WO2014032099A1 - Composition et procédé pour la croissance osseuse - Google Patents

Composition et procédé pour la croissance osseuse Download PDF

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WO2014032099A1
WO2014032099A1 PCT/AU2013/000963 AU2013000963W WO2014032099A1 WO 2014032099 A1 WO2014032099 A1 WO 2014032099A1 AU 2013000963 W AU2013000963 W AU 2013000963W WO 2014032099 A1 WO2014032099 A1 WO 2014032099A1
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Prior art keywords
bone
composition according
agent
saib
rhbmp
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PCT/AU2013/000963
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English (en)
Inventor
David Graham Little
Aaron James SCHINDELER
Tegan Laura CHENG
Nicole Y C YU
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The Sydney Children's Hospitals Network (Randwick And Westmead) (Incorporating The Royal Alexandra Hospital For Children)
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Priority claimed from AU2012903734A external-priority patent/AU2012903734A0/en
Application filed by The Sydney Children's Hospitals Network (Randwick And Westmead) (Incorporating The Royal Alexandra Hospital For Children) filed Critical The Sydney Children's Hospitals Network (Randwick And Westmead) (Incorporating The Royal Alexandra Hospital For Children)
Publication of WO2014032099A1 publication Critical patent/WO2014032099A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the classical model for bone tissue engineering involves four components contributing to the success of a bone repair strategy: an osteoinductive substance, cells able to make bone, a scaffold to define the new bone microenvironment, and the mechanical environment.
  • the mechanical environment in tissue engineering situations is often unfavourable due to a lack of loading leading to premature or excessive resorption. An optimal tissue engineering intervention would take into consideration all of these factors.
  • the present invention generally relates to synergistic combinations of agents in compositions for promoting bone growth and their uses.
  • composition for promoting bone growth comprising:
  • composition for promoting bone growth comprising:
  • the carrier has phase-transitioning properties and functions as an injectable delivery system for the other agents in the composition.
  • a preferred carrier is sucrose acetate isobutyrate (SAIB).
  • Other alternative injectable delivery systems include high viscosity liquid earner materials (HVLCMs) including other sugar based esters, stearate esters (such as those of propylene glycol, glyceryl, diethyalaminoethyl, and glycol, stearate amide, and other long-chain fatty acid amides, such as ⁇ , ⁇ '-ethyene distearamide, stearamide MEA and dEA, ethylene bistearamide, cocoamine oxide, long-chain fatty alcohols such as cetyl alcohol and stearyl alcohol, long-chain esters such as myristyl myristate, beheny erucate, and glyceryl phosphates.
  • HVLCMs high viscosity liquid earner materials
  • the carrier is a biodegradable substance having phase transitioning properties, such that it is capable of injectable delivery but forms a solid or semi-solid mass after deposition or introduction to a physiological environment. This allows for both surgical and non-surgical delivery but minimizes irregular shaped bone formation, optimizes release kinetics, and minimizes risk of the agents entering the bloodstream and acting systemically.
  • the carrier is SAIB, a non-polymeric highly viscous carrier material, which can be diluted in a suitable solvent to form a liquid suitable for administration, e.g., by injection. Preferably, when in situ the solvent dissipates away leaving the viscous carrier.
  • caprolactam aromatic amides such as N,N-dimethyl-m-toluamide, and 1- dodecylazacycloheptan-2-o-ne; and the like; and mixtures and combinations thereof.
  • Preferred solvents include ethanol, tetraglycol (glycofurol), benzyl alcohol, dimethyl sulfoxide, ethyl lactate, ethyl acetate, triacetin, N-methylpyrrolidone, propylene carbonate, glycerol formal and Solketal (isopropylideneglycerol).
  • the osteoinductive agent is an osteogenic protein.
  • the osteogenic protein is a bone morphogenetic protein (BMP), preferably recombinant human form selected from rhBMP-1 , rhBMP-2, rhBMP-3, rhBMP-4, rhBMP-5, rhBMP-6, rhBMP-7, rhBMP-8a, rhBMP-8b, rhBMP-9, rhBMP-10, and rhBMP- 5. More preferably the BMP is rhBMP-2 or rhBMP-7, which have been approved for human use.
  • BMP bone morphogenetic protein
  • the osteogenic protein is rhBMP-2.
  • suitable osteogenic proteins include rhBMP-7 (OP-1) currently approved for clinical use.
  • rhBMP-4, and other osteoinductive BMPs such as rhBMP-6, rhBMP-7, rhBMP- 9 are suitable for the present invention.
  • agents known to be associated with bone and affect the delivery and presentation of growth factors to cells are included or added.
  • agents include heparin sulphate and other glycosaminoglycans and their components, as well as specific binding proteins such as TGF- ⁇ binding protein.
  • the carrier may be seeded with bone forming cells such as progenitor cells, stem cells, whether derived from marrow, adipose or other tissue, and/or osteoblasts, preferably from the patient but alternatively a cell line or from a suitable donor.
  • bone forming cells such as progenitor cells, stem cells, whether derived from marrow, adipose or other tissue, and/or osteoblasts, preferably from the patient but alternatively a cell line or from a suitable donor.
  • rhBMP-2 or rhBMP-7 used as an osteoinductive agent in a preferred embodiment the amount used will be from about 0.1 to 20 mg, preferably about 1.0 to 12 mg in a formulation. In another embodiment for larger defects doses of up to about 40 mg per dose may be used. It will be appreciated that a suitable dose can be determined for a particular clinical situation.
  • osteoconductive agent is hydroxyapatite.
  • osteoinductive agent e.g., BMP
  • anti-resorptive agent e.g., a bisphosphonate
  • the osteoinductive agent e.g., BMP
  • the osteoconductive agent e.g., a bisphosphonate
  • the anti-resorptive agent e.g., a bisphosphonate
  • there is a synergistic interaction between the osteoinductive agent, the osteoconductive agent and the anti-resorptive agent when delivered via the sugar based high viscosity carrier which provides enhanced bone growth promotion at the site of administration of the composition.
  • the injectable composition includes:
  • a method for promoting bone growth comprising providing a composition according to the first, second or third aspects of the present invention to a site of a subject to promote bone growth at that site.
  • osteoinductive agent in the manufacture of a medicament for promoting bone growth.
  • the subject may be a mammalian subject, including an animal or a human. In preferred embodiments the subject is a human.
  • the compositions and methods of the present invention have pharmaceutical and veterinary applications.
  • compositions and methods of the present invention may be used in conjunction with other therapies.
  • the site of administration can be a bone fracture, bone graft, bone wound, bone defect, bone non-union or pseudarthrosis, the spine via a posterior or anterior approach, surface of a bone implant, or injected within a bone implant, porous scaffold, cage, balloon, membrane, or other containment device.
  • composition may be provided to a site by any suitable means such as injection, topical application, bandage, scaffold, or implantation within a containment device or apparatus.
  • suitable means such as injection, topical application, bandage, scaffold, or implantation within a containment device or apparatus.
  • the composition is provided to the site by injection.
  • composition maybe used for bone tissue engineering, fracture healing
  • a particular advantage of the present invention is the combination of agents which act synergistically to produce a large amount of new bone at even low doses of bone promoting agents (such as rhBMP-2). Reduction of the overall dose of bone promoting agents allows for reduction of risks associated rhBMP adverse events.
  • a second advantage of the present invention is the phase-transitioning property of the carrier such as SAIB/Solvent, which allows for injectable delivery to minimize infection risk and reduce the requirement for costly surgery.
  • Figure 2 shows results of effects of various agents on rhBMP-2 induced bone formation in a mouse model via injected SAIB.
  • Figure 3 shows results of Increasing doses of rhBMP-2 delivered in the SAIB construct into the quadriceps of the mouse. Quantified bone volume formation in the ectopic nodule model of the mouse. Error bars represent SD; *, p ⁇ 0.05.
  • Figure 7 shows results of mouse derived MC3T3 cell viability in the presence of ZA and/or HA. At two time points, 2% HA has a protective effect against 50 ⁇ ZA on cell proliferation. #, p ⁇ 0.05 compared to day 4 control; *, p ⁇ 0.05 compared to day 7 control.
  • Figure 8 shows results of SAIB was used to deliver rhBMP-2, as well as 2% HA and fluorescently tagged arid radiolabeled bisphosphonate to the muscle pouch of the mouse.
  • a magnetic stirrer, 60 mM acetic anhydride and 240 mM isobutyric anhydride were added to a dry round-bottom flask fitted to a reflux condenser.
  • An SAIB:Ethanol (85:15) stock solution was prepared and allowed to mix overnight. Prior to surgery, rhBMP-2 and any other agents were mixed into the stock solution of SAIB. Animals receiving an injection were pre-dosed with buprenorphine at least 30 minutes prior to surgery, where they were anesthetized using Isofluorane gas. Using a 0.5 ml insulin syringe, 20 ⁇ of the SAIB mixture was injected into the quadriceps of the mouse.
  • Collagen pellets were prepared from collagen sponges provided in rhBMP-2
  • INFUSETM kits using a 3 mm diameter biopsy punch in a sterile environment.
  • rhBMP-2 was dissolved in sterile, water, dripped onto the sponge slowly, and allowed to sit for 20 minutes prior to implantation.
  • Animals were anaesthetized by 35 mg/kg Ketamine and 0.5 mg/kg Xylazine.
  • the operative site was shaved and wiped with povidine-iodine solution.
  • An incision was made in the quadriceps of the mouse, in which the collagen pellet was placed. The incision was sutured closed, the animals were allowed to recover on a heat pad, and given post-operative analgesics and saline.
  • Bone nodule placement was monitored and checked by digital X-ray (Faxitron X-ray
  • CTAnalyser software version 1.11.8.0 (SkyScan).
  • a global threshold to define bone tissue in pellets was set at a mineral density of 0.3 g/cm 3 , and for trabecular analysis at 0.4 g/cm 3 . Samples that had fused to the femur were excluded.
  • Preferred osteoinductive agents in the compositions of the present invention are osteogenic proteins.
  • Recombinant human bone morphogenetic proteins rhBMPs
  • rhBMPs are osteogenic agents able to produce large amounts of new bone (Schindeler A et al BMC Musculoskelet Disord. 2010; 11 :105). They are currently approved for clinical use for the treatment of critical/ segmental bone defects and open fractures (Govender S et al J Bone Joint Surg Am. 2002; 84-A:2123-34, Kanakaris NK et al Injury 2008; 39:S83-90).
  • porous collagen is the clinical standard.
  • many alternative scaffolds synthesized from collagen, ceramics, polymer, and combinations of these materials are being developed.
  • An injectable or percutaneous delivery system for rhBMP-2 has multiple advantages, but reduction of infection risk is particularly pertinent.
  • Ceramic particles such as hydroxyapatite are currently used as a bone building supplement (microcrystalline hydroxyapatite) as an alternative to calcium carbonate.
  • Hydroxyapatite is also used as a coating on a number of orthopaedic implants to improve osteo-integration with adjacent bone or as a component of a bioactive coating.
  • Ceramic microparticles or nanoparticles can also be an ingredient in alternative delivery systems for bone tissue engineering.
  • a preferred formulation for ectopic bone formation is 20 microlitres containing 85:15 (v/v) SAIB to solvent. This delivers 5 micrograms rhBMP-2, 1 microgram zoledronic acid, and 2% (w/v) hydroxyapatite microparticles.
  • rhBMP-2 (20 or 40 micrograms) was delivered via SAIBrethanol versus water. Negligible bone formed via direct injection of rhBMP-2 in saline, but large bone nodules formed with the SAIB:ethanol delivery system.
  • rhBMP-2 (5 micrograms) was delivered via SAIB:ethanol together with other additives, including 2% (w/v) hydroxyapaptite as an osteoconductive agent, and 1 microgram zoledronic acid as an anti-resorptive agent.
  • the additive agents were supplied individually with the rhBMP-2, and in combination with the rhBMP-2.
  • the rhBMP- 2/zoledronic acid/SAIB:ethanol combination showed a surprising and significant increase (-5-fold increase) in bone formation relative to relative to rhBMP-2 in SAIB alone.
  • zoledronic acid (ZA) and hydroxyapatite and zoledronic acid (HA+ZA) gave a statistically significant 5-fold and 10-fold increase respectively in bone volume over rhBMP-2 in SAIB alone.
  • Other agents including cell signalling inhibitors (BADGE, SB216763, PD0325901 , SP600125), hydroxyapatite alone and other anti-resorptives (PS1 145 - an IKK inhibitor, and AFG495 a Cathepsin K inhibitor) gave increases that would normally be considered biologically relevant as they
  • compositions can be prepared as follows.
  • SAIB is decanted into a 50 ml polypropylene tube and this is weighed.
  • the specific gravity of SAIB (1.146) is used to calculate the volume of SAIB portioned.
  • the appropriate amount of ethanol is added and these are allowed to mix at room temperature on a rotating wheel overnight. This is the stock solution.
  • rhBMP-2 is weighed out into 1.5 ml polypropylene tubes, and the SAIB:ethanol mixture is pipetted on top. Any additional drugs are added at this point. The whole thing is mixed using a combination of pipette tip and vortex until it is homogenous by eye. This is then pipetted into a 50 cc insulin syringe where it is injected into mice.
  • osteoinductive agent rhBMP-2 0.5-5 mg
  • osteoinductive agent rhBMP-2 0.5-5 mg anti-resorptive agent zoledronic acid 20-500 micrograms osteoconductive agent hydroxyapatite 1-5% (w/v)
  • Component Name Amount carrier SAIB Ethanol 80-20% (v/v) 2-10 ml osteoinductive agent rhBMP-7 0.5-5 mg anti-resorptive agent zoledronic acid 20-500 pg osteoinductive agent hydroxyapatite 1-5% (w/v)
  • Component Name Amount carrier SAIB Ethanol 85-15% (v/v) 2-10 ml osteoinductive agent rhBMP-7 0.5-5 mg anti-resorptive agent zoledronic acid 20-500 Mg osteoinductive agent hydroxyapatite 1-5% (w/v)
  • Component Name Amount carrier SAIBiEthanol 80-20% (v/v) 2-10 ml osteoinductive agent rhBMP-2 0.5-5 mg anti-resorptive agent zoledronic acid 20-500 pg
  • Component Name Amount carrier SAIB Ethanol 90-10% (v/v) 2-10 ml osteoinductive agent rhBMP-2 0.5-5 mg anti-resorptive agent zoledronic acid 20-500 g
  • Component Name Amount carrier SAIB Ethanol 85-15% (v v) 2-20 ml osteoinductive agent rhBMP-2 5-12 mg anti-resorptive agent zoledronic acid 0.5-1.0 mg osteoinductive agent hydroxyapatite 1-5% (w/v)
  • Component Name Amount carrier SAIB Ethanol 90-10% (v/v) 2-20 ml osteoinductive agent rhBMP-2 5-12 mg anti-resorptive agent zoledronic acid 0.5-1.0 mg osteoinductive agent hydroxyapatite 1-5% (w/v)
  • a range of rhBMP-2 doses were delivered in SAIB in order to examine the effective concentration range.
  • Three rhBMP-2 doses (2, 5 and 10 pg) were compared to SAIB alone delivered by direct injection.
  • the ectopic nodules were harvested after three weeks in vivo, X-rayed and bone volume quantified by microCT.
  • An increasing dose of rhBMP-2 led to increased bone formation ( Figure 3), however even the lowest dose of 2 pg rhBMP-2 led to robust formation of a bone nodule.
  • SAIB is thus able to deliver rhBMP-2 percutaneously resulting in ectopic bone formation after three weeks. From this result, 5 pg of rhBMP-2 was chosen for following experiments.
  • the primary outcome measure was bone volume formation in the ectopic bone pellets as measured by microCT.
  • the mouse derived MC3T3 pre-osteoblast cell line was cultured with a dose range of ZA (0 ⁇ , 1 ⁇ , 5 ⁇ , 10 ⁇ , 50 ⁇ , and 200 ⁇ ) and the effects on cell viability were measured. Doses of 50 ⁇ and 200 ⁇ ZA were cytotoxic, with over 90% cell death at days 4 and 7.
  • MC3T3-E1 cells a pre-osteoblastic cell line, were cultured in standard tissue culture flasks using a- EM supplemented with 10% foetal bovine serum, 1% L-glutamine and 2% penicillin/streptomycin. Media was changed every 4 days and cells were removed from flasks using trypsin-EDTA solution. Cell number was calculated using a haemocytometer.
  • ZA cytotoxic dose response to ZA, cells were seeded in 24-well plates at a density of 2x 0 4 cells per well in 500 ⁇ and cultured in a range of ZA concentrations (1-200 ⁇ ). A dose of 50 ⁇ was found to be highly cytotoxic and used for subsequent HA rescue experiments. Boyden inserts (1 ⁇ pore size) were inserted into each well containing 500 ⁇ of media of the following treatments: media alone, 2% HA, 100 ⁇ ZA or 100 ⁇ ZA +2% HA.
  • Viability was measured at 4 day and 7 days post seeding. Cellular viability was assessed using the CellTitre 96 Aqueous One Solution Cell Proliferation Assay kit
  • the needle was not totally withdrawn from the tissue, it was held in place at the inlet of the insertion point for 30 seconds following injection of 20 ⁇ solution. This was done to allow time for the SAIB to become more viscous as the solvent leaves the solution, thus preventing extrusion of the solution from the injection site. Light finger pressure was applied over the injection site and the needle was withdrawn from the tissue, to discourage solution extrusion. Finally, the skin was closed with 5.0 sutures.
  • SAIB/rhBMP-2 compositions were used in a pig osteonecrosis model and there were no negative effects of then treatment in this larger animal model.
  • Potential medical indications include fracture healing (particularly of open fractures), spinal fusion, correction of small and critical sized bone defects, promoting the osteointegration of bone implants including plates, screws, frames, and joint replacement implants, restoration of osteonecrotic bone (including Perthes disease of the hip), and restoration of osteoporotic bone.
  • the combination of osteoconductive agent, osteoconductive agent, and anti- resorptive agent via the phase-transitioning carrier have shown in preclinical tests to produce an unexpectedly high amount of de novo (new) bone formation and may be a particularly favourable formulation for the treatment of a range of orthopaedic conditions where tissue engineering is required. These include the treatment of critical defects (resulting from trauma, tissue resection, or congenital deformity); treatment of delayed union, non-union or pseudarthrosis; treatment of fracture repair (particularly high-energy open fractures), and orthopaedic implant osteointegration.

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Abstract

La présente invention concerne une composition de promotion de la croissance osseuse comprenant un vecteur à viscosité élevé à base de sucre, tel que l'acétate isobutyrate de sucrose (SAIB) ; un agent ostéoinducteur, tel que la protéine morphogénétique osseuse ; un agent anti-résorption, tel qu'un bisphosphonate ; et facultativement un agent ostéoconducteur, tel que l'hydroxyapatite.
PCT/AU2013/000963 2012-08-28 2013-08-28 Composition et procédé pour la croissance osseuse WO2014032099A1 (fr)

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AU2012903734A AU2012903734A0 (en) 2012-08-28 Composition and Method for Bone Growth
AU2012903734 2012-08-28

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104147638A (zh) * 2014-07-18 2014-11-19 中国科学院金属研究所 一种三维连通多孔人工骨支架及其制备方法和应用
WO2016150876A1 (fr) 2015-03-23 2016-09-29 Bone Support Ab Substitut osseux céramique biphasique
WO2018225050A1 (fr) * 2017-06-09 2018-12-13 Association For The Advancement Of Tissue Engineering Cell Based Technologies & Therapies (A4Tec) - Associação Compositions à base de l'acétate isobutyrate de saccharose, procédés et utilisations de celles-ci
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US10238507B2 (en) 2015-01-12 2019-03-26 Surgentec, Llc Bone graft delivery system and method for using same
US11116646B2 (en) 2015-01-12 2021-09-14 Surgentec, Llc Bone graft delivery system and method for using same
WO2016150876A1 (fr) 2015-03-23 2016-09-29 Bone Support Ab Substitut osseux céramique biphasique
WO2018225050A1 (fr) * 2017-06-09 2018-12-13 Association For The Advancement Of Tissue Engineering Cell Based Technologies & Therapies (A4Tec) - Associação Compositions à base de l'acétate isobutyrate de saccharose, procédés et utilisations de celles-ci
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US10687828B2 (en) 2018-04-13 2020-06-23 Surgentec, Llc Bone graft delivery system and method for using same
US11116647B2 (en) 2018-04-13 2021-09-14 Surgentec, Llc Bone graft delivery system and method for using same
CN112675130A (zh) * 2020-12-29 2021-04-20 中国人民解放军总医院第三医学中心 空心纳米颗粒在制备骨质疏松治疗药物中的应用
CN112675130B (zh) * 2020-12-29 2023-04-25 中国人民解放军总医院第三医学中心 空心纳米颗粒在制备骨质疏松治疗药物中的应用

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