EP1478415A1 - Bioresorbierbares knochenimplantat - Google Patents

Bioresorbierbares knochenimplantat

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Publication number
EP1478415A1
EP1478415A1 EP03706149A EP03706149A EP1478415A1 EP 1478415 A1 EP1478415 A1 EP 1478415A1 EP 03706149 A EP03706149 A EP 03706149A EP 03706149 A EP03706149 A EP 03706149A EP 1478415 A1 EP1478415 A1 EP 1478415A1
Authority
EP
European Patent Office
Prior art keywords
bone
bone material
agent
multiblock
biodegradable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03706149A
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English (en)
French (fr)
Inventor
Laurent Masaro
Patrick Lapointe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biomatera Inc
Original Assignee
Biomatera Inc
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Filing date
Publication date
Application filed by Biomatera Inc filed Critical Biomatera Inc
Publication of EP1478415A1 publication Critical patent/EP1478415A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • 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 present invention relates to making implants for bone regeneration that are biocompatible, bioresorbable and present extensive malleability property. Because of this particular property, they are particularly suitable for dental applications, but can be used for any bone regeneration application.
  • a drug or other biologically active compound can be added in the composition of the implant in order to be released in vivo.
  • Dental fillers are used after tooth removal in order to fill the space left by the missing roots in the jaw. Their main original function was to avoid the gum to collapse.
  • Today, dental fillers are also used to allow bone tissue growth in and around the implant.
  • the interaction between implant and the natural supporting bone is called osseointegration, which takes place over a substantial period of time, generally ranging from several months to a year. After this period, which is characteristic of regeneration of the bone and healing of the wound, a permanent prosthetic device may be installed by surgery.
  • Implant systems can be divided in two categories based on different scientific approaches.
  • the first one is made of implants with predetermined forms.
  • implants For example, "rootform" implants that already have the form of the empty cavity to be filled up. These implants may be adjusted to fill correctly the specific cavity geometry of the patient by mechanical treatment for example.
  • the second category of implants consists of thread or tissue like compounds that are packed and condensed into the empty tooth cavity. Improvement of this technique consists in mechanical locking mechanisms such as pins, screw, etc., which needs more intensive labor and complex work.
  • Dental filler composition usually consists of alloy and resins composites. Dental amalgam alloys have been widely used as direct filling material. They provide excellent handling characteristics and physical properties.
  • dental resins which comprises polymer resins made of polyamide, polyester, polyacrylate, polyolefin, polyimide, polyacrylate, polyurethane, polyvinyl ester, polystyrene, polysulfone, polyacetal, polycarbonate, polyphenylene sulfide, epoxy based materials and the likes. All these polymers often need to be employed with the presence of organic solvents.
  • the most popular polymer resins are based on unsaturated groups, in particular acrylate and methacrylate. However, they are characterized by polymerization shrinkage and poor durability.
  • inorganic inert compounds This drawback as been partially resolved by mixing inorganic inert compounds to the polymer resin.
  • Commonly used inorganic fillers are silica, quartz, glass and various mineral silicates. Their particle size need to be smallest as possible, in order to support the bone regeneration. Typical size is in the range of 0.01 to 1.2 microns.
  • these inorganic inert compounds ensure a stronger base for permanent prosthetic device ultimately.
  • Their most important disadvantage is their non-biodegradability although they are regarded as inert. Once introduced in a patient, they remain in his body for the rest of his life.
  • inert material that could resorb during bone regeneration would represent an ideal solution.
  • One way to achieve this goal is to use mineral compounds already present into human or mammals. Hydroxyapatite, which is made of calcium phosphate, is a good example. Usually it comes from beef, but recently synthetic hydroxyapatite was regarded as less health hazardous. This compound is naturally present in human bones, it is also a good candidate to bone regeneration. However, while endogenous synthetic hydroxyapatite does not seems to be entirely bioresorbable.
  • One of its derivatives, calcium carbonate, a coral analogue of hydroxyapatite shows better bioresorbability properties according to Mora and Ouhayoun (J. Clin. Periodontol, 1995, 22, 877-884). Moreover, its gradual resorption is accompanied by bone formation according to the authors. A weaker chemical resistance in vivo may explain this specific behavior, in part. As a result, implants made of calcium carbonate are bioresorbed over less extended periods of time.
  • One object of the present invention is to provide a bone material for filling holes or cavities in a bone consisting of at least one biodegradable and- biocompatible polymer, a multiblock agent, and a bone regenerative compound.
  • the bone material may comprise an aqueous solvant.
  • Another object of the present invention is to provide bone material for favoring bone regeneration in a bone hole comprising particles comprising at least one biodegradable and biocompatible polymer, a multiblock agent, and a bone regenerative compound, wherein the multiblock agent has at least one hydrophobic domain and at least one hydrophilic domain, and the bone regenerative compound favors bone regeneration.
  • Another object of the present invention is to provide a method to produce a biodegradable, biocompatible and bioresorbable implant to favor bone regeneration.
  • the bone may be a jaw bone
  • the hole may be a jaw bone hole formed after extraction of a tooth from the jaw or a bone fracture.
  • the biodegradable and biocompatible polymer can be selected from the group consisting of polyhydroxyalkanoate (PHA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyvinyl alcohol (PVA), adipic acid, sebasic acid, aminocaproic acid, poly(butylene succinate), or a derivative or a mixture thereof, and can be in proportion of between about 1 to 99% (w/v).
  • the PHA may be used in a latex form and further lyophilized to obtain an homogeneous and malleable product.
  • the polymer particles in the bone material of the present invention may have a diameter between about 0.1 to 10 ⁇ m.
  • the bone material can be under lyophilized form, or the polymer can be lyophilized alone and followed by the addition of multiblock and bone regenerative agent.
  • the bone material can be moisturized in order to obtain a malleable material.
  • the multiblock agent that may be used in proportion of between about 1 to 50% (w/v) to obtain the bone material of the mvention, may be an amphiphilic agent which contain hydrophobic part being a fatty acid and a hydiOphilic part being poly(ethylene glycol).
  • the bone regenerative compound for forming the bone material of the invention may be selected from the group consisting of growth factors such as bone morphogenic proteins and recombinant human bone morphogenic proteins.
  • bone regenerative compound for forming the bone material of the invention may be selected from the group consisting of inorganic compounds such as hydroxyapatite, calcium phosphate, calcium carbonate, dicalcium phosphate dihydrate, dicalcium phosphate, and tetracalcium phosphate, or a derivative or a mixture thereof.
  • the inorganic compound can be in proportion of between about 0.1 to 50% w/v.
  • the bone material can be comprising a biologically active agent that can be selected from the group consisting of a differentiation factor, an antibiotic, an anti-pain, an analgesic and a cytokine.
  • a biologically active agent can be incorporated in the bone material for being released into surrounding tissue in which the bone material has been placed, during degradation of the bone material.
  • a method for favoring regeneration of bone in a bone hole comprising filling a bone hole with the bone material of the present invention.
  • Another object of the present invention is to provide a very handling biomaterial, i.e., which is sufficiently malleable to form easily by finger manipulation any desired form.
  • the biomaterial can be sized and formed with fingers or different instruments over a period of ten minutes and over without losing its texture before hardening.
  • a further object of the present invention is to provide a biomaterial that can be used as a vehicle to the release of bone regenerative and/or biologically active compounds.
  • the dental implant composition may further comprise a polymer, a multiblock compound having both hydrophilic and hydrophobic properties, bone regenerative entity(ies) and eventually water.
  • Another object of the present invention is to provide a dental implant wherein the polymer is synthetic or natural polymer, and may be selected from the group consisting of polyhydroxyalkanoate (PHA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyvinyl alcohol (PVA), adipic acid, sebasic acid, aminocaproic acid, poly(butylene succinate), or a derivative or a mixture thereof.
  • PHA polyhydroxyalkanoate
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PCL polycaprolactone
  • PVA polyvinyl alcohol
  • adipic acid sebasic acid
  • aminocaproic acid poly(butylene succinate)
  • Another object of the present invention is to provide a method of producing biocompatible, biodegradable and bioresorbable implants that could be used as dental fillers.
  • This biocompatible, biodegradable and bioresorbable dental implant which can be defmed as a biomaterial, will degrade
  • Another object of the present invention is to provide a dental implant or filler that will resorb within a specific period of time that will correspond to bone regeneration.
  • biopoiymer as used herein is intended to mean polymers obtained from natural and renewable sources and which mode of synthesis occurs naturally such as in plants or microorganisms, like PHA for example.
  • polymers as used herein is intended to mean macromolecules synthesized by chemical reaction or obtained from petroleum sources, even if one of the components (monomer, precursor, etc.) is obtained from natural and renewable sources.
  • PLA, PGA, PLGA and PCL are considered as polymers by the authors, according to this definition.
  • bone regenerative compound As used herein are intended to mean any organic or inorganic active compounds having specific therapeutic being favoring bone regeneration.
  • active agent biologically or pharmaceutically active compounds having specific therapeutic effects on animal or human, to be delivered over a predetermined period of time at a certain level.
  • dental implant or “dental filler” as used herein is intended to mean devices employed to fill up the empty space of roots in the jaw after dental removal.
  • biocompatible implant or “biocompatible filler” as used herein is intended to mean that all components of the implant or filler should be physiologically tolerated and should not cause toxic nor inflammatory effects as well as other adverse histological response when implanted in vivo.
  • biodegradable implant or “biodegradable filler” as used herein is intended to mean that polymers or biopolymers constituent the implant are subjected to chemical or enzymatic hydrolysis, resulting in a decrease of their molecular weight and breakdown into smaller subunits that will be resorbed and/or eliminated by the body over time when implanted in vivo.
  • bioresorbable implant or “bioresorbable filler” as used herein is intended to mean that the constituents of the implant or filler will undergo a degradation into smaller entities, that, will be resorbed by the body, or that the constituents will be directly resorbed by the body through natural biochemical pathway.
  • granules and particles as used herein are intended to mean spheroids shaped biopolymer segments with particle size distribution between 0.1 and 10 ⁇ m, preferably between 0.2 and 5 ⁇ m.
  • latex as used herein is intended to mean a suspension of PHA granules and/or particles in an aqueous medium.
  • the PHA granules can be either in their native state or re-suspended in water.
  • the native PHA is defined as a granule of PHA, produced by bacterial fermentation, which was never precipitated, therefore its crystallization degree remains close to or slightly higher than was it was in the bacteria, i.e., very weak.
  • the latex may have the aspect of milk in color and texture, while the viscosity may be similar to water.
  • novel biomaterials that distinguish themselves by the following properties: biocompatible, biodegradable, bioresorbable and malleability characteristics.
  • a method of producing implants that can be used into human or animals for bone regeneration applications, more precisely dental applications, more specifically dental filler.
  • implants can be also used as vehicle for the controlled release of growth factors, active compounds or drugs.
  • PHAs in latex from are suitable raw material to produce polymer resin that can be used for dental applications.
  • the Applicants have discovered a method to prepare dental fillers composed of biocompatible, biodegradable and bioresorbable PHAs resins.
  • PHA latex in which a bone regenerative compound and a multiblock additive are added is lyophilized.
  • the resulting powder is moisturized, a stable in time and very malleable biomaterial in obtained, which looks like "modeling clay” or Plasticine ® .
  • Dental implants, or fillers, described in the present invention are constituted of three distinct categories of chemical entities.
  • the first one is the biopolymer that assumes the resin structure in the final biomaterial.
  • the biopolymer which is preferably a polyhydroxyalkaiioate, presents a biodegradability characteristic never meet when the resin is made of synthetic polyacrylate or its derivatives.
  • the second category of compounds are multiblocks having both hydrophilic and hydrophobic properties. They can be amphiphilic compounds, i.e., two blocks hydrophilic-hydrophobic, or higher. Their main function is to assure the cohesion and final structure of the implant or filler once water is added.
  • the last category of compounds consists of bone regenerative material that will help in the regeneration of bones and other tissues.
  • PHA Polyhydroxyalkanoates
  • PHAs are polyesters produced and accumulated by microorganisms such as bacteria and algae. PHA is present intracellularly under the form of granules. These granules act as carbon energy storage and are biosynthesized in adverse conditions when an essential nutrient such as nitrogen, oxygen or phosphorous is limited. Under such conditions, bacteria can no longer grow or proliferate and switch their metabolism to the production of PHB in order to have a usable carbon source when conditions return back to normal. Therefore, feeding strategy becomes a critical step that will have a direct impact on the yield of production of the biopolymer. Feeding source is also an important factor that will dictate the nature of the biopolymer produced.
  • PHA poly (3- hydroxybutyrate)
  • PHBV copolymer poly (3-hydroxybutyrate-co-3- hydroxyvalerate)
  • multiblocks compound has both hydrophilic and hydrophobic properties.
  • Multiblocks are preferably diblock compounds, i.e., amphiphilic entities. Triblocks are also considered by the present invention, whether their structure is hydrophobic-hydrophilic-hydrophobic or hydrophilic-hydrophobic-hydrophilic, as well as longer multiblocks (tetra-, penta, etc.).
  • At least one multiblock compound having both hydrophilic and hydrophobic properties is added to the PHA latex solution as well as a bone regenerative compound. This solution is slightly heated in order to dissolve the multiblock sample and mix homogeneously all the constituents.
  • the resulting solution is lyophilized and ground in order to obtain a homogeneous powder that can be further moisturized to obtain the final biomaterial.
  • dental implants or dental fillers prepared from native PHA biopolymer solution and addition of multiblock sample and bone regenerative entity provide a more homogeneous powder once lyophilized which form a more homogeneous "modeling clay” after moisturization.
  • the same preparation, starting from a PHA powder leads to a more granular "modeling clay".
  • multiblock and bone regenerative compound can be added to a lyophilized and grounded PHA latex solution, in order to obtain a very malleable and homogeneous "modeling clay” like biomaterial.
  • dental implants or dental fillers compositions issued from the method of the invention may comprise biopolymer and/or polymer of polyhydroxyalkanoate, polylactic acid, polyglycolic acid, polycaprolactone and copolymers thereof.
  • the invention- is applicable to create dental implants or dental fillers from . any type of PHA biopolymers produced by plants or microbial organisms either naturally or though genetic engineering, as well as chemical synthesized PHA polymers.
  • PHA biopolymers used are polyesters composed of monomer units having the formula:
  • n is an integer from 1 up to 5 and including;
  • Ri is preferably an H, alkyl or alkenyl.
  • Alkyl and alkenyl side chains are preferably from up to C 20 carbon long.
  • PHA biopolymers can be homopolymers, with the same repeating monomer unit, and/or copolymers with at least two different repeating monomer units. Copolymers can be structured statistically, random, block, alternating or graft. Molecular weights of the PHA biopolymers are in the range of 1,000 to 5,000,000 g/mol, preferably between 5,000 and 2,500,000 g/mol, and more preferably between 10,000 and 2,000,000 g/mol. Orientation of the monomers can be head to head, head to tail or tail-to-tail.
  • PHAs that can be used according to this invention include poly(3- hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxyheptanoate), poly(3- hydroxyoctanoate), poly(4-hydroxybutyrate), medium chain length polyhydroxyalkaonates, poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3- hydiOxybutyrate-co-4-hydroxybutyrate) and poly(3 -hydroxybutyrate-co-3 - hydroxyoctanoate).
  • Copolymers of PHA, listed here above, are in the range of 40 to 100 % of monomer 3-hydroxybutyrate and preferably between 60 to 95 %.
  • PHA concentration in the latex solution is from 0.01 up to 50 % and including, preferably from 0.1 up to 45 % and more preferably from 1 up to 40 %. Concentrations are expressed weight / volume.
  • the latex can be obtained from a native biopolymer or resuspended from a dry powder. Origin of the biopolymer is also extended to those returned to amorphous state by the method described in International Patent Pub No. 99/64498.
  • PHA concentration in the final product prepared from latex solution or dry powder is between 1 and 99 %, more preferably between 2.5 and 97.5 % and more preferably between 5 and 95 %.
  • the mixing, freeze-drying and moisturizing of a PHA latex solution, multiblock and bone regeneration entities is characterized in obtaining a biocompatible, biodegradable and bioresorbable dental implant or dental filler.
  • the resulting product is characterized by an extended malleability property.
  • the final biomaterial looks like and behaves as "modeling clay”. It is possible to manipulate it with fingers for several minutes before it disintegrates. However, by adding a small quantity of water, it is possible to obtain again the initial "modeling clay" texture.
  • One structure of the multiblock corresponds to a diblock or an amphiphilic chemical compound, i.e., having both hydrophilic and hydrophobic properties.
  • Higher multiblocks compounds are also included in the present invention.
  • triblock compounds having hydrophilic-hydrophobic- hydrophilic or hydrophobic-hydrophilic-hydrophobic arrangements. It is assumed that the hydrophobic domains form weak interactions with the hydrophobic PHA polymeric chains present in the medium. Similar interaction can be assumed with some bone regenerative entities. Hydrophilic domains stabilize and maintain the water content while the powder is moisturized. As a result a "modeling clay" texture is obtained.
  • Hydrophobic domain may be for example aliphatic chains C n H 2n+2 ranging form Cj . to C 40 , linear and/or branched out. In the case of a triblock sample with hydrophobic domain at both ends, only one had to be long enough to interact with PHA chains or inorganic particles, the other one can be shorter. Unsaturated alkyl chains ranging from C 2 to C 40 , with one or more insaturation, linear and/or branched out, chains including one or more aromatic moieties are considered also.
  • Hydrophobic domain may contain one or more heteroatoms (nitrogen, oxygen, sulfur, chlorine, fluorine, etc.), individually or mixed.
  • heteroatoms nitrogen, oxygen, sulfur, chlorine, fluorine, etc.
  • poly(propylene glycol) is a hydrophobic compound with an oxygen heteroatom in the main polymeric chain and an alkyl branched out, a methyl group.
  • Hydrophobic domain can be for example saturated fatty acids with alkyl chain from C 10 up to C 30 , preferably between C 14 and C 24 .
  • Hydrophobic domain can be also unsaturated fatty acids, having one or more insaturation, with alkyl chain from C 10 up to C 30 , preferably between C 14 and C 2 .
  • Triblock compounds are made of one or two fatty acids at their ends.
  • Hydrophilic domain may be for example non-ionic chemical entities such as polyalkylene oxide, especially polyethyleneoxyde, glycoside, or polyglycerol or amine oxide. Hydrophilic domain may have ionic entities such as carboxylate, 10 sulfate, sulfonate, phosphate, phosphanate or ammonium. Hydrophilic group of the triblock compound may contain more than one chemical composition from the list above mentioned. The most suitable hydrophilic domain is the poly(ethylene glycol) and derivatives of formula;
  • n is-an-integer-varying-from-l-up-to-2 500 -preferably-between-3 to-500r
  • Hydrophilic domain may be also a hydrophilic polymer or biopolymers, such as polyvinyl alcohol, polyvinyl acetate, poly(epichlorohydrin), polyacrylates and its derivatives as well as cellulose and its derivatives (polysaccharides).
  • hydrophilic polymer or biopolymers such as polyvinyl alcohol, polyvinyl acetate, poly(epichlorohydrin), polyacrylates and its derivatives as well as cellulose and its derivatives (polysaccharides).
  • the quantity as well as the chemical structure of the multiblock 20 compound added to the biopolymer or polymer to obtain the dental implant or filler will manage the malleability of the final composition.
  • several parameters of the multiblock compound can be adjusted. Namely they are: quantity of multiblock compounds versus biopolymer or polymer and bone regenerative entity, global molecular weight of the triblock compound, length of the hydrophilic block, 25 length of each hydrophobic blocks.
  • the concentration of the multiblock in the final product is between 0.1 up to 50 %, preferably between 0.5 up to 45 % and 5 more preferably between 1 up to 40 %. Concentrations are expressed weight / volume.
  • the multiblock can be use alone or mixed at least 2 up to several 10 or so - with the same concentration or different ones.
  • the nature of the multiblock added can vary also. For example a triblock compound with a short length and another with a long length.
  • one or several amphiphilic compounds can be 10 added with one or several triblock compounds.
  • the use of a biocompatible, biodegradable and bioresorbable multiblock entity in addition to the biodegradable resin induces a more biocompatible, biodegradable and bioresorbable dental implant or dental filler.
  • the dental-implant-or-dental filler- may-be -prepared-by-moisturizing-the lyophilized powder.
  • the multiblock compound added has a fatty acid as hydrophobic group and is present in sufficient quantity, it may no be necessary to add water to obtain the "modeling clay" final aspect.
  • dental implants or 20 dental fillers compositions issued from the method of the invention may comprise bone regenerative entities such as bone morphogenic proteins, human recombinant bone morphogenic proteins, hydroxyapatite, calcium phosphate, calcium carbonate, dicalcium phosphate dihydrate, dicalcium phosphate, tetracalcium phosphate, and their derivatives.
  • bone regenerative entities such as bone morphogenic proteins, human recombinant bone morphogenic proteins, hydroxyapatite, calcium phosphate, calcium carbonate, dicalcium phosphate dihydrate, dicalcium phosphate, tetracalcium phosphate, and their derivatives.
  • calcium hydroxyde is added to the composition of the dental implant or dental filler.
  • Calcium phosphate and calcium carbonate are evaluated as ideal substitute or filler for damaged bones. Their osteoconductive and osteoinductive properties promote the healing of damaged bones and their regeneration. It is therefore and important entity that plays a critic function in the final product. Similarly calcium hydroxyde and proteins such as bone morphogenic proteins are considered important for the regeneration of bones.
  • the concentration of bone regenerative entities that interfere in the regeneration of bone tissues and cells will manage directly this specific effect.
  • the concentration of the bone regenerative entity in the final product is between 0.1 up to 50 %, preferably between 0.5 up to 45 % and more preferably between 1 up to 40 %. Concentrations are expressed weight / volume.
  • the bone regenerative compound can be use alone or mixed - at least 2 up to several 10 or so - with the same concentration or different ones.
  • the nature of the bone regenerative entity added can vary also. For example a calcium phosphate, a calcium carbonate or a protein. Calcium hydrate can also be part of the composition.
  • the use of a biocompatible, biodegradable and bioresorbable bone regenerative entity in addition to the biodegradable resin and multiblock induces a more biocompatible, biodegradable and bioresorbable dental implant or dental filler.
  • another embodiment is the use of these dental implants or dental fillers, described above, for the delivery of chemical compounds and/or cells for pharmaceutical and veterinary applications for humans and animals, respectively.
  • all the components used in the preparation of these implants or fillers are biocompatible, biodegradable or bioresorbable, the biopolymer, the multiblock and the bone regenerative entities.
  • a further embodiment is a method to prepare dental implants or filler without the use of any organic solvents.
  • the biological anchorage of the bone material of this invention to the host tissue is superior to the mechanical anchorages of the prior art.
  • the bone material overcomes the weakness problems associated with prior mechanically bonded artificial implants.
  • the host tissues identify the bone material as a biological material. Consequently, this material is incorporated within the host tissue and becomes an integral part with same. Since these bone material is continuously integrated to the host tissue and are also embedded within as described above, a long lasting biological bond is formed between an implant made of the bone material described herein and the host tissue.
  • the shear forces that develop at the implant- tissue interface are attenuated and translocated within the host tissue by the bone material of of this invention. Therefore, the main factors that cause the loosening of the mechanically secured artificial implants are eliminated as a result of the novel biological properties of the bone material of this invention and a long lasting function of the implant is made possible.
  • the implant or bone material of the present invention can be combined to other forms of prosthesis.
  • Materials which can be used for the production of prosthetic devices, such as in surgical prosthesis, can be for the production of the main body of the prosthetic device (its core);
  • Metal and Metal Alloys Metallic materials are used when the implant must withstand stress, shearing and torsion forces of considerable magnitude. Examples of such metallic materials are: austenitic stainless steel, titanium, titanium alloys and cobalt alloys. Metallic materials are used for the fabrication of orthopedic and dental implants; .
  • Plastic Substances Plastic materials are used to answer special biophysical demands.
  • the main body of a surgical ophtalmic implant is made of a plastic material like polymethymethacrylate that enables light to pass through;
  • high density polyethylene is used for the fabrication of articular surfaces of joint implants in order to answer low friction demands.
  • suitable plastic materials are: acrylics such as like polymethylmethacrylate,-aromatic acrylics, cyanoacrylate; silicone rubbers; polyethylene derivatives; polyacetal derivatives; 3) Ceramic Materials. Ceramic materials are used for the fabrication of articular surfaces of surgical joint implants when low friction and low wear surfaces are requested; and 4) Fiber Reinforced Plastic Polymers. Fiber reinforced plastic polymers are an alternative to the metallic materials for the fabrication of the main body of the surgical prosthetic device. Examples of these can be carbon reinforced polymers, carbon reinforced carbon, glass fibers reinforced polymer, plastic fibers reinforced polymer, collagen fibers reinforced polymer.
  • plastic polymers examples include acrylate derivatives, silicone rubber derivatives, polyethylene derivatives, polyacetal derivatives.
  • plastic polymers can be reinforced by fibers like: carbon fibers, glass fibers, plastic fibers, collagen fibers.
  • some collagen of different types can be used.
  • collagens used for the preparation of the biological substrate are collagen type I, collagen type II, collagen type III.
  • substances used to enrich the bone material can be, for example, but not limited to, fibronectin, platelet deriving growth factor, bone morphogenetic proteins, Vitamin D and its metabolites, growth factors, hormones, collagens types IV, V, VI, VII, VIII, IX, X.
  • Biological properties of the bone material is a biocompatible material without cytologic or toxic effects on any of the body tissues.
  • the bone material also can confer adequate mechanical strength to withstand forces that develop consequent to the long lasting implant function either within the main body or at the interfaces between the main body and other movable or non-movable parts of the prosthetic device.
  • the bone material when needed can be insoluble in any of the body fluids, thus preventing its degrading when implanted into the host.
  • an implant formed with the body material of the invention can not absorb body fluids nor change its dimension when implanted within the host.
  • PEG with molecular weight of 6,000 g/mol are added to a polyhydroxybutyrate latex solution (50 ml; 40 % weight/volume of PHB).
  • the resulting solution is mixed vigorously and placed in a freeze-dryer overnight.
  • a yellow colored foam is obtained, which is grounded in fin powder.
  • Between 5 to 10 % weight/volume of water are added to the powder, the resulting sample is mixed for few seconds to homogenize the water content. Then it is manipulate by finger in order to obtain a "modeling clay" structure that remain stable for several minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Materials For Medical Uses (AREA)
EP03706149A 2002-02-22 2003-02-19 Bioresorbierbares knochenimplantat Withdrawn EP1478415A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US35838502P 2002-02-22 2002-02-22
US358385P 2002-02-22
PCT/CA2003/000227 WO2003070292A1 (en) 2002-02-22 2003-02-19 Biodegradable bone implant

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EP1478415A1 true EP1478415A1 (de) 2004-11-24

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AU (1) AU2003208196A1 (de)
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DE102005022176B4 (de) 2005-05-09 2009-06-25 Martin-Luther-Universität Halle-Wittenberg Verfahren zur Herstellung von bioresorbierbaren Verbundmaterialien und seine Verwendung als Implantatmaterial sowie bioresorbiebaren Verbundmaterialien
US8350087B2 (en) 2006-04-12 2013-01-08 Agency For Science, Technology And Research Biodegradable thermogelling polymer
US8870871B2 (en) * 2007-01-17 2014-10-28 University Of Massachusetts Lowell Biodegradable bone plates and bonding systems
CN107349467A (zh) * 2016-05-09 2017-11-17 香港大学深圳医院 可降解型氧化镁-高分子基复合骨修复材料
US12564657B2 (en) 2019-08-31 2026-03-03 Shenzhen Corliber Scientific Co., Ltd. Mouldable artificial bone composite material and preparation method thereof

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JP3351525B2 (ja) * 1991-06-21 2002-11-25 ジェネティックス・インスティテュート・インコーポレイテッド 骨形成性蛋白医薬処方物
US5520923A (en) * 1994-09-19 1996-05-28 Genetics Institute, Inc. Formulations for delivery of osteogenic proteins
US5641502A (en) * 1995-06-07 1997-06-24 United States Surgical Corporation Biodegradable moldable surgical material
DE19858891A1 (de) * 1998-12-19 2000-06-21 Merck Patent Gmbh Verbesserte Knochensiegel
AU778081B2 (en) * 1999-03-25 2004-11-11 Tepha, Inc. Medical devices and applications of polyhydroxyalkanoate polymers

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CA2516728A1 (en) 2003-08-28
CA2516728C (en) 2014-05-20
AU2003208196A1 (en) 2003-09-09

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