WO2009053820A1 - Système pour traiter des défauts de l'os et/ou du cartilage et procédés d'utilisation de celui-ci - Google Patents

Système pour traiter des défauts de l'os et/ou du cartilage et procédés d'utilisation de celui-ci Download PDF

Info

Publication number
WO2009053820A1
WO2009053820A1 PCT/IB2008/002826 IB2008002826W WO2009053820A1 WO 2009053820 A1 WO2009053820 A1 WO 2009053820A1 IB 2008002826 W IB2008002826 W IB 2008002826W WO 2009053820 A1 WO2009053820 A1 WO 2009053820A1
Authority
WO
WIPO (PCT)
Prior art keywords
bone
subject
bmp
defect
vegf
Prior art date
Application number
PCT/IB2008/002826
Other languages
English (en)
Other versions
WO2009053820A4 (fr
Inventor
Arne Briest
Hans Jorgen Pedersen
Original Assignee
Sbf Synthetic Bone Factory Gmbh
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 Sbf Synthetic Bone Factory Gmbh filed Critical Sbf Synthetic Bone Factory Gmbh
Priority to AU2008315663A priority Critical patent/AU2008315663A1/en
Priority to CA2703340A priority patent/CA2703340A1/fr
Publication of WO2009053820A1 publication Critical patent/WO2009053820A1/fr
Publication of WO2009053820A4 publication Critical patent/WO2009053820A4/fr
Priority to IL205250A priority patent/IL205250A0/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/70—Spinal positioners or stabilisers ; Bone stabilisers comprising fluid filler in an implant
    • A61B17/7001—Screws or hooks combined with longitudinal elements which do not contact vertebrae
    • A61B17/7002—Longitudinal elements, e.g. rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/84—Fasteners therefor or fasteners being internal fixation devices
    • A61B17/86—Pins or screws or threaded wires; nuts therefor
    • 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
    • A61F2/32—Joints for the hip
    • 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
    • A61F2/44—Joints for the spine, e.g. vertebrae, spinal discs
    • A61F2/4455—Joints for the spine, e.g. vertebrae, spinal discs for the fusion of spinal bodies, e.g. intervertebral fusion of adjacent spinal bodies, e.g. fusion cages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/02—Bones

Definitions

  • Natural bone is made up of a combination of inorganic elements, organic components, and water.
  • Inorganic elements in bone for example hydroxy apatite, constitute approximately 70% of natural bone.
  • Organic components such as collagen type I constitute approximately 20% of natural bone, and water constitutes approximately 10%.
  • Bone-forming cells for example osteoblasts, produce and secrete newly made bone, and bind the organic components including in addition to collagen, non-collagen proteins such as osteocalcin, osteonectin, osteopontin, cytokine, growth inducing factor, proteoglycan and fat.
  • Natural bone is constantly involved in a process of degradation by osteoclasts and regeneration by osteoblasts, i.e. re-modeled, for example during healing of bone fractures.
  • the ability of natural bone to generate new functional bone can in certain circumstances be restricted, for example by functional disorders such as a sedentary lifestyle, advanced age or a metabolic disturbance such as a syndrome of symptoms due to vitamin D deficiency.
  • Treatment of bone defects remains an important medical need, for example in geriatric emergencies, long bone trauma arising from accidents or surgery, and orthopedic procedures such as repair to jaws, teeth and hands. Bone defects also originate from cysts, tumors, or atrophy, complicated comminute fractures, congenital deformities and loosening of implants.
  • An aspect of the present invention herein provides a system for sustained delivery at a controlled flow rate of a composition for treating a bone or a cartilage defect in a subject, the system including: at least one pump for sustained delivery that has an outlet port and at least one reservoir; at least one catheter having a proximal end and a distal end, in which the proximal end of the catheter is connected to the outlet port; and a retaining device implanted in the subject in contact with the bone or cartilage defect, in which the distal end of the catheter connects to the retaining device, and the pump and the retaining device retard release of the composition into the defect.
  • An embodiment of the invention provides the composition delivered by the system herein selected from at least one of the group consisting of a bone morphogenetic protein (BMP) and a vascular endothelial growth factor (VEGF).
  • the composition further includes a gelling agent, such as carboxymethylcellulose (CMC), an additional growth factor, an anti-microbial, a vitamin, a cytokine, and an anti-inflammatory.
  • the BMP is at least one of BMP-2 or BMP-7.
  • the BMP is recombinant human BMP.
  • the distal end of the catheter includes a biodegradable material.
  • the biodegradable material of the catheter is at least one selected from the group consisting of polygalacturonic acid (PGA), polymethylmethacrylate (PMMA), polylactate (PLA), and a magnesium alloy.
  • the retaining device includes a biodegradable material.
  • the biodegradable material of the retaining device is a collagen.
  • the collagen is mineralized.
  • the collagen is recombinant human collagen.
  • the collagen is collagen type I or collagen type III.
  • the retaining device includes a lyophil or a granulate.
  • the retaining device is selected from at least one of: a fixateur interne, a rod, a wire, a screw, a hip implant, and a spinal cage.
  • the pump is located in at least one position relative to the subject selected from the group consisting of: external; in contact; and implanted.
  • the outlet port is an outlet valve.
  • the bone or cartilage defect is associated with a trauma or accident; or is associated with a surgical procedure.
  • the bone defect is associated with osteopenia, osteoporosis, or avascular necrosis.
  • the cartilage defect is associated with at least one condition selected from the group consisting of: disk degenerative disease (DDD) and arthritis.
  • DDD disk degenerative disease
  • Another aspect of the present invention herein provides a method for treating by sustained delivery a subject having a bone or a cartilage defect, the method involves: administering to a subject an amount of a composition, in which the composition is administered by at least one pump for sustained delivery and at a controlled flow rate, the pump including at least one outlet port and at least one reservoir, in which the outlet port of the pump is connected to a proximal end of a catheter and a distal end of the catheter is in contact with the bone or cartilage defect in the subject, in which the composition includes at least one of bone morphogenetic protein (BMP) and a vascular endothelial growth factor (VEGF); and observing that the defect is treated.
  • BMP bone morphogenetic protein
  • VEGF vascular endothelial growth factor
  • the method prior to administering, further includes implanting a retaining device at a location in contact with the bone or cartilage defect in the subject, so that the retaining device retards release of the at least one composition into the bone or cartilage defect.
  • the pump is at least one selected from the group consisting of an implantable pump, a percutaneous pump, an infusion pump, and an iontophoresis device.
  • the composition administered to the subject includes BMP and VEGF.
  • the at least one composition further includes a plurality of compositions, and the at least one pump includes a plurality of pumps.
  • the plurality of compositions includes a BMP, and a VEGF.
  • the BMP and the VEGF are administered to the subject sequentially.
  • the BMP and the VEGF are administered to the subject simultaneously.
  • the composition including BMP and VEGF is administered to the subject at a steady flow rate.
  • the composition including BMP and VEGF is administered to the subject at an intermittent flow rate.
  • administering the BMP and the VEGF is at least one protocol selected from the group of: administering BMP to the subject at a steady flow rate, and administering VEGF to the subject at a steady flow rate; administering BMP to the subject at a steady flow rate, administering VEGF to the subject at an intermittent flow rate; administering BMP to the subject at an intermittent flow rate, administering VEGF to the subject at a steady flow rate; and administering BMP to the subject at an intermittent flow rate, and administering VEGF to the subject at an intermittent flow rate.
  • the bone defect is associated with osteopenia, osteoporosis, or avascular necrosis, the method further including observing an increase in bone density, or a maintenance of bone density in the subject having a treated defect.
  • the bone or cartilage defect is associated with cancer, the method further including observing an increase in bone or cartilage density, or a maintenance of bone or cartilage density in the subject having a treated defect.
  • the cartilage defect is associated with at least one condition selected from the group consisting of disk degenerative disease (DDD) or arthritis, the method further including observing an increase in cartilage density.
  • DDD disk degenerative disease
  • the bone or cartilage defect is associated with trauma or accident, the method further comprising observing repair of the trauma site in the subject having a treated defect.
  • the bone or cartilage defect is associated with a surgical procedure, the method further including observing repair of the surgical site in the subject having a treated defect.
  • observing further includes imaging the defect with at least one procedure selected from the group consisting of: X-ray, magnetic resonance imaging (MRI), computed axial tomography (CAT) scan, positron emission tomography (PET) scan, and ultrasound.
  • MRI magnetic resonance imaging
  • CAT computed axial tomography
  • PET positron emission tomography
  • osteopenia refers to a decrease in bone mineral density (BMD), such that BMD is less than a mean normal amount, and is observed and quantitated prior to an extent that is characterized as osteoporosis.
  • BMD bone mineral density
  • BMD is a measurement of the amount or level of mineral content in the bones, primarily calcium, and the magnitude of the BMD indicates density and strength of the bones.
  • a BMD that is low compared to normal peak BMD is classified as osteopenia.
  • a T-score is a statitical parameter that is used to compare BMD of a subject who is a potential patient to that of a healthy thirty-year-old of the same sex and ethnicity.
  • a normal healthy subject usually has a T-score of -1.0 or greater.
  • osteopenia is diagnosed if a subject has a T-score of less than -1.0 and greater than -2.5, a BMD that is at least one to two standard deviations lower than that of the healthy counterpart.
  • Osteopenia is common in aging subjects because natural bone, undergoing osteoclast activity, is accordingly reabsorbed by the body faster than new bone is made by osteoblast activity, particularly in sedentary urban subjects.
  • osteoporosis refers to a disease of severe bone loss and increased risk of fracture. Characteristics of osteoporosis include reduced BMD, disrupted bone microarchitecture, and altered amount and variety of non-collagenous proteins in bone.
  • a T-score of -2.5 or lower is characterized as osteoporosis, i.e, a BMD that is two and a half standard deviations below the mean of a thirty year old man or woman.
  • Development of osteoporosis is associated with etological factors in both men and women such as hormonal disorders, e.g., decrease in production of estrogen in women and decrease in production of testosterone in men; chronic diseases such as cancer, eating disorders especially in teenage women and the elderly, and endocrine disorders; smoking; and use of medications such as glucocorticoids, barbiturates, and proton pump inhibitors.
  • the present invention in various embodiments provides systems and methods for sustained delivery at a controlled flow rate of a composition for treating a bone or cartilage defect in a subject.
  • the composition has osteo-inductive properties.
  • osteo-inductivity refers to ability of a substance or material to initiate regeneration of bone (osteogenesis) and stimulate regeneration of bone (osteo- stimulation), and thus promote bone growth.
  • the composition has osteo-conductive properties.
  • osteo-conductivity refers to ability of a substance to provide regenerating bone tissue with a structure creating matrix (guide structure) with sufficient mechanical stability. Bone generating cells bind to materials with osteo-conductive properties, and then generate by secretion a bone matrix around or within this material.
  • cartilage defects Similar considerations apply to cartilage defects and to remedies for cartilage defects.
  • the term, "chondro-inductivity” as used herein refers to ability of a substance or material to initiate regeneration of cartilage (chondrogenesis) and stimulate regeneration of cartilage (chondro-stimulation), and thus promote cartilage growth.
  • the term “chondro-conductivity” as used herein refers to ability of a substance to provide regenerating cartilage tissue with a structure creating matrix (guide structure) with sufficient mechanical stability. Cartilage generating cells bind to materials with chondro-conductive properties, and then generate by secretion a cartilage matrix around or within this material.
  • compositions that are suitable for the systems and methods herein include, for example, proteins or peptides such as cytokines, glycoproteins or glycopeptides.
  • exemplary compositions for the systems and methods herein include at least one member of the TGF (Transforming Growth Factor) family.
  • TGF family growth factors include, for example, various cytokines such as members of the TGF- ⁇ family, including the BMP family (Bone Morphogenetic Proteins), for example, BMP-2 and BMP-7.
  • the composition is a BMP that is granulated with for example polylactide (micro capsules).
  • BMP proteins constitute a superfamily, members of which have ability to stimulate bone cell differentiation, promote formation of bone and cartilage, and are involved in the process of healing bone and cartilage defects. Without being limited by any particular theory or mechanism of action, it is believed that BMPs interact with specific receptors on a cell surface, referred to as bone morphogenetic protein receptors (BMPRs), such that signal transduction through BMPRs results in mobilization of other proteins, cytokines, and growth factors to initiate formation of new bone and new cartilage.
  • BMPRs bone morphogenetic protein receptors
  • BMP-2 nucleic acid sequences, amino acid sequences, structure, and compositions of BMP-2, and methods of manufacture are shown in Wang et al. (U.S. patent number 5,631,142, issued May 20, 1997).
  • Purified BMP-2 and BMP-4 proteins and processes for producing them are shown in Wang et al. (U.S. patent application number 2007/0026437, published February 1, 2007).
  • Methods of production of recombinant BMP-2 are shown in Rainer et al. (U.S. patent application number 20040018595, published January 29, 2004).
  • Recombinant human BMP-2 is commercially available from Shenandoah Biotechnology, Inc. (Warwick, PA).
  • BMP-7 proteins Purified BMP-7 proteins and processes for producing them are shown in Wozney et al. (U.S. patent number 5,366,875, issued November 22, 1994). DNA sequences encoding BMP-7 proteins are shown in Rosen et al. (U.S. patent number 5,141,905, issued August 25, 1992). Recombinant human BMP-7 is commercially available from Shenandoah Biotechnology, Inc. (Warwick, PA).
  • compositions suitable for delivery by the systems and methods provided herein include VEGF (Vascular Endothelial Growth Factor), IGFl (Insulin Growth Factor 1), FGF (Fibroblast Growth Factor) and PDGF (Platelet Derived Growth Factor).
  • VEGF Vascular Endothelial Growth Factor
  • IGFl Insulin Growth Factor 1
  • FGF Fibroblast Growth Factor
  • PDGF Platinum Derived Growth Factor
  • VEGF is a signaling protein involved both in vasculogenesis (de novo formation of the embryonic circulatory system) and angiogenesis (growth of blood vessels from preexisting vasculature).
  • VEGF can stimulate other cell types and functions of these cells, for example, monocyte/macrophage migration, neurons, cancer cells, and kidney epithelial cells.
  • VEGF structure and function and processes of isolating VEGF compositions are shown in Cunningham et al. (U.S. patent number 7,090,834, issued August 15, 2006).
  • Recombinant human VEGF is commercially available from Sigma-Aldrich (Milwaukee, WI).
  • compositions that are suitable for the systems and methods provided herein are in various embodiments recombinantly produced or are isolated from natural sources.
  • recombinant refers to proteins produced by manipulation of genetically modified organisms, for example micro-organisms such as bacteria or yeasts; eukaryotic cells such as insect cells, in vivo or in cell culture; or mammalian cells in vivo in a transgenic animal, or in cell culture, such as hamster ovary cells.
  • compositions such as BMP-2, BMP-7, and VEGF are obtained by standard procedures in recombinant DNA vectors that direct expression of the protein composition in appropriate host cells.
  • a nucleotide sequence encoding the composition, or functional equivalent is inserted into an appropriate expression vector, i.e., a vector that contains the appropriate suitable nucleic acid encoding elements that regulate transcription and translation of the inserted coding sequence.
  • a variety of expression vectors/host systems can be utilized to contain and express the sequence encoding a composition such as BMP-2, BMP-7, and VEGF.
  • microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with virus expression vectors ⁇ e.g., baculovirus); plant cell systems transfected with virus expression vectors ⁇ e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or cells transformed with a bacterial expression vector (e.g., Ti, pBR322, or pET25b plasmid); or animal cell systems.
  • a bacterial expression vector e.g., Ti, pBR322, or pET25b plasmid
  • peptide synthesis can be performed using various solid-phase techniques (Roberge et al., Science 269:202, 1995) and automated synthesis may be achieved, for example, using the 43 IA peptide synthesizer (available from Applied Biosystems of Foster City, CA) in accordance with the instructions provided by the manufacturer.
  • a functional fragment of any of the above mentioned compositions is suitable for the systems and methods herein.
  • the term "functional fragment” refers to a macro- molecule such as a protein or nucleic acid having a structure and/or sequence modified in comparison to a naturally occurring related material particularly those used in compositions herein used in systems and methods herein, and that provides the same or substantially same biological functions as those compositions.
  • Functional fragments include proteins that contain naturally occurring or engineered alterations, including any one or more of a deletion, an addition, a substitution or other modification.
  • substantially identical refers to a first amino acid sequence that contains a sufficient or minimum number of amino acid residues that are identical to aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and/or common functional activity.
  • amino acid sequences that contain a common structural domain having at least about 60%, or 65% identity, preferably at least 75% identity, more preferably at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity are substantially identical. Calculations of sequence identity between sequences are performed as follows.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid sequence for optimal alignment).
  • the amino acid residues at corresponding amino acid positions or nucleotide positions are then compared.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • Percent identity between two amino acid sequences is determined using an alignment software program using the default parameters. Suitable programs include, for example, CLUSTAL W by Thompson et al., Nuc. Acids Research 22:4673, 1994 (www.ebi.ac.uk/clustalw), BL2SEQ by Tatusova and Madden, FEMS Microbiol. Lett. 174:247, 1999 (www.ncbi.nlm.nih.gov/blast/bl2seq/bl2.html), SAGA by Notredame and Higgins, Nuc.
  • the composition further includes one or more additional agents that provide a further desired biological or structural effect with respect to systems and methods herein for treating bone or cartilage defects.
  • additional agents include one or more of, for example, a gelling agent such as carboxymethylcellulose, an additional growth factor, an anti-microbial agent, a vitamin, a cytokine, and an anti-inflammatory agent.
  • compositions for use in systems and methods herein further include stem cells.
  • stem cell refers to an undifferentiated somatic cell that is capable either of division to give rise to daughter stem cells, or differentiation into a specialized cell type in the presence of the appropriate signals.
  • the stem cells are administered as a component in the composition as undifferentiated cells.
  • the stem cells are grown in cell culture and transformed into specialized cells, such as osteoblasts, chondrocytes, or cells of hematopoietic origin, and then the specialized stem cells are administered as a component in the composition.
  • the system includes at least one pump for sustained delivery at a controlled flow rate of a composition for treating a bone or cartilage defect.
  • Pumps that are implantable or are external are suitable for delivery of the compositions.
  • the pump is in contact with the subject, i.e., affixed to a convenient location.
  • the pump is attached to a convenient location adjacent to the subject such as a bed, an IV stand, or a table.
  • Exemplary pumps for delivery to the subject include a peristaltic pump, a fluorocarbon propellant pump, and an osmotic pump including a mini-osmotic pump (Blanchard, S., 1996 Biomedical Engineering Applications, North Carolina State University).
  • Peristaltic pumps deliver a set amount of drug with each electric pulse that drives the pump head.
  • the pump, electronics and power source are located for example in a titanium housing covered in Silastic.
  • Exemplary drug reservoirs are silicone rubber pouches that withstand substantial pressure, for example, 60 psi. The reservoir is refilled percutaneously through a polypropylene port.
  • Suitable exemplary pumps further include fluorocarbon pumps that operate with a fluorocarbon liquid to drive the pump.
  • Osmotic pumps use osmotic pressure to release the compositions used herein at a steady rate.
  • An exemplary osmotic pump is the MiniMed MicroMed 407C pump (Medtronic, Inc., Northridge, Calif.).
  • a further suitable pump is an intrathecal drug delivery system (Medtronic) that includes two implantable components, an infusion pump, and an intraspinal catheter. The pump is inserted abdominally into a subcutaneous pocket, and the catheter is inserted into the intrathecal space of the spine, tunneled under the skin, and connected to the pump. Medication is delivered at a steady or intermittent flow rate.
  • Yet another suitable pump is an intraperitoneal pump, for instance an implantable pump, to deliver the compositions used herein locally, via a catheter.
  • sustained delivery refers to a protocol that is steady or is intermittent, such as cyclical, for delivery of a suitable composition for treating a bone or cartilage defect, to supply an amount of at least one composition herein to a recipient subject or patient as a function of time.
  • exemplary protocols include a period of time during which delivery is controlled and sustained for example, minutes, hours, days, weeks, and months.
  • Delivery of the suitable compositions is, in various embodiments of the systems and methods herein, steady during the entire period of use, intermittent, for example cyclical, over the period of delivery; triggered in response to a change in the environment or to an external event; or independent of variation in controls.
  • the at least one pump functions to control the flow rate at which the suitable composition is administered.
  • an outlet valve on the pump in certain embodiments further controls the flow rate at which the composition is administered.
  • the pump in various embodiments of the system and method is programmed to deliver the composition at a steady flow rate as a function of time.
  • steady refers to a flow rate that remains substantially unchanged as a function of time.
  • the period of time of steady delivery is for example, minutes, hours, days, weeks, or even months or years.
  • the pump in various embodiments of the system and method is programmed to deliver a suitable composition at an intermittent flow rate.
  • intermittent refers to a controllable flow rate in which the amount of composition delivered to the bone and/or cartilage defect as a function of time is regulated such as being alternated between two or more rates.
  • systems and methods deliver the suitable compositions at a flow rate gradient.
  • the gradient is for example, initiated at a high flow rate to the bone and/or cartilage defect, and the flow rate is reduced at a later time or stepped down at a later time.
  • the gradient is initiated at a low flow rate and the flow rate of the composition at a later time is increased or is stepped up.
  • the period of time over which delivery can be intermittent is for example, seconds, minutes, hours, days, weeks, or even months.
  • Intermittent delivery includes intervals of no administration, i.e., alternating periods of delivery and stoppage.
  • the periods can be regular, i.e., repeated units of delivery and stoppage of the same or different lengths of time, respectively, or dissimilar, i.e., programmed to a particular protocol.
  • the pump is programmed to deliver an initial high dose or "burst" of the composition.
  • the pump is programmed to deliver intermittent high and low or intermittent delivery and stoppage (no dose) as a function of time, or to shut off delivery entirely from at least one reservoir for at least an intermittent period.
  • the system has a single pump with a single reservoir. In related embodiments, the system includes a single pump with a plurality of reservoirs. In an alternative embodiment, the system includes a plurality of pumps, each pump having a single reservoir. In related embodiments, the system includes a plurality of pumps, each pump having a plurality of reservoirs.
  • the pump of the system herein includes an outlet port which is connected the proximal end of a catheter, the terms proximal and distal referring to proximity and distance, respectively, from the pump.
  • catheter refers to a tube that is inserted into a body cavity, duct, or vessel.
  • a distal end of the catheter contacts a retaining device and delivers the composition from the pump to the retaining device which is described herein.
  • One of ordinary skill in the art of medical devices readily determines the appropriate size, i.e., internal and external diameter, of the catheter to be used with the systems herein based on the extent of the bone or cartilage defect to be treated, the nature of the subject such as size, age and health condition, the rate of flow required for optimal performance, and the desired amount of composition to be delivered to the bone or cartilage defect.
  • Catheters are commercial available from, for example, Boston Scientific (Natick, MA), and these catheters are available in a variety of types, for example, having one end with a rounded tip or for example a square tip.
  • the distal end of the catheter is manufactured to include or to consist of a biodegradable material.
  • biodegradable materials are polygalacturonic acid (PGA), polymethylmethacrylate (PMMA), polylactate (PLA), and a magnesium alloy.
  • PGA polygalacturonic acid
  • PMMA polymethylmethacrylate
  • PLA polylactate
  • a biodegradable distal end of the catheter of the systems herein provides that as the bone or cartilage defect is treated, growth of new bone or cartilage at or around the distal end of the catheter is hot disrupted and the catheter remains in place and is not removed from the newly grown bone or cartilage. Instead, the distal end of the catheter is resorbed into the newly grown bone or cartilage.
  • the system of the present invention includes a retaining device implanted in the subject in contact with the bone or cartilage defect.
  • the distal end of the catheter contacts the retaining device and the retaining device retards release of the composition into the defect.
  • the retaining device functions to retard the release of the administered compositions, i.e., functions to maintain the composition for controlled release into the defect that is adjacent to the retaining device, rather than uncontrolled dispersion of the composition into general systemic circulation.
  • the retaining device in certain embodiments is formulated to contain at least one retarding release component, for example a "sticky" protein capable of substantial non-specific binding, such as a protamine or a plasma protein such as globulin, an albumin, and a fibrin.
  • An exemplary retarding component is a protamine, a member of a class of small arginine-rich alkaline nuclear proteins, having a molecular weight of about 5000 daltons. Protamines are commonly extracted from sperm of fish or other vertebrates.
  • the retaining device in various embodiments is a commercially available component such as a fixateur interne, a rod, a wire, a screw, a hip implant, or a spinal cage.
  • a fixateur interne is a posterior place spinal fixation device used for internal fixation of the thoracolumbar spine, internal fixation of impacted fractures, and transpedicular stabilization of the dorsal column.
  • the device is a sinkable implant having a long rod and Schanz fixed screws, and operates similar to long rod instrumentations using a two-point fixation system in which there is no flexibility between the longitudinal support rod and the shortened and transpedicularly Schanz fixed screws.
  • Fixateur internes are commercially available from, for example, Synthes, Inc. (West Chester, PA).
  • a spinal cage is a titanium cylinder that is surgically implanted into the diskspace, i.e., the tough elastic structure that is between the bodies of spinal vertebrae.
  • Spinal cages are porous and allow a bone graft or cartilage graft to grow from the vertebral body through the cage and into the next vertebral body.
  • a spinal cage provides fixation, so subjects do not need additional instrumentation (e.g. pedicle screws) or post-operative back braces for support.
  • Spinal cages are commercially available from, for example, Lindare Medical (Kent, United Kingdom).
  • the retaining device in general embodiments includes a collagen.
  • the collagen is of animal origin, for example bovine, porcine or equine collagen, and the animal origin of the collagen is not limiting.
  • the collagen of the retaining device is of human origin, for example the collagen is type I or type III collagen.
  • the collagen in various embodiments is a recombinantly produced collagen, for example, recombinantly produced human collagen such as human recombinant collagen type I.
  • Collagen of animal origin is commercially available in isolated form, e.g., COLLOSS ® (bovine) and COLLOSS ® E (equine) from Ossacur (Oberstenfeld, Germany). These products contain natural active substances, so that the combination of the collagen as a component of the retaining device and the compositions described above provide a natural, functional unit, the combination corresponding in a particular manner to an in vivo milieu, in which bone and/or cartilage regeneration is induced.
  • COLLOSS ® bovine
  • COLLOSS ® E equine
  • Methods of extracting collagen from natural bone are well known in the art, for example, extracted from natural bone by the following exemplary procedure: pulverizing natural bone; degreasing by extraction with an organic solvent; demineralizing with acid treatment, for example hydrochloric acid; incubating with chelating agents, for example ethylenediamine tetraacetic acid (EDTA) or 2-amino-2-hydroxymethyl-l,3-propanediol (TRIS) or a combination thereof; and extracting with guanidine, for example guanidine hydrochloride; followed by purifying the extract; and physically forming the extract into a configuration suitable for implanting.
  • chelating agents for example ethylenediamine tetraacetic acid (EDTA) or 2-amino-2-hydroxymethyl-l,3-propanediol (TRIS) or a combination thereof
  • guanidine for example guanidine hydrochloride
  • the collagen is in a porous configuration or form.
  • the collagen has a substantially spongy consistency
  • the retaining device includes a collagen sponge, having pores of a range of sizes.
  • a porous retaining device is advantageous for cell infiltration from cells of the subject recipient of the implanted retaining device into the pores of the retaining device, for example bone and/or cartilage cells, or progenitor cells thereof.
  • Pores of the collagen have diameters of at least about 100 ⁇ m, for example, diameters of about 100 ⁇ m to about 300 ⁇ m.
  • the retaining device is bioresorbable or at least partly bioresorbable.
  • the retaining device is entirely bioresorbable, and at a time following implantation, the retaining device is gradually and eventually replaced by newly formed bone and/or newly formed cartilage.
  • the collagen prior to formulation of the retaining device, is treated with at least one peptidase, for example an endopeptidase such as trypsin. Treating with an endopeptidase removes undesired proteins and peptides, for example telopeptides that are naturally found in the collagen, from the collagen fraction.
  • an endopeptidase such as trypsin is provided in an amount such that it is depleted or exhausted and does not exhibit further activity against the osteo-conductive activity of the collagen fraction.
  • the retaining device containing a collagen prepared by a method that does not include an endopeptidase treatment.
  • the systems herein are produced by methods that includes procedures to yield a product that is aseptic or sterile. Any of a variety of sterilization methods is used to obtain the system in aseptic or sterile form.
  • each individual biologic component is sterilized as a solution, for example, by filtration to remove bacteria and viruses for example using filters having a pore size of 0.5 ⁇ m or 0.2 ⁇ m.
  • Mechanical components are sterilized for example by irradiation.
  • the system is packaged in a sterile manner, to provide an aseptic system or a sterile product.
  • the retaining device is formulated as a lyophil, for example a co-lyophil.
  • Co-lyophilization of a mixture of the various protein components in the production of the retaining device results in a material that needs no mixing prior to use, i.e., the retaining device contains all the components that are assembled during manufacture. It is desirable to provide a ready-to-use retaining device that is convenient for use by a surgeon, so that the surgical procedure is not interrupted by having to formulate the device, and so that variations in dosage are not introduced during the surgical procedure.
  • the retaining device provided herein is produced in a sterile manner, and is removed directly from a sterile package and implanted during a surgical procedure in a bone or cartilage defect.
  • Another aspect herein provides a method for treating by sustained delivery a subject having a bone or a cartilage defect, the method involving: administering to a subject an amount of a composition, so that the composition is administered by at least one pump for sustained delivery and at a controlled flow rate, the pump having at least one outlet port and at least one reservoir, in which the outlet port of the pump is connected to a proximal end of a catheter, and a distal end of the catheter is in contact with the bone or cartilage defect in the subject, and in which the composition includes at least one of bone morphogenetic protein (BMP) and a vascular endothelial growth factor (VEGF); and observing that the defect is treated.
  • BMP bone morphogenetic protein
  • VEGF vascular endothelial growth factor
  • the method can further include implanting a retaining device at a location in the subject in contact with the bone or cartilage defect, so that the retaining device retards release of the at least one composition into the bone or cartilage defect.
  • Retaining devices described herein are optional, as the scope of the methods provided herein includes use of the pumps without the retaining device.
  • the method includes using a single pump with a single reservoir.
  • the method involves administering to the subject a composition including BMP, VEGF, or a mixture thereof.
  • the composition including the BMP, the VEGF, or mixture thereof can be administered to the subject at a steady flow rate, as described above.
  • the composition including BMP, VEGF, or mixture thereof can be administered to the subject at an intermittent flow rate, as described above.
  • compositions as described herein are administered to the subject simultaneously, for example, as a single composition.
  • compositions are administered consecutively, i.e., sequentially, at an interval for example of greater than one hour, greater than one day, greater than two or more days, greater than one week.
  • the exemplary compositions having BMP and VEGF are administered to the subject according to any of the following exemplary protocols: administering BMP to the subject at a steady flow rate, and administering VEGF to the subject at a steady flow rate; administering BMP to the subject at a steady flow rate, administering VEGF to the subject at an intermittent flow rate; administering BMP to the subject at an intermittent flow rate, administering VEGF to the subject at a steady flow rate; and administering BMP to the subject at an intermittent flow rate, and administering VEGF to the subject at an intermittent flow rate.
  • An embodiment of the method herein includes observing that the defect is treated.
  • the phrase "observing that the defect is treated” refers to observing an effect that is a change in a bone or cartilage defect such as a reducing, an eliminating, an ameliorating, or a reversing of a bone or cartilage defect, or a reversing of a pathological bone loss or a cartilage loss or some other change in a condition, for example, observing a stabilizing or a maintaining of the current level of bone or cartilage in a subject in which further loss would have been expected absent treatment.
  • Observing that the defect is treated is accomplished by imaging a course of the defect with at least one procedure such as X-ray, magnetic resonance imaging (MRI), computed axial tomography (CAT) scan, positron emission tomography (PET) scan, and ultrasound.
  • MRI magnetic resonance imaging
  • CAT computed axial tomography
  • PET positron emission tomography
  • ultrasound ultrasound
  • observing that the defect is treated is observing an increase in bone or cartilage density, or observing a maintenance of bone or cartilage density in the subject which is a reversal of a prior history of loss of density. In other embodiments, observing that the defect is treated is observing repair of the bone or cartilage defect at the trauma site in the subject.
  • observing that the defect is treated is observing reduction in deterioration in BMD. In another embodiment, observing that the defect is treated is observing elimination or amelioration in deterioration in BMD. In another embodiment, observing that the defect is treated is observing reversal in reduction in BMD, i.e., growth of new bone.
  • an embodiment of the method includes observing that the defect is treated by observing a reduction in deterioration or rate of deterioration of cartilage. For example, observing that the defect is treated is observing elimination or amelioration in deterioration of cartilage. For example, observing that the defect is treated is observing reversal in reduction in cartilage, i.e., growth of new cartilage.
  • Example 1 Dog ulna model for protocol with retaining device
  • Dog ulna defect has been used as a well-established model to evaluate healing of bone defects and evaluate efficacy of osteogenic agents in mammals.
  • the lower long joint of a hind leg of a dog includes two bones, an ulna and a radius.
  • Dog ulna is a bone tissue that is easily accessible, and is not essential for weight bearing, because the radius contributes stability to the joint. Further, each of the right and left hind leg can be used, one for a test defect, and the other for a control defect
  • Dogs are anesthetized using procedures well known in the art. A 2.5 cm section from the ulna bone of each of the left hind leg and the right hind leg of each dog is then removed.
  • a 2.5 cm segmental defect is removed because it has been shown to be a critical-sized defect that does not spontaneously heal.
  • a retaining device including collagen is implanted at the site of the test bone defect, the defect in the left hind leg of the dogs.
  • a distal end of a catheter is connected to the retaining device, and a proximal end of the catheter is connected to a pump having two reservoirs.
  • a sterile sponge To the defect in the right hind leg of the dogs is implanted a sterile sponge, the control bone defect.
  • a distal end of a catheter is connected to the sponge and a proximal end of the catheter is connected to a pump.
  • Each test bone defect of the dogs is administered a protocol for treatment with BMP-2 and VEGF or BMP-7 and VEGF, respectively, as shown in Examples 2-5 below.
  • the control bone defect in each of the dogs is administered bovine serum albumin.
  • Radiographic views with standard settings in radiograms are used to evaluate healing of each of the test and control defect. X-rays are taken at standard intervals to evaluate the healing process, and bone union and new bone formation are estimated from each radiograph. It is found that radiographic results show significantly greater amounts of new bone growth at the sites of the test defects administered a combination of BMP-2 and VEGF or BMP-7 and VEGF respectively, compared to the sites of the control defects.
  • Example 2 BMP-2 and VEGF administered simultaneously
  • BMP-2 and VEGF are administered simultaneously to the test defect of a dog at a steady flow rate using the system and method herein for a period of six months.
  • the control defect is administered solely bovine serum albumin for the same six month period.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-2 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 3 BMP-2 and VEGF administered sequentially
  • test defect of another dog is treated according to the following cyclic protocol:
  • This protocol is administered six times, i.e., for a total of six months of administering, using the system and method herein.
  • the control defect is administered solely bovine serum albumin for a six month period at a steady flow rate.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-2 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 4 BMP-7 and VEGF administered simultaneously
  • BMP-7 and VEGF are administered simultaneously to the test defect of a dog at a steady flow rate using the system and method herein for a period of six months.
  • the control defect is administered solely bovine serum albumin for the same six month period.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-7 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 5 BMP-7 and VEGF administered sequentially
  • test defect of another dog is treated according to the following cyclic protocol:
  • This protocol is administered six times, i.e., for a total of six months of administering, using the system and method herein.
  • the control defect is administered solely bovine serum albumin for a six month period at a steady flow rate.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-7 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 6 dog ulna model for protocol without retaining device
  • a catheter is implanted such that the distal end of the catheter is positioned adjacent to the site of the test bone defect, the defect in the left hind leg of each of the dogs.
  • a proximal end of the catheter is connected to a pump having two reservoirs.
  • Each of the dogs is administered a different protocol of BMP-2 and VEGF or BMP-7 and VEGF, respectively, as shown in examples 7-10 below.
  • a catheter is implanted such that the distal end of the catheter is positioned adjacent to the site of the control bone defect, the defect in the right hind leg of each of each of the dogs.
  • a proximal end of the catheter is connected to a pump having two reservoirs.
  • bovine serum albumin To the control defect is administered bovine serum albumin.
  • Lateral radiographic views with standard settings in radiograms are used to evaluate healing of each of the test and control defect. X-rays are taken at standard intervals to evaluate the healing process, and bone union and new bone formation are estimated from each radiograph.
  • radiographic results show significantly greater amounts of new bone growth at the sites of the test defects administered a combination of BMP-2 and VEGF or BMP-7 and VEGF respectively, compared to the sites of the control defects.
  • Example 7 BMP-2 and VEGF administered simultaneously
  • BMP-2 and VEGF are administered simultaneously to the test defect of a dog at a steady flow rate using the system and method herein for a period of six months.
  • the control defect is administered solely bovine serum albumin for the same six month period.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-2 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 8 BMP-2 and VEGF administered sequentially The test defect of another dog is treated according to the following cyclic protocol:
  • This protocol is administered six times, i.e., for a total of six months of administering, using the system and method herein.
  • the control defect is administered solely bovine serum albumin for a six month period at a steady flow rate.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-2 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 9 BMP-7 and VEGF administered simultaneously
  • BMP-7 and VEGF are administered simultaneously to the test defect of a dog at a steady flow rate using the system and method herein for a period of six months.
  • the control defect is administered solely bovine serum albumin for the same six month period.
  • test defect shows significantly more rapid growth of new bone compared to the control defect.
  • site of the test defect administered BMP-7 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.
  • Example 10 BMP-7 and VEGF administered sequentially
  • test defect of another dog is treated according to the following cyclic protocol:
  • This protocol is administered six times, i.e., for a total of six months of administering, using the system and method herein.
  • the control defect is administered solely bovine serum albumin for a six month period at a steady flow rate.
  • X-rays are taken of each of the test and control defect at weekly intervals to evaluate the healing process, and bone union and new bone formation are estimated from each radiograph.
  • the test defect shows significantly more rapid growth of new bone compared to the control defect.
  • the site of the test defect administered BMP-7 and VEGF simultaneously is observed to be treated, i.e., new bone and repair of the defect site is observed, compared to the control defect that shows minimal growth of new bone.

Landscapes

  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention porte sur un système et sur des procédés pour traiter des défauts de l'os et/ou du cartilage.
PCT/IB2008/002826 2007-10-24 2008-10-17 Système pour traiter des défauts de l'os et/ou du cartilage et procédés d'utilisation de celui-ci WO2009053820A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2008315663A AU2008315663A1 (en) 2007-10-24 2008-10-17 System for treating bone and/or cartilage defects and methods of use therefor
CA2703340A CA2703340A1 (fr) 2007-10-24 2008-10-17 Systeme pour traiter des defauts de l'os et/ou du cartilage et procedes d'utilisation de celui-ci
IL205250A IL205250A0 (en) 2007-10-24 2010-04-22 System for treating bone and/or cartilage defects and methods of use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21407P 2007-10-24 2007-10-24
US61/000,214 2007-10-24

Publications (2)

Publication Number Publication Date
WO2009053820A1 true WO2009053820A1 (fr) 2009-04-30
WO2009053820A4 WO2009053820A4 (fr) 2009-07-02

Family

ID=40433599

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/002826 WO2009053820A1 (fr) 2007-10-24 2008-10-17 Système pour traiter des défauts de l'os et/ou du cartilage et procédés d'utilisation de celui-ci

Country Status (4)

Country Link
AU (1) AU2008315663A1 (fr)
CA (1) CA2703340A1 (fr)
IL (1) IL205250A0 (fr)
WO (1) WO2009053820A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8734459B1 (en) 2013-01-17 2014-05-27 Abdulrazzaq Alobaid Device and method to prevent extravasation of bone cement used in balloon kyphoplasty

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4619989A (en) * 1981-05-05 1986-10-28 The Regents Of The University Of Cal. Bone morphogenetic protein composition
US5122114A (en) * 1991-02-01 1992-06-16 Board Of Regents, University Of Texas System Method of using intramedullary catheter
US6387098B1 (en) * 1999-10-21 2002-05-14 Peter Alexander Cole Intramedullary catheter nail apparatus and method
US20020146398A1 (en) * 2001-04-05 2002-10-10 Razi Vago Tissue growth stimulating system
WO2006112941A2 (fr) * 2005-02-16 2006-10-26 Cytori Therapeutics, Inc. Dispositifs creux resorbables destines a etre implantes et a administrer des agents therapeutiques
US20070179609A1 (en) * 2006-01-27 2007-08-02 Medicinelodge, Inc. Therapeutic agent eluding implant with percutaneous supply

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4619989A (en) * 1981-05-05 1986-10-28 The Regents Of The University Of Cal. Bone morphogenetic protein composition
US5122114A (en) * 1991-02-01 1992-06-16 Board Of Regents, University Of Texas System Method of using intramedullary catheter
US6387098B1 (en) * 1999-10-21 2002-05-14 Peter Alexander Cole Intramedullary catheter nail apparatus and method
US20020146398A1 (en) * 2001-04-05 2002-10-10 Razi Vago Tissue growth stimulating system
WO2006112941A2 (fr) * 2005-02-16 2006-10-26 Cytori Therapeutics, Inc. Dispositifs creux resorbables destines a etre implantes et a administrer des agents therapeutiques
US20070179609A1 (en) * 2006-01-27 2007-08-02 Medicinelodge, Inc. Therapeutic agent eluding implant with percutaneous supply

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8734459B1 (en) 2013-01-17 2014-05-27 Abdulrazzaq Alobaid Device and method to prevent extravasation of bone cement used in balloon kyphoplasty

Also Published As

Publication number Publication date
CA2703340A1 (fr) 2009-04-30
IL205250A0 (en) 2010-12-30
WO2009053820A4 (fr) 2009-07-02
AU2008315663A1 (en) 2009-04-30

Similar Documents

Publication Publication Date Title
Malhotra et al. Role of autologous platelet-rich plasma in treatment of long-bone nonunions: a prospective study
Duarte et al. Biomaterials and bioactive agents in spinal fusion
US8114428B2 (en) Methods for manufacturing a composition for treating bone and/or cartilage defects
US20080051800A1 (en) Method and device for reducing susceptibility to fractures in vertebral bodies
EP2129318A2 (fr) Compositions de vecteur fluide et procédés d'utilisation
AU2020204496B2 (en) Compositions and methods to promote bone formation
JP2004503596A (ja) トロンビンペプチド誘導体による骨成長の刺激
TW200307559A (en) Injectable solid hyaluronic acid carriers for delivery of osteogenic proteins
KR20200075850A (ko) 자가 골 이식편 대체재
Kimura et al. Gelatin hydrogel as a carrier of recombinant human fibroblast growth factor-2 during rat mandibular distraction
Cunningham et al. Osseointegration of autograft versus osteogenic protein–1 in posterolateral spinal arthrodesis: emphasis on the comparative mechanisms of bone induction
WO2009053820A1 (fr) Système pour traiter des défauts de l'os et/ou du cartilage et procédés d'utilisation de celui-ci
Muñoz et al. Non-setting, injectable biomaterials containing particulate hydroxyapatite can increase primary stability of bone screws in cancellous bone
Högel et al. Bone healing of critical size defects of the rat femur after the application of bone marrow aspirate and two different rh-BMP7 concentrations
AU2008247320B2 (en) A method for treating inflammation and controlled-release material capable of providing same
Tsuzuki et al. Effect of biodegradable gelatin β-tri calcium phosphate sponges containing mesenchymal stem cells and bone morphogenetic protein-2 on equine bone defect
Gantenbein et al. The Bone Morphogenetic Protein 2 Analogue L51P Enhances Spinal Fusion in Combination with BMP2 in an In Vivo Rat Tail Model
AU2022361469A1 (en) mRNA INDUCED EXPRESSION OF BONE MORPHOGENIC PROTEIN AND RECEPTOR AND METHODS RELATED THERETO
US20210169977A1 (en) Compositions of Transforming Growth Factor-Beta Type III Receptor and Uses for Ossification
Kavaseri Cell Therapy and Mechanical Stimulation to Enhance Bone Defect Healing
Mardirosian Effects of Bone Morphogenetic Protein (rhBMP-2) and Platelet Derived Growth Factor (rhPDGF-BB) on Ectopic Bone Formation In Rats
Lawtrakulngam et al. Micro-computed Tomography Analysis of Bone Regeneration Using mRNA Encoding Bone Morphogenetic Protein-2 with Implant Placement in Rat Femur
Lullo Source and Carrier Effect on the Bioactivity of BMP Bio-implants
Koh et al. Research Article BMP6-Engineered MSCs Induce Vertebral Bone Repair in a Pig Model: A Pilot Study
Lee A Pilot Study to Compare the Activity of Different Bone Morphogenetic Protein Bioimplants In Vivo

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08841968

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2008315663

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2597/DELNP/2010

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 205250

Country of ref document: IL

Ref document number: 2703340

Country of ref document: CA

Ref document number: 2010530579

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2008315663

Country of ref document: AU

Date of ref document: 20081017

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2008841968

Country of ref document: EP