US20150025161A1 - Polyurethane-grafted hydrogels - Google Patents

Polyurethane-grafted hydrogels Download PDF

Info

Publication number
US20150025161A1
US20150025161A1 US14/508,895 US201414508895A US2015025161A1 US 20150025161 A1 US20150025161 A1 US 20150025161A1 US 201414508895 A US201414508895 A US 201414508895A US 2015025161 A1 US2015025161 A1 US 2015025161A1
Authority
US
United States
Prior art keywords
polyurethane
hydrogel
bone
polymer
grafted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/508,895
Inventor
David Myung
Lampros Kourtis
Robert Ward
Michael J. Jaasma
Keith McCrea
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to US14/508,895 priority Critical patent/US20150025161A1/en
Publication of US20150025161A1 publication Critical patent/US20150025161A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/26Mixtures of macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/74Synthetic polymeric materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00Preparations for dentistry
    • A61K6/80Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/884Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
    • A61K6/891Compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A61K6/893Polyurethanes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/18Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56Porous materials, e.g. foams or sponges
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F283/00Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
    • C08F283/02Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polycarbonates or saturated polyesters
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00Polymeric products of isocyanates or isothiocyanates
    • C08G18/06Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/67Unsaturated compounds having active hydrogen
    • C08G18/671Unsaturated compounds having only one group containing active hydrogen
    • C08G18/672Esters of acrylic or alkyl acrylic acid having only one group containing active hydrogen
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/36After-treatment
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L75/00Compositions of polyureas or polyurethanes; Compositions of derivatives of such polymers
    • C08L75/04Polyurethanes
    • C08L75/14Polyurethanes having carbon-to-carbon unsaturated bonds
    • C08L75/16Polyurethanes having carbon-to-carbon unsaturated bonds having terminal carbon-to-carbon unsaturated bonds
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B32LAYERED PRODUCTS
    • B32BLAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B37/00Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding
    • B32B37/14Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the properties of the layers
    • B32B37/24Methods or apparatus for laminating, e.g. by curing or by ultrasonic bonding characterised by the properties of the layers with at least one layer not being coherent before laminating, e.g. made up from granular material sprinkled onto a substrate
    • B32B2037/243Coating
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B32LAYERED PRODUCTS
    • B32BLAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B2375/00Polyureas; Polyurethanes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B32LAYERED PRODUCTS
    • B32BLAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
    • B32B2535/00Medical equipment, e.g. bandage, prostheses, catheter
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2210/00Compositions for preparing hydrogels
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2270/00Compositions for creating interpenetrating networks
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2375/00Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
    • C08J2375/04Polyurethanes
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/31504Composite [nonstructural laminate]
    • Y10T428/31551Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/31504Composite [nonstructural laminate]
    • Y10T428/31551Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
    • Y10T428/31573Next to addition polymer of ethylenically unsaturated monomer
    • Y10T428/31583Nitrile monomer type [polyacrylonitrile, etc.]

Definitions

  • the present invention relates generally to polymers, and more specifically to methods by which hydrogel and polyurethane polymers are grafted together to form two-layered structures, and by which they are attached to bone, in ways that are useful for medical and commercial devices.
  • the invention also includes materials and articles formed by this method.
  • Hydrogels have been combined with polyurethanes to form articles with certain useful properties. Hydrogel materials have been reinforced with polyurethanes and other materials to provide a more robust backing material. Also, a hydrogel coating or overlayer can be added to a hydrophobic polymer article to improve the article's biocompatibility. Prior hydrogel/polyurethane combinations have not provided the best combination of strength and swellability, however. In addition, prior methods of making hydrogel/polyurethane combinations have used expensive and/or toxic processes.
  • Hoffman et al. U.S. Pat. No. 3,826,678 describes a process for coating an inert polymeric substrate with a reactable hydrogel polymer and then attaching a biologically active molecule in order to make a biocompatible material with a biofunctional surface.
  • Hoffman's “radiation grafting” refers to application of expensive high energy to a polymer, a treatment that causes both non-specific formation of bonds and non-specific breaking of bonds. The bonds made are non-specific bonds between the two polymers anywhere along the backbone of the chains, as well as non-specific bonds (“crosslinking”) within each polymer.
  • Conditions for using “radiation grafting” were chosen by Hoffman such that more favorable than unfavorable reactions occur.
  • Yang et al. J. Biomed Mater Res 45:133-139, 1999 describe a process for forming a graft material having both polyurethane and hydrogel.
  • Yang formed a mixture of polyurethane, acrylic acid, and photoinitiator, and treated it with UV light in the absence of a degassing step to create an homogeneous and unlayered acrylic acid/polyurethane polymer grafted throughout its composition.
  • Wang et al. (U.S. Patent Publication 2002/00524480) describe a process for forming a material having a modified surface that can be used to tether other compounds at the surface while maintaining the bulk properties of the material.
  • Wang started with a formed hydrophobic polymer, such as an acylic or polyurethane, and introduced a functional monomer such as acylate or vinyl monomer, and an initiator just at the polymer surface, such as by limited swelling of the polymer in a solvent.
  • the functional monomer was treated, such as with UV irradiation, to form a second polymer.
  • a surface modification agent, such as heparin may be attached to the second polymer.
  • IPN Interpenetrating Polymer Network
  • Gao et al. (Chinese Journal of Polymer Science Vol. 19, No. 5, (2001), 493-498) describe improvements to materials for use in improving long-term implants that become integrated into the body, such as devices put into blood vessels and in artificial hearts.
  • Gao describes two methods to create on a segmented polyurethane a hydrophilic surface containing functional groups that will adhere cells and support growth. In both methods, the segmented polyurethane was activated by a high concentration of toxic hydrogen peroxide (30%) and UV light to generate reactive groups.
  • the activated segmented polyurethane was immersed in a solution of hydrophilic monomers, such as 2-(dimethylamino)ethyl methacrylate, 2-hydroxyethyl acrylate or acrylamide, and ammonium iron (II) sulfate hexahydrate, and the monomers grafted onto the segmented polyurethane by treatment with UV light.
  • hydrophilic monomers such as 2-(dimethylamino)ethyl methacrylate, 2-hydroxyethyl acrylate or acrylamide, and ammonium iron (II) sulfate hexahydrate
  • the activated segmented polyurethane membrane was immersed in a solution of hydrophilic monomers, removed, placed under nitrogen, and the hydrophilic monomers grafted onto the reactive groups of the segmented polyurethane by treatment with UV light.
  • the membrane was rinsed with hot water for 48 hours to remove homopolymers.
  • the result was a very thin layer of hydrophilic polymer coating on the surface of the polyurethane.
  • SEM images of materials made using the “Solution Grafting Method” versus those made using “Pre-Absorbing Grafting Method” show significant differences in appearance in materials made using the different methods.
  • the present invention improves upon prior articles made from a combination of a hydrogel and a polyurethane and methods of making such articles.
  • the mechanical properties desired for certain medical applications is often outside the range of possibility of many hydrophilic starting materials.
  • one aspect of this invention takes advantage of the high mechanical strength of hydrophobic starting materials and combines those materials with hydrogels as a useful way to achieve the goal of high mechanical strength in addition to other desirable properties provided by the hydrogels without the cost and issues associated with the use of highly specialized equipment (e.g., 60 Co radiation source) or damage to and/or ambiguity about the composition of the formed material due to lack of specificity in the treatment to effect bonding (e.g., gamma irradiation).
  • highly specialized equipment e.g. 60 Co radiation source
  • damage to and/or ambiguity about the composition of the formed material due to lack of specificity in the treatment to effect bonding e.g., gamma irradiation.
  • an “interpenetrating polymer network” or “IPN” is a material comprising two or more polymer networks which are at least partially interlaced on a molecular scale, but not covalently bonded to each other, and cannot be separated unless chemical bonds are broken.
  • a “polymer” is a substance comprising macromolecules (comprising repeated units of monomers), including homopolymers and copolymers.
  • a “copolymer” is a polymer derived from two or more species of monomer.
  • a “homopolymer” is a polymer derived from a single monomeric species.
  • a “graft polymer” is a polymer of that has side chains (“graft macromolecules”) containing different atoms from those in the main chain. This definition includes side chains that are polymers.
  • a “graft copolymer” is a graft polymer in which adjacent blocks in the main (or in the side) chains comprise different species of monomer.
  • One aspect of the invention provides an article having a hydrogel layer chemically grafted to an end-functionalized polyurethane layer.
  • the hydrogel and polyurethane are interfacially grafted.
  • the polyurethane layer may be selected from a group consisting of polycarbonate urethane, polycarbonate urethane urea, polyester urethane, polyether urethane, polyurethane urea, or a silicone derivative of these.
  • the polyurethane may have hard segments, soft segments, chain extenders, and end groups.
  • the hard segments are selected from the group 1,5 naphthalene diisocyanate (NDI), isophorone isocyanate (IPDI), 3,3-bitoluene diisocyanate (TODI), methylene bis(p-cyclohexyl isocyanate) (H12MDI), cyclohexyl diiscocyanate (CHDI), 2,6 tolulene diisocyanate or 2,4 toluene diisocyanate (TDI), hexamethyl diisocyanate (HMDI), and methylene bis(p-phenyl isocyanate) (MDI).
  • NDI naphthalene diisocyanate
  • IPDI isophorone isocyanate
  • TODI 3,3-bitoluene diisocyanate
  • H12MDI methylene bis(p-cyclohexyl isocyan
  • the soft segments of the polyurethane may be selected from the group hydroxy terminated butadiene, hydroxyl terminated polyisobutylene, hydroxybutyl terminated polydimethylsiloxane (PDMS), poly (1,6 hexyl 1,2-ethyl carbonate), hydrogenated polybutadiene, polycaprolactone, polyethylene adipate, polyethylene oxide (PEO), polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, and poly(tetramethylene oxide) (PTMO).
  • the chain extenders of the polyurethane may be selected from the group 1,4 butanediol, ethylene diamine, 4,4′ methylene bis(2-chloroaniline) (MOCA), ethylene glycol, and hexane diol.
  • MOCA 4,4′ methylene bis(2-chloroaniline)
  • the polyurethane endgroups may be selected from the group acylamide, acrylate, allyl ether, methacrylate, or vinyl.
  • the hydrogel layer may be end-linked macromeric subunits, e.g. PEG or a biomolecule, or polymerized monomeric subunits.
  • the biomolecule may be, e.g., collagen, one or more growth factors, steroids, bisphosphonates, or combinations or derivatives thereof.
  • the biomolecules may be selected from the group any Bone Morphogenetic Protein, any Fibroblast Growth Factor, any Transforming Growth Factor, or any Osteogenic Protein.
  • the hydrogel layer may be a homopolymer. In some embodiments the hydrogel may be polymerized monomeric subunits. In some embodiments, the hydrogel layer may be a copolymer. The copolymer may have a polymerized subunit, such as a subunit selected from the group consisting of acrylamide, hydroxyethyl acrylamide, N-isopropyl acrylamide, 2-hydroxyethyl methacrylate, and 2-hydroxyethyl acrylate. In some embodiments, the hydrogel network may contain at least 50%, at least 75%, or at least 90% by dry weight of telechelic macromonomer.
  • the hydrogel layer may be an IPN with a first and second network.
  • the first IPN network may be end-linked macromeric subunits.
  • the polymerized macromeric subunits may be selected from the group consisting of PEG, poly(N-vinyl pyrrolidone), polydimethylsiloxane, poly(vinyl alcohol), polysaccharide, and a biomolecule.
  • the polymerized macromeric subunits may have end group or side group functionalities selected from the group consisting of acrylamide, acrylate, allyl, methacrylamide, methacrylate, N-vinyl sulfone, and vinyl.
  • the second IPN network may be polymerized subunits (monomers).
  • the subunits may be hydrophilic.
  • the hydrophilic subunit may be ionizable.
  • the ionizable subunit may be anionic.
  • the anionic subunits may include carboxylic acid and/or sulfonic acid groups.
  • the second network may be polyacrylic acid.
  • the ionizable subunit may be cationic.
  • the hydrophilic subunit may be non-ionic.
  • the non-ionic subunit may be selected from the group consisting of acrylamide, methacrylamide, N-hydroxyethyl acrylamide, N-isopropylacrylamide, methyl methacrylate, N-vinyl pyrrolidone, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, and/or derivatives of these.
  • both networks of the IPN may be grafted to the polyurethane.
  • a second polyurethane may be attached to the first polyurethane.
  • the second polyurethane may have functionalized end groups.
  • the second polyurethane may include salt such as salt with crystals of size that varies from 10 ⁇ m to 1000 ⁇ m.
  • the second polyurethane may be porous, with the pore size varying, e.g.; from 10 ⁇ m to 1000 ⁇ m.
  • the second polyurethane may contain foaming agents to create open cell porosity, with the pore size varying, e.g.; from 10 ⁇ m to 1000 ⁇ m.
  • the second polyurethane may include a biomolecule.
  • the biomolecule may be selected from the group consisting of collagen, bone morphogenetic protein, bisphosphonate, and an osteogenic protein.
  • the second polyurethane may include a bone component, i.e., a material normally found in natural bone.
  • the bone component may be one or more of carbonated apatite, hydroxyapatite, alpha tricalcium phosphate, beta tricalcium phosphate, and other calcium phosphates.
  • the second polyurethane may include entrapped fillers.
  • the second polyurethane may include an antioxidant.
  • the antioxidant may be selected from the group consisting of ascorbic acid, beta carotene, glutathione, Irganox®, lipoic acid, retinol, santowhite, uric acid, ubiquinol, and Vitamin E.
  • Another aspect of the invention provides an article having a first polyurethane, and a second polyurethane attached to the first polyurethane, the second polyurethane having a putty-like hardness.
  • the second polyurethane has reactive end groups.
  • the second polyurethane may include salt.
  • the second polyurethane may be porous.
  • the composition of the first and second polyurethane may include entrapped fillers.
  • the composition of the first and second polyurethane may include an antioxidant.
  • the antioxidant may be selected from the group consisting of ascorbic acid, Vitamin E, Irganox, santowhite, glutathione, uric acid, lipoic acid, beta carotene, retinol, and ubiquinol.
  • Another aspect of the invention provides a process for grafting a polyurethane to a hydrogel including the following steps: freezing a first solution containing either reactive hydrogel precursors or end-functionalized polyurethane precursors; applying a second solution containing either end-functionalized polyurethane precursors or reactive hydrogel precursors to the first solution; and polymerizing and crosslinking the solutions to form a laminated graft polymer having a polyurethane and a hydrogel.
  • Another aspect of the invention provides a process for grafting a polyurethane to a hydrogel including the following steps: casting a layer from a solution containing end-functionalized polyurethane precursors; applying a second solution containing reactive hydrogel precursors, the second solution containing a solvent for the polyurethane layer; and polymerizing and crosslinking the solutions to form a laminated graft polymer having a polyurethane and a hydrogel.
  • the polymerizing step uses UV light or heat.
  • the method may include the steps of immersing at least part of the laminated graft polymer in a third solution; the third solution having hydrogel precursors different from the precursors in the first or second solutions; swelling the graft polymer; and polymerizing the third solution to create a graft polymer having a polyurethane and an IPN, whereby the IPN has a second hydrogel network intertwined with a first hydrogel network.
  • the third solution may be a partial solvent for the first hydrogel, and is able to swell the first hydrogel network.
  • the solution containing the hydrogel precursors may have telechelic molecules.
  • the telechelic molecules may be poly(ethylene) glycol with one or more endgroups selected from the group consisting of acrylate, methacrylate, acrylamide, vinyl, or allyl ether.
  • the polyurethane solution may have one or more materials selected from the group consisting of vinyl terminated polyurethane, polycarbonate urethane, polyether urethane, polycarbonate urethane urea, polyester urethane, polyurethane urea and silicone derivatives of these.
  • Another aspect of the invention provides a process for making a material that can be attached to bone, including the following steps: applying a solution that contains a polyurethane precursor having reactive endgroups, and further containing solvent, photoinitiator and crosslinker to a first polyurethane that is grafted to a hydrogel; polymerizing the polyurethane precursor; and treating with heat and convection to remove the solvent to yield a second unreacted telechelic polyurethane surface coated on a polyurethane grafted hydrogel.
  • the second polyurethane may be polycarbonate urethane and in others polyether urethane.
  • the reactive endgroups may be selected from the group consisting of acrylamide, acrylate, allyl ether, methacrylate, and vinyl.
  • the solvent may be selected from the group consisting of dimethylacetamide, dimethyl sulfoxide, and tetrahydrofuran.
  • the applying step includes applying a salt.
  • Another aspect of the invention provides a process for attaching an article to a bone, the article including a porous polyurethane having a photointiator and a crosslinker, the method including the steps of placing the porous polyurethane in apposition to the bone; and polymerizing the second polyurethane to attach the article to the bone.
  • the porous polyurethane contacts and flows into the bone.
  • the article may also include a second polyurethane attached to the porous polyurethane and optionally a hydrogel.
  • the polymerizing step may include exposing the polyurethane to UV light, heat, or a chemical initiator.
  • the polyurethane-grafted hydrogels of the present invention have numerous applications in medicine and industry. In orthopaedics, there is a great need for cartilage replacement materials that emulate the properties of natural cartilage. The invention may also be useful in other areas of orthopaedics (in any joint), such as the spine, a disc or facet replacement, or as a bursal replacement. Other applications of the polyurethane-grafted hydrogels are possible, in fields including but not limited to wound care (e.g. as a wound dressing), plastic surgery, urology (e.g. catheters), or cardiology (e.g. as a stent, catheter, or valve material).
  • wound care e.g. as a wound dressing
  • plastic surgery e.g. catheters
  • cardiology e.g. as a stent, catheter, or valve material
  • the polyurethane-grafted hydrogels are useful as devices in the form of plugs, patches, caps, or cups to repair defects in joint surfaces.
  • a device is comprised of a hydrogel bearing side and a porous polyurethane bone-interface side which are chemically bonded to each other.
  • the hydrogel side provides a lubricious, “cartilage-like” bearing surface while the polyurethane side provides structural reinforcement and facilitates bone adhesion and ingrowth.
  • the bone interface side of the polyurethane-grafted hydrogel is adhered to bone through any of the above mentioned approaches.
  • FIGS. 1A-C illustrate a process by which hydrogels and polyurethanes are grafted according to one aspect of this invention.
  • FIGS. 2A-B illustrate one example of a polyethylene glycol (PEG)-dimethacrylate hydrogel grafted to a methacrylate functionalized polyurethane to yield a polyurethane grafted PEG hydrogel.
  • PEG polyethylene glycol
  • FIGS. 3A-C illustrate how an IPN is formed and grafted to a polyurethane.
  • FIGS. 4A-B illustrate how a double polymer graft is formed between polyurethane and a hydrogel IPN.
  • FIGS. 5A-C illustrate how a telechelic polyurethane adhesive is deposited on a polyurethane backing layer.
  • FIGS. 6A-B shows examples of the polyurethane backing material and polyurethane adhesive.
  • FIGS. 7A-D illustrate how the adhesive polyurethane attaches a material to bone according to one aspect of this invention
  • FIGS. 8A-B illustrate how the graft copolymer attaches to bone.
  • FIGS. 9A-C illustrate how an osteochondral graft implant formed from a polymer graft of this invention can be used to replace or augment cartilage within a joint.
  • FIG. 10 is a shows a photomicrograph of a cross-section of the polyurethane-grafted hydrogel of a material made according to one aspect of this invention.
  • FIG. 11 shows the results of testing the static material properties of a material of the current invention.
  • FIG. 12 shows the results of lap shear testing to determine the strength of material made according to the current invention.
  • a polyurethane is interfacially grafted to a hydrogel to create a layered strong, lubricious polymer graft material.
  • monomers or macromonomers of a hydrogel precursor are dissolved with photoinitiator and, optionally, a crosslinker, in an organic solvent or buffer.
  • monomers or macromonomers of a second hydrogel precursor that will form a copolymer are also dissolved.
  • biomolecules may be added.
  • Monomers or macromonomers of a polyurethane precursor are also dissolved along with photoinitator, and optionally a crosslinker, in an organic solvent or buffer; the organic solvent or buffer can be the same or different composition as the one in which the hydrogel precursors are dissolved.
  • Additional materials that will give the materials additional properties (“additives”) can be added to either or both solutions.
  • the additives can be the same or different in the two solutions.
  • Any type of organic solvent can be used to create the solutions of the monomers and macromonomers, such as dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, or chloroform.
  • photoinitiator can also be used. This includes, but is not limited to, 2-hydroxy-2-methyl-propiophenone and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone.
  • any type of compatible cross-linkers may be used to crosslink the second network in the presence of any of the aforementioned first networks such as, for example, ethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol dimethacrylate (or diacrylate), triethylene glycol dimethacrylate (or diacrylate), tetraethylene glycol dimethacrylate (or diacrylate), polyethylene glycol dimethacrylate, or polyethylene glycol diacrylate, methylene bisacrylamide, N,N′-(1,2-dihydroxyethylene) bisacrylamide, derivatives, or combinations thereof.
  • first networks such as, for example, ethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol dimethacrylate (or diacrylate), triethylene glycol dimethacrylate (or diacrylate), tetraethylene glycol dimethacrylate (or diacrylate), polyethylene glycol dimethacrylate, or polyethylene glycol diacrylate, methylene bisacrylamide, N
  • any monomer or macromonomer may be used to form the polyurethane layer.
  • the polyurethane has reactive ends. Either one or both ends of the polyurethane may be functionalized. Examples of materials that can be used are polymers having surface active endgroups. See, e.g., Ward et al, U.S. Pat. No. 5,589,563.
  • biomolecules e.g., collagen, growth factors (any Bone Morphogenetic Proteins (BMPs)), Fibroblast Growth Factors (FGFs), Transforming Growth Factors (e.g., TGF ⁇ ), Osteogenic Proteins (e.g., OP-1 or osteopontin), steroids (e.g., dexamethasone), and bisphosphonates
  • BMPs Bone Morphogenetic Proteins
  • FGFs Fibroblast Growth Factors
  • TGF ⁇ Transforming Growth Factors
  • Osteogenic Proteins e.g., OP-1 or osteopontin
  • steroids e.g., dexamethasone
  • bisphosphonates may be incorporated either as an additive or by covalent linkages, combinations, and/or derivatives thereof.
  • Bone components may also be incorporated into the device, such as hydroxyapatite, carbonated apatite, alpha tricalcium phosphate, beta tricalcium phosphate, combinations, and/or derivatives thereof
  • the hydrogel precursor solution containing initiator is cast over a mold and flash-frozen in, for example, a liquid nitrogen bath.
  • the polyurethane precursor solution containing initiator is then cast over the surface of the solidified hydrogel precursor solution.
  • the polyurethane precursor solution can be, for example, at room temperature or below. Freezing the first set of precursors before adding the second set prevents major mixing of the two sets of precursors. Polymerization and cross linking is then initiated by UV or heat.
  • the polyurethane precursor solution containing initiator is cast over a mold and flash-frozen in, for example, a liquid nitrogen bath.
  • the hydrogel precursor solution containing initiator is then cast over the surface of the solidified polyurethane precursor solution.
  • the hydrogel precursor solution can be, for example, at room temperature or below. Polymerization and cross linking is then initiated by UV or heat.
  • the polyurethane precursor solution (e.g., in dimethylacetamide or tetrahydrofuran), is cast over a mold and dried (e.g., at room temperature), to form a layer.
  • the hydrogel precursor solution containing at least in part a solvent for the polyurethane layer (e.g., dimethylacetamide or tetrahydrofuran), is applied on the surface of the polyurethane layer. Polymerization and cross linking is initiated by UV or heat.
  • FIGS. 1A-C shows a graft polymer having a polyurethane polymer grafted to a hydrogel polymer, and the method of making, according to the current invention.
  • FIG. 1A shows two layers of polymer precursors before polymerization.
  • One precursor layer is frozen (e.g., using a liquid nitrogen bath) or otherwise solidified (e.g., by drying) and then a second precursor layer is added to the solidified layer.
  • the figure shows one layer of telechelic hydrogel precursors 2 with functional endgroups 4 and 6 .
  • the telechelic ends can be the same or different structures.
  • the figure shows a second layer of telechelic polyurethane precursors 8 with hard segments 10 and soft segments 12 .
  • the functional groups, 14 and 16 on the ends of the polyurethane precursor can be the same or different structures.
  • the “bottom” (solidified) layer comprises either set of precursors, and the “top” layer comprises the other set.
  • the telechelic polyurethane precursors 8 may be frozen.
  • the hydrogel precursors 2 may be frozen.
  • the layered solutions are covered with a glass plate and polymerized through free radical polymerization, using, for example, exposure to UV light 26 . Exposure to UV light is thought to have two effects: (1) it initiates polymerization and crosslinking of the two precursor solutions, and (2) it melts at least some of the frozen hydrogel or telechelic polyurethane precursor layer, providing chain mobility at the interface between the two layers, and allowing grafting of the hydrogel to the polyurethane at the interface between the two layers.
  • the process of polymerization may generate additional heat that melts the bulk of the frozen layer, allowing the layer to polymerize and crosslink.
  • Polymerization leads to the formation of a polyurethane grafted hydrogel material 24 , as shown in FIG. 1B .
  • the hydrogel polymer 18 is covalently bound by a graft 22 to the polyurethane polymer 20 .
  • the hard segments of the polyurethane polymer 20 assemble to form hard phases 26 , as shown in the graft polymer 29 in FIG. 1C .
  • the soft segments assemble in soft phases 28 .
  • the use of an end-functionalized polyurethane precursor enables the hydrogel layer to graft to the polyurethane layer using relatively inexpensive UV polymerization while minimizing the amount of initiator (such as hydrogen peroxide) used to facilitate grafting.
  • hydrogel polymer network Any monomer or macromonomer or biomacromolecule may be used to form the hydrogel polymer network.
  • the hydrogel polymer network will be referred to as the “first” network and the polyurethane polymer network as the “second” network; but it should be understood that either solution can be solidified (e.g., frozen or dried) first.
  • preformed polyethylene glycol (PEG) macromonomers can be used as the basis of the hydrogel polymer network.
  • PEG is biocompatible, soluble in aqueous solution, and can be synthesized to give a wide range of molecular weights and chemical structures.
  • the hydroxyl end-groups of the bifunctional glycol can be modified into crosslinkable/polymerizeable end-groups to form telechelic PEG molecules with vinyl endgroups such as acrylate, methacrylate, acrylamide, methyacrylamide, vinyl, or allyl ether.
  • FIGS. 2A-B show a particular example of a graft polymer having a polyurethane polymer grafted to a hydrogel polymer.
  • FIG. 2A shows a poly(ethylene glycol) 100 having reactive dimethylacrylate endgroups 104 being polymerized and crosslinked in the presence of a polyurethane 102 having reactive methacrylate endgroups 106 .
  • the result is a polyurethane-grafted PEG hydrogel 111 having a network hydrogel polymer 110 attached via a covalent linkage 114 to a functionalized polyurethane 112 .
  • the solvent used can be water or an organic solvent, (e.g., dimethylacetamide or tetrahydrofuran).
  • poly(ethylene glycol) in addition to the poly(ethylene glycol), other macromonomers such as polycarbonate, poly(N-vinyl pyrrolidone), polydimethylsiloxane, poly(vinyl alcohol), polysacchrarides (e.g., dextran), biomacromolecules (e.g., collagen) and derivatives or combinations thereof can also be chemically modified with endgroup or side-group functionalities such as acrylates, methacrylates, allyl ethers, vinyls, acrylamides, and methacrylamides and used to form the hydrogel polymer network.
  • endgroup or side-group functionalities such as acrylates, methacrylates, allyl ethers, vinyls, acrylamides, and methacrylamides and used to form the hydrogel polymer network.
  • the first network can also be copolymerize with any number of other polymers including but not limited to those based on acrylamide, hydroxyethyl acrylamide, N-isopropylacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate or derivatives thereofhe polymerized subunit may be a derivative of an acrylate, methacrylate, vinyl, allyl ether, or acrylamide monomer.
  • the dry weight of the first polymer network is at least 50%, more preferably at least 75% by weight, and most preferably at least 95% telechelic macromonomer.
  • the polyurethane polymer of the second network can be a commercially available material or it can be a new material, including but not limited to a polycarbonate urethane, polycarbonate urethane urea, polyether urethane, segmented polyurethane urea, silicone polycarbonate urethane, or silicone polyether urethane.
  • the molecular weight of the second polymer layer is high enough to provide structural stability to the material.
  • the polyurethane precursor can be vinyl-terminated (on one or both ends) polyurethane, polycarbonate urethane, polycarbonate urethane ureas, polyester urethane, polyether urethane, polyurethane urea, as well as silicone derivatives of these or combinations thereof.
  • Isocyanates that are used to generate the hard segment include 1,5 naphthalene diisocyanate (NDI), isophorone isocyanate (IPDI), 3,3-bitoluene diisocyanate (TODI), methylene bis(p-cyclohexyl isocyanate) (H12MDI), cyclohexyl diiscocyanate (CHDI), 2,6 tolylene diisocyanate or 2,4 toluene diisocyanate (TDI), hexamethyl diisocyanate, or methylene bis(p-phenyl isocyanate).
  • NDI 1,5 naphthalene diisocyanate
  • IPDI isophorone isocyanate
  • TODI 3,3-bitoluene diisocyanate
  • H12MDI methylene bis(p-cyclohexyl isocyanate)
  • CHDI cyclohexyl diiscocyanate
  • TDI 2,6
  • Chemicals that may be used to generated the soft segment include hydroxy terminated butadiene, hydroxyl terminate polyisobutylene, hydroxybutyl terminated polydimethylsiloxane (PDMS), poly (1,6 hexyl 1,2-ethyl carbonate, and hydrogenated polybutadiene, polycaprolactone, polyethylene adipate, polyethylene oxide (PEO), polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, and poly(tetramethylene oxide) (PTMO).
  • Chain extenders include 1,4 butanediol, ethylene diamine, 4,4′methylene bis(2-chloroaniline) (MOCA), ethylene glycol, and hexane diol.
  • MOCA 4,4′methylene bis(2-chloroaniline)
  • the groups that are used to functionalize the polyurethane macromonomers can be chosen from the same group listed above to functionalize the hydrogel macromoners (e.g., acrylamides, acrylates, allyl ethers, methacrylamides, methacrylates, and vinyls).
  • the functional groups can be on one or both ends, and they can be the same groups or different groups.
  • Free radical polymerization of the above process may be initiated by other means, such as thermal-initiation and other chemistries not involving the use of ultraviolet light.
  • additives can be incorporated into the materials on either the hydrogel side or the polyurethane side. These additives can be included as entrapped fillers or as covalently attached molecules or particles.
  • anti-oxidants can be covalently linked into the hydrogel by methacryloxy-functionalization of the anti-oxidant.
  • a methacrylate group can be regioselectively attached to the primary hydroxyl group of L-ascorbic acid (Vitamin C) by reaction of 2,2,2 trifluoromethyl methacrylate with an immobilized lipase enzyme from Candida Antarctica at 60 degrees Celsius in dioxane in the presence of a polymerization inhibitor (e.g.
  • hydroquinone or di-tert-butyl methyl phenol hydroquinone or di-tert-butyl methyl phenol.
  • Other anti-oxidants can be added, including but not limited to beta carotene, glutathione, Irganox®, lipoic acid, retinol, santowhite, ubiquinol, uric acid, or Vitamin E).
  • a second hydrogel network can be added to the first hydrogel network by swelling the hydrogel grafted polyurethane or the first hydrogel network portion of the hydrogel grafted polyurethane in a second solution containing hydrogel precursors with initiator.
  • the second solution may act as a partial solvent for the hydrogel network to swell it without dissolving.
  • the precursors of the second hydrogel network are polymerized inside the first hydrogel network. The result is an interpenetrating polymer network (IPN) grafted to a polyurethane.
  • IPN interpenetrating polymer network
  • FIGS. 3A-C show an embodiment of a graft polymer having a polyurethane grafted interpenetrating polymer network hydrogel.
  • FIG. 3A shows a polyurethane grafted hydrogel 24 having a polyurethane polymer 20 grafted to a single hydrogel network 18 via graft linkage 22 .
  • the polyurethane polymer 20 has hard phases 26 and soft phases 28 .
  • the polymer graft is swollen in a solution of a second hydrogel precursor 30 as shown in FIG. 3B , along with optional crosslinker and photoinitiator (not shown).
  • the second hydrogel precursor 30 is polymerized, as by UV light 36 , to form a second hydrogel network 34 interpenetrated within a first hydrogel network 18 as shown in FIG. 3C .
  • the final result is a polyurethane-grafted interpenetrating polymer network hydrogel 32 .
  • a second hydrogel network can be added to the first hydrogel network.
  • the hydrogel grafted polyurethane is swollen in a second solution containing hydrogel precursors with optional crosslinker and photoinitiator.
  • the second solution may act as a partial solvent for the hydrogel network.
  • the precursors of the second hydrogel network are polymerized and crosslinked inside the first hydrogel network to yield a polymer graft, with both hydrogels of the interpenetrating polymer network grafted to polyurethane.
  • the polyurethane second network that is grafted to the first hydrogel network has available reactive groups, such as excess isocyanate.
  • FIGS. 4 A-B show an example of a double graft polymer having a polyurethane polymer grafted to two networks of a hydrogel IPN.
  • FIG. 4A shows a first hydrogel network 124 crosslinked 136 to a polyurethane 130 which has excess functional groups 132 such as isocyanate.
  • the first hydrogel network 124 is entangled with a second hydrogel network 126 forming a hydrogel IPN.
  • the second hydrogel network 126 has functional groups 128 such as carboxylate.
  • the functional group 128 of the second hydrogel network interacts with the reactive group 132 of the polyurethane to form a bond 134 , and yield a double polymer graft 122 , as shown in FIG. 4 .
  • the hydrophilic precursor in the second hydrogel network is ionizable and anionic (capable of being negatively charged) to yield an ionizable second hydrogel network.
  • the ionizable second hydrogel polymer network can be poly(acrylic acid) (PAA) hydrogel formed from an aqueous solution of acrylic acid monomers.
  • PAA poly(acrylic acid)
  • Other ionizable monomers include ones that contain negatively charged carboxylic acid or sulfonic acid groups, such as 2-acrylamido-2-methylpropanesulfonic acid, methacrylic acid, hyaluronic acid, heparin sulfate, chondroitin sulfate, and derivatives, or combinations thereof.
  • the second hydrogel network monomer may also be positively charged or cationic.
  • the hydrophilic precursor for the second hydrogel polymer network may also be non-ionic, such as acrylamide, methacrylamide, N-hydroxyethyl acrylamide, N-isopropylacrylamide, methylmethacrylate, N-vinyl pyrrolidone, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate or derivatives thereof.
  • these can be copolymerized with ionizable monomers, or with less hydrophilic species such as methylmethacrylate or other more hydrophobic monomers or macromonomers.
  • Crosslinked linear polymer chains i.e., macromolecules
  • these monomers may also be used in the second network, as well as biomacromolecules such as proteins and polypeptides (e.g., collagen, hyaluronic acid, or chitosan).
  • biomacromolecules such as proteins and polypeptides (e.g., collagen, hyaluronic acid, or chitosan).
  • a telechelic polyurethane with photoreactive endgroups in an organic solvent with photoinitiator and crosslinker is coated onto a polyurethane.
  • the solvent is removed under heat (e.g., 35 degrees Celsius) and convection for about 24-72 hours to yield a putty-like layer of end-linkable polyurethane layered on top of a preexisting polyurethane.
  • Coating an existing polyurethane layer in this fashion effectively bonds the two materials together through packing of the hard segments of the two polyurethanes, effectively creating a single body.
  • the putty is then pressed into a prepared surface of bone and the polyurethane exposed to a stimulus, such as UV light, to induce polymerization and crosslinking. This leads to mechanical interlocking of the polyurethane within the pores of the bone.
  • the polyurethane is polycarbonate urethane or polyether urethane.
  • the photoreactive endgroups on the polyurethane may be acrylamide, acrylate, allyl ether, methacrylate, or vinyl.
  • the organic solvent may be dimethylacetamide, dimethyl sulfoxide, or tetrahydrofuran or combinations of these.
  • the polyurethane may comprise a copolymer comprising linking monomers.
  • the linking monomers may include acrylamide, dimethyl acrylamide, HEMA, triethylene glycol dimethacrylate, methyl methacrylate, and hydroxy ethyl acrylate (HEA).
  • the linking monomers may improve the strength of the putty.
  • salts are incorporated into the bone contacting layer. Any type of salt may be used. After incorporation of the putty into the bone and over time, the salts may be dissolved (e.g., NaCl) by body fluids or resorbed (e.g., tricalcium phosphate or carbonated apatite) by the body.
  • the polyurethane may be attached to a hydrogel, such as described above.
  • thermal, chemical-initiated or other methods of causing polymerization may be used to polymerize and crosslink the putty that has been pressed into a prepared surface of bone.
  • FIGS. 5A-C show how a telechelic adhesive polyurethane is deposited onto a first polyurethane.
  • the adhesive polyurethane can be osteoconductive and/or porous.
  • FIG. 5A shows an adhesive telechelic polyurethane precursor 38 having hard segments 40 , a soft segment 42 , and functional endgroups 44 and 46 .
  • the endgroups 44 and 46 of the telechelic polyurethane can be the same or different structures.
  • the telechelic polyurethane precursor can be a macromonomer with functional endgroups having any number of repeats “n” of the hard and soft segments as shown.
  • FIG. 5A shows an adhesive telechelic polyurethane precursor 38 having hard segments 40 , a soft segment 42 , and functional endgroups 44 and 46 .
  • the endgroups 44 and 46 of the telechelic polyurethane can be the same or different structures.
  • the telechelic polyurethane precursor can be
  • FIG. 5A also shows a material 50 with a polyurethane backing layer 52 , and optionally a hydrogel layer 54 bonded to the polyurethane backing layer.
  • the material 50 can be in the shape of a device such as for orthopedic use.
  • the polyurethane precursors 38 can be coated onto the surface of the material 50 to form an unreacted putty layer 70 on the polyurethane 52 with the putty layer and the backing layer held together by crystallization of the hard segments to create a single body 68 , as shown in FIG. 5B .
  • the putty layer is cured by treatment with UV light 74 and removal of solvent 76 , to form a reacted adhesive 80 as shown in FIG. 5C .
  • salt 78 can be included in the reacted adhesive.
  • the salt causes the material to be osteoconductive, or, after its removal, to form pores which allows for ingrowth of new bone.
  • a foaming agent may be added to the polyurethane precursor solution or the second polyurethane to create open cell porosity.
  • the porosity may vary in size, e.g., from about 10 ⁇ m to about 1000 ⁇ m.
  • the solvent is removed prior to the UV curing step. In another embodiment, the solvent is removed after the UV curing step.
  • thermal, chemical-initiated or other methods of effecting polymerization are used to coat the second polyurethane onto the first polyurethane-backed hydrogel following the process above.
  • the reactive group of the second, telechelic polyurethane can be an acrylamide, acrylate, allyl ether, methacrylate, or vinyl group.
  • FIG. 6A-B show examples of materials that can be used in the present invention.
  • FIG. 6A shows the structure of Bionate® polycarbonate-urethane that can be used in a polyurethane grafted hydrogel such as those as described in FIGS. 1 and 3 , and as the backing material in FIG. 5 .
  • FIG. 6B shows Bionate® polycarbonate-urethane with acrylate functionalized end-groups that can be used as the adhesive layer such as described in FIGS. 5A-C .
  • the lowercase “m” and “n” indicate that the polyurethane can have any number of soft and hard segments.
  • FIGS. 7A-C show a schematic of how a device can be attached to a bone using the polyurethane of the present invention.
  • FIG. 7A shows a device, 200 , such as an orthopedic device, with a layer of polyurethane adhesive or putty 202 which contains salt 204 .
  • the putty attached to the device is apposed to a prepared surface of bone 206 , and the putty 202 is made to interdigitate around the bone 206 , as shown in FIG. 7B .
  • FIG. 7C with the application of UV light 214 or other stimulus, the putty cures around the bone.
  • the salt is removed, and pores 210 are left behind it its place. The pores provide a space for new bone growth 212 into the cured putty 208 as shown in FIG. 7D , thereby anchoring the device in place.
  • therapeutic agents may also be incorporated into the putty, including but not limited to antibiotics and antimicrobials.
  • a porous polyurethane is incorporated into the polyurethane backing layer of the present invention.
  • This porous polyurethane can be incorporated by casting a salt-saturated (about 25%-90% by weight) solution of polyurethane in an organic solvent (about 10%-75% by weight) such as dimethylacetamide or dimethyl sulfoxide, evaporating the solvent under heat (e.g. 80° Celsius) and convection, and then washing the salt away in water.
  • the salt can be any type of salt, including but not limited to sodium chloride or calcium phosphate or derivatives and/or combinations of these.
  • the resulting porous backing layer can serve as a surface for attachment to bone using commercially available adhesives or cements (e.g., bone cements or dental cements) while also serving as a porous scaffold for bone ingrowth.
  • biomolecules e.g., collagen, growth factors (such as Bone Morphogenetic Proteins (BMPs)), Fibroblast Growth Factors (FGFs), Transforming Growth Factors (e.g., TGF ⁇ ), Osteogenic Proteins (e.g., OP-1 or osteopontin), steroids (e.g., dexamethasone), and bisphosphonates
  • BMPs Bone Morphogenetic Proteins
  • FGFs Fibroblast Growth Factors
  • TGF ⁇ Transforming Growth Factors
  • Osteogenic Proteins e.g., OP-1 or osteopontin
  • steroids e.g., dexamethasone
  • bisphosphonates e.g., bisphosphonates
  • the porous polyurethane/polyurethane may be attached to other tissues (e.g., soft tissue, muscle, skin, dentin).
  • FIGS. 8A-B illustrate the integration of osteochondral grafts and other implants of this invention over time.
  • an osteochondral graft implant 300 formed as described above has a lubricious single network hydrogel polymer or IPN hydrogel surface 302 that transitions via a graft copolymer region 304 into the polyurethane polymer 303 .
  • the polyurethane polymer is the bone implant surface.
  • the polyurethane which may be porous and/or may contain salt is placed next to a bone 301 . After implantation and over time, bone tissue will grow from bone 301 into and through the bone contacting surface 303 , creating an overlap zone, 309 , as illustrated in FIG. 8B .
  • FIGS. 9A-C illustrate three possible configurations of osteochondral implants to repair cartilaginous join surface according to this invention.
  • implant 310 is formed as a cap having a lubricious network hydrogel or IPN hydrogel surface 311 transitioning via a graft copolymer region to a bone-contacting surface 312 formed from a polyurethane, as described above.
  • implant 310 covers the outer surface of bone 313 .
  • FIGS. 9B and 9C show configurations in which implant 314 is formed as a patch or plug (respectively) having a lubricious network hydrogel polymer or IPN surface transitioning via a graft copolymer region to a bone-contacting surface 316 formed from a polyurethane, as described above.
  • implant 314 fits within a prepared opening 317 of bone 313 .
  • a preexisting polymeric article can be dip casted in a solution of polyurethane with reactive end groups (monofunctional or telechelic).
  • the dipcasted article can then be frozen as described above, and then dipped again in a solution of hydrogel monomers along with appropriate initiator and crosslinker. This can then be frozen a second time.
  • the material would then be exposed to UV or other suitable stimulus to initiate polymerization and grafting of the hydrogel and the underlying derivatized PU layer. After drying and washing, the end result is a hydrogel grafted to the surface of the article through an intervening layer of polyurethane.
  • two polycarbonate-urethane grafted IPN hydrogels attached to polyurethane were made. The methods used were similar, and both are described here.
  • Two specimens were separately synthesized by a two-step photopolymerization process using custom-made molds.
  • the interpenetrating polymer network hydrogel components were synthesized by a two-step sequential network formation technique based on UV initiated free radical polymerization.
  • the precursor solutions for the first hydrogel network were made of purified PEG-dimethacrylate (MW 3400) (43% by weight) dissolved in dimethylacetamide with 2-hydroxy-2-methyl propiophenone as the UV sensitive free radical initiator.
  • the solutions were cast (separately) into custom-designed Pyrex glass molds, and then the solutions within the molds were flash-frozen in liquid nitrogen baths.
  • 25% solutions of polycarbonate-urethane monomethacrylate (dissolved in dimethylacetamide) were spread over the frozen surfaces of the hydrogel solutions, each was covered with a glass plate, and they were reacted under a UV light source at room temperature.
  • UV 2 mW/cm2, 350 nm, 10 minutes
  • the hydrogel and polyurethane precursor solutions in each case underwent free-radical induced gelation while also grafting to each other due to endgroup compatibility.
  • the polyurethane-grafted hydrogels were removed from the molds and immersed in 70% v/v acrylic acid solutions; in one case in organic solvent, and in the other case in water, along with 1% v/v 2-hydroxy-2-methyl propiophenone as the photoinitiator, and 1% v/v triethylene glycol dimethacrylate as the cross-linking agent for 24 h at room temperature.
  • the swollen gels were exposed to a UV source and the second networks were polymerized inside the first networks to form an IPN structure in each polymer.
  • the polyurethane-grafted hydrogels were washed in dimethylacetamide, dried in a convection oven (80 degrees Celsius), and washed extensively in phosphate buffered saline with repeated solvent exchanges for 5 days to remove any unreacted components.
  • One sample of one material was cut in cross section and analyzed by microscopy, as shown in FIG. 10 .
  • the surfaces of the polyurethane side of the hydrogels were air-dried, and then solutions of polycarbonate urethane (thermoplastic Bionate®; see FIG. 6 ) in dimethylacetamide were spread over the surface and the solvent evaporated by heat and convection.
  • An analysis of the static mechanical properties of the cured and dried polyurethane containing precursors is shown in FIG. 11 .
  • FIG. 10 shows a photomicrograph of a cross-section of the polyurethane-grafted hydrogel at 60 ⁇ magnification.
  • the hydrogel, on the left, is 1.5 mm thick, while the polyurethane on the right is 0.6 mm.
  • FIG. 11 shows the results of testing of the static mechanical properties. Uniaxial tensile tests were conducted to determine the initial Young's modulus in tension, the strain-at-break, and stress-at-break of the materials. Dog bone specimens were tested following ASTM D638. The average true stress (in MPa)—true strain curve (in %) for the joint interface polyurethane material is presented in FIG. 11 . The tensile strength is greater than 20 MPa.
  • polyether urethane was used as the starting material.
  • the material was made following the process described in Example 1.
  • polyurethane layered onto another polyurethane was made and bonded to bone.
  • Polycarbonate-urethane with methacrylate end groups was synthesized by reacting methylene diphenyl diisocyanate with polycarbonate diol (as the soft segment and 1, 4 butanediol as the chain extender at a solid concentration of 30% in dimethylacetamide at 35 degrees Celsius. The monomer 2-hydroxyethyl methacrylate was added to the reaction mixture and the solution was reacted for an additional 24 hours). The resulting polycarbonate-urethane dimethacrylate was cast on the surface of a premade polycarbonate urethane (Bionate®) and the solvent removed at 35 degrees Celsius under convection.
  • Bionate® premade polycarbonate urethane
  • the strength of the bonding was tested by performing a lap shear test, as described in ASTM D3163. Briefly, the lap shear test involved gripping the bone and the porous polyurethane graft and pulling them in opposite directions while collecting data. The shear stress (MPa) is plotted as a function of displacement (mm). As shown in FIG. 12 , the shear stress necessary to remove the polyurethane from the bone was approximately 670 kPa. Testing of nine samples gave a mean ( ⁇ S.D.) shear strength of 520 ⁇ 120 kPa.

Abstract

An article comprising two chemically grafted polymer layers comprising a hydrogel layer and an end-functionalized polyurethane layer. The invention also includes methods of making and using the article.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. application Ser. No. 13/905,028, filed on May 29, 2013, entitled “Polyurethane-Grafted Hydrogels” and issued as U.S. Pat. No. 8,853,294, which is a continuation of U.S. application Ser. No. 12/536,233, filed on Aug. 5, 2009, entitled “Polyurethane-Grafted Hydrogels” and issued as U.S. Pat. No. 8,497,023, which claims priority under 35 U.S.C §119 to U.S. Provisional Patent Application No. 61/086,442, filed Aug. 5, 2008, and entitled “Polyurethane-Grafted Hydrogels,” which are all incorporated by reference in their entirety.
  • INCORPORATION BY REFERENCE
  • All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
  • FIELD OF THE INVENTION
  • The present invention relates generally to polymers, and more specifically to methods by which hydrogel and polyurethane polymers are grafted together to form two-layered structures, and by which they are attached to bone, in ways that are useful for medical and commercial devices. The invention also includes materials and articles formed by this method.
  • BACKGROUND OF THE INVENTION
  • Some polymer networks take up water and swell. These swollen hydrogels have been created from a variety of starting materials and have been used for a variety of applications. The utility of prior hydrogels for their proposed applications is limited by the properties of these compositions, however. In addition, the starting materials and processes of making and using such prior compositions limit not only the resulting properties of the polymers but also the commercial viability of the manufacturing processes and articles made in such processes. Also, the mechanical properties of the prior polymers are often limited by the mechanical properties of the component polymers used, which in the case of most intrinsically hydrophilic, water-swellable polymers, are usually quite low.
  • Hydrogels have been combined with polyurethanes to form articles with certain useful properties. Hydrogel materials have been reinforced with polyurethanes and other materials to provide a more robust backing material. Also, a hydrogel coating or overlayer can be added to a hydrophobic polymer article to improve the article's biocompatibility. Prior hydrogel/polyurethane combinations have not provided the best combination of strength and swellability, however. In addition, prior methods of making hydrogel/polyurethane combinations have used expensive and/or toxic processes.
  • For example, Hoffman et al. U.S. Pat. No. 3,826,678 describes a process for coating an inert polymeric substrate with a reactable hydrogel polymer and then attaching a biologically active molecule in order to make a biocompatible material with a biofunctional surface. Hoffman used “radiation grafting” to attach the hydrogel to the polyurethane and used the reactable hydrogel to attach the biologically active molecules. Hoffman's “radiation grafting” refers to application of expensive high energy to a polymer, a treatment that causes both non-specific formation of bonds and non-specific breaking of bonds. The bonds made are non-specific bonds between the two polymers anywhere along the backbone of the chains, as well as non-specific bonds (“crosslinking”) within each polymer. Conditions for using “radiation grafting” were chosen by Hoffman such that more favorable than unfavorable reactions occur.
  • Hoffman used “radiation grafting” on a preformed material, such as a polyurethane, that had been contacted with a preformed hydrogel or with hydrogel monomers, and then subjected the materials to the high energy radiation (e.g., gamma irradiation or X-rays). The result was crosslinked hydrogel pieces non-specifically grafted to crosslinked polyurethane pieces. Next, the biologically active materials were attached using a specific link that bonded the biomaterial to the hydrogel. In this way, the biological materials were never subject to the fragmentation effects of the radiation treatment, and a bioactive material was made.
  • Yang et al. (J. Biomed Mater Res 45:133-139, 1999) describe a process for forming a graft material having both polyurethane and hydrogel. Yang formed a mixture of polyurethane, acrylic acid, and photoinitiator, and treated it with UV light in the absence of a degassing step to create an homogeneous and unlayered acrylic acid/polyurethane polymer grafted throughout its composition.
  • Park and Nho (Radiation Physics and Chemistry; 67 (2003): 361-365) describe making a wound dressing formed from polyurethane and hydrogel layers. First, polyurethane was dissolved in solvent and dried to form a polyurethane layer. Then a mixture of polyvinyl alcohol/poly-N-vinylpyrrolidone, chitosan and glycerin in water was poured onto the already formed polyurethane layer. The material was optionally treated with freeze-thaw cycles. Conditions were chosen to favor cross-linking reactions in the hydrogel over material degradation during irradiation treatment, and the material was subject to gamma irradiation to form a hydrogel. The result was a hydrogel adjacent a polyurethane; Park et al. do not describe the nature of any interaction between the polyurethane layer and the hydrogel layer.
  • Wang et al. (U.S. Patent Publication 2002/00524480) describe a process for forming a material having a modified surface that can be used to tether other compounds at the surface while maintaining the bulk properties of the material. Wang started with a formed hydrophobic polymer, such as an acylic or polyurethane, and introduced a functional monomer such as acylate or vinyl monomer, and an initiator just at the polymer surface, such as by limited swelling of the polymer in a solvent. The functional monomer was treated, such as with UV irradiation, to form a second polymer. A surface modification agent, such as heparin, may be attached to the second polymer. The result was an Interpenetrating Polymer Network (IPN) at the surface between the polymerized formed polymer, with only indirect interactions between the first and second polymers, and possibly modified with a modification agent covalently attached to the second polymer.
  • Gao et al. (Chinese Journal of Polymer Science Vol. 19, No. 5, (2001), 493-498) describe improvements to materials for use in improving long-term implants that become integrated into the body, such as devices put into blood vessels and in artificial hearts. Gao describes two methods to create on a segmented polyurethane a hydrophilic surface containing functional groups that will adhere cells and support growth. In both methods, the segmented polyurethane was activated by a high concentration of toxic hydrogen peroxide (30%) and UV light to generate reactive groups.
  • In the “Solution Grafting Method,” of Gao, the activated segmented polyurethane was immersed in a solution of hydrophilic monomers, such as 2-(dimethylamino)ethyl methacrylate, 2-hydroxyethyl acrylate or acrylamide, and ammonium iron (II) sulfate hexahydrate, and the monomers grafted onto the segmented polyurethane by treatment with UV light. The iron compound prevents any unwanted polymerization of the monomers in solution.
  • In the “Pre-Absorbing Grafting Method” of Gao, the activated segmented polyurethane membrane was immersed in a solution of hydrophilic monomers, removed, placed under nitrogen, and the hydrophilic monomers grafted onto the reactive groups of the segmented polyurethane by treatment with UV light. The membrane was rinsed with hot water for 48 hours to remove homopolymers. The result was a very thin layer of hydrophilic polymer coating on the surface of the polyurethane. SEM images of materials made using the “Solution Grafting Method” versus those made using “Pre-Absorbing Grafting Method” show significant differences in appearance in materials made using the different methods.
  • SUMMARY OF THE INVENTION
  • The present invention improves upon prior articles made from a combination of a hydrogel and a polyurethane and methods of making such articles. The mechanical properties desired for certain medical applications is often outside the range of possibility of many hydrophilic starting materials. Hence, one aspect of this invention takes advantage of the high mechanical strength of hydrophobic starting materials and combines those materials with hydrogels as a useful way to achieve the goal of high mechanical strength in addition to other desirable properties provided by the hydrogels without the cost and issues associated with the use of highly specialized equipment (e.g., 60Co radiation source) or damage to and/or ambiguity about the composition of the formed material due to lack of specificity in the treatment to effect bonding (e.g., gamma irradiation).
  • For purposes of this application, an “interpenetrating polymer network” or “IPN” is a material comprising two or more polymer networks which are at least partially interlaced on a molecular scale, but not covalently bonded to each other, and cannot be separated unless chemical bonds are broken.
  • A “polymer” is a substance comprising macromolecules (comprising repeated units of monomers), including homopolymers and copolymers.
  • A “copolymer” is a polymer derived from two or more species of monomer.
  • A “homopolymer” is a polymer derived from a single monomeric species.
  • A “graft polymer” is a polymer of that has side chains (“graft macromolecules”) containing different atoms from those in the main chain. This definition includes side chains that are polymers.
  • A “graft copolymer” is a graft polymer in which adjacent blocks in the main (or in the side) chains comprise different species of monomer.
  • One aspect of the invention provides an article having a hydrogel layer chemically grafted to an end-functionalized polyurethane layer. In some embodiments, the hydrogel and polyurethane are interfacially grafted. In some embodiments, the polyurethane layer may be selected from a group consisting of polycarbonate urethane, polycarbonate urethane urea, polyester urethane, polyether urethane, polyurethane urea, or a silicone derivative of these.
  • The polyurethane may have hard segments, soft segments, chain extenders, and end groups. In some embodiments the hard segments are selected from the group 1,5 naphthalene diisocyanate (NDI), isophorone isocyanate (IPDI), 3,3-bitoluene diisocyanate (TODI), methylene bis(p-cyclohexyl isocyanate) (H12MDI), cyclohexyl diiscocyanate (CHDI), 2,6 tolulene diisocyanate or 2,4 toluene diisocyanate (TDI), hexamethyl diisocyanate (HMDI), and methylene bis(p-phenyl isocyanate) (MDI).
  • In some embodiments the soft segments of the polyurethane may be selected from the group hydroxy terminated butadiene, hydroxyl terminated polyisobutylene, hydroxybutyl terminated polydimethylsiloxane (PDMS), poly (1,6 hexyl 1,2-ethyl carbonate), hydrogenated polybutadiene, polycaprolactone, polyethylene adipate, polyethylene oxide (PEO), polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, and poly(tetramethylene oxide) (PTMO).
  • In some embodiments, the chain extenders of the polyurethane may be selected from the group 1,4 butanediol, ethylene diamine, 4,4′ methylene bis(2-chloroaniline) (MOCA), ethylene glycol, and hexane diol.
  • In some embodiments, the polyurethane endgroups may be selected from the group acylamide, acrylate, allyl ether, methacrylate, or vinyl.
  • In some embodiments the hydrogel layer may be end-linked macromeric subunits, e.g. PEG or a biomolecule, or polymerized monomeric subunits. In some embodiments, the biomolecule may be, e.g., collagen, one or more growth factors, steroids, bisphosphonates, or combinations or derivatives thereof. In some embodiments the biomolecules may be selected from the group any Bone Morphogenetic Protein, any Fibroblast Growth Factor, any Transforming Growth Factor, or any Osteogenic Protein.
  • In some embodiments the hydrogel layer may be a homopolymer. In some embodiments the hydrogel may be polymerized monomeric subunits. In some embodiments, the hydrogel layer may be a copolymer. The copolymer may have a polymerized subunit, such as a subunit selected from the group consisting of acrylamide, hydroxyethyl acrylamide, N-isopropyl acrylamide, 2-hydroxyethyl methacrylate, and 2-hydroxyethyl acrylate. In some embodiments, the hydrogel network may contain at least 50%, at least 75%, or at least 90% by dry weight of telechelic macromonomer.
  • In some embodiments the hydrogel layer may be an IPN with a first and second network. In some embodiments the first IPN network may be end-linked macromeric subunits. In some embodiments, the polymerized macromeric subunits may be selected from the group consisting of PEG, poly(N-vinyl pyrrolidone), polydimethylsiloxane, poly(vinyl alcohol), polysaccharide, and a biomolecule. In some embodiments the polymerized macromeric subunits may have end group or side group functionalities selected from the group consisting of acrylamide, acrylate, allyl, methacrylamide, methacrylate, N-vinyl sulfone, and vinyl.
  • In some embodiments the second IPN network may be polymerized subunits (monomers). In some embodiments, the subunits may be hydrophilic. The hydrophilic subunit may be ionizable. The ionizable subunit may be anionic. The anionic subunits may include carboxylic acid and/or sulfonic acid groups. In some embodiments, the second network may be polyacrylic acid. In some embodiments, the ionizable subunit may be cationic. In some embodiments, the hydrophilic subunit may be non-ionic. The non-ionic subunit may be selected from the group consisting of acrylamide, methacrylamide, N-hydroxyethyl acrylamide, N-isopropylacrylamide, methyl methacrylate, N-vinyl pyrrolidone, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, and/or derivatives of these.
  • In some embodiments both networks of the IPN may be grafted to the polyurethane.
  • In some embodiments, a second polyurethane may be attached to the first polyurethane. In some embodiments, the second polyurethane may have functionalized end groups. In some embodiments, the second polyurethane may include salt such as salt with crystals of size that varies from 10 μm to 1000 μm. In some embodiments, the second polyurethane may be porous, with the pore size varying, e.g.; from 10 μm to 1000 μm. In some embodiments, the second polyurethane may contain foaming agents to create open cell porosity, with the pore size varying, e.g.; from 10 μm to 1000 μm.
  • In some embodiments the second polyurethane may include a biomolecule. In some embodiments, the biomolecule may be selected from the group consisting of collagen, bone morphogenetic protein, bisphosphonate, and an osteogenic protein. In some embodiments, the second polyurethane may include a bone component, i.e., a material normally found in natural bone. The bone component may be one or more of carbonated apatite, hydroxyapatite, alpha tricalcium phosphate, beta tricalcium phosphate, and other calcium phosphates.
  • In some embodiments, the second polyurethane may include entrapped fillers.
  • In some embodiments, the second polyurethane may include an antioxidant. The antioxidant may be selected from the group consisting of ascorbic acid, beta carotene, glutathione, Irganox®, lipoic acid, retinol, santowhite, uric acid, ubiquinol, and Vitamin E.
  • Another aspect of the invention provides an article having a first polyurethane, and a second polyurethane attached to the first polyurethane, the second polyurethane having a putty-like hardness. In some embodiments, the second polyurethane has reactive end groups. In some embodiments the second polyurethane may include salt. In some embodiments, the second polyurethane may be porous.
  • In some embodiments, the composition of the first and second polyurethane may include entrapped fillers.
  • In some embodiments, the composition of the first and second polyurethane may include an antioxidant. The antioxidant may be selected from the group consisting of ascorbic acid, Vitamin E, Irganox, santowhite, glutathione, uric acid, lipoic acid, beta carotene, retinol, and ubiquinol.
  • Another aspect of the invention provides a process for grafting a polyurethane to a hydrogel including the following steps: freezing a first solution containing either reactive hydrogel precursors or end-functionalized polyurethane precursors; applying a second solution containing either end-functionalized polyurethane precursors or reactive hydrogel precursors to the first solution; and polymerizing and crosslinking the solutions to form a laminated graft polymer having a polyurethane and a hydrogel.
  • Another aspect of the invention provides a process for grafting a polyurethane to a hydrogel including the following steps: casting a layer from a solution containing end-functionalized polyurethane precursors; applying a second solution containing reactive hydrogel precursors, the second solution containing a solvent for the polyurethane layer; and polymerizing and crosslinking the solutions to form a laminated graft polymer having a polyurethane and a hydrogel.
  • In some embodiments the polymerizing step uses UV light or heat.
  • In some embodiments, the method may include the steps of immersing at least part of the laminated graft polymer in a third solution; the third solution having hydrogel precursors different from the precursors in the first or second solutions; swelling the graft polymer; and polymerizing the third solution to create a graft polymer having a polyurethane and an IPN, whereby the IPN has a second hydrogel network intertwined with a first hydrogel network. In some embodiments the third solution may be a partial solvent for the first hydrogel, and is able to swell the first hydrogel network.
  • In some embodiments, the solution containing the hydrogel precursors may have telechelic molecules. In various embodiments, the telechelic molecules may be poly(ethylene) glycol with one or more endgroups selected from the group consisting of acrylate, methacrylate, acrylamide, vinyl, or allyl ether.
  • In some embodiments, the polyurethane solution may have one or more materials selected from the group consisting of vinyl terminated polyurethane, polycarbonate urethane, polyether urethane, polycarbonate urethane urea, polyester urethane, polyurethane urea and silicone derivatives of these.
  • Another aspect of the invention provides a process for making a material that can be attached to bone, including the following steps: applying a solution that contains a polyurethane precursor having reactive endgroups, and further containing solvent, photoinitiator and crosslinker to a first polyurethane that is grafted to a hydrogel; polymerizing the polyurethane precursor; and treating with heat and convection to remove the solvent to yield a second unreacted telechelic polyurethane surface coated on a polyurethane grafted hydrogel.
  • In some embodiments, the second polyurethane may be polycarbonate urethane and in others polyether urethane.
  • In some embodiments, the reactive endgroups may be selected from the group consisting of acrylamide, acrylate, allyl ether, methacrylate, and vinyl. In some embodiments, the solvent may be selected from the group consisting of dimethylacetamide, dimethyl sulfoxide, and tetrahydrofuran.
  • In some embodiments, the applying step includes applying a salt.
  • Another aspect of the invention provides a process for attaching an article to a bone, the article including a porous polyurethane having a photointiator and a crosslinker, the method including the steps of placing the porous polyurethane in apposition to the bone; and polymerizing the second polyurethane to attach the article to the bone. In some embodiments, the porous polyurethane contacts and flows into the bone. The article may also include a second polyurethane attached to the porous polyurethane and optionally a hydrogel. In some embodiments, the polymerizing step may include exposing the polyurethane to UV light, heat, or a chemical initiator.
  • The polyurethane-grafted hydrogels of the present invention have numerous applications in medicine and industry. In orthopaedics, there is a great need for cartilage replacement materials that emulate the properties of natural cartilage. The invention may also be useful in other areas of orthopaedics (in any joint), such as the spine, a disc or facet replacement, or as a bursal replacement. Other applications of the polyurethane-grafted hydrogels are possible, in fields including but not limited to wound care (e.g. as a wound dressing), plastic surgery, urology (e.g. catheters), or cardiology (e.g. as a stent, catheter, or valve material).
  • The polyurethane-grafted hydrogels are useful as devices in the form of plugs, patches, caps, or cups to repair defects in joint surfaces. A device is comprised of a hydrogel bearing side and a porous polyurethane bone-interface side which are chemically bonded to each other. The hydrogel side provides a lubricious, “cartilage-like” bearing surface while the polyurethane side provides structural reinforcement and facilitates bone adhesion and ingrowth. The bone interface side of the polyurethane-grafted hydrogel is adhered to bone through any of the above mentioned approaches.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
  • FIGS. 1A-C illustrate a process by which hydrogels and polyurethanes are grafted according to one aspect of this invention.
  • FIGS. 2A-B illustrate one example of a polyethylene glycol (PEG)-dimethacrylate hydrogel grafted to a methacrylate functionalized polyurethane to yield a polyurethane grafted PEG hydrogel.
  • FIGS. 3A-C illustrate how an IPN is formed and grafted to a polyurethane.
  • FIGS. 4A-B illustrate how a double polymer graft is formed between polyurethane and a hydrogel IPN.
  • FIGS. 5A-C illustrate how a telechelic polyurethane adhesive is deposited on a polyurethane backing layer.
  • FIGS. 6A-B shows examples of the polyurethane backing material and polyurethane adhesive.
  • FIGS. 7A-D illustrate how the adhesive polyurethane attaches a material to bone according to one aspect of this invention
  • FIGS. 8A-B illustrate how the graft copolymer attaches to bone.
  • FIGS. 9A-C illustrate how an osteochondral graft implant formed from a polymer graft of this invention can be used to replace or augment cartilage within a joint.
  • FIG. 10 is a shows a photomicrograph of a cross-section of the polyurethane-grafted hydrogel of a material made according to one aspect of this invention.
  • FIG. 11 shows the results of testing the static material properties of a material of the current invention.
  • FIG. 12 shows the results of lap shear testing to determine the strength of material made according to the current invention.
  • DETAILED DESCRIPTION OF THE INVENTION
  • In one embodiment, a polyurethane is interfacially grafted to a hydrogel to create a layered strong, lubricious polymer graft material. To form the polyurethane grafted hydrogel, monomers or macromonomers of a hydrogel precursor are dissolved with photoinitiator and, optionally, a crosslinker, in an organic solvent or buffer. In some embodiments, monomers or macromonomers of a second hydrogel precursor that will form a copolymer are also dissolved. In some embodiments, biomolecules may be added. Monomers or macromonomers of a polyurethane precursor are also dissolved along with photoinitator, and optionally a crosslinker, in an organic solvent or buffer; the organic solvent or buffer can be the same or different composition as the one in which the hydrogel precursors are dissolved. Additional materials that will give the materials additional properties (“additives”) can be added to either or both solutions. The additives can be the same or different in the two solutions.
  • Any type of organic solvent can be used to create the solutions of the monomers and macromonomers, such as dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, or chloroform.
  • Any type of photoinitiator can also be used. This includes, but is not limited to, 2-hydroxy-2-methyl-propiophenone and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone.
  • Any type of compatible cross-linkers may be used to crosslink the second network in the presence of any of the aforementioned first networks such as, for example, ethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol dimethacrylate (or diacrylate), triethylene glycol dimethacrylate (or diacrylate), tetraethylene glycol dimethacrylate (or diacrylate), polyethylene glycol dimethacrylate, or polyethylene glycol diacrylate, methylene bisacrylamide, N,N′-(1,2-dihydroxyethylene) bisacrylamide, derivatives, or combinations thereof.
  • Any monomer or macromonomer may be used to form the polyurethane layer. In some embodiments, the polyurethane has reactive ends. Either one or both ends of the polyurethane may be functionalized. Examples of materials that can be used are polymers having surface active endgroups. See, e.g., Ward et al, U.S. Pat. No. 5,589,563.
  • In some embodiments, biomolecules (e.g., collagen, growth factors (any Bone Morphogenetic Proteins (BMPs)), Fibroblast Growth Factors (FGFs), Transforming Growth Factors (e.g., TGFβ), Osteogenic Proteins (e.g., OP-1 or osteopontin), steroids (e.g., dexamethasone), and bisphosphonates may be incorporated either as an additive or by covalent linkages, combinations, and/or derivatives thereof. Bone components may also be incorporated into the device, such as hydroxyapatite, carbonated apatite, alpha tricalcium phosphate, beta tricalcium phosphate, combinations, and/or derivatives thereof. The pore size useful for this application ranges between about 10 micrometers to 1000 micrometers.
  • In one embodiment, the hydrogel precursor solution containing initiator is cast over a mold and flash-frozen in, for example, a liquid nitrogen bath. The polyurethane precursor solution containing initiator is then cast over the surface of the solidified hydrogel precursor solution. The polyurethane precursor solution can be, for example, at room temperature or below. Freezing the first set of precursors before adding the second set prevents major mixing of the two sets of precursors. Polymerization and cross linking is then initiated by UV or heat.
  • In another embodiment, the polyurethane precursor solution containing initiator is cast over a mold and flash-frozen in, for example, a liquid nitrogen bath. The hydrogel precursor solution containing initiator is then cast over the surface of the solidified polyurethane precursor solution. The hydrogel precursor solution can be, for example, at room temperature or below. Polymerization and cross linking is then initiated by UV or heat.
  • In another embodiment, the polyurethane precursor solution, (e.g., in dimethylacetamide or tetrahydrofuran), is cast over a mold and dried (e.g., at room temperature), to form a layer. The hydrogel precursor solution, containing at least in part a solvent for the polyurethane layer (e.g., dimethylacetamide or tetrahydrofuran), is applied on the surface of the polyurethane layer. Polymerization and cross linking is initiated by UV or heat.
  • FIGS. 1A-C shows a graft polymer having a polyurethane polymer grafted to a hydrogel polymer, and the method of making, according to the current invention.
  • FIG. 1A shows two layers of polymer precursors before polymerization. One precursor layer is frozen (e.g., using a liquid nitrogen bath) or otherwise solidified (e.g., by drying) and then a second precursor layer is added to the solidified layer. The figure shows one layer of telechelic hydrogel precursors 2 with functional endgroups 4 and 6. The telechelic ends can be the same or different structures. The figure shows a second layer of telechelic polyurethane precursors 8 with hard segments 10 and soft segments 12. The functional groups, 14 and 16, on the ends of the polyurethane precursor can be the same or different structures. The “bottom” (solidified) layer comprises either set of precursors, and the “top” layer comprises the other set. In one embodiment the telechelic polyurethane precursors 8 may be frozen. In an alternate embodiment, the hydrogel precursors 2 may be frozen. The layered solutions are covered with a glass plate and polymerized through free radical polymerization, using, for example, exposure to UV light 26. Exposure to UV light is thought to have two effects: (1) it initiates polymerization and crosslinking of the two precursor solutions, and (2) it melts at least some of the frozen hydrogel or telechelic polyurethane precursor layer, providing chain mobility at the interface between the two layers, and allowing grafting of the hydrogel to the polyurethane at the interface between the two layers. The process of polymerization may generate additional heat that melts the bulk of the frozen layer, allowing the layer to polymerize and crosslink.
  • Polymerization leads to the formation of a polyurethane grafted hydrogel material 24, as shown in FIG. 1B. The hydrogel polymer 18 is covalently bound by a graft 22 to the polyurethane polymer 20. The hard segments of the polyurethane polymer 20 assemble to form hard phases 26, as shown in the graft polymer 29 in FIG. 1C. The soft segments assemble in soft phases 28. The use of an end-functionalized polyurethane precursor enables the hydrogel layer to graft to the polyurethane layer using relatively inexpensive UV polymerization while minimizing the amount of initiator (such as hydrogen peroxide) used to facilitate grafting.
  • Any monomer or macromonomer or biomacromolecule may be used to form the hydrogel polymer network. For convenience, the hydrogel polymer network will be referred to as the “first” network and the polyurethane polymer network as the “second” network; but it should be understood that either solution can be solidified (e.g., frozen or dried) first.
  • In one embodiment, preformed polyethylene glycol (PEG) macromonomers can be used as the basis of the hydrogel polymer network. PEG is biocompatible, soluble in aqueous solution, and can be synthesized to give a wide range of molecular weights and chemical structures. The hydroxyl end-groups of the bifunctional glycol can be modified into crosslinkable/polymerizeable end-groups to form telechelic PEG molecules with vinyl endgroups such as acrylate, methacrylate, acrylamide, methyacrylamide, vinyl, or allyl ether.
  • FIGS. 2A-B show a particular example of a graft polymer having a polyurethane polymer grafted to a hydrogel polymer. FIG. 2A shows a poly(ethylene glycol) 100 having reactive dimethylacrylate endgroups 104 being polymerized and crosslinked in the presence of a polyurethane 102 having reactive methacrylate endgroups 106. The result is a polyurethane-grafted PEG hydrogel 111 having a network hydrogel polymer 110 attached via a covalent linkage 114 to a functionalized polyurethane 112. The solvent used can be water or an organic solvent, (e.g., dimethylacetamide or tetrahydrofuran).
  • In addition to the poly(ethylene glycol), other macromonomers such as polycarbonate, poly(N-vinyl pyrrolidone), polydimethylsiloxane, poly(vinyl alcohol), polysacchrarides (e.g., dextran), biomacromolecules (e.g., collagen) and derivatives or combinations thereof can also be chemically modified with endgroup or side-group functionalities such as acrylates, methacrylates, allyl ethers, vinyls, acrylamides, and methacrylamides and used to form the hydrogel polymer network.
  • The first network can also be copolymerize with any number of other polymers including but not limited to those based on acrylamide, hydroxyethyl acrylamide, N-isopropylacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate or derivatives thereofhe polymerized subunit may be a derivative of an acrylate, methacrylate, vinyl, allyl ether, or acrylamide monomer.
  • Preferably, the dry weight of the first polymer network is at least 50%, more preferably at least 75% by weight, and most preferably at least 95% telechelic macromonomer.
  • The polyurethane polymer of the second network can be a commercially available material or it can be a new material, including but not limited to a polycarbonate urethane, polycarbonate urethane urea, polyether urethane, segmented polyurethane urea, silicone polycarbonate urethane, or silicone polyether urethane. The molecular weight of the second polymer layer is high enough to provide structural stability to the material. The polyurethane precursor can be vinyl-terminated (on one or both ends) polyurethane, polycarbonate urethane, polycarbonate urethane ureas, polyester urethane, polyether urethane, polyurethane urea, as well as silicone derivatives of these or combinations thereof.
  • Any type of chemistries and stoichiometries can be used to create the polyurethane polymer. Isocyanates that are used to generate the hard segment include 1,5 naphthalene diisocyanate (NDI), isophorone isocyanate (IPDI), 3,3-bitoluene diisocyanate (TODI), methylene bis(p-cyclohexyl isocyanate) (H12MDI), cyclohexyl diiscocyanate (CHDI), 2,6 tolylene diisocyanate or 2,4 toluene diisocyanate (TDI), hexamethyl diisocyanate, or methylene bis(p-phenyl isocyanate).
  • Chemicals that may be used to generated the soft segment include hydroxy terminated butadiene, hydroxyl terminate polyisobutylene, hydroxybutyl terminated polydimethylsiloxane (PDMS), poly (1,6 hexyl 1,2-ethyl carbonate, and hydrogenated polybutadiene, polycaprolactone, polyethylene adipate, polyethylene oxide (PEO), polyhexamethylene carbonate glycol, polypropylene oxide (PPO), polytetramethylene adipate, and poly(tetramethylene oxide) (PTMO).
  • Chemicals used as chain extenders include 1,4 butanediol, ethylene diamine, 4,4′methylene bis(2-chloroaniline) (MOCA), ethylene glycol, and hexane diol.
  • The groups that are used to functionalize the polyurethane macromonomers can be chosen from the same group listed above to functionalize the hydrogel macromoners (e.g., acrylamides, acrylates, allyl ethers, methacrylamides, methacrylates, and vinyls). The functional groups can be on one or both ends, and they can be the same groups or different groups.
  • Free radical polymerization of the above process may be initiated by other means, such as thermal-initiation and other chemistries not involving the use of ultraviolet light.
  • Any number of additives can be incorporated into the materials on either the hydrogel side or the polyurethane side. These additives can be included as entrapped fillers or as covalently attached molecules or particles. For instance, anti-oxidants can be covalently linked into the hydrogel by methacryloxy-functionalization of the anti-oxidant. In one example, a methacrylate group can be regioselectively attached to the primary hydroxyl group of L-ascorbic acid (Vitamin C) by reaction of 2,2,2 trifluoromethyl methacrylate with an immobilized lipase enzyme from Candida Antarctica at 60 degrees Celsius in dioxane in the presence of a polymerization inhibitor (e.g. hydroquinone or di-tert-butyl methyl phenol). Other anti-oxidants can be added, including but not limited to beta carotene, glutathione, Irganox®, lipoic acid, retinol, santowhite, ubiquinol, uric acid, or Vitamin E).
  • In another embodiment, a second hydrogel network can be added to the first hydrogel network by swelling the hydrogel grafted polyurethane or the first hydrogel network portion of the hydrogel grafted polyurethane in a second solution containing hydrogel precursors with initiator. The second solution may act as a partial solvent for the hydrogel network to swell it without dissolving. The precursors of the second hydrogel network are polymerized inside the first hydrogel network. The result is an interpenetrating polymer network (IPN) grafted to a polyurethane.
  • FIGS. 3A-C show an embodiment of a graft polymer having a polyurethane grafted interpenetrating polymer network hydrogel.
  • FIG. 3A shows a polyurethane grafted hydrogel 24 having a polyurethane polymer 20 grafted to a single hydrogel network 18 via graft linkage 22. The polyurethane polymer 20 has hard phases 26 and soft phases 28. The polymer graft is swollen in a solution of a second hydrogel precursor 30 as shown in FIG. 3B, along with optional crosslinker and photoinitiator (not shown). The second hydrogel precursor 30 is polymerized, as by UV light 36, to form a second hydrogel network 34 interpenetrated within a first hydrogel network 18 as shown in FIG. 3C. The final result is a polyurethane-grafted interpenetrating polymer network hydrogel 32.
  • In another embodiment, a second hydrogel network can be added to the first hydrogel network. The hydrogel grafted polyurethane is swollen in a second solution containing hydrogel precursors with optional crosslinker and photoinitiator. The second solution may act as a partial solvent for the hydrogel network. Then the precursors of the second hydrogel network are polymerized and crosslinked inside the first hydrogel network to yield a polymer graft, with both hydrogels of the interpenetrating polymer network grafted to polyurethane. The polyurethane second network that is grafted to the first hydrogel network has available reactive groups, such as excess isocyanate.
  • FIGS. 4 A-B show an example of a double graft polymer having a polyurethane polymer grafted to two networks of a hydrogel IPN. FIG. 4A shows a first hydrogel network 124 crosslinked 136 to a polyurethane 130 which has excess functional groups 132 such as isocyanate. The first hydrogel network 124 is entangled with a second hydrogel network 126 forming a hydrogel IPN. The second hydrogel network 126 has functional groups 128 such as carboxylate. The functional group 128 of the second hydrogel network interacts with the reactive group 132 of the polyurethane to form a bond 134, and yield a double polymer graft 122, as shown in FIG. 4.
  • In one embodiment, the hydrophilic precursor in the second hydrogel network is ionizable and anionic (capable of being negatively charged) to yield an ionizable second hydrogel network.
  • The ionizable second hydrogel polymer network can be poly(acrylic acid) (PAA) hydrogel formed from an aqueous solution of acrylic acid monomers. Other ionizable monomers include ones that contain negatively charged carboxylic acid or sulfonic acid groups, such as 2-acrylamido-2-methylpropanesulfonic acid, methacrylic acid, hyaluronic acid, heparin sulfate, chondroitin sulfate, and derivatives, or combinations thereof.
  • The second hydrogel network monomer may also be positively charged or cationic.
  • The hydrophilic precursor for the second hydrogel polymer network may also be non-ionic, such as acrylamide, methacrylamide, N-hydroxyethyl acrylamide, N-isopropylacrylamide, methylmethacrylate, N-vinyl pyrrolidone, 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate or derivatives thereof. In other embodiments, these can be copolymerized with ionizable monomers, or with less hydrophilic species such as methylmethacrylate or other more hydrophobic monomers or macromonomers. Crosslinked linear polymer chains (i.e., macromolecules) based on these monomers may also be used in the second network, as well as biomacromolecules such as proteins and polypeptides (e.g., collagen, hyaluronic acid, or chitosan).
  • Other aspects of this invention are methods for bonding polyurethane to bone. In one embodiment, a telechelic polyurethane with photoreactive endgroups in an organic solvent with photoinitiator and crosslinker is coated onto a polyurethane. The solvent is removed under heat (e.g., 35 degrees Celsius) and convection for about 24-72 hours to yield a putty-like layer of end-linkable polyurethane layered on top of a preexisting polyurethane. Coating an existing polyurethane layer in this fashion effectively bonds the two materials together through packing of the hard segments of the two polyurethanes, effectively creating a single body. The putty is then pressed into a prepared surface of bone and the polyurethane exposed to a stimulus, such as UV light, to induce polymerization and crosslinking. This leads to mechanical interlocking of the polyurethane within the pores of the bone.
  • In some embodiments, the polyurethane is polycarbonate urethane or polyether urethane.
  • In some embodiments, the photoreactive endgroups on the polyurethane may be acrylamide, acrylate, allyl ether, methacrylate, or vinyl.
  • In some embodiments, the organic solvent may be dimethylacetamide, dimethyl sulfoxide, or tetrahydrofuran or combinations of these.
  • In some embodiments, the polyurethane may comprise a copolymer comprising linking monomers. The linking monomers may include acrylamide, dimethyl acrylamide, HEMA, triethylene glycol dimethacrylate, methyl methacrylate, and hydroxy ethyl acrylate (HEA). The linking monomers may improve the strength of the putty.
  • In another embodiment, salts are incorporated into the bone contacting layer. Any type of salt may be used. After incorporation of the putty into the bone and over time, the salts may be dissolved (e.g., NaCl) by body fluids or resorbed (e.g., tricalcium phosphate or carbonated apatite) by the body.
  • In some embodiments, the polyurethane may be attached to a hydrogel, such as described above.
  • In other embodiments, thermal, chemical-initiated or other methods of causing polymerization are used may be used to polymerize and crosslink the putty that has been pressed into a prepared surface of bone.
  • FIGS. 5A-C show how a telechelic adhesive polyurethane is deposited onto a first polyurethane. The adhesive polyurethane can be osteoconductive and/or porous.
  • FIG. 5A shows an adhesive telechelic polyurethane precursor 38 having hard segments 40, a soft segment 42, and functional endgroups 44 and 46. The endgroups 44 and 46 of the telechelic polyurethane can be the same or different structures. The telechelic polyurethane precursor can be a macromonomer with functional endgroups having any number of repeats “n” of the hard and soft segments as shown. For the purpose of illustration, the drawings in FIG. 5B and C show the simplest case in which the polyurethane precursor 38 is a single monomer with no repeats (n=1), but in practice the polyurethane precursor may have any number of repeating units (n>1). FIG. 5A also shows a material 50 with a polyurethane backing layer 52, and optionally a hydrogel layer 54 bonded to the polyurethane backing layer. The material 50 can be in the shape of a device such as for orthopedic use. In the presence of solvent 66, the polyurethane precursors 38 can be coated onto the surface of the material 50 to form an unreacted putty layer 70 on the polyurethane 52 with the putty layer and the backing layer held together by crystallization of the hard segments to create a single body 68, as shown in FIG. 5B. The putty layer is cured by treatment with UV light 74 and removal of solvent 76, to form a reacted adhesive 80 as shown in FIG. 5C. Optionally, salt 78 can be included in the reacted adhesive. The salt causes the material to be osteoconductive, or, after its removal, to form pores which allows for ingrowth of new bone.
  • In other embodiments, a foaming agent may be added to the polyurethane precursor solution or the second polyurethane to create open cell porosity. The porosity may vary in size, e.g., from about 10 μm to about 1000 μm.
  • In other embodiments, the solvent is removed prior to the UV curing step. In another embodiment, the solvent is removed after the UV curing step.
  • In other embodiments, thermal, chemical-initiated or other methods of effecting polymerization are used to coat the second polyurethane onto the first polyurethane-backed hydrogel following the process above.
  • In some embodiments, the reactive group of the second, telechelic polyurethane can be an acrylamide, acrylate, allyl ether, methacrylate, or vinyl group.
  • FIG. 6A-B show examples of materials that can be used in the present invention. FIG. 6A shows the structure of Bionate® polycarbonate-urethane that can be used in a polyurethane grafted hydrogel such as those as described in FIGS. 1 and 3, and as the backing material in FIG. 5. FIG. 6B shows Bionate® polycarbonate-urethane with acrylate functionalized end-groups that can be used as the adhesive layer such as described in FIGS. 5A-C. The lowercase “m” and “n” indicate that the polyurethane can have any number of soft and hard segments.
  • FIGS. 7A-C show a schematic of how a device can be attached to a bone using the polyurethane of the present invention. FIG. 7A shows a device, 200, such as an orthopedic device, with a layer of polyurethane adhesive or putty 202 which contains salt 204. The putty attached to the device is apposed to a prepared surface of bone 206, and the putty 202 is made to interdigitate around the bone 206, as shown in FIG. 7B. As shown in FIG. 7C, with the application of UV light 214 or other stimulus, the putty cures around the bone. With washing, or over time, the salt is removed, and pores 210 are left behind it its place. The pores provide a space for new bone growth 212 into the cured putty 208 as shown in FIG. 7D, thereby anchoring the device in place.
  • In addition, other therapeutic agents may also be incorporated into the putty, including but not limited to antibiotics and antimicrobials.
  • In another embodiment, a porous polyurethane is incorporated into the polyurethane backing layer of the present invention. This porous polyurethane can be incorporated by casting a salt-saturated (about 25%-90% by weight) solution of polyurethane in an organic solvent (about 10%-75% by weight) such as dimethylacetamide or dimethyl sulfoxide, evaporating the solvent under heat (e.g. 80° Celsius) and convection, and then washing the salt away in water. The salt can be any type of salt, including but not limited to sodium chloride or calcium phosphate or derivatives and/or combinations of these. The resulting porous backing layer can serve as a surface for attachment to bone using commercially available adhesives or cements (e.g., bone cements or dental cements) while also serving as a porous scaffold for bone ingrowth.
  • In some embodiments, biomolecules (e.g., collagen, growth factors (such as Bone Morphogenetic Proteins (BMPs)), Fibroblast Growth Factors (FGFs), Transforming Growth Factors (e.g., TGFβ), Osteogenic Proteins (e.g., OP-1 or osteopontin), steroids (e.g., dexamethasone), and bisphosphonates) may be incorporated into the device either as an additive or by covalent linkages, combinations, and/or derivatives thereof. Bone components may also be incorporated into the device, such as hydroxyapatite, carbonated apatite, alpha tricalcium phosphate, beta tricalcium phosphate, combinations, and/or derivatives thereof. The pore size useful for this application ranges between about 10 micrometers to 1000 micrometers.
  • In some embodiments, the porous polyurethane/polyurethane may be attached to other tissues (e.g., soft tissue, muscle, skin, dentin).
  • FIGS. 8A-B illustrate the integration of osteochondral grafts and other implants of this invention over time. In FIG. 8A, an osteochondral graft implant 300 formed as described above has a lubricious single network hydrogel polymer or IPN hydrogel surface 302 that transitions via a graft copolymer region 304 into the polyurethane polymer 303. The polyurethane polymer is the bone implant surface. The polyurethane, which may be porous and/or may contain salt is placed next to a bone 301. After implantation and over time, bone tissue will grow from bone 301 into and through the bone contacting surface 303, creating an overlap zone, 309, as illustrated in FIG. 8B.
  • FIGS. 9A-C illustrate three possible configurations of osteochondral implants to repair cartilaginous join surface according to this invention. In FIG. 9A, implant 310 is formed as a cap having a lubricious network hydrogel or IPN hydrogel surface 311 transitioning via a graft copolymer region to a bone-contacting surface 312 formed from a polyurethane, as described above. When implanted, implant 310 covers the outer surface of bone 313.
  • FIGS. 9B and 9C show configurations in which implant 314 is formed as a patch or plug (respectively) having a lubricious network hydrogel polymer or IPN surface transitioning via a graft copolymer region to a bone-contacting surface 316 formed from a polyurethane, as described above. When implanted, implant 314 fits within a prepared opening 317 of bone 313.
  • In another variation, a preexisting polymeric article (polyurethane or otherwise) can be dip casted in a solution of polyurethane with reactive end groups (monofunctional or telechelic). The dipcasted article can then be frozen as described above, and then dipped again in a solution of hydrogel monomers along with appropriate initiator and crosslinker. This can then be frozen a second time. The material would then be exposed to UV or other suitable stimulus to initiate polymerization and grafting of the hydrogel and the underlying derivatized PU layer. After drying and washing, the end result is a hydrogel grafted to the surface of the article through an intervening layer of polyurethane.
  • EXAMPLES Example 1
  • In one example, two polycarbonate-urethane grafted IPN hydrogels attached to polyurethane were made. The methods used were similar, and both are described here. Two specimens were separately synthesized by a two-step photopolymerization process using custom-made molds. The interpenetrating polymer network hydrogel components were synthesized by a two-step sequential network formation technique based on UV initiated free radical polymerization. The precursor solutions for the first hydrogel network were made of purified PEG-dimethacrylate (MW 3400) (43% by weight) dissolved in dimethylacetamide with 2-hydroxy-2-methyl propiophenone as the UV sensitive free radical initiator. The solutions were cast (separately) into custom-designed Pyrex glass molds, and then the solutions within the molds were flash-frozen in liquid nitrogen baths. 25% solutions of polycarbonate-urethane monomethacrylate (dissolved in dimethylacetamide) were spread over the frozen surfaces of the hydrogel solutions, each was covered with a glass plate, and they were reacted under a UV light source at room temperature. Upon exposure to UV (2 mW/cm2, 350 nm, 10 minutes), the hydrogel and polyurethane precursor solutions in each case underwent free-radical induced gelation while also grafting to each other due to endgroup compatibility. To incorporate the second hydrogel networks into the first, the polyurethane-grafted hydrogels were removed from the molds and immersed in 70% v/v acrylic acid solutions; in one case in organic solvent, and in the other case in water, along with 1% v/v 2-hydroxy-2-methyl propiophenone as the photoinitiator, and 1% v/v triethylene glycol dimethacrylate as the cross-linking agent for 24 h at room temperature. The swollen gels were exposed to a UV source and the second networks were polymerized inside the first networks to form an IPN structure in each polymer. Following synthesis, the polyurethane-grafted hydrogels were washed in dimethylacetamide, dried in a convection oven (80 degrees Celsius), and washed extensively in phosphate buffered saline with repeated solvent exchanges for 5 days to remove any unreacted components. One sample of one material was cut in cross section and analyzed by microscopy, as shown in FIG. 10. To add an additional layer of polyurethane to other samples, the surfaces of the polyurethane side of the hydrogels were air-dried, and then solutions of polycarbonate urethane (thermoplastic Bionate®; see FIG. 6) in dimethylacetamide were spread over the surface and the solvent evaporated by heat and convection. An analysis of the static mechanical properties of the cured and dried polyurethane containing precursors is shown in FIG. 11.
  • FIG. 10 shows a photomicrograph of a cross-section of the polyurethane-grafted hydrogel at 60× magnification. The hydrogel, on the left, is 1.5 mm thick, while the polyurethane on the right is 0.6 mm.
  • FIG. 11 shows the results of testing of the static mechanical properties. Uniaxial tensile tests were conducted to determine the initial Young's modulus in tension, the strain-at-break, and stress-at-break of the materials. Dog bone specimens were tested following ASTM D638. The average true stress (in MPa)—true strain curve (in %) for the joint interface polyurethane material is presented in FIG. 11. The tensile strength is greater than 20 MPa.
  • Example 2
  • In another example, polyether urethane was used as the starting material. The material was made following the process described in Example 1.
  • Example 3
  • In another example, polyurethane layered onto another polyurethane was made and bonded to bone. Polycarbonate-urethane with methacrylate end groups was synthesized by reacting methylene diphenyl diisocyanate with polycarbonate diol (as the soft segment and 1, 4 butanediol as the chain extender at a solid concentration of 30% in dimethylacetamide at 35 degrees Celsius. The monomer 2-hydroxyethyl methacrylate was added to the reaction mixture and the solution was reacted for an additional 24 hours). The resulting polycarbonate-urethane dimethacrylate was cast on the surface of a premade polycarbonate urethane (Bionate®) and the solvent removed at 35 degrees Celsius under convection.
  • After the solvent was removed, the unreacted polycarbonate-urethane dimethacrylate was pressed onto the surface of a previously prepared (cleaned and dried) bovine bone specimen, and exposed to UV light (2 mW/cm2, 350 nm, for 10 minutes). The result was polycarbonate urethane bonded to bone.
  • The strength of the bonding was tested by performing a lap shear test, as described in ASTM D3163. Briefly, the lap shear test involved gripping the bone and the porous polyurethane graft and pulling them in opposite directions while collecting data. The shear stress (MPa) is plotted as a function of displacement (mm). As shown in FIG. 12, the shear stress necessary to remove the polyurethane from the bone was approximately 670 kPa. Testing of nine samples gave a mean (±S.D.) shear strength of 520±120 kPa.
  • While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (10)

What is claimed is:
1. A method of making a material that can be attached to bone, comprising the steps of:
applying a solution comprising a polyurethane precursor comprising reactive endgroups, solvent, photoinitiator and crosslinker to a first polyurethane that is grafted to a hydrogel;
polymerizing the polyurethane precursor; and
treating with heat and convection to remove the solvent to yield a second polyurethane coated on a polyurethane grafted hydrogel.
2. The method of claim 1 wherein the second polyurethane comprises polycarbonate urethane or polyether urethane.
3. The method of claim 1 wherein the reactive endgroups comprise one or more of acrylamide, acrylate, allyl ether, methacrylate, and vinyl.
4. The method of claim 1 wherein the solvent comprises one or more of dimethyacetamide, dimethyl sulfoxide, and tetrahydrofuran.
5. The method of claim 1 wherein the applying step further comprises a salt.
6. A method of attaching an article to a bone, the article comprising a porous polyurethane comprising a photoinitiator and a crosslinker, the method comprising the steps of:
placing the porous polyurethane in apposition to the bone; and
polymerizing the porous polyurethane to attach the article to the bone.
7. The method of claim 6 further comprising causing the porous polyurethane to contact and flow into bone.
8. The method of claim 6 wherein the article further comprises a second polyurethane attached to the porous polyurethane.
9. The method of claim 8 wherein the article further comprises a hydrogel.
10. The method of claim 6 wherein the polymerizing step comprises exposing the porous polyurethane to UV light, heat, or a chemical initiator.
US14/508,895 2008-08-05 2014-10-07 Polyurethane-grafted hydrogels Abandoned US20150025161A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/508,895 US20150025161A1 (en) 2008-08-05 2014-10-07 Polyurethane-grafted hydrogels

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US8644208P 2008-08-05 2008-08-05
US12/536,233 US8497023B2 (en) 2008-08-05 2009-08-05 Polyurethane-grafted hydrogels
US13/905,028 US8853294B2 (en) 2008-08-05 2013-05-29 Polyurethane-grafted hydrogels
US14/508,895 US20150025161A1 (en) 2008-08-05 2014-10-07 Polyurethane-grafted hydrogels

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US13/905,028 Division US8853294B2 (en) 2008-08-05 2013-05-29 Polyurethane-grafted hydrogels

Publications (1)

Publication Number Publication Date
US20150025161A1 true US20150025161A1 (en) 2015-01-22

Family

ID=41651814

Family Applications (4)

Application Number Title Priority Date Filing Date
US12/536,233 Expired - Fee Related US8497023B2 (en) 2008-08-05 2009-08-05 Polyurethane-grafted hydrogels
US13/905,028 Expired - Fee Related US8853294B2 (en) 2008-08-05 2013-05-29 Polyurethane-grafted hydrogels
US14/243,843 Abandoned US20140213661A1 (en) 2008-08-05 2014-04-02 Hydrophilic interpenetrating polymer networks derived from hydrophobic polymers
US14/508,895 Abandoned US20150025161A1 (en) 2008-08-05 2014-10-07 Polyurethane-grafted hydrogels

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US12/536,233 Expired - Fee Related US8497023B2 (en) 2008-08-05 2009-08-05 Polyurethane-grafted hydrogels
US13/905,028 Expired - Fee Related US8853294B2 (en) 2008-08-05 2013-05-29 Polyurethane-grafted hydrogels
US14/243,843 Abandoned US20140213661A1 (en) 2008-08-05 2014-04-02 Hydrophilic interpenetrating polymer networks derived from hydrophobic polymers

Country Status (7)

Country Link
US (4) US8497023B2 (en)
EP (1) EP2323670A4 (en)
JP (1) JP5722773B2 (en)
KR (1) KR20110040969A (en)
AU (1) AU2009279716A1 (en)
CA (1) CA2731698A1 (en)
WO (1) WO2010017282A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180170296A1 (en) * 2016-12-15 2018-06-21 Ford Global Technologies, Llc Lap-belt length detecting seatbelt assembly
US10457803B2 (en) 2008-07-07 2019-10-29 Hyalex Orthopaedics, Inc. Orthopedic implants having gradient polymer alloys
US10792392B2 (en) 2018-07-17 2020-10-06 Hyalex Orthopedics, Inc. Ionic polymer compositions
US11015016B2 (en) 2011-10-03 2021-05-25 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
US11077228B2 (en) 2015-08-10 2021-08-03 Hyalex Orthopaedics, Inc. Interpenetrating polymer networks

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090088846A1 (en) * 2007-04-17 2009-04-02 David Myung Hydrogel arthroplasty device
US8883915B2 (en) 2008-07-07 2014-11-11 Biomimedica, Inc. Hydrophobic and hydrophilic interpenetrating polymer networks derived from hydrophobic polymers and methods of preparing the same
JP5722773B2 (en) 2008-08-05 2015-05-27 バイオミメディカ インコーポレイテッド Polyurethane grafted hydrogel
US20110152868A1 (en) * 2009-12-18 2011-06-23 Lampros Kourtis Method, device, and system for shaving and shaping of a joint
US9999702B2 (en) 2010-04-09 2018-06-19 Kci Licensing Inc. Apparatuses, methods, and compositions for the treatment and prophylaxis of chronic wounds
US8632512B2 (en) * 2010-04-09 2014-01-21 Kci Licensing, Inc. Apparatuses, methods, and compositions for the treatment and prophylaxis of chronic wounds
CN102068323B (en) * 2011-01-21 2014-03-26 南京师范大学 Cardiac or vascular patch with anticoagulant effect
US8597264B2 (en) 2011-03-24 2013-12-03 Kci Licensing, Inc. Apparatuses, methods, and compositions for the treatment and prophylaxis of chronic wounds
WO2013043529A1 (en) * 2011-09-19 2013-03-28 Emory University Bone morphogenetic protein pathway activation, compositions for ossification, and methods related thereto
WO2013078284A1 (en) 2011-11-21 2013-05-30 Biomimedica, Inc. Systems, devices, and methods for anchoring orthopaedic implants to bone
CN102526810B (en) * 2012-02-22 2014-04-09 四川大学 Artificial skin alternative material and preparation method thereof
US9574057B2 (en) * 2012-03-28 2017-02-21 Becton, Dickinson And Company Hydrogel adhesion to molded polymers
US20150282934A1 (en) * 2012-10-11 2015-10-08 Poly-Med, Inc. Multilayer polymeric compositions and methods relating thereto
ES2466065B1 (en) * 2012-12-07 2015-03-31 Universidade De Santiago De Compostela Modification of polyurethane with polymers sensitive to biocompatible stimuli for drug loading and transfer
WO2014110407A2 (en) * 2013-01-11 2014-07-17 Surmodics, Inc. Conductive polymers and uses
US10792337B2 (en) 2013-03-15 2020-10-06 Kci Licensing, Inc. Wound healing compositions
CA2910167C (en) 2013-04-26 2020-04-28 Suzanne A. Maher A multi-component non-biodegradable implant, a method of making and a method of implantation
BR102013014155B1 (en) * 2013-06-07 2021-08-31 Universidade Federal Do Pará - Ufpa Bionanocomposite for bone recovery, use of bionanocomposite
WO2014209968A1 (en) * 2013-06-25 2014-12-31 Polyone Corporation Acrylic-urethane ipn plastisol
KR101492051B1 (en) * 2013-07-08 2015-02-16 아주대학교산학협력단 hydrogel prepared by electrostatic attraction between cationic material and anionic material, and method for preparing the same
JP6292815B2 (en) * 2013-10-10 2018-03-14 京セラ株式会社 Antioxidant prosthetic material
CN103893818B (en) * 2014-03-14 2015-07-01 华南理工大学 Osteochondral three-dimensional stent with regular interpenetrating network structure and preparation method thereof
AU2015271615A1 (en) * 2014-06-04 2016-12-08 Klox Technologies Inc. Biophotonic hydrogels
JP6550276B2 (en) * 2015-06-16 2019-07-24 株式会社春日井化成工業所 Production method of urethane type molded body
US10213284B2 (en) 2015-06-30 2019-02-26 Tela Bio, Inc. Corner-lock stitch patterns
US10426587B2 (en) 2015-07-21 2019-10-01 Tela Bio, Inc. Compliance control stitching in substrate materials
US11219639B2 (en) 2015-07-24 2022-01-11 Trimph Ip Pty Ltd Antiseptic polymer and synthesis thereof
EP3334783B1 (en) * 2015-08-10 2023-04-19 Hyalex Orthopaedics, Inc. Interpenetrating polymer networks
US10668183B2 (en) 2016-03-02 2020-06-02 The Board Of Trustees Of The Leland Stanford Junior University Bone-tendon graft biomaterial, use as a medical device and method of making same
US9820843B2 (en) 2016-04-26 2017-11-21 Tela Bio, Inc. Hernia repair grafts having anti-adhesion barriers
US10941252B2 (en) 2016-11-03 2021-03-09 3M Innovative Properties Company Silicone copolymers, methods of making, and articles
JP7113429B2 (en) 2016-11-29 2022-08-05 Spiber株式会社 Protein composition, method for producing same, and method for improving thermal stability
EP3335689A1 (en) * 2016-12-14 2018-06-20 DENTSPLY DETREY GmbH Dental composition
CN111491798A (en) * 2017-11-16 2020-08-04 斯瓦蒙卢森堡有限责任公司 Thermoplastic polymer film with interpenetrating polymer network
US11590262B2 (en) 2018-03-09 2023-02-28 Tela Bio, Inc. Surgical repair graft
US10882945B2 (en) 2018-03-26 2021-01-05 Medtronic, Inc. Modified polyisobutylene-based polymers, methods of making, and medical devices
CN109111583B (en) * 2018-08-27 2020-08-21 晋江瑞碧科技有限公司 Preparation method of polyurethane nanofiber membrane grafted poly (N-isopropylacrylamide) hydrogel
CN109134887B (en) * 2018-08-27 2020-06-05 晋江瑞碧科技有限公司 Preparation method of polyurethane nanofiber membrane grafted poly (N-isopropylacrylamide-co-acrylic acid) hydrogel
CN109513045B (en) * 2018-11-20 2021-01-15 温州生物材料与工程研究所 Protein-based hydrogel with double layers of different internal pore diameter structures and preparation method thereof
EP3934575A4 (en) 2019-03-08 2022-12-28 Tela Bio, Inc. Textured medical textiles
CN110038157B (en) * 2019-04-26 2020-07-14 四川大学 Jet type photocuring hydrogel dressing precursor liquid based on polyurethane and preparation method thereof
KR102553303B1 (en) * 2020-07-08 2023-07-07 주식회사 아이센스 Functionalized thermoplastic polyurethane, method for preparing the same, method for preparing high performance composite in medical application and medical device comprising the same
US11820866B2 (en) * 2020-08-21 2023-11-21 United States Of America As Represented By The Administrator Of Nasa Copoly(urethane carbonates) with tunable properties and methods for making and using the same
CN112225919B (en) * 2020-09-11 2023-07-25 王平 Geomembrane for soil remediation engineering and preparation method thereof
TWI756908B (en) * 2020-11-05 2022-03-01 研庚實業股份有限公司 Water-repellent elastic film for wetsuits
CN113061263B (en) * 2021-04-06 2021-12-17 华东理工大学 Preparation method of photocrosslinking dynamic reversible supramolecular polymer adhesive based on lipoic acid micromolecular compound
US11801143B2 (en) 2021-07-01 2023-10-31 Hyalex Orthopaedics, Inc. Multi-layered biomimetic osteochondral implants and methods of using thereof
CN113754856A (en) * 2021-09-18 2021-12-07 天津中杰超润医药科技有限公司 Self-assembled micelle, dispersion-enhanced wear-resistant fatigue-resistant bionic meniscus and preparation method
CN114230732B (en) * 2021-12-30 2022-12-02 华中科技大学 Method for chemically grafting hydrophobic polymer and hydrogel layer
CN114405287B (en) * 2022-01-24 2022-10-28 中国科学院苏州纳米技术与纳米仿生研究所 Superstrong oil stain resistance oil-water separation membrane and preparation method and application thereof
WO2023196414A1 (en) * 2022-04-05 2023-10-12 Cornell University Systems and methods for glucose-responsive insulin delivery
CN115845135B (en) * 2022-12-01 2024-02-23 中山大学 Anti-fouling wear-resistant lubricating coating similar to articular cartilage and preparation method thereof
CN115814158B (en) * 2022-12-01 2024-02-23 中山大学 Wear-resistant lubricating coating similar to articular cartilage and preparation method thereof

Family Cites Families (334)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1032540B (en) 1957-04-15 1958-06-19 Roehm & Haas Gmbh Process for the production of acrylate-based plastics with reduced flammability
US3053251A (en) * 1959-03-30 1962-09-11 Black Maurice Joint prosthesis
US4302553A (en) 1970-10-30 1981-11-24 Harry L. Frisch Interpenetrating polymeric networks
US3702611A (en) * 1971-06-23 1972-11-14 Meyer Fishbein Surgical expansive reamer for hip socket
US3833404A (en) 1972-05-31 1974-09-03 Research Corp Vibration or sound damping coating for vibratory structures
US3826678A (en) * 1972-06-06 1974-07-30 Atomic Energy Commission Method for preparation of biocompatible and biofunctional materials and product thereof
US3939049A (en) * 1974-04-10 1976-02-17 The United States Of America As Represented By The United States Energy Research And Development Administration Process for radiation grafting hydrogels onto organic polymeric substrates
US4192827A (en) * 1974-06-27 1980-03-11 Ciba-Geigy Corporation Water-insoluble hydrophilic copolymers
DE2512407A1 (en) 1975-03-21 1976-09-23 Heinz Prof Dr Med Wagner HIP HEAD CAP FOR A HIP PROSTHESIS
US4391797A (en) 1977-01-05 1983-07-05 The Children's Hospital Medical Center Systems for the controlled release of macromolecules
US4128600A (en) 1977-01-14 1978-12-05 General Mills Chemicals, Inc. Interpenetrating dual cure resin compositions
CH612585A5 (en) 1977-05-23 1979-08-15 Sulzer Ag
DE2914737C3 (en) 1979-04-11 1981-12-10 Feldmühle AG, 4000 Düsseldorf Femoral head cap endoprosthesis
US4423099A (en) * 1980-07-28 1983-12-27 Ciba-Geigy Corporation Membrane modified hydrogels
US4320709A (en) 1980-09-29 1982-03-23 Pyro-Sciences, Inc. Hazardous materials incineration system
US4468499A (en) 1980-10-24 1984-08-28 Lehigh University Thermoplastic interpenetrating polymer network composition and process
US4439583A (en) 1980-11-12 1984-03-27 Tyndale Plains-Hunter, Ltd. Polyurethane diacrylate compositions useful in forming canulae
US4452925A (en) 1981-02-09 1984-06-05 National Patent Development Corporation Biologically stabilized compositions comprising collagen as the minor component with ethylenically unsaturated compounds used as contact lenses
US4502161A (en) 1981-09-21 1985-03-05 Wall W H Prosthetic meniscus for the repair of joints
US4477604A (en) * 1982-09-20 1984-10-16 Oechsle Iii Sixtus J Polyurethane compositions and their use as luting agents
US4973493A (en) 1982-09-29 1990-11-27 Bio-Metric Systems, Inc. Method of improving the biocompatibility of solid surfaces
US4487865A (en) 1983-12-15 1984-12-11 Biomatrix, Inc. Polymeric articles modified with hyaluronate
US4500676A (en) 1983-12-15 1985-02-19 Biomatrix, Inc. Hyaluronate modified polymeric articles
US4536554A (en) 1984-02-22 1985-08-20 Barnes-Hind, Inc. Hydrophilic polymers and contact lenses made therefrom
US4621637A (en) * 1984-07-30 1986-11-11 Meyer Fishbein Surgical device for removing bone and tissue from joint members
JPS6145765A (en) 1984-08-07 1986-03-05 宇部興産株式会社 Blood vessel prosthesis and its production
US4680336A (en) 1984-11-21 1987-07-14 Vistakon, Inc. Method of forming shaped hydrogel articles
US4966934A (en) * 1984-11-29 1990-10-30 Dentsply Research & Development Corp. Biological compatible adhesive containing a phosphorous adhesion promoter and accelerator
US4575539A (en) 1985-06-03 1986-03-11 E. R. Squibb & Sons, Inc. Drug delivery systems including novel interpenetrating polymer networks and method
WO1987005038A1 (en) 1986-02-17 1987-08-27 Commonwealth Scientific And Industrial Research Or Implantable materials
US4846841A (en) 1986-04-25 1989-07-11 Indong Oh Femoral Prosthesis
US5030230A (en) 1986-05-16 1991-07-09 Great Plains Eye Clinic, Ltd. Corneal implant
US4693715A (en) 1986-06-19 1987-09-15 Abel Robert Jr Artificial cornea
US5112350A (en) 1986-10-16 1992-05-12 Cbs Lens, A California General Partnership Method for locating on a cornea an artificial lens fabricated from a collagen-hydrogel for promoting epithelial cell growth and regeneration of the stroma
US5114627A (en) 1986-10-16 1992-05-19 Cbs Lens Method for producing a collagen hydrogel
US5100689A (en) 1987-04-10 1992-03-31 University Of Florida Surface modified surgical instruments, devices, implants, contact lenses and the like
US5290548A (en) 1987-04-10 1994-03-01 University Of Florida Surface modified ocular implants, surgical instruments, devices, prostheses, contact lenses and the like
US5094876A (en) 1987-04-10 1992-03-10 University Of Florida Surface modified surgical instruments, devices, implants, contact lenses and the like
US5282851A (en) 1987-07-07 1994-02-01 Jacob Labarre Jean Intraocular prostheses
US4865601A (en) 1987-07-07 1989-09-12 Caldwell Delmar R Intraocular prostheses
US5171318A (en) 1987-11-09 1992-12-15 Chiron Ophthalmics, Inc. Treated corneal prosthetic device
US5067961A (en) 1988-02-18 1991-11-26 Autogenesis Technologies, Inc. Non-biodegradable two phase corneal implant and method for preparing same
US5660692A (en) 1988-02-24 1997-08-26 Cedars-Sinai Medical Center Method of crosslinking amino acid-containing polymers using photoactivatable chemical crosslinkers
US5087392A (en) 1988-05-31 1992-02-11 Sola Usa, Inc. Method of mold contact lenses
US4931287A (en) 1988-06-14 1990-06-05 University Of Utah Heterogeneous interpenetrating polymer networks for the controlled release of drugs
IT215084Z2 (en) * 1988-08-03 1990-07-30 Torino A VARIABLE EXCURSION CAMBRA
US5091205A (en) * 1989-01-17 1992-02-25 Union Carbide Chemicals & Plastics Technology Corporation Hydrophilic lubricious coatings
FR2646930B1 (en) 1989-05-12 1993-04-09 Essilor Int PROCESS FOR PRODUCING A DIFFRACTIVE ELEMENT, USABLE IN PARTICULAR IN THE MANUFACTURE OF ARTIFICIAL OPTICAL LENSES, AND LENSES THUS OBTAINED
US4978352A (en) 1989-06-07 1990-12-18 Fedorov Svjatoslav N Process for producing collagen-based cross-linked biopolymer, an implant from said biopolymer, method for producing said implant, and method for hermetization of corneal or scleral wounds involved in eye injuries, using said implant
US5115056A (en) 1989-06-20 1992-05-19 Ciba-Geigy Corporation Fluorine and/or silicone containing poly(alkylene-oxide)-block copolymers and contact lenses thereof
US5843089A (en) 1990-12-28 1998-12-01 Boston Scientific Corporation Stent lining
EP0439250B1 (en) 1990-01-25 1994-11-02 Howmedica Inc. Bone cement
US5264495A (en) 1990-04-27 1993-11-23 Nippon Shokubai Kagaku Kogyo Co., Ltd. Method for production of salt-resistant absorbent resin
US5122133A (en) * 1990-10-26 1992-06-16 Smith & Nephew Richards Inc. Compression screw for a joint endoprosthesis
US5133769A (en) 1990-11-09 1992-07-28 Sulzer Brothers Cap for a femur head
CA2101773A1 (en) 1991-01-31 1992-08-01 Toyoichi Tanaka Interpenetrating-polymer network phase-transition gels
JP3007903B2 (en) 1991-03-29 2000-02-14 京セラ株式会社 Artificial disc
WO1993002639A1 (en) 1991-08-06 1993-02-18 Autogenesis Technologies, Inc. Injectable collagen-based compositions for making intraocular lens
WO1993011751A1 (en) * 1991-12-18 1993-06-24 Scimed Life Systems, Inc. Lubricous polymer network
US5425773A (en) 1992-01-06 1995-06-20 Danek Medical, Inc. Intervertebral disk arthroplasty device
JP3011768B2 (en) * 1992-02-28 2000-02-21 ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム Photopolymerizable biodegradable hydrophilic gels as tissue contacting materials and controlled release carriers
US5589563A (en) 1992-04-24 1996-12-31 The Polymer Technology Group Surface-modifying endgroups for biomedical polymers
IT1259100B (en) * 1992-05-20 1996-03-11 Lanfranco Callegaro USE OF HYDROGELS FOR THE LOCKING OF PROSTHETIC SYSTEMS
IT1260154B (en) 1992-07-03 1996-03-28 Lanfranco Callegaro HYALURONIC ACID AND ITS DERIVATIVES IN INTERPENETRATING POLYMERS (IPN)
AU650156B2 (en) 1992-08-05 1994-06-09 Lions Eye Institute Limited Keratoprosthesis and method of producing the same
CA2141850A1 (en) 1992-08-07 1994-02-17 Thomas A. Silvestrini Hybrid intrastromal corneal ring
JPH08507936A (en) 1992-10-27 1996-08-27 ネオリガメンツ・リミテッド Ligament graft harvesting method and instrument
US5374515A (en) 1992-11-13 1994-12-20 Organogenesis, Inc. In vitro cornea equivalent model
US5836313A (en) 1993-02-08 1998-11-17 Massachusetts Institute Of Technology Methods for making composite hydrogels for corneal prostheses
JPH06287443A (en) 1993-04-01 1994-10-11 Bando Chem Ind Ltd Water-swelling polyurethane composition
JP3176176B2 (en) 1993-06-01 2001-06-11 京セラ株式会社 Artificial cartilage and method for producing the same
US5763529A (en) 1994-03-31 1998-06-09 Cytec Technology Corp. Interpenetrating polymer network compositions
US5556429A (en) * 1994-05-06 1996-09-17 Advanced Bio Surfaces, Inc. Joint resurfacing system
US5591170A (en) * 1994-10-14 1997-01-07 Genesis Orthopedics Intramedullary bone cutting saw
TW325481B (en) 1994-12-05 1998-01-21 Novartis Ag Silicon-containing polymer having oxygen permeability suitable for ophthalmic applications
US5576072A (en) * 1995-02-01 1996-11-19 Schneider (Usa), Inc. Process for producing slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with at least one other, dissimilar polymer hydrogel
US6017577A (en) 1995-02-01 2000-01-25 Schneider (Usa) Inc. Slippery, tenaciously adhering hydrophilic polyurethane hydrogel coatings, coated polymer substrate materials, and coated medical devices
US5919570A (en) 1995-02-01 1999-07-06 Schneider Inc. Slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly(N-vinylpyrrolidone) polymer hydrogel, coated polymer and metal substrate materials, and coated medical devices
US5656210A (en) 1995-03-31 1997-08-12 Johnson & Johnson Vision Products, Inc. Reaction injection molding as a process to prepare contact lenses
US5674942A (en) 1995-03-31 1997-10-07 Johnson & Johnson Vision Products, Inc. Interpenetrating polymer networks for contact lens production
US5643390A (en) 1995-05-04 1997-07-01 The University Of Delaware Bonding techniques for high performance thermoplastic compositions
US6027742A (en) 1995-05-19 2000-02-22 Etex Corporation Bioresorbable ceramic composites
JP3580611B2 (en) 1995-09-18 2004-10-27 日本エヌエスシー株式会社 Crosslinkable urethane-modified acrylic composite resin aqueous dispersion and method for producing the same
AU722250B2 (en) 1995-11-15 2000-07-27 Seikagaku Corporation Photocured crosslinked-hyaluronic acid gel and method of preparation thereof
US6509098B1 (en) * 1995-11-17 2003-01-21 Massachusetts Institute Of Technology Poly(ethylene oxide) coated surfaces
US5976648A (en) 1995-12-14 1999-11-02 Kimberly-Clark Worldwide, Inc. Synthesis and use of heterogeneous polymer gels
US6238799B1 (en) 1996-02-09 2001-05-29 Surface Solutions Laboratories, Inc. Articles prepared from water-based hydrophilic coating compositions
US6005160A (en) 1996-02-22 1999-12-21 National Science Council Heterobifunctional membrane in application of artificial cornea
US5817704A (en) 1996-03-08 1998-10-06 The Procter & Gamble Company Heterogeneous foam materials
US5743918A (en) * 1996-05-13 1998-04-28 Wright Medical Technology, Inc. Instrumentation for and method for implanting a spherical prosthesis
FR2749753B1 (en) * 1996-06-14 1998-12-24 Mosseri Raphael TOTAL HIP PROSTHESIS FOR ENDO-ARTICULAR PLACEMENT AND ITS ANCILLARY DEVICE
CA2259364A1 (en) 1996-08-13 1998-02-19 H.B. Fuller Licensing & Financing, Inc. Water-based sulfonated polymer compositions
US5824079A (en) 1996-08-23 1998-10-20 Drexel University Swelling type copolymeric composite material with self-fixation characteristics
US5800412A (en) * 1996-10-10 1998-09-01 Sts Biopolymers, Inc. Hydrophilic coatings with hydrating agents
US6953594B2 (en) 1996-10-10 2005-10-11 Etex Corporation Method of preparing a poorly crystalline calcium phosphate and methods of its use
AU4986497A (en) 1996-10-15 1998-05-11 Orthopaedic Hospital, The Wear resistant surface-gradient cross-linked polyethylene
EP0891753A4 (en) 1996-11-13 1999-09-22 Menicon Co Ltd Artificial cornea
EP0873145A2 (en) 1996-11-15 1998-10-28 Advanced Bio Surfaces, Inc. Biomaterial system for in situ tissue repair
US7618451B2 (en) 2001-05-25 2009-11-17 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools facilitating increased accuracy, speed and simplicity in performing total and partial joint arthroplasty
US8882847B2 (en) 2001-05-25 2014-11-11 Conformis, Inc. Patient selectable knee joint arthroplasty devices
US7468075B2 (en) * 2001-05-25 2008-12-23 Conformis, Inc. Methods and compositions for articular repair
US8545569B2 (en) 2001-05-25 2013-10-01 Conformis, Inc. Patient selectable knee arthroplasty devices
US20070233269A1 (en) 2001-05-25 2007-10-04 Conformis, Inc. Interpositional Joint Implant
US5904927A (en) 1997-03-14 1999-05-18 Northeastern University Drug delivery using pH-sensitive semi-interpenetrating network hydrogels
US6224893B1 (en) 1997-04-11 2001-05-01 Massachusetts Institute Of Technology Semi-interpenetrating or interpenetrating polymer networks for drug delivery and tissue engineering
DE59800682D1 (en) 1997-04-14 2001-06-13 Degussa Process for modifying the surface of polymer substrates by graft polymerization
US5962005A (en) 1997-04-17 1999-10-05 Rengo Co., Ltd Transparent cellulose hydrogel and production process thereof
US5981826A (en) * 1997-05-05 1999-11-09 Georgia Tech Research Corporation Poly(vinyl alcohol) cryogel
US6011082A (en) 1997-06-02 2000-01-04 Pharmacia & Upjohn Ab Process for the modification of elastomers with surface interpreting polymer networks and elastomers formed therefrom
US6221467B1 (en) 1997-06-03 2001-04-24 Scimed Life Systems, Inc. Coating gradient for lubricious coatings on balloon catheters
US6166127A (en) 1997-06-27 2000-12-26 The Sherwin-Williams Company Interpenetrating networks of polymers
US6171300B1 (en) * 1997-09-04 2001-01-09 Linvatec Corporation Tubing cassette and method for cooling a surgical handpiece
CA2227827A1 (en) 1998-01-23 1999-07-23 Unknown In vitro artificial cornea and sclera
RU2215542C2 (en) 1998-02-23 2003-11-10 Массачусетс Инститьют Оф Текнолоджи Biodecomposing polymers able recovery of form
DK1062278T3 (en) 1998-02-23 2006-09-25 Mnemoscience Gmbh Polymers with shape memory
US6911212B2 (en) 1998-02-27 2005-06-28 Musculoskeletal Transplant Foundation Malleable putty and flowable paste with allograft bone having residual calcium for filling bone defects
US7019192B2 (en) 1998-02-27 2006-03-28 Musculoskeletal Transplant Foundation Composition for filling bone defects
US6437018B1 (en) 1998-02-27 2002-08-20 Musculoskeletal Transplant Foundation Malleable paste with high molecular weight buffered carrier for filling bone defects
BR9909085A (en) 1998-04-15 2000-12-12 Alcon Lab Inc Two-component intraocular lens and method for its preparation
DE19818210C5 (en) * 1998-04-24 2007-02-08 Ivoclar Vivadent Ag Radically polymerizable dental material
US6022925A (en) 1998-06-23 2000-02-08 The Sherwin-Williams Company Partial interpenetrating networks of polymers
WO2000002937A1 (en) 1998-07-08 2000-01-20 Sunsoft Corporation Interpenetrating polymer network hydrophilic hydrogels for contact lens
US6057406A (en) 1998-08-03 2000-05-02 The University Of Southern Mississippi Functionally gradient polymeric materials
US6630457B1 (en) 1998-09-18 2003-10-07 Orthogene Llc Functionalized derivatives of hyaluronic acid, formation of hydrogels in situ using same, and methods for making and using same
US20030114936A1 (en) 1998-10-12 2003-06-19 Therics, Inc. Complex three-dimensional composite scaffold resistant to delimination
US6331578B1 (en) 1998-11-18 2001-12-18 Josephine Turner Process for preparing interpenetrating polymer networks of controlled morphology
KR100306282B1 (en) 1998-12-10 2001-11-02 윤종용 Apparatus and for interleaving and deinterleaving frame date in communication system
US6361560B1 (en) 1998-12-23 2002-03-26 Anamed, Inc. Corneal implant and method of manufacture
WO2000043050A1 (en) 1999-01-22 2000-07-27 St. Jude Medical, Inc. Medical adhesives
US6376742B1 (en) * 1999-02-17 2002-04-23 Richard J. Zdrahala In vivo tissue engineering with biodegradable polymers
US6294187B1 (en) 1999-02-23 2001-09-25 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
US6239209B1 (en) 1999-02-23 2001-05-29 Reichhold, Inc. Air curable water-borne urethane-acrylic hybrids
EP1166156A1 (en) 1999-03-16 2002-01-02 Zms, Llc Precision integral articles
US6332887B1 (en) * 1999-04-06 2001-12-25 Benjamin D. Knox Spinal fusion instrumentation system
US6428576B1 (en) 1999-04-16 2002-08-06 Endospine, Ltd. System for repairing inter-vertebral discs
US7491235B2 (en) 1999-05-10 2009-02-17 Fell Barry M Surgically implantable knee prosthesis
US7338524B2 (en) 1999-05-10 2008-03-04 Fell Barry M Surgically implantable knee prosthesis
CH694058A5 (en) 1999-06-18 2004-06-30 Woodwelding Ag Fabric conclusive Connect.
US6368315B1 (en) 1999-06-23 2002-04-09 Durect Corporation Composite drug delivery catheter
US6673079B1 (en) * 1999-08-16 2004-01-06 Washington University Device for lengthening and reshaping bone by distraction osteogenesis
US6479565B1 (en) 1999-08-16 2002-11-12 Harold R. Stanley Bioactive ceramic cement
US7008635B1 (en) 1999-09-10 2006-03-07 Genzyme Corporation Hydrogels for orthopedic repair
US6086204A (en) 1999-09-20 2000-07-11 Magnante; Peter C. Methods and devices to design and fabricate surfaces on contact lenses and on corneal tissue that correct the eye's optical aberrations
US6264695B1 (en) 1999-09-30 2001-07-24 Replication Medical, Inc. Spinal nucleus implant
US7687462B2 (en) 1999-10-05 2010-03-30 The Regents Of The University Of California Composition for promoting cartilage formation or repair comprising a nell gene product and method of treating cartilage-related conditions using such composition
US6626945B2 (en) * 2000-03-14 2003-09-30 Chondrosite, Llc Cartilage repair plug
US6632246B1 (en) * 2000-03-14 2003-10-14 Chondrosite, Llc Cartilage repair plug
EP1197782B1 (en) * 2000-03-22 2004-06-02 Menicon Co., Ltd. Material for ocular lens
US6629997B2 (en) 2000-03-27 2003-10-07 Kevin A. Mansmann Meniscus-type implant with hydrogel surface reinforced by three-dimensional mesh
US9314339B2 (en) 2000-03-27 2016-04-19 Formae, Inc. Implants for replacing cartilage, with negatively-charged hydrogel surfaces and flexible matrix reinforcement
US6689165B2 (en) 2000-03-31 2004-02-10 Board Of Supervisors Of Louisana State University And Agricultural And Mechanical College Surface modifications for enhanced epithelialization
US6846875B2 (en) 2000-04-10 2005-01-25 Pharmacia Groningen Bv Hydrogels and methods for their production
US6254637B1 (en) 2000-04-10 2001-07-03 Lucid Korea Co., Ltd. Artificial cornea and implantation thereof
US6372815B1 (en) 2000-04-18 2002-04-16 Ocular Sciences Inc Ophthalmic lenses and compositions, and methods for producing same
US6610067B2 (en) * 2000-05-01 2003-08-26 Arthrosurface, Incorporated System and method for joint resurface repair
US7618462B2 (en) * 2000-05-01 2009-11-17 Arthrosurface Incorporated System and method for joint resurface repair
US7163541B2 (en) 2002-12-03 2007-01-16 Arthrosurface Incorporated Tibial resurfacing system
US20040230315A1 (en) 2000-05-01 2004-11-18 Ek Steven W. Articular surface implant
US7678151B2 (en) * 2000-05-01 2010-03-16 Ek Steven W System and method for joint resurface repair
US6520964B2 (en) * 2000-05-01 2003-02-18 Std Manufacturing, Inc. System and method for joint resurface repair
US6679917B2 (en) * 2000-05-01 2004-01-20 Arthrosurface, Incorporated System and method for joint resurface repair
US7713305B2 (en) * 2000-05-01 2010-05-11 Arthrosurface, Inc. Articular surface implant
DE60139262D1 (en) 2000-08-28 2009-08-27 Disc Dynamics Inc SYSTEM FOR RECONSTRUCTING JOINT SURFACES OF MAMMALS
JP2004510199A (en) 2000-09-28 2004-04-02 ノバルティス アクチエンゲゼルシャフト Perforated lens for increased tear flow and method of manufacturing the lens
US6524327B1 (en) 2000-09-29 2003-02-25 Praxis, Llc In-situ bonds
EP2085055B1 (en) 2000-10-24 2012-06-06 Warsaw Orthopedic, Inc. Spinal fusion devices
AU2002243270B2 (en) 2000-10-25 2006-03-09 Warsaw Orthopedic, Inc. Vertically expanding intervertebral body fusion device
US6692528B2 (en) * 2000-11-09 2004-02-17 The Polymer Technology Group Incorporated Devices that change size/shape via osmotic pressure
GB0100199D0 (en) 2001-01-05 2001-02-14 Mcminn Derek J W Hip prosthesis
DE10103784C1 (en) 2001-01-29 2002-10-10 Rodenstock Optik G Photochromic plastic object
US9050192B2 (en) * 2001-02-05 2015-06-09 Formae, Inc. Cartilage repair implant with soft bearing surface and flexible anchoring device
CN1162187C (en) 2001-02-22 2004-08-18 华东理工大学 Inorganic bane adhesive and its application in body's hard tissue repair
ES2271212T3 (en) 2001-03-02 2007-04-16 Woodwelding Ag IMPANTS AND DEVICE TO JOIN TISSUE PARTS.
US6949251B2 (en) 2001-03-02 2005-09-27 Stryker Corporation Porous β-tricalcium phosphate granules for regeneration of bone tissue
US6632235B2 (en) 2001-04-19 2003-10-14 Synthes (U.S.A.) Inflatable device and method for reducing fractures in bone and in treating the spine
US7615593B2 (en) * 2001-04-23 2009-11-10 Wisconsin Alumni Research Foundation Bifunctional-modified hydrogels
ATE438418T1 (en) 2001-05-01 2009-08-15 Av Topchiev Inst Petrochemical HYDROGEL COMPOSITIONS
KR100404839B1 (en) * 2001-05-15 2003-11-07 엘지전자 주식회사 Addressing Method and Apparatus of Plasma Display Panel
US20070083266A1 (en) 2001-05-25 2007-04-12 Vertegen, Inc. Devices and methods for treating facet joints, uncovertebral joints, costovertebral joints and other joints
US6482209B1 (en) * 2001-06-14 2002-11-19 Gerard A. Engh Apparatus and method for sculpting the surface of a joint
US6844028B2 (en) 2001-06-26 2005-01-18 Accelr8 Technology Corporation Functional surface coating
US20040266941A1 (en) * 2001-06-27 2004-12-30 Houston Michael R. Biomedical molding materials from semi-solid precursors
US6541281B2 (en) 2001-07-16 2003-04-01 Tachyon Semiconductors Corporation Ferroelectric circuit element that can be fabricated at low temperatures and method for making the same
US6747090B2 (en) 2001-07-16 2004-06-08 Pharmacia Groningen Bv Compositions capable of forming hydrogels in the eye
US6755865B2 (en) * 2001-09-24 2004-06-29 Imad Ed. Tarabishy Joint prosthesis and method for placement
DE10150737A1 (en) 2001-10-15 2003-04-30 Hilti Ag Multi-component foam system and its use
JP4095794B2 (en) 2001-12-03 2008-06-04 日東電工株式会社 Composite film and semiconductor product holding sheet
US20030130741A1 (en) * 2002-01-07 2003-07-10 Mcminn Derek James Wallace Hip prosthesis
US20040147466A1 (en) 2002-01-17 2004-07-29 Barman Shikha P. Nucleic acid delivery formulations
US7458991B2 (en) * 2002-02-08 2008-12-02 Howmedica Osteonics Corp. Porous metallic scaffold for tissue ingrowth
US7559928B2 (en) * 2002-02-12 2009-07-14 Alexandria Research Technologies, Llc Apparatus and method for minimally invasive total joint replacement
AU2003213037B2 (en) 2002-02-15 2006-12-14 Zms, Llc Polymerization process and materials for biomedical applications
AU2003215330B2 (en) 2002-02-21 2008-03-13 Encelle, Inc. Immobilized bioactive hydrogel matrices as surface coatings
US6955716B2 (en) 2002-03-01 2005-10-18 American Dental Association Foundation Self-hardening calcium phosphate materials with high resistance to fracture, controlled strength histories and tailored macropore formation rates
US7468192B2 (en) 2002-03-22 2008-12-23 Histogenics Corporation Method for repair of cartilage lesions
AU2003220895A1 (en) * 2002-03-28 2003-10-13 Sun Medical Co., Ltd. Paste polymerization initiator composition, dental or surgical adhesive and adhesive kit
US20060134186A1 (en) 2002-03-28 2006-06-22 Carlton Richard M Oxygenating agents for enhancing host responses to microbial infections
DE10217351B3 (en) 2002-04-18 2004-02-12 Mnemoscience Gmbh Interpenetrating networks
AU2003234159A1 (en) 2002-04-22 2003-11-03 Purdue Research Foundation Hydrogels having enhanced elasticity and mechanical strength properties
WO2003093327A1 (en) 2002-05-01 2003-11-13 Hokkaido Technology Licensing Office Co., Ltd. Gel having multiple network structure and method for preparation thereof
US7066958B2 (en) 2002-05-10 2006-06-27 Ferree Bret A Prosthetic components with partially contained compressible resilient members
US7235102B2 (en) 2002-05-10 2007-06-26 Ferree Bret A Prosthetic components with contained compressible resilient members
AU2003276137A1 (en) 2002-06-18 2003-12-31 Board Of Trustees Of The Leland Stanford Junior University Artificial cornea
US7476398B1 (en) 2002-06-28 2009-01-13 Universite Laval Corneal implant and uses thereof
AU2003247952A1 (en) 2002-07-11 2004-02-02 Advanced Bio Surfaces, Inc. Method and kit for interpositional arthroplasty
US7745532B2 (en) 2002-08-02 2010-06-29 Cambridge Polymer Group, Inc. Systems and methods for controlling and forming polymer gels
WO2004012874A1 (en) 2002-08-02 2004-02-12 The Government Of The United States Of America, Represented By The Secretary, Dept. Of Health And Human Services Cross-linked nitric oxide-releasing polyamine coated substrates, compositions comprising same and method of making same
US7485670B2 (en) 2002-08-02 2009-02-03 Cambridge Polymer Group, Inc. Systems and methods for controlling and forming polymer gels
US20040028804A1 (en) 2002-08-07 2004-02-12 Anderson Daniel G. Production of polymeric microarrays
US7959636B2 (en) 2002-08-15 2011-06-14 Arthrex, Inc. Osteochondral repair using plug fashioned from whole distal femur or condyle formed of hydrogel composition
US6955540B2 (en) 2002-08-23 2005-10-18 Woodwelding Ag Preparation for being fastened on a natural tooth part or tooth and corresponding fastening method
US7008226B2 (en) 2002-08-23 2006-03-07 Woodwelding Ag Implant, in particular a dental implant
US6984700B2 (en) * 2002-09-17 2006-01-10 Medtronic, Inc. Compounds containing silicon-containing groups, medical devices, and methods
US7264634B2 (en) 2002-09-20 2007-09-04 Arthrex, Inc. Method and instrumentation for osteochondral repair using preformed implants
US8673333B2 (en) 2002-09-25 2014-03-18 The Johns Hopkins University Cross-linked polymer matrices, and methods of making and using same
US6918914B2 (en) * 2002-10-10 2005-07-19 Clayton T. Bauer Minimally invasive adjustable acetubular reamer
US7049351B2 (en) 2002-11-01 2006-05-23 Novartis Ag Moldings and preparation and uses thereof
CN1780594A (en) 2002-11-07 2006-05-31 康复米斯公司 Methods for determining meniscal size and shape and for devising treatment
US6896965B1 (en) 2002-11-12 2005-05-24 Advanced Cardiovascular Systems, Inc. Rate limiting barriers for implantable devices
US6733533B1 (en) * 2002-11-19 2004-05-11 Zimmer Technology, Inc. Artificial spinal disc
US20040102852A1 (en) 2002-11-22 2004-05-27 Johnson Erin M. Modular knee prosthesis
US20040116564A1 (en) 2002-11-27 2004-06-17 Devlin Brian Gerrard Stabilization of poly(oxyalkylene) containing polymeric materials
US20050251267A1 (en) * 2004-05-04 2005-11-10 John Winterbottom Cell permeable structural implant
US20060127878A1 (en) 2002-12-18 2006-06-15 Salomon David H Hydrogel preparation and process of manufacture thereof
US7220491B2 (en) * 2002-12-19 2007-05-22 Kimberly-Clark Worldwide, Inc. Lubricious coating for medical devices
WO2004065450A2 (en) * 2003-01-16 2004-08-05 Carnegie Mellon University Biodegradable polyurethanes and use thereof
US6994730B2 (en) 2003-01-31 2006-02-07 Howmedica Osteonics Corp. Meniscal and tibial implants
GB2397766A (en) * 2003-02-03 2004-08-04 Univ London A Surgical Kit For Hemiarthroplasty Hip Replacement
US20040153040A1 (en) * 2003-02-05 2004-08-05 Lucie Martineau Multi-layer synthetic dressing with cooling characteristics
CN1774220A (en) 2003-02-14 2006-05-17 德普伊斯派尔公司 In-situ formed intervertebral fusion device and method
US7097646B2 (en) * 2003-02-21 2006-08-29 Zimmer Inc. Collapsible acetabular reamer
US7563483B2 (en) * 2003-02-26 2009-07-21 Advanced Cardiovascular Systems Inc. Methods for fabricating a coating for implantable medical devices
US7160305B2 (en) 2003-03-07 2007-01-09 Arthrex, Inc. Retrodrill technique for insertion of autograft, allograft or synthetic osteochondral implants
CA2521118C (en) 2003-04-11 2007-01-16 Csir Packaging with water soluble barrier layer
IES20030294A2 (en) 2003-04-17 2004-10-20 Medtronic Vascular Connaught Coating for biomedical devices
HUE035379T2 (en) 2003-04-24 2018-05-02 Coopervision Int Holding Co Lp Hydrogel contact lenses and package systems and production methods for same
US7279174B2 (en) * 2003-05-08 2007-10-09 Advanced Cardiovascular Systems, Inc. Stent coatings comprising hydrophilic additives
US7488348B2 (en) 2003-05-16 2009-02-10 Musculoskeletal Transplant Foundation Cartilage allograft plug
US7758497B2 (en) 2003-06-20 2010-07-20 Contura A/S Endoscopic attachment device
US6974862B2 (en) * 2003-06-20 2005-12-13 Kensey Nash Corporation High density fibrous polymers suitable for implant
US7176247B1 (en) 2003-06-27 2007-02-13 The United States Of America As Represented By The Secretary Of The Army Interpenetrating polymer network
WO2005016175A2 (en) 2003-06-27 2005-02-24 Advanced Bio Surfaces, Inc. Meniscus preserving implant method and apparatus
US7582698B2 (en) 2003-07-02 2009-09-01 Lubrizol Advanced Materials, Inc. Water dispersions of non-uniform polyurethane particles
JP2007500521A (en) 2003-07-31 2007-01-18 ウッドウェルディング・アクチェンゲゼルシャフト Method and apparatus for promoting tissue regeneration on wound surface
US7153325B2 (en) * 2003-08-01 2006-12-26 Ultra-Kinetics, Inc. Prosthetic intervertebral disc and methods for using the same
EP1680151A1 (en) 2003-08-08 2006-07-19 Contura S.A. Implantable hydrogel with resorbable shell for use as an endoprothesis
US7794476B2 (en) 2003-08-08 2010-09-14 Warsaw Orthopedic, Inc. Implants formed of shape memory polymeric material for spinal fixation
US10583220B2 (en) 2003-08-11 2020-03-10 DePuy Synthes Products, Inc. Method and apparatus for resurfacing an articular surface
US7217294B2 (en) 2003-08-20 2007-05-15 Histogenics Corp. Acellular matrix implants for treatment of articular cartilage, bone or osteochondral defects and injuries and method for use thereof
US7544381B2 (en) 2003-09-09 2009-06-09 Boston Scientific Scimed, Inc. Lubricious coatings for medical device
US20050054774A1 (en) 2003-09-09 2005-03-10 Scimed Life Systems, Inc. Lubricious coating
EP1722717B1 (en) 2003-10-02 2013-06-19 Kevin A. Mansmann Hydrogels having charged surfaces for cartilage replacement
EP1694228B1 (en) 2003-10-23 2011-08-31 TRANS1, Inc. Spinal mobility preservation apparatus
CA2536188A1 (en) * 2003-11-20 2005-06-09 Angiotech International Ag Electrical devices and anti-scarring agents
US20050113836A1 (en) * 2003-11-25 2005-05-26 Lozier Antony J. Expandable reamer
EP1701672A4 (en) 2003-12-19 2011-04-27 Osteotech Inc Tissue-derived mesh for orthopedic regeneration
US7842667B2 (en) 2003-12-22 2010-11-30 Regentis Biomaterials Ltd. Matrix composed of a naturally-occurring protein backbone cross linked by a synthetic polymer and methods of generating and using same
WO2005069957A2 (en) 2004-01-20 2005-08-04 Alexander Michalow Unicondylar knee implant
US7709439B2 (en) * 2004-02-20 2010-05-04 Boston Scientific Scimed, Inc. Biomaterials for enhanced healing
AU2005215073B2 (en) 2004-02-20 2011-02-03 Woodwelding Ag Implant that can be implanted in osseous tissue, method for producing said implant and corresponding implant
US20070100457A1 (en) 2004-03-04 2007-05-03 Hyde Edward R Jr Paramagnetic liquid interface
GB0405059D0 (en) * 2004-03-05 2004-04-07 Benoist Girard Sas Prosthetic acetabular cup inserter
US7829071B2 (en) * 2004-03-09 2010-11-09 Interpolymer Corporation Personal care fixative
US20050218541A1 (en) * 2004-04-02 2005-10-06 Peng Henry T Method of producing interpenetrating polymer network
US8657881B2 (en) 2004-04-20 2014-02-25 Depuy Mitek, Llc Meniscal repair scaffold
US20050267482A1 (en) * 2004-04-22 2005-12-01 Hyde Edward R Jr Bone treatment method with implants and instrumentation
US20050256576A1 (en) 2004-05-13 2005-11-17 Moskowitz Nathan C Artificial expansile total lumbar and thoracic discs for posterior placement without supplemental instrumentation and its adaptation for anterior placement of artificial cervical, thoracic and lumbar discs
US20050278025A1 (en) 2004-06-10 2005-12-15 Salumedica Llc Meniscus prosthesis
JP4709956B2 (en) 2004-06-18 2011-06-29 国立大学法人北海道大学 Artificial meniscus
DE102004042183A1 (en) * 2004-06-22 2006-01-19 Plus Endoprothetik Ag Device for setting or removing joints or joint sockets
EP1611877A1 (en) 2004-06-28 2006-01-04 Universidade de Coimbra Method for preparing sustained-release therapeutic ophthalmic articles using compressed fluids for impregnation of drugs
EP1627615A3 (en) 2004-08-18 2006-11-02 Arthrex, Inc. Modular joint replacement implant with hydrogel surface
US7857447B2 (en) * 2004-10-05 2010-12-28 The Board Of Trustees Of The Leland Stanford Junior University Interpenetrating polymer network hydrogel contact lenses
US20060287721A1 (en) 2004-10-05 2006-12-21 David Myung Artificial cornea
US7857849B2 (en) 2004-10-05 2010-12-28 The Board Of Trustees Of The Leland Stanford Junior Iniversity Artificial corneal implant
US8821583B2 (en) * 2004-10-05 2014-09-02 The Board Of Trustees Of The Leland Stanford Junior University Interpenetrating polymer network hydrogel
US7909867B2 (en) 2004-10-05 2011-03-22 The Board Of Trustees Of The Leland Stanford Junior University Interpenetrating polymer network hydrogel corneal prosthesis
US20090088846A1 (en) * 2007-04-17 2009-04-02 David Myung Hydrogel arthroplasty device
US7235592B2 (en) 2004-10-12 2007-06-26 Zimmer Gmbh PVA hydrogel
FR2876278B1 (en) * 2004-10-13 2007-10-26 Thomas Gradel COTYL APPLICATION INSTRUMENTS
US20060282169A1 (en) 2004-12-17 2006-12-14 Felt Jeffrey C System and method for upper extremity joint arthroplasty
DE102004062225A1 (en) 2004-12-23 2006-07-06 Hilti Ag Multi-component foam system for the production of interpenetrating polymeric networks and its use
TW200640061A (en) 2005-01-04 2006-11-16 Hitachi Chemical Co Ltd Phase separation type polymer electrolyte film, electrode/phase separation type polymer electrolyte film assembly employing the same, processes for producing the same, and fuel cell employing the same
WO2006091530A2 (en) 2005-02-22 2006-08-31 Transform Pharmaceuticals, Inc. Combinatorial hydrogel formulation
JP2008531769A (en) 2005-02-23 2008-08-14 ズィマー・テクノロジー・インコーポレーテッド Blend hydrogel and method for producing the same
US20060224244A1 (en) 2005-03-31 2006-10-05 Zimmer Technology, Inc. Hydrogel implant
US20060235542A1 (en) 2005-04-15 2006-10-19 Zimmer Technology, Inc. Flexible segmented bearing implant
US7291169B2 (en) 2005-04-15 2007-11-06 Zimmer Technology, Inc. Cartilage implant
US20060241759A1 (en) 2005-04-25 2006-10-26 Sdgi Holdings, Inc. Oriented polymeric spinal implants
US7182783B2 (en) 2005-04-25 2007-02-27 Sdgi Holdings, Inc. Selectively expandable composite structures for spinal arthroplasty
EP1919375A1 (en) 2005-05-24 2008-05-14 Gary Botimer Expandable surgical reaming tool
US7547319B2 (en) * 2005-06-15 2009-06-16 Ouroboros Medical Mechanical apparatus and method for artificial disc replacement
GB0514076D0 (en) * 2005-07-08 2005-08-17 Depuy Int Ltd Bioactive bone cement composition
US7959681B2 (en) * 2005-08-22 2011-06-14 Vilex In Tennessee, Inc. Cannulated hemi-implant and methods of use thereof
US7651701B2 (en) 2005-08-29 2010-01-26 Sanatis Gmbh Bone cement composition and method of making the same
US8420605B2 (en) 2005-09-07 2013-04-16 The University Of Strathclyde Hydrogel compositions
SG165337A1 (en) 2005-09-09 2010-10-28 Ottawa Hospital Res Inst Interpenetrating networks, and related methods and compositions
US20070088444A1 (en) 2005-10-13 2007-04-19 Robert A Hodorek Method for repairing a bone defect using a formable implant which hardens in vivo
US20070118218A1 (en) 2005-11-22 2007-05-24 Hooper David M Facet joint implant and procedure
AU2006321809A1 (en) 2005-12-07 2007-06-14 Zimmer, Inc. Methods of bonding or modifying hydrogels using irradiation
US20070141108A1 (en) 2005-12-20 2007-06-21 Zimmer, Inc. Fiber-reinforced water-swellable articles
WO2007084725A2 (en) * 2006-01-19 2007-07-26 Osteotech, Inc. Injectable and moldable bone substitute materials
US8038920B2 (en) 2006-01-25 2011-10-18 Carticept Medical, Inc. Methods of producing PVA hydrogel implants and related devices
US20070179607A1 (en) 2006-01-31 2007-08-02 Zimmer Technology, Inc. Cartilage resurfacing implant
AU2007212033B2 (en) 2006-02-06 2014-01-23 Conformis, Inc. Patient selectable joint arthroplasty devices and surgical tools
US8858632B2 (en) 2006-03-23 2014-10-14 Formae, Inc. Implants for replacing hyaline cartilage, with hydrogel reinforced by three-dimensional fiber arrays
US8110242B2 (en) 2006-03-24 2012-02-07 Zimmer, Inc. Methods of preparing hydrogel coatings
US9017380B2 (en) 2006-04-03 2015-04-28 Woodwelding Ag Surgical method, kit of parts, and implant
US20080058954A1 (en) * 2006-08-22 2008-03-06 Hai Trieu Methods of treating spinal injuries using injectable flowable compositions comprising organic materials
US20080103505A1 (en) 2006-10-26 2008-05-01 Hendrik Raoul Andre Fransen Containment device for site-specific delivery of a therapeutic material and methods of use
EP2094235A2 (en) 2006-11-06 2009-09-02 Novartis AG Ocular devices and methods of making and using thereof
WO2008097616A1 (en) 2007-02-06 2008-08-14 The Board Of Trustees Of The Leland Stanford Junior University Hydrogel-metal assembly
US7731988B2 (en) 2007-08-03 2010-06-08 Zimmer, Inc. Multi-polymer hydrogels
US20090062423A1 (en) 2007-08-29 2009-03-05 Salumedica, Llc Orthopaedic cement mixtures with low weight percent polyvinyl alcohol (pva) solution
US8062739B2 (en) 2007-08-31 2011-11-22 Zimmer, Inc. Hydrogels with gradient
WO2009070429A1 (en) 2007-11-29 2009-06-04 Bausch & Lomb Incorporated Process for making biomedical devices
US20090176891A1 (en) * 2007-12-06 2009-07-09 Sami Chogle Dental composition and method of use
GB0724020D0 (en) 2007-12-08 2008-01-23 Depuy Int Ltd An instrument
WO2009086182A1 (en) 2007-12-21 2009-07-09 Carticept Medical, Inc. Articular injection system
GB0803041D0 (en) * 2008-02-20 2008-03-26 Depuy Int Ltd Surgical instrument
US20090233887A1 (en) * 2008-03-12 2009-09-17 Shalaby Shalaby W Hydroswellable, Segmented, Aliphatic Polyurethanes and Polyurethane Ureas
US20100056646A1 (en) * 2008-03-12 2010-03-04 Shalaby Shalaby W Hydroswellable, segmented, aliphatic polyurethane ureas and intra-articular devices therefrom
AU2009225416A1 (en) * 2008-03-21 2009-09-24 Biomimedica, Inc Methods, devices and compositions for adhering hydrated polymer implants to bone
CA2727791A1 (en) 2008-06-13 2009-12-17 Pivot Medical, Inc. Methods and apparatus for joint distraction
US8883915B2 (en) * 2008-07-07 2014-11-11 Biomimedica, Inc. Hydrophobic and hydrophilic interpenetrating polymer networks derived from hydrophobic polymers and methods of preparing the same
EP2297217B1 (en) 2008-07-07 2021-10-20 Hyalex Orthopaedics, Inc. Hydrophilic interpenetrating polymer networks derived from hydrophobic polymers
US20120209396A1 (en) 2008-07-07 2012-08-16 David Myung Orthopedic implants having gradient polymer alloys
JP5722773B2 (en) 2008-08-05 2015-05-27 バイオミメディカ インコーポレイテッド Polyurethane grafted hydrogel
DE102008049661A1 (en) 2008-09-30 2010-04-01 Smith & Nephew Orthopaedics Ag Instrument for handling a joint component
US10258473B2 (en) 2008-11-19 2019-04-16 Softjoint Corporation Device and method for restoring joints with artificial cartilage
CA2805021C (en) 2009-07-10 2019-09-10 Milux Holding S.A. Hip joint device and method
US20110152868A1 (en) 2009-12-18 2011-06-23 Lampros Kourtis Method, device, and system for shaving and shaping of a joint
EP3357518B1 (en) 2011-10-03 2020-12-02 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
WO2013078284A1 (en) 2011-11-21 2013-05-30 Biomimedica, Inc. Systems, devices, and methods for anchoring orthopaedic implants to bone

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10457803B2 (en) 2008-07-07 2019-10-29 Hyalex Orthopaedics, Inc. Orthopedic implants having gradient polymer alloys
US10752768B2 (en) 2008-07-07 2020-08-25 Hyalex Orthopaedics, Inc. Orthopedic implants having gradient polymer alloys
US11015016B2 (en) 2011-10-03 2021-05-25 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
US11760830B2 (en) 2011-10-03 2023-09-19 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
US11077228B2 (en) 2015-08-10 2021-08-03 Hyalex Orthopaedics, Inc. Interpenetrating polymer networks
US20180170296A1 (en) * 2016-12-15 2018-06-21 Ford Global Technologies, Llc Lap-belt length detecting seatbelt assembly
US10792392B2 (en) 2018-07-17 2020-10-06 Hyalex Orthopedics, Inc. Ionic polymer compositions
US10869950B2 (en) 2018-07-17 2020-12-22 Hyalex Orthopaedics, Inc. Ionic polymer compositions
US11110200B2 (en) 2018-07-17 2021-09-07 Hyalex Orthopaedics, Inc. Ionic polymer compositions
US11364322B2 (en) 2018-07-17 2022-06-21 Hyalex Orthopaedics, Inc. Ionic polymer compositions

Also Published As

Publication number Publication date
CA2731698A1 (en) 2010-02-11
EP2323670A1 (en) 2011-05-25
JP5722773B2 (en) 2015-05-27
EP2323670A4 (en) 2013-12-25
US20140213661A1 (en) 2014-07-31
US8853294B2 (en) 2014-10-07
US8497023B2 (en) 2013-07-30
US20100032090A1 (en) 2010-02-11
JP2011530336A (en) 2011-12-22
WO2010017282A1 (en) 2010-02-11
US20130261212A1 (en) 2013-10-03
KR20110040969A (en) 2011-04-20
AU2009279716A1 (en) 2010-02-11

Similar Documents

Publication Publication Date Title
US8853294B2 (en) Polyurethane-grafted hydrogels
US10752768B2 (en) Orthopedic implants having gradient polymer alloys
US8883915B2 (en) Hydrophobic and hydrophilic interpenetrating polymer networks derived from hydrophobic polymers and methods of preparing the same
EP2297217B1 (en) Hydrophilic interpenetrating polymer networks derived from hydrophobic polymers
US20200087440A1 (en) Polymeric adhesive for anchoring compliant materials to another surface
JP2019005624A (en) Orthopedic implants having gradient polymer alloys
US20190218386A1 (en) Ionic polymer compositions
Alves et al. Biomedical polyurethanes-based materials

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION