+

US20020072584A1 - Biostability of polymeric structures - Google Patents

Biostability of polymeric structures Download PDF

Info

Publication number
US20020072584A1
US20020072584A1 US09/985,821 US98582101A US2002072584A1 US 20020072584 A1 US20020072584 A1 US 20020072584A1 US 98582101 A US98582101 A US 98582101A US 2002072584 A1 US2002072584 A1 US 2002072584A1
Authority
US
United States
Prior art keywords
solvent
polymeric material
extraction
swelling
solubility parameter
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
US09/985,821
Other languages
English (en)
Inventor
Eamon Brady
Ann Cannon
Fergal Farrell
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.)
Salviac Ltd
Original Assignee
Salviac Ltd
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
Priority claimed from PCT/IE1999/000038 external-priority patent/WO2000067812A1/fr
Priority claimed from PCT/IE1999/000037 external-priority patent/WO2000067811A1/fr
Application filed by Salviac Ltd filed Critical Salviac Ltd
Assigned to SALVIAC LIMITED reassignment SALVIAC LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CANNON, ANN MARLE, FARRELL, FERGAL, BRADY, EAMON
Publication of US20020072584A1 publication Critical patent/US20020072584A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0068—General culture methods using substrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2101/00—Manufacture of cellular products
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2110/00—Foam properties
    • C08G2110/0008—Foam properties flexible
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2110/00—Foam properties
    • C08G2110/0083—Foam properties prepared using water as the sole blowing agent
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2531/00—Microcarriers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers

Definitions

  • This invention relates to biocompatible polymeric structures suitable for long term implantation within a living human body, and as a substratum for cell, tissue and organ growth technologies.
  • a serious limitation associated with the processes and materials available to the biomedical designer today is the fact that virtually all materials available today require some level of additives.
  • An additional limitation of current materials is that polymerization reactions are far from perfect and generate materials which contain low molecular weight material, oligomers, unreacted monomers, catalysts, stabilizers and a host of other additives within the material. Irrespective of the source, these chemicals present a serious problem as they can leach into the tissue surrounding the implant.
  • This invention therefore is directed towards providing process and material technologies that can produce leachable free polymer systems with properties suitable for implantation.
  • solvent extracting the polymeric material with an extraction solvent the solvent being a solvent which generates a volumetric swelling and having a solubility parameter of from 17 to 27 MPa 0.5 .
  • the solvent extraction technique involves extracting the polymer in the presence of a swelling solvent.
  • the solvent swells the material of the implant by more than 30%, more preferably by more than 100% and still more preferably by more than 150%.
  • the solubility parameter of the solvent extraction system is selected for compatibility with the solubility parameter of the polymeric material or its phases.
  • the solubility parameter of the solvent extraction system is within ⁇ 4 MPa 1 ⁇ 2 of the solubility parameter of the polymer or its phases.
  • solubility parameter is from 18-24 MPa 1 ⁇ 2 .
  • the hydrogen-bonding component of the solvent solubility parameter is in excess of 3 MPa 1 ⁇ 2 .
  • the solvent solubility parameter is selected such that it is similar to that of material leachables.
  • the solvent is miscible with water.
  • the solvent has a vapour pressure in excess of 2 kPa. More preferably the vapour pressure is in excess of 5 kPa. Even more preferably the vapour pressure is in excess of 10 kPa.
  • the vapour pressure of MEK is 12.6 kPa, while the vapour pressure of THF is 21.6 kPa at room temperature.
  • the solvent selected has a low content of stabilizers and other additives and is non-reactive.
  • MEK is the preferred solvent due to its excellent ability to swell cross-linked polyurethanes, its miscibility with water, its high vapour pressure, its stability and it can be obtained at high level of purity.
  • the method includes the step of removing residual solvent from the structure, after solvent extraction.
  • residual solvent is removed by treatment with water.
  • the solvent is removed by freeze drying or by thermally induced phase separation.
  • the biocompatible material may for example be a polyether polyurethane, a polycarbonate urethane, a polydimethylsiloxane urethane, a polyester urethane, a fatty acid derived polyurethane, a polybutadiene polyurethane, a urethane urea of any of the above or mixtures.
  • the polyurethane is a polyether polyurethane, a polycarbonate polyurethane or a polydimethylsiloxane polyurethane.
  • the material is in the form of a medical implant.
  • the implant may be a septal defect occluder, a vessel occluder, a vessel defect occluder, a mammary prosthesis, a muscle bulking agent, a gynecological implant, a vascular graft, an embolising implant, a pacemaker housing cover, or an embolic filter.
  • the material may be in the form of a porous substratum for cell growth, tissue growth, organ growth or organ reconstruction.
  • the article may be formed from an organic diisocyanate, a polyol, a chain extender and a blowing agent.
  • a cross-lining agent may be employed to enhance the cross-linking of the material.
  • a catalyst and surfactant may also be employed.
  • the blowing agent is preferably water.
  • the ratios of the reaction components are selected to promote the formation of a three dimensional porous molecular structure of polyurethane biomaterial.
  • the article may be processed by a metering and mixing process, wherein the chemical components are aggressively mixed and dispensed into a vessel and chain extension and blowing reactions occur substantially simultaneously.
  • the article is processed by a reactive moulding process, wherein the chemical components are mixed and dispensed into a vessel wherein chain extension occurs.
  • the polyurethane scaffold has a pore size of from 10 microns to 300 microns. Ideally the scaffold has a pore size of between 35 microns to 200 microns.
  • the biocompatible, leachable free polyurethanes of this invention are derived from organic diisocyanates and polyols.
  • the reaction step converts the chemical precursors into a 3 dimensional molecular cross-linked structure.
  • a 3-dimensional network of this kind is insoluble and intractable.
  • the biomaterial is a three dimensional structure at a molecular level allows it to be processed aggressively to remove leachable chemicals from the material.
  • Low molecular weight chemicals have the potential to leach from the article and result in toxic reactions in living cells.
  • the severity of the inflammation, following implantation of a synthetic material is strongly dependent on the type and quantity of chemicals that can migrate from the implant to the surrounding tissue.
  • the processes of the invention expand the biomaterials volume at a molecular level. This expansion facilitates the removal of leachables such as monomers, oligomers, high molecular weight linear polymers, catalysts, surfactants, and other additives.
  • the solvent extraction process also reduces any internal stresses within the material.
  • the solvent expands the material by separating the molecular chains and suspending the chains in a solvent matrix. This loss of interchain attraction seriously compromises the mechanical properties of the matrix during the extraction step.
  • the 3-dimensional cross-links however provide the materials with molecular memory and prevent the molecular structure from being completely solubilised.
  • the recovery step removes the solvent and de-swells the material to its original state.
  • multiple solvent swelling extractions may be carried out. These extractions preferably use solvents that have an affinity for different leachables.
  • Low solubility parameter solvents have an affinity for surfactant leachables.
  • Moderate solubility parameter solvents are used to remove the bulk of the leachables including soft phase monomers, oligomers and diols.
  • High solubility parameter solvents have an affinity for hard phase monomers, dimers, oligomers and amine catalysts.
  • affinity of a particular leachable to a solvent must be off set against the ability of the solvent to swell the matrix. Higher swelling ratio solvents tend to be most effective in removing a wide spectrum of leachables.
  • the process of the invention is specifically designed to the treatment of polyurethane polymers. More specifically the invention is designed to treat polyurethane porous structures and scaffolds. However it is recognised that the principles of the invention can be applied to other materials. Indeed, most cross-linked polymer materials can be treated by the processes of the invention. The optimum swelling solvents will naturally have different solubility parameters to those specified for polyurethanes.
  • This process enhances the material biocompatible for use as an implantable medical device or as a 3 dimensional matrix for use as a cell scaffold in tissue engineering applications.
  • Altering the chemical precursors and the processing conditions of the material may alter the pore size and the density of the material, as required, to meet the requirements of the application.
  • the scaffold is immersed in the swelling solvent and placed in an ultrasonic chamber for a minimum of six hours.
  • the ultrasonic bath facilitates solvent penetration of the scaffold and assists in the migration of leachables from the polymer into the solvent.
  • the solvent is diluted by the drop wise addition of non-solvent, miscible with the solvent over a period of 1-3 hours.
  • the concentration of solvent should be less than 5% after the addition of non-solvent.
  • the scaffold is then immersed in pure non-solvent for 7-8 hours.
  • the scaffold is dried in an oven for 72 hours to remove all traces of the non-solvent.
  • This process is carried out in a fashion whereby material is subjected to minimal mechanical stress during the processing. This is particularly important during the swollen phase.
  • Achieving incredibly low levels of leachables may require multiple solvent swelling extraction steps. Different solvents may be used in each extraction steps.
  • Leachable levels can be measured gravimetrically or analytically (chromatography). HPLC grade water extraction of the materials or scaffold at 40° C. should produce a leachables content less than 1.0 mg per g. More preferably the water extracted leachables content is less than 10 ⁇ g per g: Even more preferably the water extracted leachables content is less than 0.1 ⁇ g per g. Extraction times in excess of 12 hours should be employed. These levels are near or below the level of detection for many analytical systems and may be demonstrated by extrapolation.
  • the exposure of the processed scaffold to a solvent whose solubility parameter is between 18 MPa 1 ⁇ 2 and 24 MPa ⁇ fraction (1/2) ⁇ , at 40° C. should produce a leachables content less than 10.0 mg per g in the solvent. More preferably the solvent extracted leachables content is less than 100 ⁇ g per g. Even more preferably the solvent extracted leachables content of the scaffold is less than 10.0 ⁇ g per g.
  • Suitable solvents for this assessment of polyurethane biomaterials include MEK, DMA and THF.
  • Solvents that provide the maximum swelling are preferred per this invention.
  • the volume swelling during solvent extraction should be above 30%.
  • the solvent swelling should be in excess of 100%. Even more preferable is solvent swelling in excess of 150%.
  • the level of solvent swelling decreases as the average molecular weight between cross-links decreases. However a minimum cross-link density is necessary to provide solvent swelling memory.
  • the molecular weight between cross-links of the material should preferably be between 300 and 6,000. Preferably the molecular weight between cross-links of the material is between 800 and 2,000. At very high cross-link densities the ability of the polymer to swell in the presence of a swelling solvent is diminished. At very low cross-ink densities large amounts of the polymer structure become solubilised. This creates recovery problems or results in a loss of structure.
  • the 3-dimensional molecular structure is important to achieving the physical and chemical characteristics of the invention.
  • the three dimensional aspect is achieved with polyurethane's either by incorporating a trifunctional entity within the formulation or by employing an isocyanate index in excess of 1.
  • Linear polymer systems cannot be subjected to such an aggressive solvent extraction since the use of a solvent with a similar solubility parameter will cause both the polymer and it's leachables to dissolve.
  • the biocompatible polyurethanes of this invention are useful for the manufacture of catheters, vascular grafts, septal occluders, vessel occluders, embolisation devices, mammary prosthesis, pacemaker housing covers, a stent cuffs, a stent covering, a tissue bridge, a vessel defect occluder, a muscle bulking agent, a gynecological implant, a vascular graft, an embolic filter and other such implant and blood contacting devices.
  • the material is in the form of a medical implant.
  • the material may be in the form of a porous substratum for cell growth, tissue growth, organ growth or organ reconstruction.
  • biostable polyurethanes of this invention are based on organic diisocyanates, polyols, and diol, diamine or water chain extenders and combinations thereof.
  • organic diisocyanates are of the general formula:
  • R is an aliphatic, aromatic, cycloaliphatic, or an aliphatic-aromatic hydrocarbon entity containing between 4 and 24 carbon atoms and “n” varies between 2.0 and 3. More preferably, R contains between 4 and 15 carbon atoms. Where n is 2, a polymer with a linear molecular structure may be produced. A three dimensional molecular network may be produced where n varies from 2.0 to 3.0. Ideally n should be 2.
  • Suitable isocyanates include: p-phenylene diisocyanate, tetramethylene diisocyanate, cyclohexane 1,2-diisocyanate, m-tetramethylxylene diisocyanate, hexamethylene diisocyanate, 2,4 diphenylmethane diisocyanate, 4,4 diphenylmethane diisocyanate, 2,4 toluene diisocyanate, 2,6 toluene diisocyanate, cyclohexane 1,4 diisocyanate, isophorone diisocyanate, 4,4-dicyclohexylmethane diisocyanate, 4,4-dicyclohexylmethane diisocyanate, and mixtures of the above.
  • isocyanates can be used to manufacture suitable materials; 2,4 diphenylmethane diisocyanate, 4,4 diphenylmethane diisocyanate, 2,4 toluene diisocyanate, 2, 6 toluene diisocyanate, cyclohexane 1,4 diisocyanate, isophorone diisocyanate, 4,4-dicyclohexylmethane diisocyanate, and mixtures of the above.
  • polyols may be used per this invention. These include polyether polyols, polyester polyols, polycarbonate polyols, silicone based polyols, fatty acid derived polyols, polybutadiene polyols.
  • the molecular weights of the polyols is in excess of 400 and less than 6000. More preferably the molecular weight is between 600 and 2500.
  • Polyether polyols, PDMS polyols and polycarbonate polyols are preferred for long term implantation applications.
  • Polyether polyols that may be used include products obtained by the polymerisation of cyclic oxide, for example, ethylene oxide, propylene oxide, butylene oxide, or tetrahydrofuran.
  • Useful polyether polyols include polytetramethylene glycols obtained by the polymerisation of tetrahydrofuran. Polyols of differing molecular weights can be used together in a single formulation. Multiple polyols can be used in a single formulation.
  • the polyurethanes of this invention are based on diol, diamine, alkanolamine, water chain extenders or mixtures of these.
  • Diol chain extenders react with isocyanate to generate urethane linkages.
  • Most diols or diamines make suitable chain extenders.
  • chain extenders include, ethylene glycol, 1,4 butanediol, diethylene glycol, triethylene glycol, 1,2 propane diol, 1,3 propane diol, 1,5 pentane diol, ethylene diamine, 1,4 diaminobutane, 1,6 diaminohexane, 1,7 diaminoheptane, 1,8 diaminooctane, and 1,5 diaminopentane.
  • Useful catalysts are widely available in the marketplace and include organic and inorganic salts of bismuth, lead, tin, iron, antimony, cadmium, cobalt, aluminum, mercury, zinc, cerium, molybdenum, vanadium, copper, manganese and zirconium, as well as phosphines and tertiary amines.
  • Tertiary amines are an important class of catalyst in which the nitrogen atom is not directly attached to an aromatic ring.
  • tertiary armines are: triethylamine, N,N,N′,N′-tetramethylenediamine, N-N,N′,N′-tetramethyl-1,3-butanediamine, bis-2-dimethylaminoethyl ether, N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, 1,4-diazabicyclo-[2.2.2] octane and the like.
  • Standard cross-linking agents may also be employed to improve the cross-linked aspect of the material.
  • TEA is an exemplary example.
  • the one shot process, the quasiprepolymer method or the prepolymer method can be used to prepare the polyurethanes of this invention.
  • the solubility parameter and hydrogen bonding parameters of the solvent will affect the suitability of the solvent.
  • the solubility of the solvents of the invention is typically in the region of 17-27 MPa 1 ⁇ 2 . More preferably the solubility parameter is from 18-24 MPa 1 ⁇ 2 .
  • the solvent system used for the extract system should have a solubility parameter in the same range as that of the biomaterial or scaffold.
  • Solvents that may be used include methylethyl ketone, tetrahydrofuran, 1,2-dichloroethane, propan-2-ol, and combinations of the above. Many other solvents have suitable properties and could equally be employed.
  • the materials are mixed at 50-60° C. for a minimum of 25-30 minutes.
  • the polyol resin is stored in containers, under a blanket of nitrogen gas.
  • An isocyanate pre-polymer is prepared from flake MDI (Desmodur from Bayer) and PTMEG (Terathane 1000 MW from DuPont). The amount of MDI and polyol used yield a NCO % content by weight of 15.6% and can be readily determined by those skilled in the art.
  • a number of polyether polyurethane biomaterials are prepared at varying isocyanate indices using techniques described in our copending patent. The following isocyanate index materials were reacted and cured in a cylindrical mould; 0.95, 0.99, 1.04, 1.08, 1.13, 1.18, 1.23 and 1.29. The samples were cut to a length of 15 mm and had a diameter of 21.5 mm.
  • a 250 ml wide necked conical flask was filled with MEK to the 250 ml mark.
  • a separate flask was used for samples of each index. Five samples were placed in each flask. The flasks were stoppered and placed in a water filled ultrasonic bath. The bath was at room temperature. The flasks were sonified for 6 hours. After the 6 hours the samples were removed from the flask by pouring the contents into a sieve. The samples were rinsed in water and placed in an oven at 80° C. to dry. The samples were weighed at 30 minute intervals until the weight stabilised. The weight loss for each sample was measured.
  • This biomaterial scored zero when subjected to the Cytotoxicity test as outlined in ISO standard 10993-5. This is the lowest possible score with this test method. This means that when cell growth media, previously incubated with the biomaterial, supported the growth of L-929 cells and did not induce a cytopathic effect. Media incubated with cytotoxic materials induce cytopathic effects when incubated with L-929 cells. The extent of cytopathic effect can be correlated to the cytotoxicity of the biomaterial.
  • This polyether polyurethane biomaterial was also implanted in the gluteal muscle of rats and left for up to 6 months. The histological analysis conducted on the explants indicated that the implant was well tolerated in the animal model and did not induce any adverse inflammatory response.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Biotechnology (AREA)
  • Vascular Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Surgery (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Polymers & Plastics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Polyurethanes Or Polyureas (AREA)
  • Materials For Medical Uses (AREA)
US09/985,821 1999-05-07 2001-11-06 Biostability of polymeric structures Abandoned US20020072584A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IEPCT/IE99/00037 1999-05-07
IEPCT/IE99/00038 1999-05-07
PCT/IE1999/000038 WO2000067812A1 (fr) 1999-05-07 1999-05-07 Biostabilite de structures polymeres
PCT/IE1999/000037 WO2000067811A1 (fr) 1999-05-07 1999-05-07 Produit de polyether-polyurethane biostable
PCT/IE2000/000058 WO2000067814A1 (fr) 1999-05-07 2000-05-08 Biostabilite de structures polymeriques

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IE2000/000058 Continuation WO2000067814A1 (fr) 1999-05-07 2000-05-08 Biostabilite de structures polymeriques

Publications (1)

Publication Number Publication Date
US20020072584A1 true US20020072584A1 (en) 2002-06-13

Family

ID=26320278

Family Applications (4)

Application Number Title Priority Date Filing Date
US09/985,819 Abandoned US20020072550A1 (en) 1999-05-07 2001-11-06 Biostable polyurethane products
US09/985,821 Abandoned US20020072584A1 (en) 1999-05-07 2001-11-06 Biostability of polymeric structures
US11/152,780 Abandoned US20070003594A1 (en) 1999-05-07 2005-06-15 Tissue engineering scaffold
US12/271,336 Expired - Fee Related US8168431B2 (en) 1999-05-07 2008-11-14 Tissue engineering scaffold comprising polyurethane material having voids interconnected by pores

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09/985,819 Abandoned US20020072550A1 (en) 1999-05-07 2001-11-06 Biostable polyurethane products

Family Applications After (2)

Application Number Title Priority Date Filing Date
US11/152,780 Abandoned US20070003594A1 (en) 1999-05-07 2005-06-15 Tissue engineering scaffold
US12/271,336 Expired - Fee Related US8168431B2 (en) 1999-05-07 2008-11-14 Tissue engineering scaffold comprising polyurethane material having voids interconnected by pores

Country Status (5)

Country Link
US (4) US20020072550A1 (fr)
EP (3) EP1176994A1 (fr)
AU (3) AU4426600A (fr)
DE (1) DE60003178T2 (fr)
WO (3) WO2000067813A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10243965A1 (de) * 2002-09-20 2004-04-01 Adiam Life Science Ag Verfahren zur Herstellung von biokompatiblen Polyurethanen
US20100234955A1 (en) * 2007-02-14 2010-09-16 Santerre J Paul Fibrous scaffold for use in soft tissue engineering

Families Citing this family (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7964207B2 (en) 2002-03-22 2011-06-21 Doctor's Research Group, Inc. Methods of performing medical procedures that promote bone growth, method of making compositions that promote bone growth, and apparatus for use in such methods
US20040127563A1 (en) * 2002-03-22 2004-07-01 Deslauriers Richard J. Methods of performing medical procedures which promote bone growth, compositions which promote bone growth, and methods of making such compositions
US7303575B2 (en) * 2002-08-01 2007-12-04 Lumen Biomedical, Inc. Embolism protection devices
DE10243966A1 (de) * 2002-09-20 2004-04-01 Adiam Life Science Ag Verfahren zur Herstellung von biokompatiblen Polyurethanen
US20050043585A1 (en) * 2003-01-03 2005-02-24 Arindam Datta Reticulated elastomeric matrices, their manufacture and use in implantable devices
EP1633275B1 (fr) * 2003-05-15 2017-11-29 Biomerix Corporation Matrices elastomeres reticulees, leur production et leur utilisation dans des dispositifs implantables
US8048042B2 (en) * 2003-07-22 2011-11-01 Medtronic Vascular, Inc. Medical articles incorporating surface capillary fiber
US7879062B2 (en) * 2003-07-22 2011-02-01 Lumen Biomedical, Inc. Fiber based embolism protection device
US7763077B2 (en) 2003-12-24 2010-07-27 Biomerix Corporation Repair of spinal annular defects and annulo-nucleoplasty regeneration
US20050165480A1 (en) * 2004-01-23 2005-07-28 Maybelle Jordan Endovascular treatment devices and methods
CN1942497B (zh) 2004-03-03 2012-02-01 宝利诺沃生物材料有限公司 用于二阶段或多阶段固化的生物相容性聚合物组合物
EP1729675A4 (fr) * 2004-03-05 2011-05-18 Univ Columbia Echafaudage composite biodegradable d'integration osseuse a phases multiples pour la fixation biologique du tissu mou musculo-squelettique a l'os
US20070190108A1 (en) * 2004-05-17 2007-08-16 Arindam Datta High performance reticulated elastomeric matrix preparation, properties, reinforcement, and use in surgical devices, tissue augmentation and/or tissue repair
US8258198B2 (en) * 2004-05-28 2012-09-04 Air Products And Chemicals, Inc. Fast demold/extended cream time polyurethane formulations
US8771294B2 (en) 2004-11-26 2014-07-08 Biomerix Corporation Aneurysm treatment devices and methods
EP1945690B1 (fr) 2005-09-20 2016-07-27 Polynovo Biomaterials Pty Limited Allongeurs de chaîne
US8052714B2 (en) * 2005-11-22 2011-11-08 Medtronic Vascular, Inc. Radiopaque fibers and filtration matrices
JP2009544437A (ja) 2006-08-02 2009-12-17 ポリィノボ バイオマテリアルズ ピーティワイ リミテッド 生体適合性ポリマー組成物
US8753391B2 (en) * 2007-02-12 2014-06-17 The Trustees Of Columbia University In The City Of New York Fully synthetic implantable multi-phased scaffold
CN101896526B (zh) 2007-10-03 2013-09-11 新型聚合物生物材料有限公司 高模量聚氨酯和聚氨酯/脲组合物
US7923486B2 (en) * 2007-10-04 2011-04-12 Board Of Regents, The University Of Texas System Bio-polymer and scaffold-sheet method for tissue engineering
EA201071225A1 (ru) 2008-04-21 2011-06-30 Нфокус Ньюромедикал, Инк. Устройства для эмболизации с армированным сеткой баллоном и системы подачи
WO2009140437A1 (fr) 2008-05-13 2009-11-19 Nfocus Neuromedical, Inc. Systèmes de pose d'implant tressé
WO2010088699A2 (fr) * 2009-02-02 2010-08-05 Biomerix Corporation Dispositifs maillés composites et procédés de réparation des tissus mous
SG175373A1 (en) 2009-04-28 2011-11-28 Surmodics Inc Devices and methods for delivery of bioactive agents
EP2275466A1 (fr) * 2009-07-16 2011-01-19 Bayer MaterialScience AG Adhésif tissulaire à base de polyurée
CN102695528B (zh) * 2009-08-21 2016-07-13 诺万公司 创伤敷料、其使用方法及其形成方法
US20110207166A1 (en) * 2009-11-06 2011-08-25 Sarah Rivkah Vaiselbuh Human bone marrow microenvironments and uses thereof
WO2011130322A1 (fr) * 2010-04-12 2011-10-20 University Of Miami Échafaudages biotechnologiques macroporeux pour la transplantation de cellules
US9554888B2 (en) * 2010-04-20 2017-01-31 University Of Utah Research Foundation Phase separation sprayed scaffold
US9288089B2 (en) 2010-04-30 2016-03-15 Ecole Polytechnique Federale De Lausanne (Epfl) Orthogonal differential vector signaling
US9479369B1 (en) 2010-05-20 2016-10-25 Kandou Labs, S.A. Vector signaling codes with high pin-efficiency for chip-to-chip communication and storage
US9106238B1 (en) 2010-12-30 2015-08-11 Kandou Labs, S.A. Sorting decoder
US9985634B2 (en) 2010-05-20 2018-05-29 Kandou Labs, S.A. Data-driven voltage regulator
US9077386B1 (en) 2010-05-20 2015-07-07 Kandou Labs, S.A. Methods and systems for selection of unions of vector signaling codes for power and pin efficient chip-to-chip communication
US9401828B2 (en) 2010-05-20 2016-07-26 Kandou Labs, S.A. Methods and systems for low-power and pin-efficient communications with superposition signaling codes
US8593305B1 (en) 2011-07-05 2013-11-26 Kandou Labs, S.A. Efficient processing and detection of balanced codes
US9288082B1 (en) 2010-05-20 2016-03-15 Kandou Labs, S.A. Circuits for efficient detection of vector signaling codes for chip-to-chip communication using sums of differences
WO2012107375A1 (fr) * 2011-02-09 2012-08-16 Bayer Materialscience Ag Adhésif tissulaire à base d'aspartates modifiés par azote
US10610616B2 (en) 2011-03-23 2020-04-07 The Regents Of The University Of California Mesh enclosed tissue constructs
US9968446B2 (en) 2011-03-23 2018-05-15 The Regents Of The University Of California Tubular scaffold for fabrication of heart valves
US9925296B2 (en) 2011-03-23 2018-03-27 The Regents Of The University Of California Mesh enclosed tissue constructs
US8936650B2 (en) 2011-03-23 2015-01-20 The Regents Of The University Of California Mesh enclosed tissue constructs
WO2012143356A1 (fr) * 2011-04-19 2012-10-26 Bayer Materialscience Ag Adhésif médical pour stopper des saignements
US9861727B2 (en) 2011-05-20 2018-01-09 Surmodics, Inc. Delivery of hydrophobic active agent particles
US11246963B2 (en) 2012-11-05 2022-02-15 Surmodics, Inc. Compositions and methods for delivery of hydrophobic active agents
EP3574850B1 (fr) 2012-11-13 2022-07-06 Covidien LP Dispositifs occlusifs
CN105122758B (zh) 2013-02-11 2018-07-10 康杜实验室公司 高带宽芯片间通信接口方法和系统
US11399842B2 (en) * 2013-03-13 2022-08-02 Conformal Medical, Inc. Devices and methods for excluding the left atrial appendage
US10682436B2 (en) * 2013-03-15 2020-06-16 Arsenal Medial, Inc. In-Situ forming foam for the treatment of vascular dissections
EP2983643A4 (fr) 2013-04-12 2016-12-28 Univ Columbia Procédés pour l'écotropisme de cellules hôtes et la régénération de pulpe dentaire
US9106465B2 (en) 2013-11-22 2015-08-11 Kandou Labs, S.A. Multiwire linear equalizer for vector signaling code receiver
US9806761B1 (en) 2014-01-31 2017-10-31 Kandou Labs, S.A. Methods and systems for reduction of nearest-neighbor crosstalk
WO2015117102A1 (fr) 2014-02-02 2015-08-06 Kandou Labs SA Procédé et appareil pour communications puce à puce de faible puissance à rapport isi contraint
DE102014201889A1 (de) 2014-02-03 2015-08-20 Aesculap Ag Medizinisches Produkt zur Anwendung bei der Behandlung von Hernien
CN106105123B (zh) 2014-02-28 2019-06-28 康杜实验室公司 用于发送时钟嵌入式向量信令码的方法和系统
US9148087B1 (en) 2014-05-16 2015-09-29 Kandou Labs, S.A. Symmetric is linear equalization circuit with increased gain
US9852806B2 (en) 2014-06-20 2017-12-26 Kandou Labs, S.A. System for generating a test pattern to detect and isolate stuck faults for an interface using transition coding
US9112550B1 (en) 2014-06-25 2015-08-18 Kandou Labs, SA Multilevel driver for high speed chip-to-chip communications
KR102288337B1 (ko) 2014-07-10 2021-08-11 칸도우 랩스 에스에이 증가한 신호대잡음 특징을 갖는 벡터 시그널링 코드
US9432082B2 (en) 2014-07-17 2016-08-30 Kandou Labs, S.A. Bus reversable orthogonal differential vector signaling codes
CN110008166B (zh) 2014-08-01 2023-07-18 康杜实验室公司 带内嵌时钟的正交差分向量信令码
RU2018139473A (ru) * 2016-04-11 2020-05-13 Басф Се Пористые термопластичные мембраны
US11426172B2 (en) 2016-10-27 2022-08-30 Conformal Medical, Inc. Devices and methods for excluding the left atrial appendage
JP7071350B2 (ja) 2016-10-27 2022-05-18 コンフォーマル・メディカル・インコーポレイテッド 左心耳を排除するためのデバイスおよび方法
US10898446B2 (en) 2016-12-20 2021-01-26 Surmodics, Inc. Delivery of hydrophobic active agents from hydrophilic polyether block amide copolymer surfaces
CN108276556B (zh) * 2018-02-06 2021-04-27 昆明医科大学 医用聚氨酯材料及其制备方法和修复支架
AU2019218789B2 (en) * 2018-02-07 2023-11-30 Cidra Corporate Services Llc Open-network foam of hydrophobic material for selective separation of mineral particles
IL285436B2 (en) * 2019-02-07 2024-02-01 Biorez Inc Composite scaffold for repair, restoration and regeneration of soft tissues
US12144508B2 (en) 2019-02-08 2024-11-19 Conformal Medical, Inc. Devices and methods for excluding the left atrial appendage
US12226552B2 (en) 2019-09-30 2025-02-18 Surmodics, Inc. Active agent depots formed in situ
CN114615943A (zh) 2019-11-04 2022-06-10 柯惠有限合伙公司 用于治疗动脉瘤的系统和方法
US20250009518A1 (en) * 2021-11-17 2025-01-09 The Provost, Fellows, Scholars And Other Members Of Board Of Trinity College Dublin A tissue regeneration scaffold

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4186448A (en) * 1976-04-16 1980-02-05 Brekke John H Device and method for treating and healing a newly created bone void
US4182827A (en) * 1978-08-31 1980-01-08 Union Carbide Corporation Polyurethane hydrogels having enhanced wetting rates
US4383867A (en) * 1980-03-11 1983-05-17 The United States Of America As Represented By The Secretary Of The Air Force Solvent mixture for removing cured polyurethane coatings
US4604762A (en) * 1981-02-13 1986-08-12 Thoratec Laboratories Corporation Arterial graft prosthesis
US4687482A (en) * 1984-04-27 1987-08-18 Scripps Clinic And Research Foundation Vascular prosthesis
US4600652A (en) * 1985-04-01 1986-07-15 Warner-Lambert Company Permanently bonded antithrombogenic polyurethane surface
DE3603996A1 (de) * 1986-02-08 1987-08-13 Bayer Ag Verfahren zur kontinuierlichen herstellung von waessrigen polyurethandispersionen und ihre verwendung als beschichtungsmittel oder als klebstoff
US4743629A (en) * 1987-07-02 1988-05-10 Becton, Dickinson And Company Crosslinked polyetherurethane membranes useful in blood electrolyte sensors
US5376117A (en) * 1991-10-25 1994-12-27 Corvita Corporation Breast prostheses
US5478867A (en) * 1993-07-07 1995-12-26 The Dow Chemical Company Microporous isocyanate-based polymer compositions and method of preparation
US5545708A (en) * 1993-07-14 1996-08-13 Becton, Dickinson And Company Thermoplastic polyurethane method of making same and forming a medical article therefrom
US5502092A (en) * 1994-02-18 1996-03-26 Minnesota Mining And Manufacturing Company Biocompatible porous matrix of bioabsorbable material
US5795633A (en) * 1994-08-22 1998-08-18 Nippon Zeon Co., Ltd. Material composition and shaped article
US6147168A (en) * 1995-03-06 2000-11-14 Ethicon, Inc. Copolymers of absorbable polyoxaesters
US5716413A (en) * 1995-10-11 1998-02-10 Osteobiologics, Inc. Moldable, hand-shapable biodegradable implant material
US5993972A (en) * 1996-08-26 1999-11-30 Tyndale Plains-Hunter, Ltd. Hydrophilic and hydrophobic polyether polyurethanes and uses therefor
US6130309A (en) * 1996-09-20 2000-10-10 Tyndale Plains-Hunter, Ltd. Hydrophilic polyether polyurethanes containing carboxylic acid
EP0873145A2 (fr) * 1996-11-15 1998-10-28 Advanced Bio Surfaces, Inc. Systeme de materiaux biocompatibles pour la reparation in situ de tissus
WO1999024084A1 (fr) * 1997-11-07 1999-05-20 Salviac Limited Produits polycarbonates urethanes biostables
US6245090B1 (en) * 1997-11-07 2001-06-12 Salviac Limited Transcatheter occluding implant
CA2221195A1 (fr) * 1997-11-14 1999-05-14 Chantal E. Holy Matrice en polymere biodegradable
US6187329B1 (en) * 1997-12-23 2001-02-13 Board Of Regents Of The University Of Texas System Variable permeability bone implants, methods for their preparation and use

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10243965A1 (de) * 2002-09-20 2004-04-01 Adiam Life Science Ag Verfahren zur Herstellung von biokompatiblen Polyurethanen
US20100234955A1 (en) * 2007-02-14 2010-09-16 Santerre J Paul Fibrous scaffold for use in soft tissue engineering
US8696750B2 (en) * 2007-02-14 2014-04-15 Mount Sinai Hospital Fibrous scaffold for use in soft tissue engineering

Also Published As

Publication number Publication date
DE60003178D1 (de) 2003-07-10
WO2000067814A1 (fr) 2000-11-16
US8168431B2 (en) 2012-05-01
WO2000067813A1 (fr) 2000-11-16
US20090163612A1 (en) 2009-06-25
EP1176993B1 (fr) 2003-06-04
EP1176995A1 (fr) 2002-02-06
AU4606700A (en) 2000-11-21
EP1176994A1 (fr) 2002-02-06
AU4426600A (en) 2000-11-21
AU4606600A (en) 2000-11-21
US20020072550A1 (en) 2002-06-13
WO2000067815A1 (fr) 2000-11-16
US20070003594A1 (en) 2007-01-04
EP1176993A1 (fr) 2002-02-06
DE60003178T2 (de) 2004-04-08

Similar Documents

Publication Publication Date Title
US20020072584A1 (en) Biostability of polymeric structures
US5863627A (en) Hydrolytically-and proteolytically-stable polycarbonate polyurethane silicone copolymers
US20110028661A1 (en) Hybrid polyurethane block copolymers with thermoplastic processability and thermoset properties
Park et al. PDMS-based polyurethanes with MPEG grafts: synthesis, characterization and platelet adhesion study
Gunatillake et al. Designing biostable polyurethane elastomers for biomedical implants
US5254662A (en) Biostable polyurethane products
JPH04226119A (ja) 生体内で安定なポリウレタンおよびその製造方法
US4906465A (en) Antithrombogenic devices containing polysiloxanes
JPH05507953A (ja) ポリウレタンまたはポリウレタン尿素エラストマー組成物
US20020142413A1 (en) Tissue engineering scaffold
WO2007112485A1 (fr) Polyurethanes biologiquement stables
CN114456346A (zh) 具有生物稳定性和力学稳定性的聚氨酯及制备方法与应用
IE20000346A1 (en) A polymeric structure
CA2091564A1 (fr) Produits de polyurethane stables en milieu biologique
WO2000067812A1 (fr) Biostabilite de structures polymeres
CN112831013A (zh) 一种功能化聚氨酯及其制备方法和应用
IE20000347A1 (en) Tissue Engineering
EP4442287A1 (fr) Dispositif médical
Tang Surface modifying macromolecules for biomaterials.
EP4316541A1 (fr) Composition à usage médical et son application
Vlad Hydrolytic stability of some thermoplastic poly (ether-urethane-urea) s
CN119735783A (zh) 一种抗钙化血液相容耐疲劳多重硅整合聚氨酯及其制备方法和应用
BRPI1106992A2 (pt) Uso de membranas biopoliméricas em próteses cardiovasculares
CN118085226A (zh) 一种抗污材料及其制备方法和应用
Zhang Synthesis and characterization of biodegradable polyurethanes for biomedical application

Legal Events

Date Code Title Description
AS Assignment

Owner name: SALVIAC LIMITED, IRELAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BRADY, EAMON;CANNON, ANN MARLE;FARRELL, FERGAL;REEL/FRAME:012299/0150;SIGNING DATES FROM 20011003 TO 20011005

STCB Information on status: application discontinuation

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

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载