Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F2/00—Processes of polymerisation
  • C08F2/44—Polymerisation in the presence of compounding ingredients, e.g. plasticisers, dyestuffs, fillers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
• • 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
  • A61L27/58—Materials at least partially resorbable by the body
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L31/127—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing fillers of phosphorus-containing inorganic materials
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
• • 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
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/148—Materials at least partially resorbable by the body
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
  • C08K3/00—Use of inorganic substances as compounding ingredients
  • C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
  • C08K3/24—Acids; Salts thereof
  • C08K3/26—Carbonates; Bicarbonates
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
  • C08K3/00—Use of inorganic substances as compounding ingredients
  • C08K3/32—Phosphorus-containing compounds
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
  • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
• • 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
  • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
  • C08K3/00—Use of inorganic substances as compounding ingredients
  • C08K3/18—Oxygen-containing compounds, e.g. metal carbonyls
  • C08K3/24—Acids; Salts thereof
  • C08K3/26—Carbonates; Bicarbonates
  • C08K2003/265—Calcium, strontium or barium carbonate

Definitions

• the present invention relates generally to orthopaedic implants and more particularly to bioresorbable polymer composites comprising nanoparticles, wherein the nanoparticles are capable of buffering the acidic degradation products of the polymer.
• Fracture fixation plates are the most commonly employed devices for surgical support of fractured bone.
• the plates are placed across the site of fractures bones and exert pressure on the fractured ends of the bone, thereby improving the rigidity until unity of the fracture is complete.
• the plates are manufactured of a rigid metal, such as stainless steel, cobalt chrome alloys and titanium alloys.
• the large difference in elastic modulus between the underlying bone (14-24 GPa) and the metallic implants (100-240 GPa) causes a majority of the load of the body to be carried by the implant while fracture healing is taking place.
• bioresorbable polymers such as polylactide (PLA), polyglycolide (PGA) and their copolymers.
• PLA polylactide
• PGA polyglycolide
• the potential of bioresorbable plates produced by polymers such as PLA and PGA is limited by the modest initial mechanical properties with respect to bone, the rate of loss of these polymers, and the evolution of acidic degradation products on hydrolytic cleavage of the polymer backbone, as detailed in Pietrzak et al., Bone, Vol. 19, pp. 109S-
• CaCO 3 , ⁇ -tricalcium phosphate and hydroxyapatite exhibit a buffering capability when used to reinforce bioresorbable polymers derived from glycolide and lactide, as further described in Agrawal et al., Journal of Biomedicals Material Research, Vol. 38, pp105-114 (1997).
• the mechanical properties of a composite are dependent on the strength of the interface between the two different phases, i.e. the matrix and the reinforcement. Strong adhesion between the two phases is often difficult to achieve when microparticles are used as the reinforcing element, as further described in Gasser, Injury International Journal of the Care of the Injured, Vol. 31 , pp. S-D48-53 (2000) and Liu et al., Biomaterials, Vol. 18, 1263-1270 (1997). In Uecla et al, Biomaterials, Vol. 24, pp.
• nanoparticles comprising a neutralising agent for incorporation within a bioresorbable polymer to neutralise the acidic degradation products of said bioresorbable polymer.
• the neutralising agent is typically a basic nanoparticulate filler.
• the neutralising agent is a salt capable of neutralising the acidic degradation products.
• suitable salts include, but are not limited to, a carbonate, a bicarbonate, or a phosphate salt.
• the neutralising agent is a hydroxide.
• a particularly advantageous neutralising agent is one which is also a source of free calcium ions.
• Calcium ions are known to be osteogenic and therefore their release from the bioresorbable polymer can also promote osteogenesis.
• the neutralising agent is a calcium carbonate (CaCO 3 ) or a calcium phosphate.
• An example of a suitable calcium phosphate is apatite.
• Apatite is a group of phosphate minerals, usually referring to hydroxylapatite, fluorapatite, and chlorapatite, named for high concentrations of OH “ , F " , or Cl " ions, respectively, in the crystal.
• the formula of the admixture of the three most common species is written as Ca 5 (PO 4 ) 3 (OH, F, Cl), and the formulae of the individual minerals are written as Ca 5 (PO 4 )S(OH), Ca 5 (PO 4 ) 3 F and Ca 5 (PO 4 J 3 CI, respectively.
• the apatite is hydroxyapatite.
• the concentration of the neutralising agent within the polymer is from between about 5-20 wt %, specifically from about 7-15 wt %.
• the diameter of the nanoparticle is less than about 100nm.
• the larger surface area to volume ratio of the nanoparticles improves the bonding between the matrix and reinforcement phase when compared to microparticfes of the basic fillers.
• the larger surface area to volume ratio of the nanoparticles also significantly reduces the concentration of the basic fillers required to provide the same buffering capability as microparticlulate fillers.
• large quantities of filler particles within a composite can result in particle agglomeration due to the attractive van der Waals forces [13].
• Lower concentrations of particles, optionally with the use of a surfactant allow these forces to be overcome by the repulsive forces, resulting in a composite with the filler homogenously dispersed within the polymer matrix.
• a bioresorbable polymer includes all bioresorbable polymers except poly-L-lactic acid (PLLA). This includes, without limitation, the following:
• Lactide/e-caprolactone copolymers PLA/polyethylene oxide copolymers
• Polyesteramides Polyesters of oxalic acid
• Polydihydropyrans Polyalkyl-2-cyanocrylates Polyurethanes (PU) Polyvinylalcohol (PVA) Polypeptides Poly-b-malic acid (PM LA)
• Polymers comprising nanoparticles of a neutralising agent can be manufactured in a similar way to their micron-sized equivalents, through dissolution of the polymer in a solvent followed by the addition of the nanoparticles.
• a polymeric composite comprising a first polymer and a second polymer, wherein the first polymer has a molecular weight less than the second polymer, and wherein nanoparticles of a neutralising agent are distributed throughout at least the first polymer.
• both the first polymer and the second polymer is poly-DL-lactic acid (PDLLA) or copolymers thereof and the first polymer comprises nanoparticles of calcium carbonate.
• PLLA poly-DL-lactic acid
• a method of manufacturing a composite comprising a first polymer including a nanoparticulate neutralising agent distributed throughout and a second polymer, the method comprising the steps of; a) polymerising the first polymer with the nanoparticulate agent to form a combination; and b) blending the combination produced in a) with the second polymer, the second polymer having a high molecular weight than the first polymer.
• the first polymer is PDLLA or copolymers thereof and the nanoparticulate agent is calcium carbonate.
• a composite comprising a polymer material and a nanoparticulate neutralising agent distributed throughout the polymer material, wherein the polymer material consists of PDLLA or copolymers thereof.
• a composite comprising a polymer material and a nanoparticulate neutralising agent distributed throughout the polymer material, wherein the polymer material is any polymer material other than PLLA.
• the polymer included in the polymer/nanoparticulate neutralising agent composite is a polymer having a molecular weight of less than 20 kD.
• the higher molecular weight polymer that the composite is blended with is a polymer having a molecular weight of greater than 20 kD.
• FIG.1 Transmission electron micrograph of nano-particulate calcium carbonate.
• FIG.2 Variation in pH of the solution holding the composites with degradation time. Values are mean ⁇ standard error for triplicate samples.
• FIG.3 Variation in number average molecular weight (M n ) and weight average molecular weight (M w ) of nCaCOyPDLLA composites polymerised for 5 days at 130 0 C using 0.01 wt % SnOCt 2 . The resultant samples were then utilised for melt processing. Values are mean ⁇ standard error for repeated duplicate samples.
• FiG.4 Variation in time with the response of the GPC detector for (a) 100 wt % PDLLA, (b) 30 wt % PDLLAAiCaCO 3 composite and ⁇ c) 15 wt % PDLLAZnCaCO 3 composite, produced by melt processing equal quantities of PDLLA and 30 wt % PDLLA/nCaCO 3 composite.
• FIG.5 Difference in number average molecular weight (M n ) and weight average molecular weight (M w ) of nCaCOs/PDLLA composites following extrusion and injection moulding. Values are mean ⁇ standard error for repeated duplicate samples.
• FIG. ⁇ i SEM micrographs (a-f) illustrating the melt processed composites containing varying concentrations of CaCO 3 . Those images taken in back- scattered electron mode are indicated with BS.
• FIG.6U SEM micrographs (g-j) illustrating the melt processed composites containing varying concentrations of CaCO 3 . Those images taken in back- scattered electron mode are indicated with BS.
• FIG.7 Change in pH of the starting solution holding the PDLLMiCaCO 3 composites versus degradation time. Values are mean + standard error for repeated triplicate samples.
• FIG.8 Variation in mass lass of the composites as they degrade. Values are mean + standard error for repeated triplicate samples.
• FIG.9 Change in (a) number average molecular weight and (b) percentage reduction in number average molecular weight (M n ) with composite degradation time. Values are mean ⁇ standard error for repeated duplicate samples
• FIG.10 Change in the concentration of calcium ions present within the composites. Values are mean for repeated ⁇ standard error for repeated triplicate samples.
• FIG.11 Change in elastic modulus with nCaCO 3 content within PDLLA and processing condition, as determined using dynamic mechanical analysis. Values are calculated at 25 0 C and are mean ⁇ standard error for a minimum of 5 sampfes.
• FIG.12 Variation in storage modulus with nCaCO 3 content within PDLLA and processing condition, as determined using dynamic mechanical analysis. Values were calculated at 37 0 C and are mean ⁇ standard error for a minimum of 5 samples.
• Nano-particulate calcium carbonate (nCaCOa) with a narrow particle size distribution (all particles less than 100 nm) and a low tendency to agglomerate (Figure 1) was precipitated through carbonation of an aqueous solution of calcium hydroxide (Ca(OH) 2 ) in methanol.
• nCaCO 3 was dried thoroughly overnight prior to use and ground together with the monomer before being placed in borosilicate glass boiling tubes.
• D-L lactide, 0.01 wt % Sn ⁇ ct 2 and precipitated nCaCO 3 (14, 17, 20, 25 and 30 wt %) were added to borosilicate glass boiling tubes and polymerised at 130 0 C for 5 days within an inert nitrogen atmosphere.
• Table 1 Molecular weights of the PDLLA/nCaCO 3 composites prior to processing with a higher molecular weight polymer
• the number average molecular weight (M n ) and weight average molecular weight (M w ) of pure PDLLA and the composites were determined using gel permeation chromatography (GPC) (see Table 2). Approximately 0.1 g of the samples were dissolved in 5 ml chloroform and GPC analysis (Polymer
• Composite degradation was measured in terms of mass loss and water absorption, change in polymer molecular weight, pH of the surrounding solution and change in calcium concentration of the solution with time. Rectangles approximately 12 x 4 x 2 mm in size were cut from the injection moulded nCaCCVPDLLA samples using a heated scalpel, the mass recorded and placed individually in a 24 well plate. Samples (10 x 10 x 0.5 mm) were also cut from the pressed 10 wt % fCaCCVPDLLA sheet.
• DMEM phenol red free Dulbecco's Modified Eagle's Medium
• FBS foetal bovine serum
• DMEM was also added to empty wells within the well plate in order to act as blanks.
• the well plates were then placed in an incubator at 37 0 C and 5 % CO 2 for 10 weeks. At pre-determined time points (4, 7, 14, 21 , 35, 42, 49, 56, and 70 days) these were removed and the mass recorded. Hydrolysed samples were also dried under vacuum at 10 ⁇ 1 -10 ⁇ 2 mbar for 48 hours and the dry mass measured, allowing determination of percentage weight loss and water absorption.
• a buffer solution of ammonium chloride-ammonium hydroxide (NH 2 OH I-ICI) was prepared by dissolving 67.6 g ammonium chloride (NH 4 CI) in 200 ml dH 2 O, followed by the addition of 570 ml concentrated ammonium hydroxide (NH 4 OH). To this 5.0O g of magnesium salt of EDTA was added, diluted to 1000 ml with dH 2 O and stored in a tightly stoppered vessel.
• a standard 0.01 IvI EDTA solution was produced by dissolving 3.72 g disodium ethylenediaminetetraacetic acid (Na 2 EDTA; Fisher Scientific) dihydrate (dried overnight) in dH 2 O and diluted to 1000 ml in a volumetric flask. The molarity of this solution was verified by titrating 25.0 ml of CaCO 3 standard solution. This was created by suspending 1.000 g CaCO 3 which was dried prior to weighing for 1 h at 180 0 C, in approximately 600 ml dH 2 O and dissolving with a minimal amount of dilute HCI. The resultant solution was diluted to 1000 ml in a volumetric flask.
• Ammonium purpurate (1.0 g) was mixed thoroughly with 200 g sucrose in a sealed vessel and subsequently used in 0.2 g quantities as an indicator. An aliquot of known volume of solution with unknown calcium ion concentration was placed in a volumetric flask, 1 ml NH 2 OH HCI, 1 ml NaOH (80 g I "1 ) and ammonium purpurate added, and titrated with EDTA until a colour change from pink to purple was achieved. The EDTA volume was recorded and the calcium concentration determined. The change in molecular weight of the dried samples was also established through the use of GPC.
• the mechanical properties of the nCaCOa/PDLLA composites and pure PDLLA, produced as described above were determined using dynamic mechanical analysis (DMA; TA Instruments).
• the DMA was used in the tensile mode, testing both the extruded fibres and the central long axis of the injection moulded tensile test specimens (ends were removed using a hot scalpel). Two different tests were used; a strain sweep and a temperature sweep. The strain sweep was carried out at 25 0 C, using a pre-load force of 0.01 N and the amplitude gradually increased from 0.5 to 6 ⁇ m. A stress versus strain graph was then plotted and the elastic modulus determined from the gradient.
• DMA dynamic mechanical analysis
• the temperature was gradually increased from 25 to 70 0 C at a rate of 3 0 C min '1 with a constant frequency and amplitude of 1 Hz and 6 ⁇ m respectively.
• the resultant graphs were used to establish the storage modulus at 37 0 C.
• nCaCCVPDLLA composites when determined with DMA, increased with the addition of nCaCO 3 and reached a maximum with 12.5 wt % nCaCO 3 ( Figures 1 1 and 12). Both were significantly higher than pure PDLLA and this was the case for both the extruded and injection moulded samples. However, values were significantly lower for the injection moulded samples in comparison to those which were extruded. These results indicate that nCaCO 3 is effective in reinforcing PDLLA.

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Materials Engineering (AREA)
• Composite Materials (AREA)
• Inorganic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Polymers & Plastics (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Transplantation (AREA)
• Vascular Medicine (AREA)
• Dermatology (AREA)
• Heart & Thoracic Surgery (AREA)
• Surgery (AREA)
• Nanotechnology (AREA)
• Condensed Matter Physics & Semiconductors (AREA)
• General Physics & Mathematics (AREA)
• Crystallography & Structural Chemistry (AREA)
• Physics & Mathematics (AREA)
• Compositions Of Macromolecular Compounds (AREA)
• Materials For Medical Uses (AREA)
• Compounds Of Alkaline-Earth Elements, Aluminum Or Rare-Earth Metals (AREA)
• Biological Depolymerization Polymers (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=38461314

Family Applications (1)

Country Status (5)

Families Citing this family (6)

Family Cites Families (5)

• 2007
  • 2007-07-10 GB GBGB0713351.5A patent/GB0713351D0/en not_active Ceased
• 2008
  • 2008-07-08 AU AU2008275226A patent/AU2008275226B2/en not_active Ceased
  • 2008-07-08 EP EP08781477A patent/EP2170983A2/en not_active Withdrawn
  • 2008-07-08 WO PCT/US2008/069391 patent/WO2009009520A2/en active Application Filing
  • 2008-07-08 JP JP2010516192A patent/JP5753687B2/ja not_active Expired - Fee Related

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events