WO2021019255A1 - Monomères durcissables et compositions - Google Patents

Monomères durcissables et compositions Download PDF

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Publication number
WO2021019255A1
WO2021019255A1 PCT/GB2020/051850 GB2020051850W WO2021019255A1 WO 2021019255 A1 WO2021019255 A1 WO 2021019255A1 GB 2020051850 W GB2020051850 W GB 2020051850W WO 2021019255 A1 WO2021019255 A1 WO 2021019255A1
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polymer precursor
polylactic acid
precursor
polycaprolactone
composition according
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PCT/GB2020/051850
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English (en)
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Ahmed Samir HAMIDI
William PALIN
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The University Of Birmingham
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Publication of WO2021019255A1 publication Critical patent/WO2021019255A1/fr

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    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • 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
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/52—Polycarboxylic acids or polyhydroxy compounds in which at least one of the two components contains aliphatic unsaturation
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/91—Polymers modified by chemical after-treatment
    • C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
    • 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
    • C08L67/06—Unsaturated polyesters
    • C08L67/07—Unsaturated polyesters having terminal carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • 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
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group

Definitions

  • This invention relates generally to curable monomers and compositions. More specifically, although not exclusively, this invention relates to curable monomers and their use in compositions, for example, to form biocompatible materials.
  • a biomaterial is a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of a therapeutic or diagnostic procedure.
  • Such materials may be formed from or comprise, for example, metallic, polymeric, ceramic, and/or composite materials.
  • Such materials may be engineered to function in a specific application, e.g. as scaffolds for tissue engineering applications of soft or hard tissue, for drug delivery purposes, for implants or bone replacements, and so on.
  • biomaterials for use in the regeneration of hard tissue, such as bone requires consideration of several different factors such as in situ biocompatibility and the likelihood or potential for degradability into non-toxic biproducts.
  • the biomaterial must also provide the necessary biomechanics required during the healing process.
  • Bone cement which consists essentially of polymethylmethacrylate, has been widely and successfully used to anchor artificial joint replacement. It has been proposed to use this material as a bone stabilisation system in the case of extremity fractures, wherein the material is injected and photocured using a light tube. However, the curing process may take up to 10 minutes with an increase in temperature of more than 70°C, which is detrimental to the surrounding tissue (Vegt P et al. Med Devices (Aucki) 2014;7:453-461. Zani BG et al. J Biomed Mater Res B Appl Biomater. 2016; 104(2):291— 299).
  • US2008/039854 discloses the use of an cationic epoxy and a cationic photo-initiator which is curable under UV illumination as a bone reinforcing mixture.
  • the epoxy may be fortified with carbon nanotubes to increase the elastic modulus thereof.
  • the cationic photoinitiator systems are based on sulfonium or iodonium salts leading to high thermal excursions of 62°C and above during UV light curing. Moreover, iodonium salts in general are toxic in neat form.
  • WO2012/138732 A1 describes the use of biocompatible polycaprolactone fumarate formulations for use as scaffolds for tissue engineering applications to support nerve regeneration. It is suggested that the polycaprolactone fumarate copolymer is crosslinkable via the alkene of the fumarate unit as well as being physically crosslinkable. Scaffolds were fabricated by photocuring using Irgacure 819 as a photoinitiator under UV light at 315 to 380 nm. The mechanical properties were suitable for use in nerve regeneration but were unsuitable for hard tissue applications.
  • Dental composite resins for use, for example in filling cavities are known. These resins are cured in situ and harden to form the solid filling.
  • a well-known dental composite is bis-GMA (bisphenol A-glycidyl methacrylate), which forms a crosslinked polymer.
  • Other diacrylate monomers are also known such as UDMA (urethane dimethacrylate). These are often used with triethylene glycol di methacrylate (TEGDMA) in various mixing ratios.
  • TEGDMA triethylene glycol di methacrylate
  • these polymers are known to release undesirable biproducts such as bisphenol A.
  • biomaterial that may be used as an alternative to a metallic implant, said biomaterial having the flexibility to fit any defect with minimal surgical intervention.
  • a photocurable composition comprising a precursor resin, the precursor resin comprising:
  • polylactic acid polymer precursor comprising a backbone chain, the backbone chain comprising at least one acrylate moiety
  • a polycaprolactone polymer precursor comprising a backbone chain, the backbone chain comprising at least one acrylate moiety and at least one alkene (e.g. a 1 ,2- substituted alkene) moiety;
  • polylactic acid polymer precursor and the polycaprolactone polymer precursor are crosslinkable.
  • a composition comprising a polylactic acid polymer precursor blended with a polycaprolactone precursor according to the invention may be photocured to provide a cross-linked polymer, which may be used as a biomaterial with advantageous properties. It has been found that the polylactic acid polymer precursor is brittle, whereas the polycaprolactone polymer precursor is more flexible. Consequently, the mechanical properties of the cross-linked polymer may be tuned by adjusting the proportions of the polymer precursors within the photocurable composition.
  • the photocurable composition of the invention may be tuned to provide a cross-linked polymer with optimal properties for different applications, e.g. different applications of biomaterials.
  • the at least one acrylate moiety of both the polylactic acid polymer precursor and the polycaprolactone polymer precursor enables the polymer precursors of the precursor resin to crosslink with one another to form a highly crosslinked polymer network.
  • the composition is photocurable, which enables the acrylate moieties to react upon irradiation with an appropriate light source.
  • the photocurable composition of the invention may be photo-polymerised using conventional light curing technologies.
  • a polylactic acid polymer precursor refers to a polymer chain comprising at least one block of repeating subunits of lactic acid, e.g. between 4 and 5 subunits, for example, 8, 9, or 10 (i.e. monomers) of lactic acid, for example, formed from lactide.
  • the polylactic acid copolymer may comprise a polymer chain comprising two blocks of repeating subunits of lactic acid, e.g. between 4 and 5 subunits (i.e. monomers) of lactic acid, such that there is a total of 8 to 10 subunits (i.e.
  • the polylactic acid copolymer may comprise a polymer chain comprising more than two blocks of repeating subunits of lactic acid e.g. between 4 and 5 subunits (i.e. monomers) of lactic acid.
  • the polylactic acid polymer precursor according to the invention may further comprise additional monomers and/or blocks of repeating subunits of monomers that are different to lactic acid within the polymer chain.
  • a polycaprolactone polymer precursor refers to a polymer chain comprising at least one of repeating subunits of hexanoate, e.g. between 1 and 4 subunits, for example, 1 , 2, 3, or 4 subunits (i.e. monomers) of hexanoate, for example, formed from caprolactone.
  • the polycaprolactone polymer precursor according to the invention may further comprise additional monomers and/or blocks of repeating subunits of monomers that are different to the hexanoate subunits within the polymer chain.
  • the polylactic acid polymer precursor may be present in more than 0 and less than 100 wt.% of the precursor resin, and the polycaprolactone polymer precursor may be present in more than 0 and less than 100 wt.% of the precursor resin.
  • the polylactic acid polymer precursor may be present in the composition in a quantity of between greater than or equal to any one of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 wt. % to less than or equal to any one of 95, 90, 85, 80, 75, 70, 65,
  • the polycaprolactone polymer precursor may be present in the composition in a quantity of between greater than or equal to any one of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 wt. % to less than or equal to any one of 95, 90, 85, 80, 75, 70, 65,
  • the polylactic acid polymer precursor may be present in greater than or equal to 50 wt.% and less or equal to than 90 wt.% of the precursor resin, and the polycaprolactone polymer precursor may be present in less than or equal to 50 wt.% and greater than or equal to 10 wt.% of the precursor resin
  • the precursor resin consists of the polylactic acid polymer precursor and the polycaprolactone polymer precursor an optional initiator and an optional filler.
  • the precursor resin consists of the polylactic acid polymer precursor, the polycaprolactone polymer precursor and a photo-initiator an optional co-initiator and an optional filler.
  • the photo-initiator may be present in up to 2 w/w%, preferably up to 1w/w%, most preferably less than 0.9, 0.8, 0.7, 0.6, 0.5 w/w%.
  • the photo-initiator may be active at low visible wavelengths, e.g. UV or blue light wavelengths.
  • a suitable photo-initiator is camphorquinone.
  • the co-initiator may be dimethylamino-ethyl dimethacarylate (DMAEMA).
  • the photoinitiator is a titanocene compound or derivative with an absorption band between 400 to 500 nm.
  • the co-initiator may be present in less than 2 w/w%, say less than 1.5 w/w%, for example, less than 1.4, 1.3, 1.2, 1.1 , 1.0 w/w%.
  • the co-initiator may be N-phenyl glycine (NPG) and/or benzodioxole and derivatives thereof.
  • the at least one acrylate moiety of either or both of the polylactic acid polymer precursor and/or the polycaprolactone polymer precursor comprises or is a terminal acrylate moiety.
  • the polylactic acid polymer precursor and/or the polycaprolactone polymer precursor may comprise a first terminal acrylate moiety and a second terminal acrylate moiety, located at opposite terminal ends of the backbone chain.
  • the polylactic acid polymer precursor and/or the polycaprolactone polymer precursor may comprise a diol unit.
  • the diol unit is one of propanediol, butanediol, pentanediol, hexanediol, octanediol, decanediol and isomers thereof, e.g. 2-methyl-1 , 3-propanediol, 2-butyl-2-ethyl- 1 , 3-propanediol, 1 ,4-butanediol, and/or 3-methyl-1 ,3-butanediol.
  • the one or more diol units may comprise an aromatic diol.
  • the one or more diol units may comprise between 1 to 10 carbon atoms, and/or may further comprise one or more heteroatoms, e.g. selected from an oxygen atom, a nitrogen atom, a sulphur atom.
  • the one or more diol units may be one or more of diethylene glycol, dipropylene glycol, or dibutylene glycol.
  • the use of a 1 ,4-butanediol subunit within the polylactic acid polymer precursor and/or the polycaprolactone polymer precursor provides non-toxic degradation products in respect of this monomer.
  • 1 ,4-butanediol ultimately metabolises to gamma-butanoic acid (GABA) and succinic acid, which are neurotransmitter and a key intermediate in the TCA cycle, respectively.
  • GABA gamma-butanoic acid
  • succinic acid succinic acid
  • the polylactic acid polymer precursor may be a polylactic acid copolymer comprising one or more butanediol units and further comprising one or more acrylate units, e.g. one or more methacrylate units.
  • acrylate to encompass any suitable acrylic acid or enoic acid, wherein the hydrogen atom of the CH group of the alkene may be substituted with an alkyl group, e.g. comprising 1 , 2, 3, 4, or 5 carbon atoms, for example a CH 3 , C2H5, C 3 H7, C4H 9 , or C5H11 group.
  • one some or all of the one or more acrylate units may comprise or consist of one or more methacrylate units (i.e. wherein the alkyl group is CH 3 ).
  • one some or all of the one or more acrylate units may comprise or consist or be formed from one or more 2-ethylacrylic acid units.
  • one some or all of the one or more acrylate units may comprise or consist or be formed from one or more 2- propylacrylic acid units, or 2-butylacrylate acid units, or 2-pentylacrylate acid units.
  • the polylactic acid polymer precursor may be a polylactic acid copolymer comprising one butanediol unit located in the backbone chain, a first acrylate unit located at a first terminus of the backbone chain, and a second acrylate unit located at a second terminus of the backbone chain.
  • the polylactic acid polymer precursor may comprise the following structure:
  • n is a number between 1.00 to 10.00, for example, between 2.00 to 9.00, or between 3.00 to 8.00, or between 4.00 to 7.00, or between 5.00 to 6.00.
  • n is a number between 4 to 5, e.g. 4.00, 4.10, 4.20, 4.30, 4.40, 4.50, 4.60, 4.70, 4.80, 4.90, or 5.00.
  • n may be between any one of 4.00, 4.10, 4.20, 4.30, 4.40, 4.50, 4.60, 4.70, 4.80 or 4.90 to any one of 4.10, 4.20, 4.30, 4.40, 4.50, 4.60, 4.70, 4.80, 4.90, or 5.00.
  • the polylactic acid copolymer comprises blocks of lactic acid subunits wherein the number of subunits is between 4.00 and 5.00 (i.e. n is a number between 4.00 and 5.00), advantageously, this provides a copolymer with optimal physical properties, including improved handleability.
  • the polylactic acid polymer precursor may be prepared by reacting 1 ,4- butane-diol with lactide, e.g. L-lactide, to produce an intermediate, the intermediate may be further reacted with an acrylate, e.g. methacrylic acid/methacryloyl chloride to produce the polylactic acid polymer precursor.
  • lactide e.g. L-lactide
  • the polylactic acid polymer precursor may be prepared by reacting one mole equivalent of 1 ,4-butane-diol with 2n mole equivalents of lactide, e.g. L-lactide, to produce an intermediate, the intermediate is further reacted with 2n mole equivalents of an acrylate, e.g. methacrylic acid or methacryloyl chloride to produce the polylactic acid polymer precursor.
  • lactide e.g. L-lactide
  • the molecular weight of the polylactic acid polymer precursor as measured using 1 H NMR (CDCh) may be between 600 g/mol and 1300 g/mol, e.g. between 700 g/mol and 1200 g/mol, or between 800 g/mol and 1100 g/mol, or between 900 g/mol and 1000 g/mol.
  • the molecular weight as measured using 1 H NMR (CDCh) may be 917 g/mol.
  • the molecular weight Mn of the polylactic acid polymer precursor may be between 500 to 1500 g/mol, e.g. between 800 to 1200 g/mol, e.g. 1015 g/mol.
  • the molecular weight Mw of the polylactic acid polymer precursor may be between 500 to 1500 g/mol, e.g. between 700 to 1300 g/mol, e.g. 1290 g/mol.
  • the polydispersity index Ip of the polylactic acid polymer precursor may be between 1.0 to 1.5, e.g. 1.10 to 1.40, or 1.20 to 1.30.
  • the polylactic acid polymer precursor may be optically active and/or may have an enantiomeric excess, e.g. of between 90 to 100 % ee, for example, greater than 95% ee.
  • composition according to the invention comprising an enantiomerically pure (or at least substantially enantiomerically pure, i.e. >90% ee or >95% ee) polylactic acid polymer precursor is able to form crosslinked polymers with advantageous properties.
  • polylactic acid polymer precursors fabricated using enantiomerically pure L-lactide are semi-crystalline.
  • racemic polylactic acid fabricated from a mixture of D- and L- lactide monomers
  • the crystalline phase of polylactic acid, fabricated using L-lactide only has a greater biostability and life span.
  • tissue regeneration e.g. hard tissue regeneration
  • polylactic acid influenced cell response with higher adhesion patterns on semi-crystalline substrates as reported by A. J. Salgado et al. in Materials Science Forum, Vols. 514-516, pp. 1020-1024, 2006
  • mechanical properties of the biomaterial e.g. implant, remains uncompromised.
  • the at least one alkene moiety of the polycaprolactone polymer precursor may be a 1 , 1 -substituted alkene moiety (e.g. a 1 , 1 -disubstituted alkene).
  • the at least one alkene moiety of the polycaprolactone polymer precursor may be a 1 , 1- disubstituted alkene, wherein the 1 , 1 -substituents form the backbone chain, and for example, a least one of (e.g. both of) the 2,2-substituents may be selected from hydrogen or deuterium atoms.
  • the at least one alkene moiety of the polycaprolactone polymer precursor may be a 1 ,2-substituted alkene moiety (e.g. a 1 ,2-disubstituted alkene moiety).
  • the at least one alkene moiety of the polycaprolactone polymer precursor may be an in-chain 1 ,2-disubstituted alkene moiety (e.g. located in the backbone chain of the polycaprolactone polymer precursor).
  • the polycaprolactone polymer precursor may comprise one or more 1 ,2-disubstituted alkene moieties), and for example, at least one of (e.g. both of) the remaining substituents may be selected from hydrogen or deuterium.
  • the 1 ,2-disubstituted alkene moiety may be E or Z (i.e. cis or trans).
  • the at least one alkene moiety of the polycaprolactone polymer precursor may be a 1 ,1 ,2-substitued alkene (e.g. a tri-substituted alkene). In embodiments, the at least one alkene moiety of the polycaprolactone polymer precursor may be a 1 , 1 ,2,2- substitued alkene (e.g. a tetra-substituted alkene).
  • the substituents on the at least one alkene moiety of the polycaprolactone polymer precursor that do not form part of the backbone chain may be selected from hydrogen, deuterium, an alkyl group, or an aryl group.
  • the polycaprolactone polymer precursor may be a polycaprolactone copolymer comprising one or more butanediol units, one or more units of a dicarboxylic acid or a dicarboxylate or a derivative thereof (e.g. one or more fumarate units), and further comprising one or more acrylate units, e.g. methacrylate units.
  • acrylate to encompass any suitable acrylic acid or enoic acid, wherein the hydrogen atom of the CH group of the alkene may be substituted with an alkyl group, e.g. comprising 1 , 2, 3, 4, or 5 carbon atoms, for example a CH 3 , C2H5, C 3 H7, C4H 9 , or C5H11 group.
  • one some or all of the one or more acrylate units may comprise or consist of one or more methacrylate units (i.e. wherein the alkyl group is CH 3 ).
  • one some or all of the one or more acrylate units may comprise or consist or be formed from one or more 2-ethylacrylic acid units.
  • one some or all of the one or more acrylate units may comprise or consist or be formed from one or more 2- propylacrylic acid units, or 2-butylacrylate acid units, or 2-pentylacrylate acid units.
  • the polycaprolactone polymer comprises one or more units of a dicarboxylic acid or a dicarboxylate or a derivative thereof (e.g. one or more fumarate units).
  • the unit of a dicarboxylic acid or a dicarboxylate or a derivative thereof may comprise a 1 ,2-alkene.
  • the dicarboxylic acid or derivative thereof may be selected from maleic acid or a derivative thereof.
  • the dicarboxylic acid or derivative thereof may be selected from fumaric acid or a derivative thereof (e.g. fumaryl chloride).
  • the 1 ,2-alkene (e.g. in the fumarate unit) may be usable to cross-link with the polycaprolactone polymer precursor (e.g. via the 1 ,2-alkene, for example, via the alkene of a or the fumarate unit and/or at least one acrylate unit) and/or the polylactic acid polymer precursor (e.g. the at least one acrylate unit).
  • This cross-linking action may be in addition to the acrylate-acrylate crosslinking of the polymer precursors within the photocurable composition of the invention. More advantageously, in embodiments, there is no need for a crosslinker to be added to photocure and/or crosslink the photocurable composition according to the invention.
  • fumarate is biocompatible because it is converted to fumaric acid, which is consumed by cells in the citric acid cycle.
  • the polycaprolactone polymer precursor may be a polycaprolactone copolymer comprising one fumarate unit located in the backbone chain, at least two butanediol units located in the backbone chain, a first acrylate unit, e.g. methacrylate unit, located at a first terminus of the backbone chain, and a second acrylate unit, e.g. methacrylate unit, located at a second terminus of the backbone chain.
  • the polycaprolactone polymer precursor may have the following structure:
  • n is a number between 1.0 and 1.10, e.g. 1.01 , 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09 or 1.10.
  • n is 1.35.
  • the molecular weight of the polycaprolactone polymer precursor as measured using 1 H NMR (CDCh) may be between 900 g/mol and 1100 g/mol, e.g. between 950 g/mol and 1050 g/mol, or between 975 g/mol and 1050 g/mol.
  • the molecular weight as measured using 1 H NMR (CDCh) may be 1000 g/mol or 1045 g/mol.
  • the molecular weight Mn of the polycaprolactone polymer precursor may be between 1000 to 2000 g/mol, e.g. between 1200 to 1800 g/mol.
  • the molecular weight Mw of the polycaprolactone polymer precursor may be between 2000 to 3500 g/mol, e.g. between 2200 to 3200 g/mol.
  • the polydispersity index Ip of the polycaprolactone polymer precursor may be between 1.5 to 2.0, e.g. 1.60 to 1.90, or 1.70 to 1.80.
  • the polycaprolactone polymer precursor may be prepared by reacting 1 ,4- butanediol with caprolactone to produce a first intermediate, the first intermediate may further reacted with fumaric acid or fumaryl chloride to produce a second intermediate, the second intermediate may further reacted with an acrylate, e.g. methacrylic acid and/or methacryloyl chloride, to produce the polycaprolactone polymer precursor.
  • the polycaprolactone polymer precursor may be prepared by reacting 1 mole equivalent of 1 ,4-butanediol with 2m mole equivalents (e.g. between 2 and 4 mole equivalents) of caprolactone to produce a first intermediate, the first intermediate may further reacted with 0.5 mole equivalents of fumaric acid or fumaryl chloride to produce a second intermediate, the second intermediate may further reacted with 2 mole equivalents of an acrylate, e.g. methacrylic acid and/or methacryloyl chloride, to produce the polycaprolactone polymer precursor.
  • 2m mole equivalents e.g. between 2 and 4 mole equivalents
  • the polycaprolactone copolymer may be prepared by reacting 1 equivalent of caprolactonediol (CAS number: 31831-53-5) with 0.5 mole equivalents of fumaric acid or fumaryl chloride to produce an intermediate, the intermediate is further reacted with 2 mole equivalents of an acrylate, e.g. methacrylic acid and/or methacryloyl chloride.
  • the composition may comprise a photoinitiator and/or a co-initiator.
  • the co-initiator may be dimethylamino-ethyl dimethacarylate (DMAEMA).
  • the photoinitiator is a titanocene compound or derivative with an absorption band between 400 to 500 nm.
  • the co-initiator may be present in less than 2 w/w%, say less than 1.5 w/w%, for example, less than 1.4, 1.3, 1.2, 1.1 , 1.0 w/w%.
  • the co-initiator may be N-phenyl glycine (NPG) and/or benzodioxole and derivatives thereof.
  • the at least one acrylate moiety of the polylactic acid polymer precursor and the at least one acrylate moiety of the polycaprolactone polymer precursor may be cross-linked by photopolymerisation using conventional UV light and/or blue light photoinitiator chemistry. It has been found that photocurable compositions according to the invention are able to photopolymerise in less than 60 seconds using a CQ/amine (e.g. dimethylamino-ethyl dimethacarylate) photoinitiator/co-initiator system, with the final degree of conversion of monomers to a polymer matrix of 94-95%.
  • CQ/amine e.g. dimethylamino-ethyl dimethacarylate
  • the photoinitiator may be present in up to 1 wt.% of the total composition, e.g. up to 0.5 wt.%.
  • the co-initiator may be present in up to 1 wt.% of the total composition.
  • the photoinitiator and the co-initiator may be present in a ratio of 1 :2 wt.% of the total system, e.g. 0.4 wt.% photoinitiator and 0.8 wt.% co-initiator, for example, 0.4 wt.% camphorquinone (CQ) and 0.8 wt.% dimethylamino-ethyl dimethacarylate (DMAEMA).
  • CQ camphorquinone
  • DMAEMA dimethylamino-ethyl dimethacarylate
  • the composition further comprises a filler.
  • the filler may comprise a single material or a plurality of materials.
  • the filler may be or may comprise a ceramic filler.
  • the filler may comprise a metal pyrophosphate and/or a metal orthophosphate.
  • the filler may comprise a calcium phosphate-based filler such as calcium pyrophosphate and/or calcium orthophosphate.
  • the filler may comprise an apatite, for example hydroxyapatite.
  • the filler may comprise one or more of brushite, a/b tricalcium phosphate (TCP), calcium pyrophosphate (amorphous and crystalline), e.g.
  • Photocurable compositions comprising a filler according to the invention may be photocured to provide resin-based composite materials. These may find application as, for example, dental fillers. Without wishing to be bound by any particular theory, the inventors believe that ceramic-based fillers, e.g. calcium pyrophosphate, may improve biocompatibility and/or mechanical properties of the resin-based composite material.
  • resin-based composites comprising a filler, e.g. a ceramic filler, for example calcium pyrophosphate
  • a filler e.g. a ceramic filler, for example calcium pyrophosphate
  • in-vivo bone remodelling e.g. a ceramic filler, for example calcium pyrophosphate
  • calcium pyrophosphate is usable to stimulate new bone growth and to act as a conduit for new bone ingression into a defect (i.e. to be osteo-inductive and osteo-conductive).
  • the photocurable composition comprising a filler according to the invention may be applied or injected followed by photocuring to form a resin-based composite biomaterial with stability during the entire healing procedure. More advantageously, the resin-based composite biomaterial may degrade with resorption and excretion from the system without further surgical intervention.
  • the filler may be present in the photocurable composition in greater than or equal to 5 wt.% and less than or equal to 10 wt.% of the photocurable composition. It is important to note that there may be a refractive index mismatch between the filler and the precursor resin comprising the polylactic acid polymer precursor and the polycaprolactone polymer precursor. In certain embodiments, the filler may prevent light from penetrating the composition, which may at least partially inhibit deep curing. The amount of filler in the composition may be tuned such that there is a balance between the mechanical properties of the resulting resin-based composite and the photocuring depth.
  • the resin composition polymerises only a slight temperature rise is experienced.
  • the temperature rise may be less than 35°C, say less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21 , 20°C.
  • the low exothermicity is beneficial when the composition is used in vivo as it limits or avoids causing damage (e.g. thermal damage) to adjacent or proximate cells.
  • a further aspect of the invention provides a cross-linked polymer comprising a biodegradable matrix, the cross-linked polymer being formed from the photocurable composition according to the invention.
  • a yet further aspect of the invention provides a cross-linked polymer comprising a biodegradable matrix, the matrix formed from a crosslinked precursor resin, the precursor resin comprising a polylactic acid polymer precursor and a polycaprolactone polymer precursor;
  • the polylactic acid polymer precursor comprising a polylactic acid copolymer comprising at least one butanediol unit, and further comprising at least one acrylate moiety, e.g. at least one methacrylate moiety;
  • the polycaprolactone polymer precursor comprising a polycaprolactone copolymer comprising at least one butanediol unit, and further comprising at least one acrylate moiety, e.g. at least one methacrylate moiety.
  • a yet further aspect of the invention provides a scaffold for use in the replacement and/or regeneration of tissue, e.g. hard tissue such as bone, the scaffold comprising and/or being formed from the cross-linked polymer of the invention.
  • a yet further aspect of the invention provides a method of making a cross-linked polymer and/or a scaffold according to the invention, the method comprising:
  • a. taking a resin composition comprising a precursor resin, the precursor resin comprising:
  • polylactic acid polymer precursor comprising a backbone chain, the backbone chain comprising at least one acrylate moiety
  • a polycaprolactone polymer precursor comprising a backbone chain, the backbone chain comprising at least one acrylate moiety and an alkene (e.g. a 1 ,2-substituted alkene) moiety;
  • polylactic acid polymer precursor and the polycaprolactone polymer precursor are crosslinkable
  • the resin composition b. exposing the resin composition to light, e.g. UV light and/or blue light, to initiate cross-linking of the polylactic acid polymer precursor and the polycaprolactone polymer precursor.
  • light e.g. UV light and/or blue light
  • the method may further comprise step a. comprising mixing the polylactic acid polymer precursor, the polycaprolactone polymer precursor, and/or a or the photoinitiator and/or a or the filler, to form the resin composition.
  • the filler may comprise a ceramic filler, e.g. a calcium pyrophosphate filler.
  • the photocurable composition according to the invention may be used for the development of an injectable, photo-curable, and/or biodegradable biomaterials, e.g. for use in hard tissue restoration such as upper and lower extremity fractures.
  • the photocurable composition according to the invention is a‘flowable’ biomaterial, which has the flexibility and versatility to conform into any cavity.
  • the photocurable composition may be photo-cured in-situ with minimal surgical intervention.
  • the potential application of the photocurable composition and resulting photocured crosslinked materials find a wide range of applications in, for example, biomedical applications such as implants, surgical sutures, restorative dentistry, drug delivery, and tissue engineering.
  • the photocurable composition according to the invention may be utilised in additive manufacture such as 3D-printing to fabricate bespoke objects for use in a wide range of applications.
  • Figure 1 is a synthetic route to Monomer 1 , a first embodiment of the invention
  • Figure 2 is a synthetic route to Monomer 2, a second embodiment of the invention
  • Figure 3A is a schematic experimental set-up for measuring the curing kinetics by FTNIRS of the formulations F1 to F5 according to the invention
  • Figure 3B is a schematic experimental set-up for measuring the curing kinetics by ATR of the formulations F1 to F5 according to the invention
  • Figure 4A is a graph showing the real-time photopolymerisation reaction of formulations F1 to F5 at a sample thickness of 0.5 mm;
  • Figure 4B is a graph showing the real-time photopolymerisation reaction of formulations F1 to F5 at a sample thickness of 3 mm;
  • Figure 5 is a graph showing the dynamic reaction temperature profile during photopolymerisation
  • Figure 6A is a graph showing the real-time ATR measurements of the photocuring reaction of formulations F1 to F5 at a sample thickness of 0.5 mm
  • Figure 6B is a graph showing the real-time ATR measurements of the photocuring reaction of formulations F1 to F5 at a sample thickness of 3 mm;
  • Figure 6C is a graph showing the real-time ATR measurements of the photocuring reaction of formulations F1 to F5 at a sample thickness of 6 mm;
  • Figure 7A is a graph showing real-time ATR measurements of the photocuring of Composite 1 at different curing depths
  • Figure 7B is a graph showing real-time ATR measurements of the photocuring of Composite 2 at different curing depths
  • Figure 8 is a schematic representation of micro-tensile testing using a split ASTM D638 Type V sample mould
  • Figure 9 is a graph showing the mass loss (%) vs. time of formulations according to the invention.
  • Figure 10 shows two graph showing cytocompatibility results of formulations according to the invention.
  • Figure 11 is shows two graph showing cytocompatibility results of formulations according to the invention.
  • Figure 12 is a series of SEM images showing soas-2 cells following 24 hours of seeding onto photocured formulations according to the invention.
  • FIG. 1 there is shown a synthetic route 1 to Monomer 1 according to an embodiment of the invention.
  • Intermediate 1 1 There is shown Intermediate 1 1 and Monomer 1.
  • Monomer 1 was synthesised in a two-step process as follows using 1 ,4-butanediol (CAS: 110-63-4), L- lactide (CAS: 451 1-42-6), stannous 2-ethylhexanoate (CAS: 301-10-0), methacryloyl chloride (CAS: 920-46-7).
  • Step 1 In a first round bottom flask L-Lactide (20g, 139 mmol, 6.26eq) was dissolved in dry toluene (80g). The mixture was purged with argon under magnetic stirring and heated to 90°C for 1 h until full solubilization.
  • Step 2 Intermediate 11 was co-evaporated twice with tetrahydrofuran to remove all traces of water.
  • Intermediate 1 1 (17.7g, 37.3 mmol, 1 eq) and triethylamine (4.91 g, 49 mmol, 1.3 eq) were dissolved in dry tetrahydrofuran (85g).
  • the mixture was cooled at 0°C and freshly distilled methacryloyl chloride (4.29g, 41 mmol, 1.1 eq) was added drop-wise. The mixture was stirred at room temperature overnight. The extent of reaction was evaluated by 1 H NMR. 1 H analysis revealed 100% conversion.
  • FIG. 2 there is shown a synthetic route 2 to Monomer 2 according to an embodiment of the invention.
  • caprolactonediol 21 There is shown caprolactonediol 21 , Intermediate 22, and Monomer 2.
  • Monomer 2 was synthesised in a two-step process as follows using CAPA2043 (CAS: 31831-53-5), fumaryl chloride (627-63-4), and methacryloyl chloride 920-46-7.
  • Step 1 Caprolactonediol 21 (CAPA2043) was co-evaporated twice with tetrahydrofuran to remove all trace of water.
  • a solution of fumaryl chloride (3.82g, 25 mmol, 0.5 eq) in chloroform (40g) was added drop-wise at room temperature to a mixture of caprolactonediol 21 (CAPA2043, 20g, 50 mmol, 1 eq) and potassium carbonate (15.2g, 110 mmol, 2.2 eq) in chloroform (80g).
  • the mixture was stirred at room temperature for 4h.
  • the extent of reaction was evaluated by 1 H NMR. 1 H NMR analysis revealed 100% of conversion.
  • Step 2 Intermediate 22 was co-evaporated with tetrahydrofuran to remove all trace of water.
  • Intermediate 22 (18g, 37.3 mmol, 1 eq) was dissolved in dry dichloromethane (1 10g).
  • Triethylamine (4.9g, 48.5 mmol, 1.3 eq) was added.
  • the mixture was cooled at 0°C and freshly distilled methacryloyl chloride (4.67g, 45 mmol, 1.2 eq) was added drop-wise. The mixture was stirred at room temperature overnight.
  • the extent of reaction was evaluated by 1 H NMR. 1 H analysis revealed 100% of conversion.
  • Formulation F8 was also used, which had the composition 20:80 Monomer 1 to Monomer 2.
  • Density measurements were performed using a helium pycnometer at room temperature (20°C).
  • Viscosity measurements were performed on a Discovery Hybrid Rheometer HR-1 by TA Instruments (Brusselsesteenweg 500, 1731 Asse, Belgium). Measurements were performed with a shear rate sweep of 1- 2000 (1/s), using 20 mm cone-plate with cone angle of 2 degrees (991437). The plate temperature was adjusted accordingly (25 °C and/or 37 °C).
  • CE1 was prepared as a comparative formulation using 80 wt.% 2,2 bis[4-2(2-hydroxy-3-methacroyloxypropoxy) phenyl] propane (Bis-GMA) and 20 wt.% triethyleneglycol di methacrylate (TEGDMA).
  • the formulations F1 to F5, and CE1 were photocured using camphorquinone (CQ) as a blue light photoinitiator present as 0.4 wt.% of the total formulation, and dimethylamino- ethyl dimethacarylate (DMAEMA) as a co-initiator present as 0.8 wt.% of the total formulation.
  • CQ camphorquinone
  • DMAEMA dimethylamino- ethyl dimethacarylate
  • the real-time degree of conversion (DC) and rate of polymerisation of the formulations F1 to F5 were measured using Fourier transformed infra-red spectroscopy (FTIRS), both in near IR (Transmission mode) and mid-IR range (attenuated total reflectance (ATR) mode).
  • FIRS Fourier transformed infra-red spectroscopy
  • ATR attenuated total reflectance
  • FIG. 3A there is shown a schematic experimental set-up 3 for measuring the real-time degree of conversion (DC) and curing kinetics of the formulations F1 to F5 using FTNIR (Fourier transformed near infra-red spectroscopy).
  • DC real-time degree of conversion
  • FTNIR Frection transformed near infra-red spectroscopy
  • the inventors use a SPECTRA X light engine(RTM) manufactured by Lumencor(RTM) of 14940 NW Greenbrier Parkway, Beaverton, OR 97006 USA, which was calibrated to deliver a light intensity of -1000 mW/cm 2 .
  • thermocouple 32 was used to take reaction temperature measurements during the photopolymerisation.
  • FIG. 3B there is shown a schematic experimental set-up 3 for measuring the real-time degree of photopolymerisation of the formulations F1 to F5 using mid-range IR (ATR).
  • ATR mid-range IR
  • a light source 3T a thermocouple 32’, and the sample 33’ of formulation F1 to F5, or CE1.
  • FIG. 4A there is shown a graph 4A showing the real-time photopolymerisation reaction of formulations F1 to F5 at a sample thickness of 0.5 mm.
  • FIG. 4B there is shown a graph 4B showing the real-time photopolymerisation reaction of formulations F1 to F5 at a sample thickness of 3 mm.
  • Tables 2 and 3 there is shown mean values for the degree of conversion of each formulation (F1 to F5, CE1) immediately after irradiation (final DC) and post irradiation for a further 170 seconds (dark curing) for a sample thickness of 0.5mm (Table 2) and 3mm (Table 3).
  • the reaction temperature increase values in Table 3 were measured using the equipment shown in Figure 3A at 25°C.
  • Real time photocuring measurements of formulations F1 to F5 in the mid-infrared range were determined using attenuated total reflectance (ATR) device composed of a horizontal multiple-reflection diamond crystal with 45° mirror angle. Static scans of pre- and post- curing of all formulations (F1 to F5 and CE1) were performed to obtain a baseline and establish an isosbestic point as an internal reference.
  • ATR attenuated total reflectance
  • Resin (uncured) was measured using the absorption wavenumber 1453cm 1 corresponding to a methylene group (CH2) because it remained unchanged during polymerisation.
  • FIG. 5 shows a graph 5 showing the dynamic reaction temperature profile during photopolymerisation of Formulations of the invention and Comparative Examples. This data was measured using the set-up shown in Figure 3B.
  • Figure 5 shows data for the Comparative Example“BT2” (a commercial dental resin mixture comprising BisGMA/TEGDMA in an 80:20 ratio), Formulation F4 with 5 wt.% calcium pyrophosphate of the total composition (C1), Formulation F4 with 10 wt.% calcium pyrophosphate of the total composition (C2), and Comparative Example BT2 with 10 wt.% calcium pyrophosphate of the total composition (BT2 C1).
  • BT2 a commercial dental resin mixture comprising BisGMA/TEGDMA in an 80:20 ratio
  • Formulation F4 with 5 wt.% calcium pyrophosphate of the total composition
  • C2 Formulation F4 with 10 wt.% calcium pyrophosphate of the total composition
  • Comparative Example BT2 with 10 wt.% calcium pyr
  • a temperature control ATR platform (Pike Technologies, 6125 Cottonwood Dr, Fitchburg, Wl 53719, USA) was utilised and calibrated to deliver a platform temperature of physiological temperature at 37°C ( ⁇ 0.5 °C).
  • the increase in reaction temperature was measured using the thermocouple 32’ shown in Figure 3B.
  • temperature change was monitored for further 250 seconds with another dose of irradiation for 120 seconds. This measurement was used to correct the data by subtracting it from the initial temperature rise in order to achieve‘true’ reaction temperature rise during polymerisation. It is shown that there is a significant difference in reaction temperature increase between CE1 and the formulations according to the invention (F1 to F5) at physiological temperature.
  • the high reaction temperatures of CE1 would be detrimental to local cellular tissues.
  • FIG 6A there is shown a graph 6A showing the real-time ATR measurements of the photocuring reaction of formulations F1 to F5 at a sample thickness of 0.5 mm.
  • FIG. 6B there is shown a graph 6B showing the real-time ATR measurements of the photocuring reaction of formulations F1 to F5 at a sample thickness of 3 mm.
  • FIG. 6C there is shown a graph 6C showing the real-time ATR measurements of the photocuring reaction of formulations F1 to F5 at a sample thickness of 6 mm.
  • Resin-based composites were developed comprising the resin composition formulations F1 to F5, and further comprising a filler, the filler comprising bioactive crystalline calcium pyrophosphate.
  • Calcium pyrophosphate was made according to an established protocol described in W02008/006204.
  • the star-shaped pyrophosphate crystals were milled using a zirconia ball miller followed by a series of sieving to obtain 40-63 pm size filler particles. This minimised the void and porosity in the resulting resin-based composite.
  • a relatively low pyrophosphate content e.g. 5 to 10 wt.%, was the optimal content for providing good mechanical properties without compromising photo polymerisation. This enables light to be delivered to achieve deep curing (>2mm).
  • Composite 1 (C1) A resin-based composite was fabricated using resin composition formulation F4 and 5 wt.% calcium pyrophosphate of the total composition. The mixture was photocured to form Composite 1.
  • Composite 2 A resin-based composite was fabricated using resin composition formulation F4 and 10 wt.% calcium pyrophosphate of the total composition. The mixture was photocured to form Composite 2.
  • Figure 7A and 7B there is shown a graph showing real-time ATR measurements of the photocuring of Composite 1 (Figure 7 A) and Composite 2 ( Figure 7B) at different curing depths (0.5mm, 3mm, and 6mm). The ATR measurements were taken during irradiation (up to 120 seconds) and post-irradiation (up to 300 seconds from the beginning of curing).
  • FIG 8 there is shown a schematic representation of micro-tensile testing using a split ASTM D638 Type V sample mould with 3.81 mm gauge length and 1.65 mm width.
  • ESPE Visio Beta Vario Light Unit (3M) was used to ensure uniform polymerisation and avoid overlapping (due to the size of the sample) caused by spot curing.
  • This light unit is equipped with four fluorescent tubes to deliver 400mW/cm 2 at a wavelength of 400-500nm. Samples were irradiated for several minutes to achieve ideal condition (complete curing).
  • the resin-based composites, e.g. C1 and C2 are designed to target and provide stability for hard tissue fracture. Therefore, the mechanical properties of neat polymer systems at physiological strain rates were assessed. Referring now to Tables 16 and 17, there is shown the mean values of E-modulus, tensile strength, and ultimate strength, for each of the formulations F1 to F5, F8, CE1 , and composites C1 and C2, according to Examples of the invention.
  • strain rates of 1 s 1 (Table 16) and 0.05 (Table 17).
  • a strain rate of 0.05 s 1 corresponds to the maximum strain rate during sprinting and downhill running, whereas a strain rate of 1 s 1 represents the critical strain rate of a human femur beyond which the energy absorption capacity begins to decline resulting in failure.
  • the elastic modulus (the ratio of stress over strain) was determined by a line of regression at two points in the elastic region.
  • T ensile strength was determined at 0.2% strain tolerance, which is a commonly used tolerance point in industry (C.T.F. ROSS, 2 - Stress and Strain, Editor(s): C.T.F. ROSS, In Woodhead Publishing Series in Civil and Structural Engineering, Mechanics of Solids, Woodhead Publishing, 1999, Pages 54-87, ISBN 9781898563679).
  • Ultimate strength corresponds to the strength of a material just before breaking/necking.
  • Monomer 1 comprising a copolymer of polylactic acid and butanediol, is inherently more brittle than Monomer 2. Therefore, increasing the proportion of Monomer 1 from F1 to F5 improves the overall modulus and tensile strength.
  • the formulations and composites according to the invention are particularly suitable for use in bone scaffolds.
  • the elastic modulus of human cortical bone in the longitudinal direction is reported to be in the range of 4-23 GPa ( ⁇ 18 (compression)), although this is dependent on various factors such as age, mineral content, porosity, and anatomical location.
  • trabecular bone has an ultimate strength of around 50 MPa and 8 MPa under compression and tensile respectively. Its elastic modulus has been reported to be 400 MPa longitudinally (Hart et. al.; J Musculoskelet. Neuronal. Interact. 2017; 17(3): 114-139).
  • a degradation study was conducted on the hydrolytic and enzymatic degradation of photocured Formulation F4 of the invention and also on Comparative Examples.
  • the aim of this study was to evaluate the effects of hydrolytic degradation on mass loss, water content, and mechanical properties of these materials.
  • the degradation study was carried out using identical cylindrical blocks (6x12mm) of the formulation F4.
  • the blocks were prepared using F4 blends, which were either filled with beta-calcium pyrophosphate (b-q8 2 R 2 q 7 , b-CaPP) or were not filled (unfilled).
  • the b-CaPP was made in accordance with the protocol of W02008006204.
  • the study was run for a total of 8 weeks (time points at 1 , 2, 4, 6 and 8 weeks, wherein n 3 per timepoint) per treatment/control group.
  • Lipase (EC 3.1.1.3) from Rhizopus orzyae (Protein content: 50 U/mg) was dissolved in a sterile Dulbecco’s Phosphate Buffered Saline (DPBS), supplemented with penicillin-streptomycin (100U/mL - 100pg/mL) to minimise any possible risk of microbial infection.
  • DPBS Phosphate Buffered Saline
  • penicillin-streptomycin 100U/mL - 100pg/mL
  • Comparative Examples were also prepared comprising a BT2 formulation.
  • the BT2 formulation is a commercial dental resin mixture comprising BisGMA/TEGDMA in an 80:20 ratio.
  • the filled BT2 blend comprised 10 wt.% of b-CaPP (beta-calcium pyrophosphate, b-q8 2 R 2 q 7 ).
  • FIG. 10 there is shown a graph 10 showing the mass loss (%) of photocured neat and b-CaPP-filled system as a result of hydrolytic degradation over time in DPBS medium at 37 °C.
  • the graph 10 shows the degradation of the following materials: Formulation F4 (1 1); Formulation F4 LP1 (12); Formulation F4 LP2 (13); BT2 LP2 (14); cured Formulation F4 + 10wt.% b-CaPP (15); cured Formulation F4 + 10wt.% b-03RR-I_R2 (16); cured BT2 + 10wt.% b-08RR-I_R2 (17).
  • Extract solutions of neat monomers and respective components of their unpolymerized formulations were prepared in Dulbecco’s modified Eagle’s medium (DMEM) (Biosera, Heathfield, UK) supplemented with 10% foetal bovine serum (FBS) (Biosera, Heathfield, UK), L-glutamine (100 pg/mL) and penicillin-streptomycin (100 U/mL - 100 pg/mL). Extracts were prepared using 0.1 g unpolymerized monomer or formulation per mL of supplemented DMEM. Once prepared, solutions were aged in Bijou vials in an incubator (37 °C under 5% CO2 humidified atmosphere) for‘24 hours’ and 7 days’ time period, separately.
  • DMEM Dulbecco’s modified Eagle’s medium
  • FBS foetal bovine serum
  • Extracts were prepared using 0.1 g unpolymerized monomer or formulation per mL of supplemented DMEM.
  • media extracts were sterile filtered using a 0.22 pm membrane filter with additional spotting on an agar plate (48 hours at 37 °C in a 5% CO2 humidified atmosphere) to rule out any possible risk of infection that may arise during cell treatment.
  • specimens were cotton swabbed with 70% ethanol and immersed in supplemented DM EM. Media volumes were adjusted to 0.1g/ml_ accordingly, before incubating for separate periods of time (24 hours and 7 days) at 37 °C under 5% CO2 humidified atmosphere. Following the pre-defined ageing period, extracted media were sterile filtered and spotted on an agar plate as precautionary measures, prior to cell treatment.
  • AB alamarBlue
  • AB is a fluorometric/calorimetric bioassay designed to detect metabolic activity based on an oxidation-reduction (REDOX) growth indicator, known as resazurin. Innate cellular metabolic activity results in the chemical reduction of resazurin (Non-fluorescent, blue) into resorufin (Fluorescent, red). While continuous growth of (viable) cells maintain a reduced environment, inhibition in cell metabolic activity and subsequent growth leads to an oxidized environment. This served to determine cytocompatibility based on change in the absorbance measurement from oxidised form (Resazurin, 600 nm) to reduced AB form (Resorufin, 570 nm), following treatment with media extracts.
  • REDOX oxidation-reduction
  • soas-2 cells Upon reaching near confluency in a T75 flask, soas-2 cells were seeded in 96 flat bottom black well plates (Costar, Corning Corporation, USA) at cell seeding density of 20 cell/cm 2 (per well) and incubated at 37 °C with 5% CO2 in a humidified atmosphere, for 24 hours. Post 24 hours, old media was aspirated, and wells were washed three times with DPBS before treating with 50 mI_ of collected media extracts (24 hours/ 7 days). Additional 50 mI_ of freshly supplemented DMEM was added to give a total volume of 100 mI_ with a media extract to fresh DMEM ratio of 1 : 1 , per well.
  • the graphs show the reduction of AB (Resazurin) into resorufin (%) by soas-2 cells treated with 24 hours (graph a) and 7 day old media extracts (graph b) of unpolymerized monomers and their corresponding formulation components, for 24 hours.
  • the dashed lines represent untreated groups (Control).
  • Columns and errors bars represent mean and standard error of mean (SEM) in percent, respectively.
  • Asterisks (* p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.005, **** p ⁇ 0.001) indicate statistically significant differences between groups, based on post-hoc Bonferroni multiple comparison tests following one-way ANOVA.
  • the graphs show the cytocompatibility of Monomer 1 (PLLA-DM), Monomer 2 (PCF-DM), Formulation F4 (F4), Formulation F4 + b-CaPP (F4+ b-CaPP), Bis-GMA (BisGMA), TEGDMA (TEGDMA), BT2 (BT2), BT2+ b-CaPP (BT2+ b-CaPP), and b-CaPP.
  • Graph (a) and Graph (b) show the cytocompatibility of soas-2 cells treated with two different media extracts per group: low concentration (24 hour-aged extracts), and graph (b) high concentration (7 day-aged media extracts), for both unpolymerized and fully cured samples.
  • the time period of 24 hours and 7 days refers to the ageing period of supplemented DMEM with a given monomer or blend or formulation
  • the graphs show the reduction of AB (Resazurin) into resorufin (%) by soas-2 cells treated with 24 hours (graph a) and 7 day old (graph b) media extracts of photocured formulations, for 24 hours. Filled systems were incorporated with 10 wt.% b-CaPP as filler. Dashed lines represent untreated groups (Control). Columns and errors bars represent mean and standard error of mean (SEM) in percent, respectively.
  • FIG. 13 there is shown a series of SEM images of soas-2 cells following 24 hours of seeding on surfaces of photocured disk specimens of unfilled and filled (10 wt.%) composites of F4 and BT2, that were not preconditioned in DMEM.
  • Thermanox® coverslips were used as a positive control. Cells appear to have attached with morphology generally associated with soas-2 cell lines (Polygonal). On both Thermanox and unfilled BT2 surfaces, cell attachments had taken place in small isolated clusters with most cells appear as round, typically associated with initial phases of substrate adhesion.
  • the monomers, formulations, and corresponding crosslinked or cured polymers of the invention exhibit improved cytocompatibility and reduced cytotoxicity than those materials of the prior art.
  • the materials of the invention appear to degrade slightly more readily under hydrolytic and enzymatic conditions, it has been surprisingly shown that the degradation products exhibit greater cytocompatibility (and less cytotoxicity) in comparison to the materials of the prior art. Therefore, the polymers of the invention are usable as improved dental composite resins.

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  • Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

Composition photodurcissable comprenant une résine précurseur, la résine précurseur comprenant : un précurseur polymère d'acide polylactique comprenant une chaîne principale, la chaîne principale comprenant au moins une fraction acrylate ; et un précurseur polymère de polycaprolactone comprenant une chaîne principale, la chaîne principale comprenant au moins une fraction acrylate et un alcène (par exemple, un alcène substitué en 1,2) ; le précurseur polymère d'acide polylactique et le précurseur polymère de polycaprolactone étant réticulables.
PCT/GB2020/051850 2019-07-31 2020-07-31 Monomères durcissables et compositions WO2021019255A1 (fr)

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