WO2022136667A1 - Membrane de régénération osseuse guidée - Google Patents

Membrane de régénération osseuse guidée Download PDF

Info

Publication number
WO2022136667A1
WO2022136667A1 PCT/EP2021/087559 EP2021087559W WO2022136667A1 WO 2022136667 A1 WO2022136667 A1 WO 2022136667A1 EP 2021087559 W EP2021087559 W EP 2021087559W WO 2022136667 A1 WO2022136667 A1 WO 2022136667A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyanoacrylate
layer
polymer
bioresorbable polymer
gbr
Prior art date
Application number
PCT/EP2021/087559
Other languages
English (en)
Inventor
Sankalp AGARWARL
Original Assignee
Technological University Dublin
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 Technological University Dublin filed Critical Technological University Dublin
Publication of WO2022136667A1 publication Critical patent/WO2022136667A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • 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
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • 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 invention relates to guided bone regeneration (GBR) membranes, methods of making a GBR membrane, and methods of making a layer of bioresorbable polymer for a GBR membrane.
  • GBR guided bone regeneration
  • the invention also extends to medical uses and methods of treatment using the GBR membrane.
  • Bone is capable of regenerating itself after it has been damaged. Consequently, clinicians rely on bone regeneration to, for example, replace bone tissue that has been extracted as a result of dental surgery.
  • surrounding soft connective tissue in order to create an environment that promotes regeneration of craniofacial-maxillofacial bone (i.e. an osteogenic environment), surrounding soft connective tissue must be prevented from infiltrating the bone defect/damaged bone.
  • GBR membranes are used to seal bone defects and thus prevent the invasion of surrounding soft connective tissue without obstructing the exchange of the surrounding body fluids.
  • Non- degradable materials such as extended-PTFE (e-PTFE) and titanium, have successfully been used to create GBR membranes.
  • e-PTFE extended-PTFE
  • some of the drawbacks of using such membranes include that they cause infections, they have a low success rate in healing bone defects, and they require a second surgical intervention in order to be removed.
  • a guided bone regeneration (GBR) membrane comprising at least one layer of bioresorbable polymer having an adhesive component and bone mineral nanoparticles.
  • the GBR membrane according to the invention can be used to seal (dental or craniomaxillofacial) bone defects, enhance the healing of bone defects, prevent the invasion of surrounding soft connective tissue, provide an osteogenic environment, and enhance (3D) bone regeneration.
  • the GBR membrane is advantageous because it can be tuned to create a membrane with ideal mechanical properties and a predictable degradation rate.
  • the GBR membrane is biocompatible (i.e. inert and non-toxic to a mammalian body) and bioresorbable. Thus, as the GBR membrane degrades new bone can grow into the space previously occupied by the membrane.
  • the GBR membrane may comprise a first layer of layer of bioresorbable polymer bonded to a further/second layer of material.
  • the second layer of material may comprise polymer (e.g. a non-bioresorbable polymer, or a second layer of layer of bioresorbable polymer), or a non-degradable material (such as extended-PTFE (e- PTFE) or titanium).
  • the second layer comprises a layer of bioresorbable polymer.
  • the GBR membrane may comprise a first layer of bioresorbable polymer bonded to a second layer of bioresorbable polymer by an adhesive component, wherein the first layer and/or the second layer of bioresorbable polymer comprise bone mineral nanoparticles.
  • the first layer and/or second layer of bioresorbable polymer may comprise an aliphatic synthetic polymer, such as an aliphatic synthetic polyester.
  • the polymer of the GBR membrane acts as a barrier that prevents cells and connective tissue entering into a bone defect.
  • bioresorbable polymer refers to a polymer which, when placed in a mammalian organism, completely degrades and is then absorbed by the organism.
  • the GBR membrane of the invention is advantageous because it does not need to be removed after insertion into a bone defect, unlike GBR membranes made from non-bioresorbable/non-degradable polymers.
  • the bioresorbable polymer may degrade by being dissolved or by metabolised (enzymatic degradation).
  • the polymer may be degraded by hydrolysis.
  • the degradation may be partial or complete.
  • Most synthetic aliphatic polymers and their co-polymers are degraded by hydrolysis.
  • the layer of bioresorbable polymer may comprise an aliphatic synthetic polymer, such as an aliphatic synthetic polyester (e.g. polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), polyy-valerolactone (PVL) or polylactic-co-glycolic acid (PLGA)).
  • an aliphatic synthetic polymer such as an aliphatic synthetic polyester (e.g. polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), polyy-valerolactone (PVL) or polylactic-co-glycolic acid (PLGA)).
  • PVA polylactic acid
  • PCL polycaprolactone
  • PGA polyglycolic acid
  • PVL polyy-valerolactone
  • PLGA polylactic-co-glycolic acid
  • Collagen Collagen, glycosamine glycans (hyaluronic acid, chondroitin sulphate, dermatan sulphate and keratan sulphate), silk fibres, chitosan, alginate, signalling peptides including BMP2 and RGD, cellulose, agarose, starch, lecithin and polyamino acids also improve the bone healing process.
  • glycosamine glycans hyaluronic acid, chondroitin sulphate, dermatan sulphate and keratan sulphate
  • silk fibres chitosan
  • alginate signalling peptides including BMP2 and RGD
  • signalling peptides including BMP2 and RGD
  • cellulose agarose
  • starch starch
  • lecithin polyamino acids
  • the bioresorbable polymer may comprise one or more polymers selected from the following group consisting of polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA) or polylactic-co-glycolic acid (PLGA), polyy-valerolactone (PVL), polycarbonate, polyfumarate, polyorthoester, elastomeric polyesters including poly-(diol citrate) elastomers, poly (butylene succinate-co-glycolate), polyurethanes, organic-inorganic hybrid silanes, organic silanes, inorganic silanes, polyanhydrides, polyvinylpyrrolidinones, polyorthoester, polyanhydride, poly(ethylene glycol), poly(glycerol sebacate), poly(trimethylene carbonate), collagen, glycosamine glycans (hyaluronic acid, chondroitin sulphate, dermatan sulphate or keratan sulphide
  • the bioresorbable polymers are also are biocompatible, and thus do not require a follow up surgery to be removed.
  • the polymers are biomimetic because they are made from biopolymers that promote wound healing and bone regeneration.
  • GBR membranes made from bioresorbable, aliphatic synthetic polymers are also advantageous because they provide GBR membranes with appropriate levels of tensile strength and are capable of drug encapsulation.
  • the bioresorbable polymer comprises one or more polymers selected from the group consisting of PLA, PCL, PGA, PVL, PLGA, hyaluronic acid (HA) and collagen.
  • the (first) layer of bioresorbable polymer comprises PLGA or PCL.
  • PLGA, PCL, poly(propylene fumarate) and poly(diol citrate) are biocompatible and osteoinductive.
  • the second layer of bioresorbable polymer comprises hyaluronic acid and/or collagen.
  • Hyaluronic acid and collagen are both components of bone extracellular matrix, collagen is osteoinductive and hyaluronic acid aids promotes attachment and proliferation of cells that promote bone regeneration.
  • the first layer of bioresorbable polymer comprises PLGA or PCL
  • the second layer of bioresorbable polymer comprises hyaluronic acid and/or collagen.
  • the GBR membrane may comprise three or more, four or more, five or more, six or more, or seven or more layers of (bioresorbable) polymer bonded to each other.
  • the first layer and/or the second layer of bioresorbable polymer may be bonded by a first adhesive component, whereas the third or more layers of polymer may be bonded by a second adhesive component.
  • the second adhesive component may or may not be identical to the first adhesive component.
  • the third or more layers of polymer may comprise a non-bioresorbable polymer, a non-degradable material (such as extended- PTFE (e-PTFE) or titanium) or layer(s) of bioresorbable polymer.
  • Each of the polymer layers of the GBR membrane may comprise different polymers or the same polymer(s).
  • the first and the second layer of bioresorbable polymer may comprise the same polymer.
  • the first and the second layer of bioresorbable polymer may comprise a different polymer.
  • the first and second layer of bioresorbable polymer may comprise the same polymer, whereas the remaining polymer layers may comprise a different polymer.
  • One or more of the layers of the bioresorbable polymer may or may not be porous.
  • the pores in the bioresorbable polymer may be introduced by a cyanoacrylate adhesive.
  • the at least one layer of bioresorbable polymer may be porous or non- porous.
  • the first layer and/or the second layer of bioresorbable polymer may be porous or non-porous.
  • the porosity of the GBR membrane (e.g. the first and/or the second bioresorbable polymer layer) may be between about 0% and about 99% void/volume, between about 10% and about 90% void/volume, between about 20% and about 80% void/volume, between about 20% and about 70% void/volume, between about 20% and about 60% void/volume or between 30% and 50% void/volume.
  • the porosity is between about 30% and 50% void/volume.
  • the average length/diameter of the pores may be between about 0.1 pm and 200 pm.
  • the pores enable fluid exchange but block/prevent the passage of connective tissue, epithelial cells and others cells that are detrimental to bone formation. Fluid exchange is important because it enables essential nutrients and other biological factors (e.g. growth factors, enzymes and ions) to assist the healing process.
  • One or more of the bioresorbable polymer layers of the GBR membrane may comprise a therapeutic agent.
  • the at least one layer of bioresorbable polymer or the first and/or the second layer may comprise a therapeutic agent.
  • the therapeutic agent may include, but is not limited to, an analgesic; an NSAID; a local anaesthetic; an antimicrobial agent; an antifungal agent; a genetically engineered peptides/protein; a glycoprotein; a lipoprotein; an immunomodulatory stimulator; an immunomodulatory inhibitor; a growth factor; an oligonucleotide; a chemotherapeutic agent; fibrin; fibronectin; and blood coagulation agents.
  • the adhesive component may cause the formation of pores in the bioresorbable polymer layers of the GBR membrane. Where appropriate, the adhesive component may bond the layers of bioresorbable polymer together and thus retain a laminated structure of the GBR membrane.
  • the adhesive may be bioresorbable.
  • the GBR membrane as a whole may be bioresorbable.
  • the bioresorbable adhesive component comprises a cyanoacrylate adhesive. Cyanoacrylate adhesives are biocompatible (inert and non-toxic to a mammalian body) and bioresorbable. Cyanoacrylate adhesives degrade and are absorbed by the user as bone tissue grows into the space occupied by the GBR membrane.
  • Cyanoacrylates adhesives are formed from cyanoacrylate monomers. Cyanoacrylate adhesives may be formed from monomers that polymerise in an anionic environment (e.g. in the presence of water molecules, biopolymers or body fluids containing functional groups such as -NH2, -OH, -COO ). A cyanoacrylate adhesive may be a mono-a cyanoacrylate or a bis- a cyanoacrylate.
  • a mono-a cyanoacrylate adhesive may be one or more selected from the group consisting of: alkyl- and cycloalkyl-a- cyanoacrylates such as methyl-a-cyanoacrylate, ethyl-a-cyanoacrylate, propyl-a- cyanoacrylate, butyl-a-cyanoacrylate, and cyclohexyl-a-cyanoacrylate; alkenyl- and cycloalkenyl-a-cyanoacrylates such as allyl-a-cyanoacrylate, methacryl-a- cyanoacrylate, and cyclohexenyl-a-cyanoacrylate; alkynyl-a-cyanoacrylates such as propangyl-a-cyanoacrylate; aryl-a-cyanoacrylates such as phenyl-a-cyanoacrylate and tolyl-a-cyanoacrylate; alkoxyalkyl-a-cyanoacrylates such as methoxymethyl-a- cyano
  • the cyanoacrylate adhesive may be one or more selected from the group consisting of: n-butyl cyanoacrylate, methyl-2 cyanoacrylate, ethyl-2 cyanoacrylate, octyl cyanoacrylate (OCA), and octyl- 2 cyanoacrylate.
  • the cyanoacrylate is octyl cyanoacrylate (OCA) due to its lack of toxicity and weak ability to induce irritation.
  • the adhesive may bond bioresorbable polymer layers together by cross-linking.
  • the cross-linkages may define pores in the adhesive and/or the bioresorbable polymer layer(s).
  • the adhesive component may be porous or non-porous.
  • the adhesive component e.g. a cyanoacrylate, such as OCA
  • the (second) adhesive component that bonds the remaining bioresorbable polymer layers may or may not be porous.
  • the pores in the porous adhesive component enable fluid exchange but prevent the passage of connective tissue, epithelial cells and others cells that are detrimental to bone formation.
  • the invention is advantageous because it can be tuned so as to control the rate of degradation of the GBR membrane.
  • a GBR membrane comprising an adhesive component (e.g. a cyanoacrylate) with cross-links decreases the rate of degradation compared to a GBR membrane without cross-links.
  • the porosity of the adhesive may be between about 1% and about 99% void/volume, 0% and about 99% void/volume, between about 10% and about 90% void/volume, between about 20% and about 80% void/volume, between about 20% and about 70% void/volume, between about 20% and about 60% void/volume or between 30% and 50% void/volume.
  • the porosity is between about 30% and 50% void/volume.
  • the pore size may be between about 0.1 pm to about 1800 pm, or between about 1 pm to about 900 pm or between about 10 pm and about 400 pm.
  • the pore size is between about 10 pm and about 400 pm.
  • the inventors have found that the concentration of cyanoacrylate present in the adhesive may be used to control the ductility of the GBR membrane (see Example 1) and the porosity of the GBR membrane (see Example 2).
  • the cyanoacrylate may be mixed with a liquid form of the GBR membrane (e.g. a liquid/solution of the bioresorbable polymer).
  • concentration of cyanoacrylate (e.g. OCA) in the GBR membrane may be between about 0.1%v/v and about 3%v/v.
  • the pores of the adhesive component e.g. a cyanoacrylate, such as OCA
  • OCA cyanoacrylate
  • An interconnected network of crevices or pores may further enhance fluid exchange.
  • the concentration of cyanoacrylate may be less than about 3% v/v, less than about 2.5%v/v, or less than about 2% v/v.
  • the concentration of cyanoacrylate may be greater than about 0.1 %v/v, may be greater than about 0.5 %v/v, or may be greater than about 1 %v/v.
  • the concentration of cyanoacrylate e.g. OCA
  • the concentration of cyanoacrylate (e.g. OCA) may be about 2%v/v.
  • the concentration of cyanoacrylate (e.g. OCA) is between about 0.5%v/v and 2% v/v. This preferred concentration range ensures that the adhesive component forms an interconnected network of regular pores.
  • the adhesive e.g. a cyanoacrylate, such as OCA
  • the adhesive may be dissolved or mixed with a selection of one or more of the following: Tetrahydrofuran, dimethylsulfoxide, Dimethyl formamide, dichloromethane, chloroform, pentane, heptane, methyl cycloheaxane, toluene, dichlorobenzene, bromonaphthalene, nitroethane, nitromethane, diethyl ethers, n-butyl acetate, dioctylpthalate, ethyl acetate, acetone, dibutyl phthalate, di-methyl phthalate, propylene carbonat and ethylene carbonate.
  • Tetrahydrofuran dimethylsulfoxide, Dimethyl formamide, dichloromethane, chloroform, pentane, heptane, methyl cycloheaxane, toluene, dichlorobenzen
  • the adhesive e.g. a cyanoacrylate, such as OCA
  • the adhesive is diluted or mixed with chloroform, dichloromethane or THF.
  • the adhesive e.g. a cyanoacrylate, such as OCA
  • the adhesive is dissolved or mixed with chloroform.
  • Most synthetic aliphatic polyesters e.g. PLGA, PCL, PLA, PGA and other related polymers
  • cyanoacrylates do not react with chloroform, dichloromethane or THF.
  • the GBR membrane according to the invention may have a %strain of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 99%.
  • the adhesive component may be formed by coating (e.g. dip-coating or spraying) the at least one layer of bioresorbable polymer layer with adhesive.
  • the thickness of the adhesive component coating on the bioresorbable polymer layers may be between about 10 nm and about 200 pm. Preferably the thickness of the adhesive component coating on the bioresorbable polymer layers is between about 1pm and 50 pm.
  • the adhesive component may bond a longitudinal surface of a first layer of bioresorbable polymer to a longitudinal surface of a second layer of bioresorbable polymer.
  • the bioresorbable polymer layers of the GBR membrane may be bonded to each other such that they are coincident (i.e. line up).
  • the adhesive component may bond a longitudinal surface of first layer of bioresorbable polymer to a longitudinal surface of the second layer of bioresorbable polymer so that the first and the second layers are coincident with each other.
  • the adhesive component may or may not be a 2D or 3D layer.
  • the adhesive component may be an interdigitating network.
  • the adhesive component may be between (and optionally within) the bioresorbable polymer layers.
  • the interdigitating network may extend continuously from one end of the GBR membrane to the opposing end.
  • the interdigitating network may be discontinuous.
  • Bone mineral nanoparticles can refer to inorganic minerals found naturally in the bone of a mammal, such as a human being.
  • the bone mineral nanoparticle may be magnesium oxide (MgO).
  • the bone mineral nanoparticle may be magnesium hydroxide (Mg(OH)2).
  • the bone mineral nanoparticle may be hydroxyapatite (HA).
  • Bone mineral nanoparticles such as MgO, HA and (Mg(OH)2 promotes proliferation of osteoblasts.
  • bone mineral nanoparticles in the GBR membrane e.g. first and/or the second layer of bioresorbable polymer
  • the GBR membrane mimic the (organic and inorganic) ultrastructure of bone. Consequently, the bone mineral nanoparticles encourage bone formation and cell occlusion.
  • nanoparticle-sized bone minerals can be uniformly distributed throughout the GBR membrane (e.g. the adhesive component and/or the layer(s) of bioresorbable polymer).
  • the bone mineral nanoparticles may be inorganic mineral salts, such as magnesium salts and/or calcium salts.
  • the bone mineral nanoparticles may comprise a selection of one or more members of the group consisting of: magnesium oxide (MgO), magnesium hydroxide (Mg(OH)2), hydroxyapatite (HA/ Ca5(PO4)3(OH)), P-tricalcium phosphates, copper oxides, zinc oxides (e.g.
  • the bone mineral nanoparticles are HA and MgO; HA and Mg(OH)2, or Mg(OH)2.
  • HA, MgO and Mg(OH)2 each separately promote (3D) bone growth/repair.
  • the bone mineral nanoparticles do not comprise pure magnesium particles, granules or powder (e.g. particles, granules or powder that is greater than 99% by weight magnesium). Magnesium particles, granules and powder are highly reactive and produce large amounts of localised hydrogen gas and alkalinity which hamper the bone healing process.
  • the bone mineral nanoparticles may be any shape, for example, spherical or polygonal.
  • the length/diameter of the nanoparticles may be on average less than 1000 nm e.g. about 1 nm to 1000 nm.
  • the bone mineral nanoparticles may have an average length/diameter of less than about 500nm, less than about 400nm, less than about 300nm, less than about 200nm, or less than about 150nm.
  • the bone mineral nanoparticles e.g.
  • MgO, Mg(OH)2 and/or hydroxyapatite may have an average length/diameter of about 10 nm to 450nm, about 20 nm to 400nm, about 30 nm to 300nm, about 40 nm to 200nm, about 50 nm to 150nm.
  • the average length/diameter of the bone mineral nanoparticles is about 50 nm to 150nm.
  • the size of the bone mineral nanoparticles discussed herein refers to the average size in the population/composition of the bone mineral nanoparticles.
  • the at least one layer of bioresorbable polymer may comprise uniformly distributed bone mineral nanoparticles.
  • the adhesive component may comprise bone mineral nanoparticles, preferably uniformly distributed. Uniform distribution of the bone mineral nanoparticles improves the mechanical properties of the GBR membrane, improves the bone repairing activity and promotes 3D growth of bone.
  • the polymer layers of the GBR membrane may comprise different bone mineral nanoparticles or the same bone mineral nanoparticles.
  • the first and the second layer of bioresorbable polymer may comprise the same bone mineral nanoparticles (e.g. HA and MgO).
  • the first and the second layer of bioresorbable polymer may comprise different bone mineral nanoparticles.
  • the first and second layer of bioresorbable polymer may comprise the same bone mineral nanoparticles (e.g. HA and MgO), whereas the remaining polymer layers may comprise different bone mineral nanoparticles.
  • One or more, two or more, three or more, four or more, five or more, six or more of the layers of the bioresorbable polymer may not comprise bone mineral nanoparticles.
  • the first layer and/or the second layer of bioresorbable polymer may not comprise bone mineral nanoparticles.
  • the GBR membrane may comprise bone mineral particles at a density of between about 1% w/w and about 90% w/w with respect to the weight of the polymer layers and the adhesive component.
  • the GBR membrane may comprise bone mineral particles at density of less than about 90% w/w, less than about 85% w/w, less than about 80% w/w, less than about 75% w/w, less than about 70% w/w, less than about 65% w/w, less than about 60% w/w, less than about 55% w/w, less than about 50% w/w, less than about 45% w/w, less than about 40% w/w, less than about 35% w/w, less than about 30% w/w, less than about 25% w/w, less than about 20% w/w, less than about 15% w/w, less than about 10% w/w, or less than about 5% w/w.
  • the GBR membrane may comprise bone mineral particles at a density of between about 5% w/w and about 87.5% w/w, between about 7.5% w/w and about 87.5% w/w, between about 10% w/w and about 85% w/w, between about 15% w/w and about 82.5% w/w, between about 20% w/w and about 80% w/w, between about 25% w/w and about 77.5% w/w, between about 30% w/w and about 70% w/w, between about 35% w/w and about 65% w/w, between about 40% w/w and about 60% w/w, or between about 45% w/w and about 55% w/w.
  • Preferably polymer layer(s) of the GBR membrane comprise bone mineral particles at a density of between about 45% w/w and about 55% w/w, or at a density of about 50% w/w.
  • the bioresorbable polymer layer(s) e.g. the first and/or second bioresorbable polymer layers
  • the GBR membrane according to the invention may comprise a uniform distribution of the bone mineral nanoparticles, HA, Mg(OH)2 and/or MgO.
  • Bone mineral nanoparticles such as MgO and Mg(OH)2 generate alkaline conditions.
  • the inventors have found that these alkaline conditions neutralise the acidic environment required for enzymatic hydrolysis of the bioresorbable polymer, such as aliphatic synthetic polymers. Consequently, this can delay degradation of the bioresorbable polymer.
  • the GBR membrane may further comprise a dispersant.
  • the first and/or second bioresorbable polymer layer may comprise a dispersant.
  • the dispersant may be added to the GBR membrane in order to reduce clumping or aggregation of the bone mineral nanoparticles. The dispersant may therefore encourage uniform distribution of bone mineral nanoparticles within the bioresorbable polymer and/or the adhesive component.
  • the dispersant may be added to a liquid form of the GBR membrane (e.g. a liquid/solution of the bioresorbable polymer, the adhesive and/or the bone mineral nanoparticles).
  • the dispersant may be basic/alkaline in nature.
  • the dispersant, particularly basic dispersants may cause uniform distribution of the bone mineral nanoparticles due to electrostatic interactions with the bone mineral nanoparticles in the liquid form of the GBR membrane (e.g. a liquid/solution of the bioresorbable polymer and/or the adhesive).
  • the dispersant may be a surfactant.
  • the dispersant may comprise one or more members selected from the group consisting of triethanolamine (TEOA), allylamine, 2-butoxy ethanol (2-BU), polyethyleneimineamine, propyltriethoxy silane, bis(trimethoxysilylpropyl)amine and a glycolether.
  • the glycolether may be one more members from the group consisting of ethylene glycol ethers; propylene glycol ethers; butylglycolether; mono-, di-, and triglycol ethers; and phenyl-glycol ethers.
  • the dispersant is TEOA and/or allylamine.
  • the dispersants particularly those that comprise an amine group, such as triethanolamine (TEOA), allylamine, polyethyleneimineamine, propyltriethoxy silane and bis(trimethoxysilylpropyl)amine, may also initiate the polymerisation of cyanoacrylate adhesives.
  • TEOA triethanolamine
  • allylamine polyethyleneimineamine
  • propyltriethoxy silane propyltriethoxy silane
  • bis(trimethoxysilylpropyl)amine may also initiate the polymerisation of cyanoacrylate adhesives.
  • the GBR membrane (e.g. the first and/or second layer of bioresorbable polymer and the adhesive) may comprise a dispersant, such as TEOA and/or allylamine.
  • the concentration of the dispersant e.g. TEOA and/or allylamine
  • concentration of the dispersant e.g. TEOA and/or allylamine
  • GBR membrane may comprise between about 0.1% v/v and 20% v/v TEOA.
  • the adhesive component may comprise between about 0.1% v/v and 20% v/v TEOA.
  • GBR membrane comprises between about 0.3% and 10% v/v TEOA.
  • the dispersant e.g. TEOA and/or allylamine
  • the dispersant may be used to improve surface wettability and/or increase the rate of surface wettability of the polymer layers of the GBR membrane.
  • Increasing wettability of the GBR membrane makes the surface more hydrophilic and thus increases absorption of water.
  • the increased hydrophilic nature of the GBR membrane thus also promotes fluid exchange across the GBR membrane.
  • the dispersant may further increase the porosity of the GBR membrane.
  • the dispersant may enable the surface of the bioresorbable polymer to be coated with a natural polymer.
  • the natural polymer may be one or more polymers selected from the group consisting of collagen, glucosamine glycans (hyaluronic acid), chondroitin sulphate, dermatan sulphate or keratin sulphate), silk fibres, chitosan, alginate, signalling peptides including BMP2 and RGD, cellulose, agarose, starch, lecithin and polyamine acids.
  • Surface modification/coating of the GBR membrane with natural polymers promotes adhesion of bone-forming and bone-degrading cells that ultimately repair of the bone.
  • Surface modification/coating of the GBR membrane with natural polymers also improves the wettability of the membrane. Wettability of the GBR membrane is also improved by the presence of bone mineral nanoparticles.
  • a guided bone regeneration (GBR) membrane may comprise a layer of bioresorbable polymer (e.g. PLA, PGA, PVL, PCL and/or PLGA) having an adhesive component (e.g. a cyanoacrylate) and one or more types of nanoparticle selected from the group consisting of: hydroxyapatite (HA) nanoparticles, magnesium hydroxide nanoparticles and magnesium oxide nanoparticles.
  • a layer of bioresorbable polymer e.g. PLA, PGA, PVL, PCL and/or PLGA
  • an adhesive component e.g. a cyanoacrylate
  • nanoparticle selected from the group consisting of: hydroxyapatite (HA) nanoparticles, magnesium hydroxide nanoparticles and magnesium oxide nanoparticles.
  • a guided bone regeneration (GBR) membrane may comprise a first layer of bioresorbable polymer (e.g. PLA, PGA, PVL, PCL or PLGA) bonded to a second layer of bioresorbable polymer (e.g. PLA, PGA, PVL, PCL, PLGA, collagen or HA) by an adhesive component (e.g. a cyanoacrylate), wherein the first layer and/or the second layer of bioresorbable polymer comprise hydroxyapatite (HA) nanoparticles, magnesium hydroxide nanoparticles and/or magnesium oxide nanoparticles.
  • HA hydroxyapatite
  • a guided bone regeneration (GBR) membrane may comprise a layer of bioresorbable polymer having an adhesive component (e.g. a cyanoacrylate) and bone mineral nanoparticles (e.g. hydroxyapatite (HA) nanoparticles, magnesium oxide nanoparticles and/or magnesium hydroxide nanoparticles), wherein the layer of bioresorbable polymer comprises one or more polymers selected from the group consisting of PLA, PGA, PCL, PVL, PLGA, HA and collagen.
  • an adhesive component e.g. a cyanoacrylate
  • bone mineral nanoparticles e.g. hydroxyapatite (HA) nanoparticles, magnesium oxide nanoparticles and/or magnesium hydroxide nanoparticles
  • the layer of bioresorbable polymer comprises one or more polymers selected from the group consisting of PLA, PGA, PCL, PVL, PLGA, HA and collagen.
  • a guided bone regeneration (GBR) membrane may comprise a first layer of bioresorbable polymer bonded to a second layer of bioresorbable polymer by an adhesive component (e.g. a cyanoacrylate), wherein the first layer and/or the second layer of bioresorbable polymer comprise bone mineral nanoparticles (e.g. hydroxyapatite (HA) nanoparticles, magnesium oxide nanoparticles and/or magnesium hydroxide nanoparticles), and wherein the first layer and/or the second layer of bioresorbable polymer comprises one or more polymers selected from the group consisting of PLA, PGA, PCL, PVL, PLGA, HA and collagen.
  • an adhesive component e.g. a cyanoacrylate
  • the first layer and/or the second layer of bioresorbable polymer comprise bone mineral nanoparticles (e.g. hydroxyapatite (HA) nanoparticles, magnesium oxide nanoparticles and/or magnesium hydroxide nanoparticles)
  • a guided bone regeneration (GBR) membrane may comprise a layer of bioresorbable polymer (e.g. collagen, PLA, PGA, PVL, PCL and/or PLGA) having a cyanoacrylate (e.g. OCA) adhesive component and bone mineral nanoparticles (e.g. hydroxyapatite (HA) nanoparticles and/or magnesium oxide nanoparticles).
  • a layer of bioresorbable polymer e.g. collagen, PLA, PGA, PVL, PCL and/or PLGA
  • a cyanoacrylate (e.g. OCA) adhesive component e.g. cyanoacrylate (e.g. OCA) adhesive component
  • bone mineral nanoparticles e.g. hydroxyapatite (HA) nanoparticles and/or magnesium oxide nanoparticles.
  • a guided bone regeneration (GBR) membrane may comprise a first layer of bioresorbable polymer (e.g. collagen, PLA, PGA, PVL, PCL and/or PLGA) bonded to a second layer of bioresorbable polymer (e.g. collagen, PLA, PGA, PVL, PCL and/or PLGA) by an adhesive component comprising a cyanoacrylate (e.g. OCA), wherein the first layer and/or the second layer of bioresorbable polymer comprise bone mineral nanoparticles (e.g. hydroxyapatite (HA) nanoparticles and/or magnesium oxide nanoparticles).
  • a first layer of bioresorbable polymer e.g. collagen, PLA, PGA, PVL, PCL and/or PLGA
  • an adhesive component comprising a cyanoacrylate (e.g. OCA)
  • the first layer and/or the second layer of bioresorbable polymer comprise bone mineral nanoparticles (e.g. hydroxyapatite (HA
  • the at least one layer of bioresorbable polymer may comprise collagen.
  • the at least one layer of bioresorbable polymer may comprise may comprise PLA.
  • the at least one layer of bioresorbable polymer may comprise may comprise PGA.
  • the at least one layer of bioresorbable polymer may comprise may comprise PCL.
  • the at least one layer of bioresorbable polymer may comprise PVL.
  • the at least one layer of bioresorbable polymer may comprise PLGA.
  • the at least one layer of bioresorbable polymer may comprise may comprise HA.
  • the first layer of bioresorbable polymer comprises PLGA or PCL.
  • the second layer of bioresorbable polymer comprises hyaluronic acid and/or collagen.
  • the GBR membrane (e.g. the first and/or second layer of bioresorbable polymer and the adhesive component) may comprise pores.
  • the porosity the GBR membrane may be between about 5% and about 90% void/volume.
  • Preferably the porosity of the GBR membrane is between about 30% and about 50% void/volume.
  • the adhesive component may comprise a cyanoacrylate.
  • the cyanoacrylate may be OCA.
  • the cyanoacrylate may be n-butyl cyanoacrylate.
  • the cyanoacrylate may be methyl-2 cyanoacrylate.
  • the cyanoacrylate may be ethyl-2 cyanoacrylate.
  • the cyanoacrylate may be octyl-2 cyanoacrylate.
  • the adhesive component comprises cyanoacrylate, such as OCA.
  • the concentration of cyanoacrylate (e.g. OCA) in the GBR membrane may be between about 0.5%v/v and 2% v/v.
  • the bone mineral nanoparticles may comprise HA.
  • the bone mineral nanoparticles may comprise MgO.
  • the bone mineral nanoparticles may comprise Mg(OH)2.
  • Preferably the bone mineral nanoparticles comprise HA and MgO.
  • the GBR membrane may further comprise a dispersant.
  • the dispersant may be triethanolamine (TEOA).
  • the dispersant may be allylamine.
  • the dispersant may be 2- butoxy ethanol.
  • Preferably the dispersant is TEOA.
  • the GBR membrane (e.g. the first and/or second layer of bioresorbable polymer and/or the adhesive component) may comprise between about 0.3% and 10% v/v TEOA.
  • the GBR membrane comprises a layer of PCL having an OCA adhesive component, hydroxyapatite (HA) nanoparticles and magnesium oxide nanoparticles.
  • the GBR membrane comprises a first layer of PCL bonded to a second layer of bioresorbable polymer by an OCA adhesive component, wherein the first layer and/or the second layer of bioresorbable polymer comprise hydroxyapatite (HA) nanoparticles and magnesium oxide nanoparticles.
  • HA hydroxyapatite
  • the GBR membrane comprises a first layer of PCL bonded to a second layer of bioresorbable polymer by an OCA adhesive component, wherein the first layer and/or the second layer of PCL comprise hydroxyapatite (HA) nanoparticles, magnesium oxide nanoparticles and a dispersant (e.g. TEOA).
  • the first layer of PCL and/or second layer of bioresorbable polymer may comprise between about 0.3% and 10% v/v TEOA.
  • the GBR membrane according to the invention may exhibit one or more of the following characteristics: • biocompatibility due, at least, to the bioresorbable polymer and the bone mineral nanoparticles;
  • a method of producing a GBR membrane comprising: coating a first layer of bioresorbable polymer with a cyanoacrylate adhesive to create a coated first layer of bioresorbable polymer, and contacting a second layer of polymer with the coated first layer of bioresorbable polymer to form a GBR membrane, wherein the first layer of bioresorbable polymer and/or the second layer of polymer comprise bone mineral nanoparticles.
  • the first or second layer may comprise a polymer (such as a non-bioresorbable polymer or a bioresorbable polymer) or a non-degradable material (such as extended- PTFE (e-PTFE) or titanium), preferably the first and second layers comprise a bioresorbable polymer.
  • a polymer such as a non-bioresorbable polymer or a bioresorbable polymer
  • a non-degradable material such as extended- PTFE (e-PTFE) or titanium
  • the coating step may comprise immersion coating, spray-coating, dip-coating and/or spin-coating with cyanoacrylate adhesive.
  • Contacting a second layer of bioresorbable polymer with the coat of cyanoacrylate adhesive may comprise applying pressure to the first and/or second layer of bioresorbable polymer to further bond the two layers together.
  • Contacting a second layer of bioresorbable polymer with the coated first layer may comprise bonding a longitudinal surface of the first layer of bioresorbable polymer to a longitudinal surface of the second layer of bioresorbable polymer.
  • the bioresorbable polymer layers of the GBR membrane may be bonded such that they are coincident (i.e. line up).
  • the contacting step may comprise the cyanoacrylate adhesive bonding a longitudinal surface of first layer of bioresorbable polymer to a longitudinal surface of the second layer of bioresorbable polymer so that the first and the second layers are coincident with each other.
  • the cyanoacrylate adhesive may or may not be a 2D or 3D layer.
  • the adhesive component may be an interdigitating network.
  • the adhesive component may be between (and optionally within) the bioresorbable polymer layers.
  • the interdigitating network may extend continuously from one end of the GBR membrane to the opposing end.
  • the interdigitating network may be discontinuous.
  • the method according to the invention may further comprise drying GBR membrane after the contacting step.
  • the method according to the invention may comprise contacting a second layer of polymer with the coated first layer of bioresorbable polymer to form a GBR membrane, wherein the first layer and/or the second layer of bioresorbable polymer comprise bone mineral nanoparticles.
  • the second layer of polymer may be a layer of bioresorbable polymer.
  • the method according to the second aspect of the invention may comprise making a GBR membrane according to the first aspect of the invention.
  • a method of producing a solid layer of bioresorbable polymer or a GBR membrane comprising: mixing a liquid of cyanoacrylate adhesive with a liquid of bioresorbable polymer to create a polymer-cyanoacrylate mixture, and drying the polymer-cyanoacrylate mixture to create a (first) solid layer of bioresorbable polymer or a GBR membrane.
  • the method of the invention is rapid and cost effective, particularly when compared to known techniques used to prepare GBR membranes (e.g. freeze-drying and electrospinning).
  • the method is also advantageous because it allows the elasticity of the membrane as well as the porosity to be tuned accordingly.
  • the liquid of bioresorbable polymer may be made by dissolving the polymer with a solvent.
  • the liquid of cyanoacrylate adhesive may be made by dissolving the polymer with a solvent.
  • the solvent may be chloroform, dichloromethane and/or tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the solvent is chloroform.
  • the bioresorbable polymer may comprise a selection of one or more from the following group consisting of PLA, PCL, PVL, PGA, PLGA, polycarbonate, polyfumarate, polyorthoester, elastomeric polyesters including poly-(diol citrate) elastomers, poly (butylene succinate-co-glycolate), polyurethanes, organic-inorganic hybrid silanes, organic silanes, inorganic silanes, polyanhydrides, polyvinylpyrrolidinones, polyorthoester, polyanhydride, poly(ethylene glycol), poly(glycerol sebacate), poly(trimethylene carbonate), collagen, glycosamine glycans (hyaluronic acid, chondroitin sulphate, dermatan sulphate or keratan sulphate), silk fibres, chitosan, alginate, BMP2, RGD, cellulose, agarose, starch, lecithin, poly
  • the cyanoacrylate adhesive may be a mono-a cyanoacrylate or a bis- a cyanoacrylate.
  • a mono-a cyanoacrylate adhesive may be one or more selected from the group consisting of: alkyl- and cycloalkyl-a-cyanoacrylates such as methyl-a-cyanoacrylate, ethyl-a-cyanoacrylate, propyl-a-cyanoacrylate, butyl-a-cyanoacrylate, and cyclohexyl-a-cyanoacrylate; alkenyl- and cycloalkenyl-a-cyanoacrylates such as allyl- a-cyanoacrylate, methacryl-a-cyanoacrylate, and cyclohexenyl-a-cyanoacrylate; alkynyl-a-cyanoacrylates such as propangyl-a-cyanoacrylate; aryl-a-cyanoacrylates such as phenyl-a-cyanoacrylate and tolyl-
  • the cyanoacrylate adhesive may be one or more selected from the group consisting of: n-butyl cyanoacrylate, methyl-2 cyanoacrylate, ethyl-2 cyanoacrylate, octyl cyanoacrylate (OCA), and octyl-2 cyanoacrylate.
  • the cyanoacrylate is octyl cyanoacrylate (OCA) due to its lack of toxicity and weak ability to induce irritation.
  • the method may further comprise adding bone mineral nanoparticles to the liquid of bioresorbable polymer.
  • the bone mineral nanoparticles may be added to the liquid of bioresorbable polymer before the mixing step.
  • Preferably the bone mineral nanoparticles are added to the liquid of bioresorbable polymer during the mixing step.
  • the bone mineral nanoparticles may be inorganic mineral salts, such as magnesium salts and/or calcium salts.
  • the bone mineral nanoparticles may comprise a selection of one or more members of the group consisting of: magnesium oxide (MgO), magnesium hydroxide (Mg(OH)2), hydroxyapatite (HA/ CasCPC COH)), P-tricalcium phosphates, copper oxides, zinc oxides (e.g.
  • the bone mineral nanoparticles are HA and MgO, HA and Mg(OH)2, or Mg(OH)2.
  • HA, MgO and Mg(OH)2 each separately promote (3D) bone growth/repair.
  • the bone mineral nanoparticles do not comprise pure magnesium particles, granules or powder (e.g. particles, granules or powder that is greater than 99% by weight magnesium). Magnesium particles, granules and powder are highly reactive and produce large amounts of localised hydrogen gas and alkalinity which hamper the bone healing process.
  • the solid layer of bioresorbable polymer may be porous or non-porous.
  • Pores form because the tensile property of the cyanoacrylate adhesive increases. This stretches the bioresorbable polymer and introduces crevices or irregular shaped pores (see Figure 2). Pores also form in the solid layer of bioresorbable polymer due to crosslinking caused by the cyanoacrylate adhesive.
  • the method may further comprise adding a dispersant to the polymer-cyanoacrylate mixture.
  • a dispersant is added during the mixing step.
  • the dispersant may be basic/alkaline in nature.
  • the dispersant, particularly basic dispersants may cause uniform distribution of the bone mineral nanoparticle due to electrostatic interactions with the bone mineral nanoparticles in the liquid form of the GBR membrane (e.g. a liquid/solution of the bioresorbable polymer and/or the adhesive).
  • the liquid of bioresorbable polymer may comprise a therapeutic agent.
  • the therapeutic agent may be immersed in the bioresorbable polymer at least 12 hours before the mixing step, at least 24 hours before the mixing step, at least 48 hours before the mixing step.
  • the therapeutic agent may include, but is not limited to, an analgesic; an NSAID; a local anaesthetic; an antimicrobial agent; an antifungal agent; a genetically engineered peptides/protein; a glycoprotein; a lipoprotein; an immunomodulatory stimulator; an immunomodulatory inhibitor; a growth factor; an oligonucleotide; a chemotherapeutic agent; fibrin; fibronectin and blood coagulation agents.
  • the method may further comprise placing the polymer-cyanoacrylate mixture in a cast (before the drying step).
  • the cast may be used to provide the solid polymer layer with an appropriate shape, such as a rectangle, a square or a hexagon, when the mixture has dried.
  • the skilled person will appreciate that the dimensions of the cast and the volume of the mixture placed in the cast will determine the thickness of the layer of bioresorbable polymer.
  • the polymer-cyanoacrylate mixture may be coated onto a metal substrate to improve osseointegration of an orthopaedic implant.
  • the method may comprise coating the metal substrate with the polymer-cyanoacrylate mixture.
  • the metal substrate may comprise a selection of one or more members from the group consisting of: Ti, Ti alloys, Mg, Mg alloys, NiTi, Cr-co alloys, Fe-Mn alloys, Zn, Zn alloys, steel and aluminium alloys.
  • the metal substrate may be a sheet, a 3D-printed device, or a rod.
  • the metal substrate may be coated with the polymer-cyanoacrylate mixture by using immersion coating, an electrospinning, spin coating, dip coating or spray coating.
  • the metal substrate is coated with the polymer-cyanoacrylate mixture by dip coating or immersion coating.
  • the metal substrate is coated by dip coating or immersion coating the substrate in the polymer-cyanoacrylate mixture for about 1 to about 30 minutes.
  • the method may further comprise contacting the (first) layer of bioresorbable polymer with a second layer of material to create a GBR membrane according to the invention.
  • the second layer of material may comprise a polymer (such as a non-bioresorbable polymer) or a non-degradable 2D or 3D material (such as extended-PTFE (e-PTFE) or a material comprising titanium).
  • the second layer comprises a bioresorbable polymer.
  • the second layer of material (or subsequent layer) may be prepared using any appropriate method (e.g. UV-irradiation, chemical functionalisation, clickchemistry, spray-coating, dip and spin coating, and immersion methods), including a method according to the invention.
  • Contacting a second layer of bioresorbable polymer with the cyanoacrylate adhesive of the first layer may comprise applying pressure to the first and/or second layer of bioresorbable polymer to bond the two layers together.
  • Contacting a second layer of bioresorbable polymer with the cyanoacrylate adhesive of the first layer may comprise adhesive component bonding a longitudinal surface of the first layer of bioresorbable polymer to a longitudinal surface of the second layer of bioresorbable polymer.
  • the bioresorbable polymer layers of the GBR membrane may be bonded such that they are coincident (i.e. lined up).
  • the contacting step may comprise the cyanoacrylate adhesive bonding a longitudinal surface of first layer of bioresorbable polymer to a longitudinal surface of the second layer of bioresorbable polymer so that the first and the second layers are coincident with each other.
  • the cyanoacrylate adhesive may or may not be a 2D or 3D layer.
  • the adhesive component may be an interdigitating network.
  • the adhesive component may be between (and optionally within) the bioresorbable polymer layers.
  • the interdigitating network may extend continuously from one end of the GBR membrane to the opposing end.
  • the interdigitating network may be discontinuous
  • the contacting step of the method according to the invention may comprise crosslinking the second layer of bioresorbable polymer with the first layer of bioresorbable polymer using the cyanoacrylate adhesive.
  • concentration of cyanoacrylate (e.g. OCA) in the adhesive may be less than about 3% v/v, less than about 2.5%v/v, or less than about 2% v/v.
  • concentration of cyanoacrylate (e.g. OCA) in the adhesive may be greater than about 0.1 %v/v, may be greater than about 0.5 %v/v, or may be greater than about 1 %v/v.
  • the concentration of cyanoacrylate e.g.
  • OCA in the adhesive component
  • the concentration of cyanoacrylate (e.g. OCA) in the adhesive component may be about 2%v/v.
  • concentration of cyanoacrylate (e.g. OCA) in the adhesive component is between about 0.5%v/v and 2% v/v. This preferred concentration range ensures that the adhesive component forms an interconnected network of regular pores.
  • the crosslinks may be formed by polymerising cyanoacrylate monomers.
  • the cyanoacrylate monomers may be monomers of a mono-a cyanoacrylate or a bis- a cyanoacrylate.
  • the mono-a cyanoacrylate adhesive may be one or more selected from the group consisting of: alkyl- and cycloalkyl-a-cyanoacrylates such as methyl-a- cyanoacrylate, ethyl-a-cyanoacrylate, propyl-a-cyanoacrylate, butyl-a-cyanoacrylate, and cyclohexyl-a-cyanoacrylate; alkenyl- and cycloalkenyl-a-cyanoacrylates such as allyl-a-cyanoacrylate, methacryl-a-cyanoacrylate, and cyclohexenyl-a-cyanoacrylate; alkynyl-a-cyanoacrylates such as propangyl-a-cyanoacrylate; aryl
  • the cyanoacrylate adhesive may be one or more selected from the group consisting of: n-butyl cyanoacrylate, methyl-2 cyanoacrylate, ethyl-2 cyanoacrylate, octyl cyanoacrylate (OCA), and octyl-2 cyanoacrylate.
  • the cyanoacrylate is octyl cyanoacrylate (OCA) due to its lack of toxicity and minimal irritant effects.
  • the monomers may be polymerised in an anionic environment (e.g. in the presence of water molecules, biopolymers or body fluids containing functional groups such as - NH 2 , -OH, -COO ).
  • the drying step of the method according to the invention may comprise heating the polymer-cyanoacrylate mixture or GBR membrane to a temperature of about 20°C or more, at about 25 °C or more, at about 30°C or more, at about 35°C or more, at about 40°C or more, at about 45°C or more, at about 50°C or more, at about 55°C or more, or at about 60°C.
  • the drying step may be performed at about 20°C to about 80°C, at about 30°C to about 75°C, at about 40°C to about 70°C or at about 50°C to about 70°C.
  • the mixture may be dried for at least about 10 minutes, for at least about 5 minutes, for at least about 10 minutes, for at least about 20 minutes, for at least about 30 minutes, for at least about 40 minutes, for at least about 50 minutes, for at least about 60 minutes, for at least about 2 hours, for at least about 4 hours, for at least about 8 hours, for at least about 12 hours.
  • the mixture is dried for at least 12 hours or for about 12 hours.
  • the mixture may be dried for between about 5 minutes and 120 minutes, between about 5 minutes and 110 minutes, between about 5 minutes and 100 minutes, between about 5 minutes and 90 minutes, between about 5 minutes and 60 minutes or between about 5 minutes and 30 minutes.
  • the mixture may be dried for between about 6 hours and 24 hours, or between about 8 hours and 12 hours.
  • the mixture is dried for between about 5 minutes and 30 minutes or between about 8 hours and 12 hours.
  • the mixture is dried at about 50°C to about 70°C for between about 5 minutes and 30 minutes, or at about 20°C for at least 12 hours.
  • the method according to the third aspect of the invention may comprise making a GBR membrane according to the first aspect of the invention.
  • a guided bone regeneration membrane according to the first aspect or produced by the method according to the second or third aspect of the invention for use in therapy (e.g. surgery).
  • a guided bone regeneration membrane according to the first aspect or produced by the method according to the second or third aspect of the invention for use in the treatment of a disease or a condition of a subject.
  • a guided bone regeneration membrane according to the first aspect or produced by the method according to the second or third aspect, for use in the regeneration of bone or the repair of a bone defect in a subject.
  • a method of regenerating bone or repairing a bone defect in a subject comprising inserting a guided bone regeneration membrane according to the first aspect or produced by the method according to the second or third aspect, into a bone defect of a subject.
  • the method according to the invention may comprise inserting a guided bone regeneration membrane into a bone defect of a subject.
  • the invention may be used to regenerate a dental or craniofacial -maxillofacial bone.
  • the invention may be used to regenerate bone around an implant in a tooth socket or regenerate bone to reserve a socket for the implantation of false teeth.
  • the invention may be used to repair a craniofacial-maxillofacial bone defect.
  • the bone defect may be peri-implantitis or a cystic cavity.
  • the invention may be used to repair a dental or craniofacial- maxillofacial bone defect caused by surgery.
  • the surgery may be a sinus lift elevation, dental implantation, removal of tooth or a cystectomy.
  • treatment means the management and care of a subject for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the subject is suffering, including alleviating symptoms or complications, delaying the progression of the disease, disorder or condition, alleviating or relieving the symptoms and complications, and/or to cure or eliminating the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a subject for the purpose of combating the disease, condition, or disorder and includes the administration of the ligand to prevent the onset of the symptoms or complications.
  • the “subject” is preferably a mammal, in particular a human, but it may also include animals, such as dogs, cats, horses, cows, sheep and pigs.
  • bone defect can refer to a damaged bone.
  • the damage to the bone may be caused by surgery, injury and/or disease.
  • Figure 1 is a schematic representation of a GBR membrane placed within a bone defect
  • Figure 2 is a summary of the characterisation of OCA crosslinked PCL-HA-MgO membranes (a) Mechanical properties, (b) time-dependent wettability and (c) droplet absorption on HA-MgO-PCL-TEOA-OCA 100 membranes.
  • Figure 3 is a SEM-EDX of OCA crosslinked PCL-HA-MgO membranes (a) HA-MgO- PCL-TEOA-OCA 100, (b) HA-MgO-PCL-TEOA-OCA 200, (C) HA-MgO-PCL-TEOA and (d) HA-MgO-PCL.
  • Figure 4 is an image of a GBR membrane (HA-MgO-PCL-TEOA-OCA 100) made using a method of the invention.
  • Figure 5 is an image of (a) uncoated and (b) coated 3D-Ti substrate with GBR membrane.
  • Figure 6 shows the results of an Alamar blue assay- proliferation of osteoblast cells on PCL-based GNR membranes over 7 days.
  • Statistical analysis Two-way Anova (**P ⁇ 0.01) Examples
  • the PCL was dissolved in chloroform, followed by the addition of HA, MgO and TEOA. These components were stirred for 5 minutes in a closed container. OCA was added to the mixture and stirred until the volume of the mixture had been reduced by 50%. The mixture was then poured in a rectangle cast (made of PTFE) and allowed to dry at room temperature over night or 30 °C for 1 hour. After drying, the membrane was removed from the cast. See table 1 below for details of the formulations used to create the exemplified GBR membranes.
  • Figure 4 shows an image of a GBR membrane made of HA-MgO-PCL-TEOA-OCA 100 using the above mentioned solvent cast method.
  • HA-MgO-PCL-TEOA-OCA 100 showed 33% increase in elongation to break when compared to respective controls (HA-MgO-PCL-TEOA and HA-MgO-PCL), however, a reduction of 50% in elongation to break was observed when compared to HA-MgO-PCL-TEOA-OCA-200.
  • HA- MgO-PCL-TEOA-OCA 100 showed rapid water absorption efficiency as shown in Figure 2(b) and (c). It can be observed that with the increase in the concentration of OCA, elongation to breakpoint increases, whereas time-dependent wettability decreases. In addition, the water contact angle increases with the concentration of OCA as well as higher when compared to respective controls at time near-zero is shown in Figure 2(b).
  • HA-MgO-PCL-TEOA-OCA 100 showed narrow interconnected crevices network (indicated by black arrows) which facilitate the rapid water absorption and may also promote the cell occlusion.
  • HA- MgO-PCL-TEOA-OCA 200 showed irregularly arranged large pores, which not only reduce the water absorption efficiency but may reduce the cell occlusion efficiency.
  • HA-MgO-PCL-TEOA showed regularly arranged pores, which facilitate water absorption but not better than HA-MgO-PCL-TEOA-OCA 100, but lacks the presence of Ca/P/MgO minerals on the surface, thus limiting the biomimetic nature of the membrane.
  • HA-MgO-PCL membrane is very uniform without any porosity.
  • SEM-EDX elemental maps and quantification tables of HA-MgO-PCL- TEOA-OCA 100 showed the presence of the greater amount of hydroxyapatite (Ca/P) and MgO (Mg) particles on the surface instead of embedded in the PCL matrix as observed for other samples, indicating a better biomimetic and porous surface.
  • 1% PLGA was dissolved in 5 trichloromethane.
  • HA and MgO HA:MgO- 1/0.5 %w/v was then added to the PLGA.
  • the mixture of PLGA, HA and MgO was then stirred for 10 minutes for the proper mixing of these component.
  • 1 ml of 2-BU (2-butoxy ethanol) was then added to the mixture, followed by 1% v/v OCA under constant stirring. The mixture was then allowed to concentrate by stirring it vigorously until the mixture reduced by about 50% in volume.
  • a Ti substrate was then placed in mixture for 1 minute to 30 minutes (preferably 1 minute).
  • the substrate was removed, and PLGA mixture was allowed to dry for 12 hours at room temperature or placed in an oven at 50-70°Celsius for 5 to 30 mins. The samples were then washed with water for 5 minutes to remove the loosely bound HA and MgO. Finally, the samples were dried at room temperature overnight or for 5 to 30 min at 50 to 70°Celcius to get the GBR membrane showed optimised surface in terms of uniform coverage without blocking the pores.
  • Example 5 The proliferation of MC3T3E1 osteoblast cells on PCL only, PCL-HAp, PCL-HAp-MgO and PCL-MgO membrane
  • the formulation used to prepare these membranes is provided in Table 2 below.
  • the TEOA was removed by washing in DI water for 45 mins.
  • the preferred washing time of these membranes is 15 mins for 3 times, however, this duration can be increased up to 12 hours, then dried at 40-50 degrees Celsius for 30-120 mins (preferred time 30 mins at 40 degrees Celsius).
  • the membranes were sterilised by treating with 70% ethanol (70% absolute ethanol: 30% autoclaved deionised water) and exposed to 365 nm UV- light for 40-120 mins each side of the membranes (preferred UV exposure time is 40 mins each side of the membrane).
  • Table 2 formulations of the PCL-based GBR membranes used for cell proliferation study. samples (see Figure 6). Amongst different membranes, PCL-HA-MgO showed a significantly higher cell growth when compared to PCL, PCL-HA and PCL-MgO membranes. Also, PCL-HA and PCL-MgO also showed significantly higher cell proliferation when compared to PCL alone. However, no statistically significant difference in the cell growth on PCL-HA and PCL-MgO was observed. These results indicate a synergistic effect of HA and MgO inorganic minerals on the growth of osteoblasts in the case of PCL-HA-MgO composite GBR membrane.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Materials Engineering (AREA)
  • Composite Materials (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Molecular Biology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne une membrane de régénération osseuse guidée qui peut être utilisée pour obturer des défauts osseux et empêcher l'invasion de tissu conjonctif mou environnant sans obstruer l'échange des fluides corporels environnants.
PCT/EP2021/087559 2020-12-23 2021-12-23 Membrane de régénération osseuse guidée WO2022136667A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB2020550.6A GB202020550D0 (en) 2020-12-23 2020-12-23 Guided bone regeneration membrane
GB2020550.6 2020-12-23

Publications (1)

Publication Number Publication Date
WO2022136667A1 true WO2022136667A1 (fr) 2022-06-30

Family

ID=74221036

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/087559 WO2022136667A1 (fr) 2020-12-23 2021-12-23 Membrane de régénération osseuse guidée

Country Status (2)

Country Link
GB (1) GB202020550D0 (fr)
WO (1) WO2022136667A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115227879A (zh) * 2022-09-15 2022-10-25 北京天星博迈迪医疗器械有限公司 一种用于可降解关节球囊的组合物及其应用、一种可降解关节球囊及其制备方法
CN115518206A (zh) * 2022-10-18 2022-12-27 华中科技大学同济医学院附属协和医院 一种自矿化gbr膜及其制备方法
CN115581816A (zh) * 2022-10-09 2023-01-10 深圳先进技术研究院 生物活性多级结构引导组织再生膜及其制备方法
CN115737938A (zh) * 2022-07-25 2023-03-07 上海大学 用于牙槽骨缺损修复的聚氨基酸复合引导骨再生膜及其制备方法
WO2024077418A1 (fr) * 2022-10-09 2024-04-18 深圳先进技术研究院 Membrane de régénération tissulaire guidée à structure multi-niveaux bioactive et son procédé de préparation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114425104B (zh) * 2021-12-21 2023-03-03 中国人民解放军空军军医大学 一种载药骨引导/诱导复合结构及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100028409A1 (en) * 2007-03-26 2010-02-04 Yesbio Co., Ltd. Barrier Membranes For Guided Bone Regeneration
WO2018209101A1 (fr) * 2017-05-10 2018-11-15 Marquette University Biomatériaux médicaux et dentaires multiphases intégrés pour la reconstruction/régénération d'un seul tissu ou de plusieurs tissus

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100028409A1 (en) * 2007-03-26 2010-02-04 Yesbio Co., Ltd. Barrier Membranes For Guided Bone Regeneration
WO2018209101A1 (fr) * 2017-05-10 2018-11-15 Marquette University Biomatériaux médicaux et dentaires multiphases intégrés pour la reconstruction/régénération d'un seul tissu ou de plusieurs tissus

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANG F ET AL: "Development of an electrospun nano-apatite/PCL composite membrane for GTR/GBR application", ACTA BIOMATERIALIA, ELSEVIER, AMSTERDAM, NL, vol. 5, no. 9, 1 November 2009 (2009-11-01), pages 3295 - 3304, XP026693804, ISSN: 1742-7061, [retrieved on 20090524], DOI: 10.1016/J.ACTBIO.2009.05.023 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115737938A (zh) * 2022-07-25 2023-03-07 上海大学 用于牙槽骨缺损修复的聚氨基酸复合引导骨再生膜及其制备方法
CN115227879A (zh) * 2022-09-15 2022-10-25 北京天星博迈迪医疗器械有限公司 一种用于可降解关节球囊的组合物及其应用、一种可降解关节球囊及其制备方法
CN115581816A (zh) * 2022-10-09 2023-01-10 深圳先进技术研究院 生物活性多级结构引导组织再生膜及其制备方法
WO2024077418A1 (fr) * 2022-10-09 2024-04-18 深圳先进技术研究院 Membrane de régénération tissulaire guidée à structure multi-niveaux bioactive et son procédé de préparation
CN115518206A (zh) * 2022-10-18 2022-12-27 华中科技大学同济医学院附属协和医院 一种自矿化gbr膜及其制备方法
CN115518206B (zh) * 2022-10-18 2024-01-23 华中科技大学同济医学院附属协和医院 一种自矿化gbr膜及其制备方法

Also Published As

Publication number Publication date
GB202020550D0 (en) 2021-02-03

Similar Documents

Publication Publication Date Title
WO2022136667A1 (fr) Membrane de régénération osseuse guidée
Kmiec et al. Chitosan-properties and applications in dentistry
Baino et al. Bioactive glasses: Special applications outside the skeletal system
Guo et al. Biocompatibility and osteogenic activity of guided bone regeneration membrane based on chitosan-coated magnesium alloy
US20110060419A1 (en) Medical devices with galvanic particulates
WO2010068654A1 (fr) Systèmes à libération prolongé du phosphate d'acide ascorbique
WO2012004407A2 (fr) Membrane de régénération osseuse et procédé de formation d'une membrane de régénération osseuse
JP2012521804A (ja) ガルバーニ微粒子を備えた医療機器
Félix Lanao et al. Porous calcium phosphate cement for alveolar bone regeneration
Li et al. Application of bioactive metal ions in the treatment of bone defects
WO2011130112A1 (fr) Dispositifs médicaux à matières particulaires galvaniques
Jang et al. PCL/HA hybrid microspheres for effective osteogenic differentiation and bone regeneration
Lagares Nanobiomaterials in hard tissue engineering
de Souza Balbinot et al. Polybutylene-adipate-terephthalate and niobium-containing bioactive glasses composites: Development of barrier membranes with adjusted properties for guided bone regeneration
Yan et al. Copper-loaded biodegradable bone wax with antibacterial and angiogenic properties in early bone repair
Zhou et al. An antibacterial chitosan-based hydrogel as a potential degradable bio-scaffold for alveolar ridge preservation
Babo et al. Membranes for periodontal tissues regeneration
Tsurumi et al. Enhancement of apatite precipitation on an alkaline hydrolyzed poly (lactic acid-ε-Caprolactone) film in simulated body fluid
Makiishi et al. In vitro/in vivo evaluation of the efficacy of gatifloxacine-loaded PLGA and hydroxyapatite composite for treating osteomyelitis
Kim et al. Osteogenic effect of a biodegradable BMP-2 hydrogel injected into a cannulated mg screw
WO2022143582A1 (fr) Dispositif médical implantable pour fixation interne orthopédique
Shariatinia et al. Perovskite oxides as efficient bioactive inorganic materials in tissue engineering: A review
US20110153029A1 (en) Bioresorbable and flexible membranes exhibiting asymmetric osteoconductive behavior in both faces
Yanovska et al. Composite materials based on hydroxyapatite embedded in biopolymer matrices: Ways of synthesis and application
Han et al. Advances in reparative materials for infectious bone defects and their applications in maxillofacial regions

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: 21844729

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21844729

Country of ref document: EP

Kind code of ref document: A1