 [0115]
  • U.S. Pat. No. 4,394,370 [0116]
  • U.S. Pat. No. 4,472,840 [0117]
  • U.S. Pat. No. 4,678,470 [0118]
  • WO 89/04646 [0119]

Claims (37)

1. An implantable bone paste composition comprising gelatin as a carrier for substantially bioabsorbable osteogenic components for use in a recipient in need thereof.
2. The bone paste of claim 1 for use in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, arthrodesis of spinal or other joints, spinal fusion procedures, and implant fixation.
3. The composition of claim 1 wherein the gelatin is thermally cross-linkable at or slightly above the temperature of the organism into which it is to be implanted.
4. The composition of claim 3 wherein said composition gels at about 38° C.
5. The composition of claim 3 wherein said gelatin is present at a concentration of between about 20-45% (w/w) gelatin as a fraction of the weight of the composition.
6. The composition of claim 5 wherein the osteogenic component is selected from the group consisting of:
(i) demineralized bone matrix (DBM);
(ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, or mixtures thereof;
(iii) bone morphogenetic protein, TGF-beta, PDGF, or mixtures thereof, natural or recombinant; and
(iv) mixtures of (i)-(iii).
7. The composition of claim 6 wherein the gelatin, the demineralized bone matrix, or both are derived from the species into which the bone paste is to be implanted.
8. The composition of claim 7 wherein DBM is present at between about 0-40% (w/w) of the total composite weight.
9. The composition of claim 8 wherein DBM is present at between about 15-33% (w/w) of the total composite weight.
10. The composition of claim 6 wherein the bioactive glass is BIOGLASS®.
11. The composition of claim 6 wherein component (ii) is present at between about 0-40% (w/w) of the total composition mass.
12. The composition of claim 6 comprising antibiotics, bone morphogenetic or other proteins, whether derived from natural or recombinant sources, wetting agents, glycerol, carboxymethyl cellulose (CMC), growth factors, steroids, non-steroidal anti-inflammatory compounds, or combinations thereof.
13. The composition of claim 6 comprising between about 0.0001 to 0.1 mg/ml bone morphogenetic protein.
14. The composition of claim 1 which is a frozen solution or is freeze-dried.
15. The composition of claim 1 wherein the gelatin is human, bovine, ovine, equine, canine or mixtures thereof.
16. The composition of claim 1 wherein the gelatin is derived from human collagen sources via enzymatic, acid or alkaline extraction.
17. The composition of claim 16 wherein said human collagen sources are human skin, bone, cartilage, tendon, connective tissue, or mixtures thereof.
18. The composition of claim 17 produced by treating the collagen source with pepsin at about 33° C., heat denaturing the thus treated collagen under controlled conditions to produce gelatin, and mixing the thus produced gelatin with an osteogenic compound such that the gelatin is present at a final concentration of about 20-45% (w/w).
19. The composition of claim 18 wherein the denaturation is achieved by heating to at least 50° C.
20. The composition of claim 19 wherein the gelatin has a molecular weight of greater than about 50,000 daltons.
21. The composition of claim 1 wherein the osteogenic component is deminineralized bone matrix in a powdered form, and is composed of particles in the size range between about 80-850 μm in diameter.
22. The composition of claim 21 comprising about 0-40% (w/w) demineralized bone matrix powder, provided that if the demineralized bone matrix is powder is absent, then a bone growth factor is present at a concetration of at least 0.0001 mg/ml.
23. The composition of claim 22 wherein said bone growth factor is morphogenetic protein, TGF-β, PDGF, or mixtures thereof, natural or recombinant.
24. The composition of claim 6 wherein the bioactive glass is BIOGLASS® having a diameter of between about 0.5-710 μm.
25. The composition of claim 1 further comprising cortical, cancellous or cortical and cancerous bone chips.
26. The composition of claim 25 wherein said bone chips are in the size range of 80 μm to 10 mm.
27. The composition of claim 1 which is injection molded, vacuum molded, rotation molded, blow molded, extruded or otherwise formed into a solid form.
28. The composition of claim 27 wherein said form is selected from vertebral disks, acetabular hemispheres, tubes, ellipsoid, oblong, and “U” shapes for void filling, intramedullary plug formation, and impaction grafting.
29. A method for inducing bone formation in vivo in a recipient in need thereof which comprises implanting an effective amount of an implantable bone paste composition comprising gelatin as a carrier for substantially bioabsorbable osteogenic components.
30. The method claim 29 which comprises repairing non-union fractures, achieving periodontal ridge augmentation, conducting craniofacial surgery, securing implants, arthrodesis of spinal or other joints, spinal fusion procedures, or impaction grafting, which comprises implanting said composition at the site in vivo in need of such treatment.
31. The method according to claim 30 which comprises formation of a series of small apertures in an interverterbral space and injection of said composition into said space to induce artherodesis.
32. The method according to claim 30 which comprises extruding said composition from a syringe at a temperature at a first temperature at which it remains liquid or highly maleable, and forming a resilient, sticky and easily formable shape from said composition as it gels at a second temperature at or slightly above the body temperature of the organism into which it is implanted.
33. A method for making an implantable graft which comprises preparing a composition comprising a thermally cross-linkable gelatin carrier and suspending therein a substantially bioabsorbable osteogenic component.
34. The method of claim 33 wherein said osteogenic component is selected from:
(i) demineralized bone matrix (DBM);
(ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, or like material;
(iii) bone morphogenetic protein, TGF-β, PDGF, or mixtures thereof, natural or recombinant; and
(iv) mixtures of (i)-(iii).
35. The method of claim 34 which further comprises injection molding, vacuum molding, rotation molding, blow molding, extruding or otherwise forming said composition into the desired form of a solid graft, and allowing the composition to solidify at a temperature at which the gelatin becomes thermally cross-linked.
36. The method of claim 35 wherein said form is selected from vertebral disks, acetabular hemispheres, tubes, ellipsoid, oblong, and “U” shapes for void filling, intramedullary plug formation, and impaction grafting.
37. The method of claim 36 which comprises raising the temperature of the composition above its liquefaction temperature and allowing the composition to gel in a mold of appropriate shape.
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Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030113360A1 (en) * 1999-12-22 2003-06-19 Ludwig Baumgartner Method for producing a bone material enriched with bone growth factors
US20040146543A1 (en) * 2002-08-12 2004-07-29 Shimp Lawrence A. Synthesis of a bone-polymer composite material
US6773699B1 (en) 2001-10-09 2004-08-10 Tissue Adhesive Technologies, Inc. Light energized tissue adhesive conformal patch
US6780840B1 (en) 2001-10-09 2004-08-24 Tissue Adhesive Technologies, Inc. Method for making a light energized tissue adhesive
WO2004071547A1 (en) * 2003-02-12 2004-08-26 Ethicon Gmbh Bone filling material comprising anabolic steroid
EP1464345A2 (en) * 2003-04-03 2004-10-06 Dennis W. Szymaitis Bone growth and adjacent tissue regeneration composition
US20050008620A1 (en) * 2002-10-08 2005-01-13 Shimp Lawrence A. Coupling agents for orthopedic biomaterials
US20050008672A1 (en) * 2002-12-12 2005-01-13 John Winterbottom Formable and settable polymer bone composite and method of production thereof
US6875427B1 (en) 2001-10-09 2005-04-05 Tissue Adhesive Technologies, Inc. Light energized tissue adhesive
US20050084542A1 (en) * 2003-04-11 2005-04-21 Rosenberg Aron D. Osteoinductive bone material
US6939364B1 (en) * 2001-10-09 2005-09-06 Tissue Adhesive Technologies, Inc. Composite tissue adhesive
US20050209696A1 (en) * 2004-01-16 2005-09-22 Jo-Wen Lin Implant frames for use with settable materials and related methods of use
US6992172B1 (en) * 1999-11-12 2006-01-31 Fibrogen, Inc. Recombinant gelatins
US20060051427A1 (en) * 2004-03-02 2006-03-09 Nanotherapeutics, Inc. Compositions for repairing bone and methods for preparing and using such compositions
US20060067971A1 (en) * 2004-09-27 2006-03-30 Story Brooks J Bone void filler
US20060074422A1 (en) * 2004-09-27 2006-04-06 Story Brooks J Suture anchor and void filler combination
US20060083769A1 (en) * 2004-10-14 2006-04-20 Mukesh Kumar Method and apparatus for preparing bone
US20060084602A1 (en) * 2004-10-14 2006-04-20 Lynch Samuel E Platelet-derived growth factor compositions and methods of use thereof
US20060204544A1 (en) * 2002-05-20 2006-09-14 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
US20060233849A1 (en) * 2005-04-13 2006-10-19 Simon Bruce J Composite bone graft material
US20060233851A1 (en) * 2005-04-13 2006-10-19 Ebi, L.P. Composite bone graft material
US7132110B2 (en) 2001-08-30 2006-11-07 Isotis Orthobiologics, Inc. Tissue repair compositions and methods for their manufacture and use
US20060280803A1 (en) * 2004-10-14 2006-12-14 Mukesh Kumar Method and apparatus for repairing bone
US20070191963A1 (en) * 2002-12-12 2007-08-16 John Winterbottom Injectable and moldable bone substitute materials
US20070190083A1 (en) * 2006-02-01 2007-08-16 Scifert Jeffrey L Medical implants with reservoir (s), and materials preparable from same
US20070202191A1 (en) * 2006-02-27 2007-08-30 Mark Borden Bone graft materials derived from mineralized gelatin
US20070202190A1 (en) * 2006-02-27 2007-08-30 Mark Borden Bone graft materials derived from mineralized gelatin
US20080028992A1 (en) * 2004-04-15 2008-02-07 Lee Dosuk D Delayed-Setting Calcium Phosphate Pastes
US20080069852A1 (en) * 2006-01-19 2008-03-20 Shimp Lawrence A Porous osteoimplant
US20080195476A1 (en) * 2007-02-09 2008-08-14 Marchese Michael A Abandonment remarketing system
US20080221701A1 (en) * 2007-03-09 2008-09-11 Jipin Zhong Osteostimulative settable bone graft putty
US20090142385A1 (en) * 2007-12-04 2009-06-04 Warsaw Orthopedic, Inc. Compositions for treating bone defects
US20090246244A1 (en) * 2008-03-27 2009-10-01 Warsaw Orthopedic, Inc. Malleable multi-component implants and materials therefor
US7718616B2 (en) 2006-12-21 2010-05-18 Zimmer Orthobiologics, Inc. Bone growth particles and osteoinductive composition thereof
US20100129421A1 (en) * 2007-01-15 2010-05-27 Hans Biomed.Cor Composition for promoting bone regeneration and restoration
US7799754B2 (en) 2004-10-14 2010-09-21 Biomimetic Therapeutics, Inc. Compositions and methods for treating bone
US7943573B2 (en) 2008-02-07 2011-05-17 Biomimetic Therapeutics, Inc. Methods for treatment of distraction osteogenesis using PDGF
US8106008B2 (en) 2006-11-03 2012-01-31 Biomimetic Therapeutics, Inc. Compositions and methods for arthrodetic procedures
US8114841B2 (en) 2004-10-14 2012-02-14 Biomimetic Therapeutics, Inc. Maxillofacial bone augmentation using rhPDGF-BB and a biocompatible matrix
US8147860B2 (en) 2005-12-06 2012-04-03 Etex Corporation Porous calcium phosphate bone material
US8492335B2 (en) 2010-02-22 2013-07-23 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies
US8551525B2 (en) 2010-12-23 2013-10-08 Biostructures, Llc Bone graft materials and methods
US8613938B2 (en) 2010-11-15 2013-12-24 Zimmer Orthobiologics, Inc. Bone void fillers
US8690874B2 (en) 2000-12-22 2014-04-08 Zimmer Orthobiologics, Inc. Composition and process for bone growth and repair
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US8926710B2 (en) 2010-10-25 2015-01-06 Warsaw Orthopedic, Inc. Osteoinductive bone graft injectable cement
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US10016529B2 (en) 2015-06-10 2018-07-10 Globus Medical, Inc. Biomaterial compositions, implants, and methods of making the same
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US10532131B2 (en) * 2006-02-17 2020-01-14 NuVasive Netherlands B.V. Osteoinductive calcium phosphates
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Families Citing this family (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020076429A1 (en) * 1998-01-28 2002-06-20 John F. Wironen Bone paste subjected to irradiative and thermal treatment
US20040081704A1 (en) * 1998-02-13 2004-04-29 Centerpulse Biologics Inc. Implantable putty material
US20030147860A1 (en) 2002-02-07 2003-08-07 Marchosky J. Alexander Compositions and methods for forming and strengthening bone
AU770196B2 (en) 1999-02-04 2004-02-12 Warsaw Orthopedic, Inc. Osteogenic paste compositions and uses thereof
US7371408B1 (en) 1999-06-07 2008-05-13 Wright Medical Technology, Inc. Bone graft substitute composition
AU782394B2 (en) * 1999-06-29 2005-07-21 J. Alexander Marchosky Compositions and methods for forming and strengthening bone
US20010037091A1 (en) 1999-12-29 2001-11-01 Wironen John F. System for reconstituting pastes and methods of using same
AU2001236632A1 (en) * 2000-02-03 2001-08-14 Regeneration Technologies, Inc. Extraction of growth factors from tissue
US7182781B1 (en) 2000-03-02 2007-02-27 Regeneration Technologies, Inc. Cervical tapered dowel
AU2001248766A1 (en) 2000-04-19 2001-10-30 Shionogi And Co., Ltd. Process for preparation of sulfonamide derivatives and crystals thereof
US9387094B2 (en) 2000-07-19 2016-07-12 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
AU2001280962A1 (en) * 2000-08-01 2002-02-13 Regeneration Technologies, Inc. Diaphysial cortical dowel
US6576249B1 (en) * 2000-11-13 2003-06-10 El Gendler Bone putty and method
WO2002058755A2 (en) * 2001-01-25 2002-08-01 Regeneration Technologies, Inc. Injectable porous bone graft materials
US20020176893A1 (en) * 2001-02-02 2002-11-28 Wironen John F. Compositions, implants, methods, and kits for closure of lumen openings, repair of ruptured tissue, and for bulking of tissue
US6685626B2 (en) 2001-02-02 2004-02-03 Regeneration Technologies, Inc. Compositions, devices, methods, and kits for induction of adhesions
TWI267378B (en) 2001-06-08 2006-12-01 Wyeth Corp Calcium phosphate delivery vehicles for osteoinductive proteins
ES2181593B2 (en) * 2001-06-14 2004-04-16 Universidad Complutense De Madrid METHOD FOR OBTAINING USEFUL BIOACTIVE IMPLANTS AS CONTROLLED RELEASE SYSTEMS OF ANTIBIOTICS.
US7105182B2 (en) 2001-07-25 2006-09-12 Szymaitis Dennis W Periodontal regeneration composition and method of using same
US20030026770A1 (en) 2001-07-25 2003-02-06 Szymaitis Dennis W. Periodontal regeneration composition and method of using same
US7371409B2 (en) 2001-09-06 2008-05-13 Wright Medical Technology, Inc. Bone graft substitute composition
US7357947B2 (en) * 2001-09-10 2008-04-15 Biomet, Inc. Bone graft material incorporating demineralized bone matrix and lipids
AU2002308204B9 (en) 2001-11-19 2008-06-12 Scil Technology Gmbh Device having osteoinductive and osteoconductive properties
CA2480839C (en) 2002-03-29 2011-01-04 Wright Medical Technology, Inc. Bone graft substitute composition
US7166133B2 (en) 2002-06-13 2007-01-23 Kensey Nash Corporation Devices and methods for treating defects in the tissue of a living being
AU2003240196A1 (en) 2002-06-20 2004-01-23 Nicolaas Duneas Osteoinductive biomaterials
US7291179B2 (en) 2002-06-24 2007-11-06 Wright Medical Technology, Inc. Bone graft substitute composition
US6652887B1 (en) 2002-06-24 2003-11-25 Wright Medical Technology, Inc. Bone graft substitute composition
ES2260685T3 (en) 2002-09-10 2006-11-01 Scil Technology Gmbh METALLIC IMPLANT COVERED, TO A REDUCED OXYGEN CONCENTRATION, WITH OSTEOINDUCTING PROTEIN.
US7582309B2 (en) 2002-11-15 2009-09-01 Etex Corporation Cohesive demineralized bone compositions
US7507257B2 (en) 2003-02-04 2009-03-24 Wright Medical Technology, Inc. Injectable resorbable bone graft material, powder for forming same and methods relating thereto for treating bone defects
NZ544050A (en) 2003-06-11 2009-03-31 Osteotech Inc Osteoimplants and methods for their manufacture
US7771755B2 (en) 2003-09-12 2010-08-10 Wyeth Injectable calcium phosphate solid rods and pastes for delivery of osteogenic proteins
JP2005211477A (en) * 2004-01-30 2005-08-11 Gunze Ltd Support for regenerative medicine
WO2006026731A1 (en) 2004-08-30 2006-03-09 Spineovations, Inc. Method of treating spinal internal disk derangement
US8127770B2 (en) 2004-08-30 2012-03-06 Spineovations, Inc. Method of using an implant for treament of ligaments and tendons
US7250550B2 (en) 2004-10-22 2007-07-31 Wright Medical Technology, Inc. Synthetic bone substitute material
DE602006016956D1 (en) 2005-04-06 2010-10-28 Mallinckrodt Inc Systems and methods for managing information regarding medical fluids and containers therefor
US8025903B2 (en) 2005-09-09 2011-09-27 Wright Medical Technology, Inc. Composite bone graft substitute cement and articles produced therefrom
ES2402651T3 (en) 2005-09-09 2013-05-07 Agnovos Healthcare, Llc Cement substitute for bone graft of composite material and articles produced from it
DE102006033168A1 (en) 2006-07-10 2008-01-17 Gelita Ag Use of gelatin and a crosslinking agent for the preparation of a crosslinking therapeutic composition
DE102006033167A1 (en) 2006-07-10 2008-01-24 Gelita Ag Use of gelatin and a crosslinking agent for the preparation of a crosslinking medical adhesive
US20080096976A1 (en) * 2006-10-24 2008-04-24 Neville Alleyne Method of treating spinal internal disk derangement
AU2013203287B2 (en) * 2006-11-03 2015-12-17 Biomimetic Therapeutics, Llc. Compositions and methods for arthrodetic procedures
PT3345607T (en) * 2006-12-29 2022-11-21 Ossifi Mab Llc Methods of altering bone growth by administration of sost or wise antagonist or agonist
US9700584B2 (en) * 2007-12-21 2017-07-11 Rti Surgical, Inc. Osteoinductive putties and methods of making and using such putties
EP2080528B1 (en) 2008-01-17 2014-06-25 Tadeusz Cieslik Preparation for regeneration of postoperative and post-traumatic bone defects
US8469961B2 (en) 2008-03-05 2013-06-25 Neville Alleyne Methods and compositions for minimally invasive capsular augmentation of canine coxofemoral joints
US9248165B2 (en) 2008-11-05 2016-02-02 Hancock-Jaffe Laboratories, Inc. Composite containing collagen and elastin as a dermal expander and tissue filler
US9320761B2 (en) 2008-12-18 2016-04-26 Vivex Biomedical, Inc. Bone induction system and methods
WO2011008111A1 (en) * 2009-07-17 2011-01-20 Tadeusz Cieslik Preparation for regeneration of postoperative, post-traumatic bone defects and method for implantation of this preparation
WO2011137292A2 (en) * 2010-04-30 2011-11-03 University Of Maryland, Baltimore Injectable, load-bearing cell/microbead/calcium phosphate bone paste for bone tissue engineering
US10130736B1 (en) 2010-05-14 2018-11-20 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US9352003B1 (en) 2010-05-14 2016-05-31 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
WO2012018241A2 (en) * 2010-08-05 2012-02-09 Um In Woong Method for processing bone graft material using teeth, and bone graft material processed thereby
EP2789353B1 (en) * 2011-12-05 2018-08-15 Hitachi Chemical Company, Ltd. Membrane for inducing regeneration of bone/tissue, and method for producing same
US9180116B2 (en) 2012-07-19 2015-11-10 Cayman Chemical Company, Inc. Difluorolactam compounds as EP4 receptor-selective agonists for use in the treatment of EP4-mediated diseases and conditions
WO2014110284A1 (en) 2013-01-09 2014-07-17 Bacterin International, Inc. Bone graft substitute containing a temporary contrast agent and a method of generating such and a method of use thereof
US9539363B2 (en) * 2014-04-24 2017-01-10 Warsaw Orthopedic, Inc. Collagen matrix
ES2693579T3 (en) 2015-01-16 2018-12-12 Spineovations, Inc. Method of treatment of the intervertebral disc
US10531957B2 (en) 2015-05-21 2020-01-14 Musculoskeletal Transplant Foundation Modified demineralized cortical bone fibers
AU2017254618B2 (en) 2016-04-19 2021-04-01 Warsaw Orthopedic, Inc. An implantable composite containing carbonated hydroxyapatite
KR102285323B1 (en) * 2017-10-11 2021-08-03 포항공과대학교 산학협력단 Bone graft substitutes based on coccoliths and carbonated hydroxyapatite synthesized from coccoliths
US11285177B2 (en) * 2018-01-03 2022-03-29 Globus Medical, Inc. Allografts containing viable cells and methods thereof
CN110302431A (en) * 2019-06-21 2019-10-08 湖北联结生物材料有限公司 A kind of injectable type bioactivity glass of the DBM containing decalcified bone matrix and its preparation method and application

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3034852A (en) 1960-01-26 1962-05-15 Japan Leather Mfg Co Ltd Solubilization of insoluble collagen fibers and reconstitution thereof
DE2657370C2 (en) 1976-12-17 1982-11-11 Hans Dr.med. Dr.med.dent. 8000 München Scheicher Means for covering and / or filling in bone defects
US4294753A (en) 1980-08-04 1981-10-13 The Regents Of The University Of California Bone morphogenetic protein process
CA1190855A (en) 1980-09-03 1985-07-23 Rolf W. Pfirrmann Treatment of osteitis
US4394370A (en) 1981-09-21 1983-07-19 Jefferies Steven R Bone graft material for osseous defects and method of making same
US4472840A (en) 1981-09-21 1984-09-25 Jefferies Steven R Method of inducing osseous formation by implanting bone graft material
US4440750A (en) 1982-02-12 1984-04-03 Collagen Corporation Osteogenic composition and method
GB8328074D0 (en) * 1983-10-20 1983-11-23 Geistlich Soehne Ag Chemical compositions
US4678470A (en) 1985-05-29 1987-07-07 American Hospital Supply Corporation Bone-grafting material
FR2601371B1 (en) 1986-07-11 1989-05-12 Merieux Inst PROCESS FOR TREATING COLLAGEN WITH A VIEW TO, IN PARTICULAR, FACILITATING CROSS-LINKING AND COLLAGEN OBTAINED BY APPLICATION OF SAID PROCESS
JPS63181770A (en) * 1987-01-21 1988-07-26 永瀬 守 Artificial bone cured and formed by mixing calcium triphosphate, acid, protein and water
JPS6432371A (en) * 1987-07-29 1989-02-02 Nec Corp Inter-processor communicator system
CA1339083C (en) 1987-11-13 1997-07-29 Steven R. Jefferies Bone repair material and delayed drug delivery system
IT1215881B (en) 1988-02-16 1990-02-22 Giancarlo Foresti OSTEOTROPIC ACTION SURGICAL AID.
US4975526A (en) 1989-02-23 1990-12-04 Creative Biomolecules, Inc. Bone collagen matrix for zenogenic implants
JPH01288269A (en) * 1988-05-16 1989-11-20 Tonen Corp Composite molding
US5422340A (en) 1989-09-01 1995-06-06 Ammann; Arthur J. TGF-βformulation for inducing bone growth
US5073373A (en) 1989-09-21 1991-12-17 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
US5290558A (en) 1989-09-21 1994-03-01 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
US5236456A (en) 1989-11-09 1993-08-17 Osteotech, Inc. Osteogenic composition and implant containing same
US5206023A (en) * 1991-01-31 1993-04-27 Robert F. Shaw Method and compositions for the treatment and repair of defects or lesions in cartilage
US5356629A (en) 1991-07-12 1994-10-18 United States Surgical Corporation Composition for effecting bone repair
US5270300A (en) * 1991-09-06 1993-12-14 Robert Francis Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone
JP2984112B2 (en) * 1991-10-31 1999-11-29 京セラ株式会社 Bone filler
US5314476A (en) 1992-02-04 1994-05-24 Osteotech, Inc. Demineralized bone particles and flowable osteogenic composition containing same
JP3170339B2 (en) * 1992-03-31 2001-05-28 京セラ株式会社 Biotransplant material
DE4216496C2 (en) * 1992-05-19 1994-09-22 Werner Prof Dr Med Sattel Use of a lead body for insertion into a bone cavity, in particular in the medullary cavity of a long bone
US5531791A (en) 1993-07-23 1996-07-02 Bioscience Consultants Composition for repair of defects in osseous tissues, method of making, and prosthesis
US5503558A (en) 1993-11-12 1996-04-02 Mcgill University Osseointegration promoting implant composition, implant assembly and method therefor
US5707962A (en) 1994-09-28 1998-01-13 Gensci Regeneration Sciences Inc. Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof
WO1996039203A1 (en) * 1995-06-06 1996-12-12 Gensci Regeneration Laboratories, Inc. Modified osteogenic materials
US5776193A (en) 1995-10-16 1998-07-07 Orquest, Inc. Bone grafting matrix
US20010037091A1 (en) * 1999-12-29 2001-11-01 Wironen John F. System for reconstituting pastes and methods of using same

Cited By (137)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6992172B1 (en) * 1999-11-12 2006-01-31 Fibrogen, Inc. Recombinant gelatins
US7655615B2 (en) * 1999-12-22 2010-02-02 Tutogen Medical Gmbh Method for producing a bone material enriched with bone growth factors
US20030113360A1 (en) * 1999-12-22 2003-06-19 Ludwig Baumgartner Method for producing a bone material enriched with bone growth factors
US8690874B2 (en) 2000-12-22 2014-04-08 Zimmer Orthobiologics, Inc. Composition and process for bone growth and repair
US20060251729A1 (en) * 2001-08-30 2006-11-09 Isotis Orthobiologics, Inc. Tissue repair compositions and methods for their manufacture and use
US7132110B2 (en) 2001-08-30 2006-11-07 Isotis Orthobiologics, Inc. Tissue repair compositions and methods for their manufacture and use
US7811608B2 (en) 2001-08-30 2010-10-12 Isotis Orthobiologics, Inc. Tissue repair compositions and methods for their manufacture and use
US6780840B1 (en) 2001-10-09 2004-08-24 Tissue Adhesive Technologies, Inc. Method for making a light energized tissue adhesive
US6773699B1 (en) 2001-10-09 2004-08-10 Tissue Adhesive Technologies, Inc. Light energized tissue adhesive conformal patch
US6875427B1 (en) 2001-10-09 2005-04-05 Tissue Adhesive Technologies, Inc. Light energized tissue adhesive
US6939364B1 (en) * 2001-10-09 2005-09-06 Tissue Adhesive Technologies, Inc. Composite tissue adhesive
US20090269388A1 (en) * 2002-05-20 2009-10-29 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
US20060204544A1 (en) * 2002-05-20 2006-09-14 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
US8771719B2 (en) 2002-08-12 2014-07-08 Warsaw Orthopedic, Inc. Synthesis of a bone-polymer composite material
AU2003262660B2 (en) * 2002-08-12 2009-07-16 Warsaw Orthopedic, Inc. Synthesis of a bone-polymer composite material
US20040146543A1 (en) * 2002-08-12 2004-07-29 Shimp Lawrence A. Synthesis of a bone-polymer composite material
SG145565A1 (en) * 2002-08-12 2008-09-29 Osteotech Inc Synthesis of a bone-polymer composite material
EP2392359A3 (en) * 2002-08-12 2012-03-07 Warsaw Orthopedic, Inc. Synthesis of a bone-polymer composite material
WO2004014452A3 (en) * 2002-08-12 2004-08-26 Osteotech Inc Synthesis of a bone-polymer composite material
AU2009202477B2 (en) * 2002-08-12 2012-08-23 Warsaw Orthopedic, Inc. Synthesis of a bone-polymer composite material
US20050008620A1 (en) * 2002-10-08 2005-01-13 Shimp Lawrence A. Coupling agents for orthopedic biomaterials
US7270813B2 (en) 2002-10-08 2007-09-18 Osteotech, Inc. Coupling agents for orthopedic biomaterials
US8686064B2 (en) 2002-10-08 2014-04-01 Warsaw Orthopedic, Inc. Coupling agents for orthopedic biomaterials
US20080063684A1 (en) * 2002-12-12 2008-03-13 John Winterbottom Formable and Settable Polymer Bone Composite and Methods of Production Thereof
US7291345B2 (en) 2002-12-12 2007-11-06 Osteotech, Inc. Formable and settable polymer bone composite and method of production thereof
US10080661B2 (en) 2002-12-12 2018-09-25 Warsaw Orthopedic, Inc. Injectable and moldable bone substitute materials
US20070191963A1 (en) * 2002-12-12 2007-08-16 John Winterbottom Injectable and moldable bone substitute materials
US9333080B2 (en) 2002-12-12 2016-05-10 Warsaw Orthopedic, Inc. Injectable and moldable bone substitute materials
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
US20050008672A1 (en) * 2002-12-12 2005-01-13 John Winterbottom Formable and settable polymer bone composite and method of production thereof
US9144631B2 (en) 2003-01-27 2015-09-29 Benedicte Asius Ceramic-based injectable implants which are used to fill wrinkles, cutaneous depressions and scars, and preparation method thereof
WO2004071547A1 (en) * 2003-02-12 2004-08-26 Ethicon Gmbh Bone filling material comprising anabolic steroid
EP1464345A3 (en) * 2003-04-03 2006-03-29 Dennis W. Szymaitis Bone growth and adjacent tissue regeneration composition
EP1464345A2 (en) * 2003-04-03 2004-10-06 Dennis W. Szymaitis Bone growth and adjacent tissue regeneration composition
US20050084542A1 (en) * 2003-04-11 2005-04-21 Rosenberg Aron D. Osteoinductive bone material
US8454988B2 (en) 2003-04-11 2013-06-04 Etex Corporation Osteoinductive bone material
US20080188946A1 (en) * 2003-04-11 2008-08-07 Etex Corporation Osteoinductive bone material
US8221781B2 (en) 2003-04-11 2012-07-17 Etex Corporation Osteoinductive bone material
US8012210B2 (en) 2004-01-16 2011-09-06 Warsaw Orthopedic, Inc. Implant frames for use with settable materials and related methods of use
US20050209696A1 (en) * 2004-01-16 2005-09-22 Jo-Wen Lin Implant frames for use with settable materials and related methods of use
US7829105B2 (en) 2004-03-02 2010-11-09 Nanotherapeutics, Inc. Compositions for repairing bone
US7846459B2 (en) 2004-03-02 2010-12-07 Nanotherapeutics, Inc. Methods for preparing compositions for repairing bone
US20060051427A1 (en) * 2004-03-02 2006-03-09 Nanotherapeutics, Inc. Compositions for repairing bone and methods for preparing and using such compositions
US20080014279A1 (en) * 2004-03-02 2008-01-17 Nanotherapeutics, Inc. Methods for Preparing Compositions for Repairing Bone
US8216359B2 (en) 2004-04-15 2012-07-10 Etex Corporation Delayed-setting calcium phosphate pastes
US20080028992A1 (en) * 2004-04-15 2008-02-07 Lee Dosuk D Delayed-Setting Calcium Phosphate Pastes
US20060067971A1 (en) * 2004-09-27 2006-03-30 Story Brooks J Bone void filler
US20060074422A1 (en) * 2004-09-27 2006-04-06 Story Brooks J Suture anchor and void filler combination
US9545377B2 (en) 2004-10-14 2017-01-17 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US20060084602A1 (en) * 2004-10-14 2006-04-20 Lynch Samuel E Platelet-derived growth factor compositions and methods of use thereof
US20060280803A1 (en) * 2004-10-14 2006-12-14 Mukesh Kumar Method and apparatus for repairing bone
US11318230B2 (en) 2004-10-14 2022-05-03 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US8114841B2 (en) 2004-10-14 2012-02-14 Biomimetic Therapeutics, Inc. Maxillofacial bone augmentation using rhPDGF-BB and a biocompatible matrix
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US11571497B2 (en) 2004-10-14 2023-02-07 Biomimetic Therapeutics, Llc 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
US20070259814A1 (en) * 2004-10-14 2007-11-08 Lynch Samuel E Platelet Derived Growth Factor and Methods of Use Thereof
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
US10258566B2 (en) 2004-10-14 2019-04-16 Biomimetic Therapeutics, Llc Compositions and methods for treating bone
US7799754B2 (en) 2004-10-14 2010-09-21 Biomimetic Therapeutics, Inc. Compositions and methods for treating bone
US11364325B2 (en) 2004-10-14 2022-06-21 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods of use thereof
US7621963B2 (en) 2005-04-13 2009-11-24 Ebi, Llc Composite bone graft material
US20060233851A1 (en) * 2005-04-13 2006-10-19 Ebi, L.P. Composite bone graft material
US20060233849A1 (en) * 2005-04-13 2006-10-19 Simon Bruce J Composite bone graft material
US8147860B2 (en) 2005-12-06 2012-04-03 Etex Corporation Porous calcium phosphate bone material
US8545858B2 (en) 2005-12-06 2013-10-01 Etex Corporation Porous calcium phosphate bone material
US20080069852A1 (en) * 2006-01-19 2008-03-20 Shimp Lawrence A Porous osteoimplant
US9034356B2 (en) 2006-01-19 2015-05-19 Warsaw Orthopedic, Inc. Porous osteoimplant
US20070190083A1 (en) * 2006-02-01 2007-08-16 Scifert Jeffrey L Medical implants with reservoir (s), and materials preparable from same
US9320708B2 (en) 2006-02-01 2016-04-26 Warsaw Orthopedic, Inc. Medical implants with reservoir(s)
US7824703B2 (en) 2006-02-01 2010-11-02 Warsaw Orthopedics, Inc. Medical implants with reservoir(s), and materials preparable from same
US9931435B2 (en) 2006-02-01 2018-04-03 Warsaw Orthopedic, Inc. Medical implants with reservoir(s), and materials preparable from same
US20100298815A1 (en) * 2006-02-01 2010-11-25 Warsaw Orthopedic, Inc. Medical implants with reservoir(s), and materials preparable from same
US8697114B2 (en) 2006-02-01 2014-04-15 Jeffrey L. Scifert Medical implants with reservoir(s), and materials preparable from same
US10532131B2 (en) * 2006-02-17 2020-01-14 NuVasive Netherlands B.V. Osteoinductive calcium phosphates
US20200108180A1 (en) * 2006-02-17 2020-04-09 NuVasive Netherlands B.V. Osteoinductive Calcium Phosphates
US11590263B2 (en) * 2006-02-17 2023-02-28 NuVasive Netherlands B.V. Osteoinductive calcium phosphates
US9138508B2 (en) 2006-02-27 2015-09-22 Globus Medical, Inc. Bone graft materials derived from mineralized gelatin
US7785634B2 (en) 2006-02-27 2010-08-31 Globus Medical, Inc. Bone graft materials derived from mineralized gelatin
US7892577B2 (en) 2006-02-27 2011-02-22 Globus Medical, Inc. Bone graft materials derived from mineralized gelatin
WO2007101171A3 (en) * 2006-02-27 2008-08-21 Globus Medical Inc Bone graft materials derived from mineralized gelatin
US20110104299A1 (en) * 2006-02-27 2011-05-05 Mark Borden Bone graft materials derived from mineralized gelatin
US20070202190A1 (en) * 2006-02-27 2007-08-30 Mark Borden Bone graft materials derived from mineralized gelatin
US20070202191A1 (en) * 2006-02-27 2007-08-30 Mark Borden Bone graft materials derived from mineralized gelatin
US8394419B2 (en) 2006-02-27 2013-03-12 Global Medical, Inc. Bone graft materials derived from mineralized gelatin
US8658197B2 (en) 2006-04-14 2014-02-25 Warsaw Orthopedic, Inc. Disruptable medical implants with reservoir (s), and materials preparable from same
US11058801B2 (en) 2006-06-30 2021-07-13 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
US9642891B2 (en) 2006-06-30 2017-05-09 Biomimetic Therapeutics, Llc 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
US10456450B2 (en) 2006-06-30 2019-10-29 Biomimetic Therapeutics, Llc Compositions and methods for treating rotator cuff injuries
US8399409B2 (en) 2006-11-03 2013-03-19 Biomimetic Therapeutics Inc. Compositions and methods for arthrodetic procedures
US8106008B2 (en) 2006-11-03 2012-01-31 Biomimetic Therapeutics, Inc. Compositions and methods for arthrodetic procedures
US8742072B2 (en) 2006-12-21 2014-06-03 Zimmer Orthobiologics, Inc. Bone growth particles and osteoinductive composition thereof
US7718616B2 (en) 2006-12-21 2010-05-18 Zimmer Orthobiologics, Inc. Bone growth particles and osteoinductive composition thereof
US8192751B2 (en) * 2007-01-15 2012-06-05 Hans Biomed.Cor Composition for promoting bone regeneration and restoration
US20100129421A1 (en) * 2007-01-15 2010-05-27 Hans Biomed.Cor Composition for promoting bone regeneration and restoration
US20080195476A1 (en) * 2007-02-09 2008-08-14 Marchese Michael A Abandonment remarketing system
US20080221701A1 (en) * 2007-03-09 2008-09-11 Jipin Zhong Osteostimulative settable bone graft putty
US9433704B2 (en) 2007-03-09 2016-09-06 Novabone Products, Llc Osteostimulative settable bone graft putty
US9056150B2 (en) 2007-12-04 2015-06-16 Warsaw Orthopedic, Inc. Compositions for treating bone defects
US10441679B2 (en) 2007-12-04 2019-10-15 Warsaw Orthopedic, Inc. Compositions for treating bone defects
US10080819B2 (en) 2007-12-04 2018-09-25 Warsaw Orthopedic, Inc Compositions for treating bone defects
US20090142385A1 (en) * 2007-12-04 2009-06-04 Warsaw Orthopedic, Inc. Compositions for treating bone defects
US7943573B2 (en) 2008-02-07 2011-05-17 Biomimetic Therapeutics, Inc. Methods for treatment of distraction osteogenesis using PDGF
US8349796B2 (en) 2008-02-07 2013-01-08 Biomimetic Therapeutics Inc. Methods for treatment of distraction osteogenesis using PDGF
US20090246244A1 (en) * 2008-03-27 2009-10-01 Warsaw Orthopedic, Inc. Malleable multi-component implants and materials therefor
US9730982B2 (en) 2008-03-27 2017-08-15 Warsaw Orthopedic, Inc. Malleable multi-component implants and materials therefor
US8840913B2 (en) 2008-03-27 2014-09-23 Warsaw Orthopedic, Inc. Malleable multi-component implants and materials therefor
US8870954B2 (en) 2008-09-09 2014-10-28 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
US11135341B2 (en) 2008-09-09 2021-10-05 Biomimetic Therapeutics, Llc Platelet-derived growth factor composition and methods for the treatment of tendon and ligament injuries
US11235030B2 (en) 2010-02-22 2022-02-01 Biomimetic Therapeutics, Llc Platelet-derived growth factor compositions and methods for the treatment of tendinopathies
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US8926710B2 (en) 2010-10-25 2015-01-06 Warsaw Orthopedic, Inc. Osteoinductive bone graft injectable cement
US8613938B2 (en) 2010-11-15 2013-12-24 Zimmer Orthobiologics, Inc. Bone void fillers
US8551525B2 (en) 2010-12-23 2013-10-08 Biostructures, Llc Bone graft materials and methods
US9220596B2 (en) 2010-12-23 2015-12-29 Biostructures, Llc Bone graft materials and methods
US9849215B2 (en) 2011-04-20 2017-12-26 Warsaw Orthopedic, Inc. Implantable compositions and methods for preparing the same
US9265830B2 (en) 2011-04-20 2016-02-23 Warsaw Orthopedic, Inc. Implantable compositions and methods for preparing the same
US10792397B2 (en) 2012-06-11 2020-10-06 Globus Medical, Inc. Bioactive bone graft substitutes
US10207027B2 (en) 2012-06-11 2019-02-19 Globus Medical, Inc. Bioactive bone graft substitutes
US9486483B2 (en) 2013-10-18 2016-11-08 Globus Medical, Inc. Bone grafts including osteogenic stem cells, and methods relating to the same
US10022474B2 (en) 2013-10-18 2018-07-17 Globus Medical, Inc. Bone grafts including osteogenic stem cells, and methods relating to the same
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US9579421B2 (en) 2014-02-07 2017-02-28 Globus Medical Inc. Bone grafts and methods of making and using bone grafts
US9463264B2 (en) 2014-02-11 2016-10-11 Globus Medical, Inc. Bone grafts and methods of making and using bone grafts
US10016529B2 (en) 2015-06-10 2018-07-10 Globus Medical, Inc. Biomaterial compositions, implants, and methods of making the same
US11426489B2 (en) 2015-06-10 2022-08-30 Globus Medical, Inc. Biomaterial compositions, implants, and methods of making the same
WO2018009091A1 (en) * 2016-07-04 2018-01-11 ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ "НОВОСИБИРСКИЙ НАУЧНО-ИССЛЕДОВАТЕЛЬСКИЙ ИНСТИТУТ ТРАВМАТОЛОГИИ И ОРТОПЕДИИ ИМ. Я.Л.ЦИВЬЯНА" МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ (ФГБУ "ННИИТО им. Я.Л. ЦИВЬЯНА" МИНЗДРАВА РОССИИ) Method for producing bone-plastic material
CN111564213A (en) * 2020-05-12 2020-08-21 成都铂润信息技术有限公司 Health state early warning method and system suitable for ruminant livestock
US11896736B2 (en) 2020-07-13 2024-02-13 Globus Medical, Inc Biomaterial implants and methods of making the same
CN114569787A (en) * 2021-04-13 2022-06-03 健诺维(成都)生物科技有限公司 Bone repair material and preparation method and application thereof
CN114569787B (en) * 2021-04-13 2022-11-18 健诺维(成都)生物科技有限公司 Bone repair material and preparation method and application thereof
CN114509535A (en) * 2021-12-27 2022-05-17 安徽丰原明胶有限公司 Method for detecting maturity of ossein in bone gelatin production
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WO1998040113A1 (en) 1998-09-17
JP2001514565A (en) 2001-09-11
EP0984797A1 (en) 2000-03-15
HUP0001811A3 (en) 2001-02-28
SK125799A3 (en) 2000-08-14
HUP0001811A2 (en) 2000-10-28
US8652503B2 (en) 2014-02-18
AU6552898A (en) 1998-09-29
PL335800A1 (en) 2000-05-22
US20070003593A1 (en) 2007-01-04

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