EP1311309A2 - Procede de traitement et de deshydratation d'os pour implant et os resultant - Google Patents

Procede de traitement et de deshydratation d'os pour implant et os resultant

Info

Publication number
EP1311309A2
EP1311309A2 EP01966222A EP01966222A EP1311309A2 EP 1311309 A2 EP1311309 A2 EP 1311309A2 EP 01966222 A EP01966222 A EP 01966222A EP 01966222 A EP01966222 A EP 01966222A EP 1311309 A2 EP1311309 A2 EP 1311309A2
Authority
EP
European Patent Office
Prior art keywords
bone
mechanical strength
conserving
agent
conserving agent
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01966222A
Other languages
German (de)
English (en)
Inventor
Todd M. Boyce
Lawrence A. Shimp
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Osteotech Inc
Original Assignee
Osteotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Osteotech Inc filed Critical Osteotech Inc
Publication of EP1311309A2 publication Critical patent/EP1311309A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/46—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
    • A61F2/4644—Preparation of bone graft, bone plugs or bone dowels, e.g. grinding or milling bone material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • A61L27/365—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/3094—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30108—Shapes
    • A61F2002/3011—Cross-sections or two-dimensional shapes
    • A61F2002/30112—Rounded shapes, e.g. with rounded corners
    • A61F2002/30131—Rounded shapes, e.g. with rounded corners horseshoe- or crescent- or C-shaped or U-shaped
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30878—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves with non-sharp protrusions, for instance contacting the bone for anchoring, e.g. keels, pegs, pins, posts, shanks, stems, struts
    • A61F2002/30879—Ribs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30878—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves with non-sharp protrusions, for instance contacting the bone for anchoring, e.g. keels, pegs, pins, posts, shanks, stems, struts
    • A61F2002/30891—Plurality of protrusions
    • A61F2002/30892—Plurality of protrusions parallel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2/30771—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves
    • A61F2002/30904—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes or grooves serrated profile, i.e. saw-toothed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2/46—Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
    • A61F2/4644—Preparation of bone graft, bone plugs or bone dowels, e.g. grinding or milling bone material
    • A61F2002/4649—Bone graft or bone dowel harvest sites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0004—Rounded shapes, e.g. with rounded corners
    • A61F2230/0013—Horseshoe-shaped, e.g. crescent-shaped, C-shaped, U-shaped
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • Monolithic bone intended for implantation is treated in order to conserve its
  • This treatment is useful when combined with a number of methods of dehydrating the bone, e.g. dehydrating under ambient or near ambient conditions,
  • processing e.g., to preserve the graft for later use and to remove immunogenic cellular materials
  • the porous matrix is typically contacted with one or more treatment fluids to variously clean, defat, sterilize, virally inactivate, disinfect, and/or demineralize the bone or to impregnate the bone with one or more pharmacological agents (antibiotics, bone growth factors, etc.) so the bone can act as a drug delivery system.
  • one or more treatment fluids to variously clean, defat, sterilize, virally inactivate, disinfect, and/or demineralize the bone or to impregnate the bone with one or more pharmacological agents (antibiotics, bone growth factors, etc.) so the bone can act as a drug delivery system.
  • Some treatment processes can work against conservation of the mechanical strength of bone and can lessen the bone's weight bearing properties. Processing requirements can also create dimensional changes in the allograft bone. Such changes of dimension can create damage within the tissue, and may also make it difficult for a machined piece to mechanically engage with surgical instruments, other allografts, or the prepared surgical
  • Lyophilization freeze-drying, i.e., freezing, then sublimation of moisture
  • Lyophilization can result in damage to the bone due to dimensional changes that occur during the freezing and dehydrating operations.
  • the adverse mechanical changes appear to be associated with damage occurring in the bone matrix, specifically, ultrastructural cracks along the collagen fibers.
  • the mechanical strength- conserving agent is not acting as a cryopreservative (i.e., minimizing crystal growth during freezing) but rather in some new, not entirely understood, manner to diminish the dimensional changes associated with lyophilization. It has been determined that the diminishment of dimensional changes is related to the extent to which the mechanical strength- conserving agent is not acting as a cryopreservative (i.e., minimizing crystal growth during freezing) but rather in some new, not entirely understood, manner to diminish the dimensional changes associated with lyophilization. It has been determined that the diminishment of dimensional changes is related to the extent to which the mechanical
  • monolithic bone intended for implantation in order to conserve the mechanical strength of the bone during its dehydration and subsequent packaging and storage and to substantially maintain such strength throughout its rehydration and subsequent
  • dehydrated monolithic bone so that the bone may be stored at ambient temperatures for an extended period of time, e.g., up to five years or longer without excessive loss of its
  • implant containing a mechanical strength-conserving agent and, optionally, one or more medically/surgically useful substances, e.g., an osteogenic material such as bone
  • BMPs morphogenic proteins
  • the method comprises: contacting the bone with a mechanical strength-conserving amount of at least one
  • biocompatible mechanical strength-conserving agent said agent being a liquid organic material or solution, mixture, or suspension thereof, which is capable of penetrating and remaining in the bone during its dehydration, packaging and storage; dehydrating the bone containing the mechanical strength-conserving agent; and,
  • the invention includes the dehydrated bone obtained by the foregoing method(s) and use of bone obtained by the invention herein.
  • pieces of human or animal bone i.e., pieces of bone, autograft, allograft or xenograft, that are of such size as to be capable of withstanding the sort of mechanical loads to which
  • the monolithic bone of this invention is to be distinguished from particles, filaments, threads, etc. as disclosed in U. S. Patent Nos. 5,073,373, 5,314,476 and 5,507,813, which, due to their relatively small dimensions, are incapable of sustaining significant mechanical loads, either individually
  • monolithic bone refers to fully mineralized bone, i.e., bone with its full natural level of mineral content, and to such bone that has been demineralized to some minor extent, i.e., to an extent which reduces the original mechanical strength of the bone by no more than about 50 percent.
  • the monolithic bone can be provided as a single integral piece of bone or as a piece of bone permanently assembled from a number of smaller bone elements, e.g., as
  • osteogenic monolithic bone
  • additional materials e.g., as disclosed in U.S. Patent No. 5,290,558 the contents of which are incorporated herein by reference, which will remain with the bone after its rehydration and will be present at the time of
  • toughness as utilized herein is intended to refer to any characteristic that qualitatively can be described as the way in which the bone fails, i.e., how the bone undergoes deformation prior to fracture. For example, bone which exhibits improvement in toughness would be more desirable than bone having less toughness.
  • toughness is a measure of the energy absorbed by the osteoimplant prior to breakage and is expressed in units of Newton-meters (N-m).
  • conserving agent shall demonstrate at least about 2% less decrease in length dimension as compared to bone that has been lyophilized. That is, bone treated in accordance with the invention herein will demonstrate less shrinkage after dehydration than bone that is lyophilized in the absence of a mechanical strength-conserving agent.
  • the monolithic bone treated in accordance with the invention i.e., dehydrating such bone in the presence of a mechanical strength- conserving agent shall demonstrate at least greater than about 19 percent increase in toughness as compared to bone that has been lyophilized in the absence of a mechanical strength-conserving agent. That is, bone treated in accordance with the invention herein
  • biocompatible and expressions of like import shall be understood to mean the absence of stimulation of an undesired severe, long-lived or escalating biological response to an implant and is distinguished from a mild, transient
  • Figure 1 is a graphical representation of a standard freeze-drying process.
  • Figure 2 is a graphical representation of an alternative freeze-drying process in which the tissue is subjected to some level of dehydration prior to freezing and sublimation of any remaining moisture.
  • Figure 3 is a representation of a ramp-shaped implant.
  • Figure 4 is a graphical representation of the dimension change of bone implant prepared as in Example 5.
  • Figure 5 is a graphical representation of the treatment effects on dimensional change.
  • Bone for implantation is obtained, e.g., aseptically in a morgue or an operating
  • the bone is cleansed, e.g., using 70% ethanol and washed with
  • the bone may be treated with antibiotics such as polymyxin B sulfate, bacitracin, and/or gentamicin, and may contain trace amounts of
  • Cleansing, cutting, sizing, shaping, container sterilization, filling, lyophilization, and stoppering may be functions are performed under conditions following industry standards for tissue handling.
  • the bone employed in the invention is of monolithic proportions in contrast to "particles,” “filaments,” “threads,” “strips,” etc.,
  • the bone treated according to the method of the invention is generally a relatively large piece or segment of donor bone and is intended for implantation into a correspondingly relatively large defect or other implantation site.
  • the bone herein will possess dimensions of length on the order of about 2 mm to about 500 mm and preferably at least
  • the prepared bone Prior to dehydration, the prepared bone is contacted with a mechanical strength- conserving amount of a biocompatible mechanical strength-conserving agent.
  • the biocompatible mechanical strength-conserving agent appropriate to the invention is a compound- or solution that is liquid at the temperature at which it is contacted with the bone, more preferably from about 5°C. to about 65°C, and which penetrates the small pores of the bone remaining therein after being dehydrated.
  • the conserving agent is
  • a suitable conserving agent will meet these criteria even if mixed with water or other volatile solvent and then subsequently the water or solvent is removed during dehydration leaving the conserving agent behind, i.e., it has a eutectic point significantly
  • conserving agent examples include polyhydroxy compound, polyhydroxy ester, fatty alcohol, fatty alcohol ester, fatty acid, fatty acid ester, liquid silicone, mixtures thereof, and the like.
  • Suitable conserving agent include, but are not limited to: (i) Polyhydroxy compound, for example, glycerol, 1,4-butylene glycol, diethylene
  • glycol triethylene glycol, tetraethylene glycol, propylene glycol, dipropylene glycol; polysaccharides and their derivatives, e.g., hyaluronic acid; polyoxyethylene- polyoxypropylene copolymer, e.g., of the type known and commercially available under the trade names Pluronic and Emkalyx; polyoxyethylene-polyoxypropylene block copolymer, e.g., of the type known and commercially available under the trade name
  • Poloxamer alkylphenolhydroxypolyoxyethylene, e.g., of the type known and commercially available under the trade name Triton, and the like.
  • Polyhydroxy ester for example, monoacetin, triacetin, poly(oxyalkylene) glycol ester, and the like.
  • Fatty alcohol for example primary alcohols, usually straight chain having from 6 to 13 carbon atoms, including caproic alcohol, caprylic alcohol, undecyl alcohol, lauryl alcohol, and tridecanol.
  • Fatty alcohol ester for example, ethyl hexyl palmitate, isodecyl neopentate, octadodecyl benzoate, diethyl hexyl maleate, and the like.
  • Fatty acid ester for example, polyoxyethylene-sorbitan-fatty acid esters; e.g., mono- and tri-lauryl, palmityl, stearyl, and oleyl esters; e.g., of the type available under the trade name Tween from Imperial Chemical Industries; polyoxyethylene fatty acid esters;
  • polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj; propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate; propylene glycol dilaurate, propylene glycol hydroxy
  • stearate propylene glycol isostearate, propylene glycol laureate, propylene glycol ricinoleate, propylene glycol stearate, and propylene glycol caprylic-capric acid diester available under the trade name Miglyol; mono-, di-, and mono/di-glycerides, such as the esterification products of caprylic or caproic acid with glycerol; e.g., of the type known and commercially available under the trade name Imwitor; sorbitan fatty acid esters, e.g., of the type known and commercially available under the trade name Span, including sorbitan-monolauryl, -monopalmityl, -monostearyl, -tristearyl, -monooleyl and trioleylesters; monoglycerides, e.g., glycerol mono oleate, glycerol mono palmitate and
  • glycerol monostearate for example as known and commercially available under the trade names Myvatex, Myvaplex and Myverol
  • acetylated e.g., mono- and di-acetylated monoglycerides, for example as known and commercially available under the trade name
  • Myvacet isobutyl tallowate, n-butylstearate, n-butyl oleate, and n-propyl oleate.
  • Liquid silicone for example, polyalkyl siloxanes such as polymethyl siloxane and poly(dimethyl siloxane) and polyalkyl arylsiloxane.
  • the suitable biocompatible mechanical strength-conserving agent selected from the examples above preferably is capable of penetrating the small pores of
  • a solution of a conserving agent can be utilized.
  • This solution can be aqueous or can be one utilizing a polar organic solvent or other volatile
  • volatile solvent as utilized herein is intended to refer to any suitable solvent or mixture of solvents having a vapor pressure at relevant temperature
  • volatile solvent(s) will be suitable even if ordinarily considered to be toxic so long as the amount of volatile solvent, if any, present at the time of implantation does not produce a toxic response.
  • volatile solvents useful in the invention herein would include but not be limited to, water;
  • alcohols typically a low molecular weight alcohol such as methanol, ethanol, isopropanol, butanol, isobutanol, ethylbutanol, acetonitrile, pyridine, industrial methylated spirit, etc.; graded series of dehydrating agents in solution with the conserving
  • solvent e.g., dimethylsulfoxide, small ketones, acetone; chloroform; methylene chloride and ethylene chloride; straight chain hydrocarbons, e.g., hexane, pentane and similar alkanes; low molecular weight alkenes; esters; ether, e.g., ethyl ether, tetrahydrofuran, dioxane, ethylene glycol monoethyl ether, crown ethers, etc.; aldehyde or solutions containing aldehydes, e.g., formaldehyde, formalin, etc., at low temperatures such that cross-linking does not proceed; super critical fluids, e.g., carbon dioxide or hydrogen sulfide at supercritical pressures, mixtures of any of the above liquids, etc.
  • volatile solvents when present prior to lyophilization or other method of dehydration, will typically represent between about 20 to about 80, preferably about 30 to about 60 percent
  • biocompatible mechanical strength-conserving agent neat or solution
  • the preferred biocompatible mechanical strength-conserving agent is glycerol, more preferably a 50% aqueous or alcoholic
  • the bone is contacted with a mechanical strength-conserving amount of the mechanical strength-conserving agent in a suitable container, e.g., a 120 ml or 500 ml bottle, optionally with mechanical stirring.
  • a suitable container e.g., a 120 ml or 500 ml bottle
  • the conserving agent can be applied by infusing, e.g., employing a pressurized system such as that described in U.S. Patent No. 5,846,484 the contents of which are incorporated herein by reference or by
  • the conserving agent can be contacted with the bone in the presence of a low pressure atmosphere such as that described in U.S. Patent No. 5,513,662 the contents of which are incorporated herein by reference or in the low pressure atmosphere provided by vacuum packaging the bone and strength-conserving agent utilizing a vacuum sealer.
  • the conserving agent can be contacted with the bone in the presence of alternating vacuum and positive pressure such as that
  • HypercenterTM XP Enclosed Tissue Processor commercially available from Shandon Lipshaw USA or preferably a Sakura Tissue-TEK® VIPTM vacuum infusion tissue processor commercially available from Sakura Finetek, USA.
  • the optimal times and levels of alternating vacuum-positive pressure or alternating positive pressure can be determined through
  • the tissue processor allows for the simultaneous contacting of the bone with a mechanical strength-conserving agent and dehydrating of the bone when
  • a graded series of dehydrating agents is used as the volatile solvent for the strength- conserving agent. Such simultaneous contacting/dehydrating may result in an implant having better mechanical properties than one that is lyophilized after being contacted with a strength-conserving agent.
  • the bone and agent can be advantageously subjected to sonication. It has been determined that contacting the bone with strength-conserving agent in an ultrasonic bath improves the penetration of the agent into the tissue. Sonicating bone is well known
  • the bone can be rough cut, processed with strength-conserving agent, further shaped as desired, then subjected to further processing
  • bottle containing bone and conserving agent is subjected to, e.g., processes including but not limited to: contacting the bone with a graded series of dehydrating liquids; subjecting the bone to microwave energy such as described in U.S. Pat. No. 4,656,047 the contents of which are incorporated by reference herein; subjecting the bone to heat at ambient or sub-atmospheric pressures, e.g., drying oven at temperatures from about 35°C. to about
  • a desiccant e.g., closed container subjected to vacuum optionally containing a desiccant such as anhydrous calcium chloride, anhydrous silica gel or the like; subjecting the bone to ambient temperatures at ambient or sub-atmospheric pressures such as typically found in a laboratory bench-top or conventional fume hood; alternative lyophilization procedures such as starting the lyophilization cycle at a higher temperature to dehydrate the tissue then reducing the
  • bone treated according to the invention herein demonstrates at least about 2% less decrease in length dimension as compared to bone
  • bone treated according to the invention herein shows at least greater than 19% improvement in overall toughness after dehydrating as compared to bone that has been lyophilized without being treated according to the invention herein.
  • the bone can optionally be further shaped prior to packaging.
  • dehydrated bone can be rehydrated prior to implantation. Soaking the dehydrated bone in rehydrating solution at normal atmospheric pressure can perform rehydration. Alternatively, the dehydrated bone can be rehydrated in a low atmospheric pressure environment, for example, the rehydration solution can be introduced via hypodermic needle through the sealed rubber stopper.
  • strength-conserving agent also acts as a wetting agent decreasing the time necessary to rehydrate the bone at the time of use.
  • the rehydration solution can be any of a number of suitable agents such as sterile water, normal saline, physiologically buffered saline, dextrose solution, antibiotic solutions, and others of this sort.
  • suitable agents such as sterile water, normal saline, physiologically buffered saline, dextrose solution, antibiotic solutions, and others of this sort.
  • it can contain one or more wetting agents such as any of the PluronicTM agents or any of a variety of medically/surgically useful
  • antiviral agents particularly those effective against HIV and hepatitis
  • antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin B, tetracycline, viomycin, chloromycetin and streptomycin, cetazolin, ampicillin, azactam, tobramycin, clindamycin, gentamicin, etc.
  • inorganic elements co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.; polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; antigenic agents; cytoskeletal agents; bone morphogenic proteins (BMPs),
  • TGF-beta insulin-like growth factor
  • IGF-1 insulin-like growth factor
  • IGF-2 insulin-like growth factor two
  • PDGF platelet derived growth factor
  • growth hormones such as somatotropin.
  • the rehydrated dehydrated monolithic bone prepared according to the method herein is intended to be applied at a bone defect site, e.g., one resulting from injury, defect brought about during the course of surgery, infection, malignancy or development malformation.
  • a bone defect site e.g., one resulting from injury, defect brought about during the course of surgery, infection, malignancy or development malformation.
  • the bone suitably sized and shaped as required, can be utilized as a graft
  • orthopedic, neurosurgical and oral and maxillofacial surgical procedures such as the repair of simple and compound fractures and nonunions, external and internal fixations, joint reconstruction such as arthrodesis, general arthroplasty, cup arthroplasty of the hip, femoral and humeral head replacement, femoral head surface replacement and total joint replacement, repairs of the vertebral column including spinal fusion and internal fixation, tumor surgery, e.g., deficit filling,
  • Specific bones which can be repaired with the bone-derived implant herein include the ethmoid, frontal, nasal, occipital, parietal, temporal, mandible, maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbar vertebra, sacrum, rib, sternum, clavicle, scapula, humerus, radius, ulna, carpal bones, metacarpal bones,
  • phalanges - ilium, ischium, pubis, femur, tibia, fibula, patella, calcaneus, tarsal and metatarsal bones.
  • Human cortical bone specimens from the diaphysis of a long bone are manufactured into the shape of a threaded cylindrical dowel. Specimens are then treated
  • the specimen remains in the oven for a period of time necessary to evaporate off the remaining solvent, to remove the remaining water from the tissue, and to allow
  • adherent treatment solution to penetrate. This time is determined by standard assays of solvent content and of moisture content. The samples are then packaged for surgical use.
  • Human cortical bone specimens prepared by cutting on a band saw into strut allografts, are placed into the retort chamber of an automated tissue-processing machine,
  • Human cortical bone specimens prepared by cutting on a bandsaw into diaphyseal cross-sections, are placed into a closed container with a 50% ethanol/50%
  • glycerol solution The specimen is stirred continuously for 24-48 hours, then the container is opened under a hood to allow the volatile ethanol solvent to evaporate at ambient pressure. Specimens are then removed from the container, and placed into a
  • Specimens were individually placed in KapakTM bags, and partially filled with 50% (v/v) aqueous glycerol solution. The bags were then sealed in a vacuum sealing device so that the air was removed prior to sealing and the implants were each surrounded by the glycerol solution at a reduced pressure. Specimens were allowed to equilibrate in the
  • Bovine cortical bone specimens 4mm x 4mm x 40mm (nominal) were prepared
  • Glycerol application prior to lyophilization reduces brittleness in the bone
  • penetration was affected by either of two treatment processes: Specimens suspended in a stirred solution; and specimens suspended in an ultrasonic bath.
  • the treatment solution used was 50% (v/v) aqueous glycerol, and also contained 0.5%(w/v) methylene blue dye to allow assessment of penetration. Specimens of each group were removed at 1 hour, 4 hours, 11 hours, 24
  • table 3 summarizes penetration into Haversian Canals (HC) and Matrix (M) regions of the middle ( 1 cm) section.
  • Human bone was treated for viral inactivation using processes described in US patent 5,846,484. From these treated bones, human diaphyseal bone segments were shaped into a ramped structure (figure 3) using processes described in U.S. Patent Appln.
  • the threaded hole was also tested using a mating screw prior to the
  • Results in Figure 5 show the difference between final and initial measurements for the overall length (OL) and overall width (OW).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Transplantation (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Botany (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Zoology (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
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Abstract

L'invention concerne un os monolithique pour implant, traité pour conserver sa résistance mécanique en phase de déshydratation et de conditionnement ultérieur, l'objectif étant également de maintenir la résistance de l'os en cours de stockage, avant la réhydratation et l'implantation. On met l'os en contact avec une quantité d'au moins un agent biocompatible de conservation de résistance mécanique. Il s'agit d'un matériau organique liquide capable de pénétrer dans l'os et de s'y maintenir durant la déshydratation, le conditionnement et le stockage de l'os. Ensuite, on déshydrate l'os renfermant l'agent considéré et on le conditionne.
EP01966222A 2000-08-24 2001-08-24 Procede de traitement et de deshydratation d'os pour implant et os resultant Withdrawn EP1311309A2 (fr)

Applications Claiming Priority (3)

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US64452100A 2000-08-24 2000-08-24
US644521 2000-08-24
PCT/US2001/026553 WO2002015948A2 (fr) 2000-08-24 2001-08-24 Procede de traitement et de deshydratation d'os pour implant et os resultant

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CN101371609B (zh) 2006-01-18 2013-05-29 艾利森电话股份有限公司 集中式和分布式传输
WO2008073582A2 (fr) * 2006-10-27 2008-06-19 Edwards Lifesciences Corporation Tissu biologique pour implantation chirurgicale
US8846390B2 (en) 2010-03-23 2014-09-30 Edwards Lifesciences Corporation Methods of conditioning sheet bioprosthetic tissue

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JPS6045602B2 (ja) * 1978-09-28 1985-10-11 正隆 片桐 生物性移植体とその製作法
US5513662A (en) * 1991-12-31 1996-05-07 Osteotech, Inc. Preparation of bone for transplantation
US5797871A (en) * 1994-08-19 1998-08-25 Lifenet Research Foundation Ultrasonic cleaning of allograft bone
WO1999051170A1 (fr) * 1998-04-02 1999-10-14 Crosscart, Inc. Xenogreffes osseuses
US6630001B2 (en) * 1998-06-24 2003-10-07 International Heart Institute Of Montana Foundation Compliant dehyrated tissue for implantation and process of making the same
US6293970B1 (en) * 1998-06-30 2001-09-25 Lifenet Plasticized bone and soft tissue grafts and methods of making and using same
US6162258A (en) * 1999-08-25 2000-12-19 Osteotech, Inc. Lyophilized monolithic bone implant and method for treating bone

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WO2002015948A2 (fr) 2002-02-28

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