Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/14—Eye parts, e.g. lenses, corneal implants; Implanting instruments specially adapted therefor; Artificial eyes
  • A61F2/16—Intraocular lenses
• • 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
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
  • A61L2/20—Gaseous substances, e.g. vapours
  • A61L2/206—Ethylene oxide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/34—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/08—Materials for coatings
  • A61L29/085—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
  • A61L33/06—Use of macromolecular materials
  • A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

• This invention relates to implantable medical devices. More particularly, this invention relates to cross-linked polyethylene oxide coating materials and methods which preserve the biocompatibility of implantable medical devices that are sterilized by ethylene oxide sterilization procedures.
• the biocompatibility of implantable medical devices can be improved by a variety of known methods, most notably by surface modification, such as the addition of a coating material.
• ophthalmic lenses may be coated with a coating material.
• U.S. Patent No. 4,170,043 discloses intraocular lenses (lOLs) coated with a film that dissolves slowly in water. This helps prevent endothelial damage upon implantation of the IOL. The coating dissolves within about 24 hours after implantation.
• U.S. Patent No. 4,731,080 discloses a coated IOL, wherein the lens is coated with a non-smudging, biologically compatible hydrophobic cross-linked vinyl-containing silicone polymer coating material.
• U.S. Patent No. 5,080,924 discloses a method of modifying the surface of a substrate using radio frequency plasma-induced grafting.
• a first biocompatible material preferably having pendant carboxylic acid or amine groups
• a second biocompatible material then may be grafted to the first biocompatible material using a cross-linking agent.
• a series of patents disclose contact lenses which are coated by various materials including polyethylene oxide (PEO). Such patents include Nos. 4,280,970; 4,871,785; 4,740,533; 5,070,166; and 5,096,626.
• U.S. Patent No. 4,280,970 discloses coating a contact lens by grafting PEO thereto.
• U.S. Patent No. 5,308,641 discloses an improved spacer material for improving the biocompatibility of a biomaterial and a method for making it in which a polyalkylimine is covalently attached to an aminated substrate and combined with a cross-linking agent which is at least difunctional in aldehyde groups.
• the polyalkylimine can be, for example, polyethyleneimine and the cross-linking agent can be, for example, glutaraldehyde.
• the cross-linking agent is applied in dilute solution and at a pH suitable to accomplish light cross-linking of the polyalkylimine and also provide aldehyde linkages at the interface between the biomolecule and the spacer.
• the PEO coating is created using gamma radiation to polymerize vinyl-functionalized PEO directly onto the surface of the instrument, device, etc.
• U.S. Patent 4,973,493 discloses a method for modifying a surface to improve its biocompatibility.
• the method employs molecules of a biocompatible agent and a chemical linking moiety possessing two different photochemically reactive groups, one group which reacts with the surface and one which reacts with the biocompatible agent.
• the method comprises applying stimulus to sequentially activate the groups to covalently bind the linking moiety to the molecules of the biocompatible agent and to photochemically covalently bind the linking moiety to the surface of the device.
• the molecules of the biocompatible material are joined together to form a film that is attached to the surface of the device by the linking moiety.
• the biocompatible agent desirably may be hyaluronic acid or albumin.
• a biocompatible device having such a film attached may be an artificial hip joint coated with a film of hyaluronic acid. No mention is made of sterilization of the devices.
• the present invention provides PEO coatings and methods for improving the biocompatibility of implantable medical devices.
• the PEO coatings of the present invention comprise PEO which is capped with functionalized groups on at least one end, wherein the PEO coatings are formed by attaching one functionalized end of the PEO compounds to the implantable medical device and then cross-linking the PEO compounds.
• Cross-linking can be achieved by either 1) exposing the PEO compounds to a high energy source (hereinafter referred to as the "high-energy method") or 2) alternatively, in the case where the PEO compounds have at least two or more functionalized end groups, at least one or more of the opposite or free functionalized ends of a sufficient number of bound PEO compounds may be crosslinked with other bound PEO compounds by means of a cross-linking compound (hereinafter referred to as the "cross-linker method").
• the present invention is based on the finding that cross ⁇ linking PEO coating compounds reduces the coating's loss of protein and/or cell repulsion ability that the coating suffers when subjected to EtO sterilization procedures.
• implantable medical device means any article, derived from synthetic or semi-synthetic material, that when placed in the appropriate biological location serves to replace or enhance or monitor the performance of a target tissue/ organ.
• implantable medical device means any article, derived from synthetic or semi-synthetic material, that when placed in the appropriate biological location serves to replace or enhance or monitor the performance of a target tissue/ organ.
• substitute blood vessels catheters, intraocular lenses, contact lenses, electrodes, hydrocephalus and abdominal shunts, etc.
• biocompatible or “biocompatibility” means being compatible with biological tissue/ fluids either in a living organism or a system consisting of a mixture of biological components (protein and/or cell based), not eliciting any changes in the structure or function of any of the biological components that will ultimately compromise or negatively affect the biological system or organism.
• high energy source means a source which results in the formation of free radicals, ions, electrons, protons, neutrons, alpha particles, beta particles, gamma radiation, X-ray radiation and ultraviolet radiation.
• energy sources include but are not limited to radio-frequency glow discharge plasma (rf- plasma), electron beam, gamma, and ultraviolet sources.
• the coatings of the present invention may be applied to the surface of any implantable medical device on which it may be desirable to minimize protein adsorption and cellular deposition.
• any implantable medical device For purposes of illustration, examples relating to lOLs will be presented; however, one skilled in the art will readily appreciate that the coatings of the present invention may be applied to any implantable medical device.
• the improved coatings of the present invention may be applied to any of the well known hard lOLs, such as those formed from polymethylmethacrylate (PMMA).
• PMMA polymethylmethacrylate
• the improved coatings of the present invention may also be applied to soft acrylic lenses, such as those disclosed in U.S. Patent Nos.
• improved coatings of the present invention are applied to lenses formed from a copolymer with an elongation of at least 150% wherein the copolymer is formed from two monomers, the first of which is 2-phenylethyl acrylate and the second of which is 2-phenylethyl methacrylate, and a copolymerizable cross-linking monomer having a plurality of polymerizable ethylenically unsaturated groups such as 1 ,4-butanediol diacrylate.
• the first monomer may be present at a concentration about 65 wt.% and the second monomer may be present at a concentration of about 30 wt.%.
• An ultraviolet absorbing material such as 2-(3'-methallyr-2-hydroxy-5'-methyl-phenyl) benzotriazole may also be included.
• the biocompatibility of lOLs or other implantable medical devices is substantially improved by coating them with a PEO coating which is cross-linked prior to sterilization.
• the PEO-coated lenses or other devices have improved resistance to protein adsorption. This results in a lens or other device which is "non-fouling" and resistant to cell deposition.
• the PEO coatings of the present invention are first tethered to the substrate surface.
• these known methods include, for example, wet chemical methods, such as those providing electrostatic interactions or covalent bonding, and dry methods such as high energy plasma deposition.
• the PEO coating is attached to the IOL or substrate surface through covalent bonding.
• the substrate surface is first provided with an active coating or layer.
• the active layer is a polymer coating containing a primary amine.
• other active layers which function to tie PEO compounds to substrate surfaces may also be used.
• the primary amine layer is preferably formed by contacting the substrate surface with an allyl amine or a lower alkyl amine of the formula RNH 2 , wherein R is an alkyl or allyl group of about 3-12 carbon atoms.
• R is an alkyl or allyl group of about 3-12 carbon atoms.
• the alkyl or allyl amine is one of intermediate chain-length wherein R is an alkyl group of 5-8 carbons.
• the alkyl or allyl amine is n-heptyl amine.
• the alkyl or allyl amine may be applied to the substrate surface in any desired manner; however, it is preferred to create the active primary amine layer by plasma deposition of the alkyl or allyl amine.
• Plasma deposition in general is known in the art as shown for example in U.S. Patents 4,312,575 and 4,656,083. the disclosures of which are incorporated by reference.
• Plasma deposition of the primary amine layer on the substrate surface is preferably carried out in two steps.
• the lens is first placed in an electrical glow discharge apparatus, preferably oriented with the optical surfaces parallel to direction of gas flow.
• a gaseous atmosphere is provided, (e.g., argon), and then the gaseous atmosphere is subjected to an electrical glow discharge to clean the surface. The gas is then removed.
• plasma ignition is carried out in the presence of the vapor of the primary amine under conditions to cause the amine to deposit or form a plasma and produce an ultrathin coating of about 5-300 Angstroms on the surface of the lens.
• the substrate surface containing the amine layer is then reacted with functionalized end-capped PEO in the presence of a reducing agent to give a stable PEO coating covalently bound to the substrate surface.
• the PEO should have terminal groups or caps which are reactive with the amine coating. If the high-energy method of cross-linking is to be utilized, it is not necessary that both ends of the PEO chains have reactive terminal groups. Nevertheless, a preferred PEO utilized in the present invention is an ⁇ , ⁇ -aldehyde-terminated PEO having a molecular weight in the range of 200 to 100,000, preferably 1500-15,000.
• ⁇ , ⁇ -aldehyde-capped PEO having a molecular weight of about 8000.
• ⁇ , ⁇ -aldehyde-capped PEO having a molecular weight of about 3400.
• Mono- and di-aldehyde-capped polyethylene oxides are known in the art, e.g., Harris, US Pat. No. 5,252,714.
• the PEO which is reacted with the substrate surface containing the amine layer is multi-functionalized, end-capped PEO.
• multi-functionalized, end-capped PEO means PEO which has at least two functionalized end groups, one of which is reactive with the substrate surface or active coating, and the other of which can be crosslinked with other PEO compounds attached to the substrate surface.
• Suitable PEO compounds for use in the present invention include, for example, straight chain PEO. branched chain PEO, and star-shaped PEO molecules (such as those described in U.S. Patent
• a preferred straight chain PEO utilized in the present invention is an ⁇ , ⁇ - aldehyde-terminated PEO which has a molecular weight in the range of 200 to
• the IOL or substrate surface is first etched prior to amine deposition for best results.
• etching of the surface is conducted by contact with an argon plasma.
• An argon flow rate in the range of 60-120 cm 3 /min, and a chamber pressure of 200-300 mTorr is satisfactory.
• the IOL or other implantable medical device is placed in a holder and centered in a plasma chamber with the desired argon-plasma flow rate to argon etch prior to amine deposition.
• a container for the amine is connected to the plasma chamber unit.
• the plasma chamber is then evacuated to its baseline pressure and, while under the argon flow rate, is ignited for a short period, for example, 60W for six minutes.
• the plasma chamber is evacuated to its baseline pressure, the amine vapor is evacuated into the chamber, the plasma ignited, and the deposition permitted to be maintained until a thickness in the range of 5-500, preferably 100-300 Angstroms, is achieved.
• the chamber conditions are maintained for a short period, for example, 1-5 minutes.
• the chamber is then brought to atmospheric conditions and the sample removed to a sealed container.
• PEO e.g., ⁇ , ⁇ -aldehyde-capped polyethylene oxide
• a buffer solution in a concentration in the range of 5-50 mg/ml.
• This solution is then added to each container with the amine-plasma coated IOL or other device.
• Stabilization of the coating is then carried out, for example, by treating the IOL or other device with a stabilizing agent, such as an alkali metal borohydride, dissolved in a buffer in a concentration of 10-50 mg/ml.
• the reaction is then carried out at a low temperature, for example, 25-50 °C for about ten to thirty hours. Low temperatures are used in order to avoid thermal degradation of the PEO compounds.
• the preferred stabilizing agent is sodium cyanoborohydride of the formula NaCNBH 3 , a commercially available material. Reduction of the PEO-imine bond with the alkali metal borohydride will provide a stable PEO coating of about 5-500 Angstroms, preferably 100-300 Angstroms. In a preferred procedure, stabilization is repeated and the lOLs or other implantable medical devices are again heated. Each IOL or other device is then washed in deionized water and the water removed.
• the procedure described above is only one method of tethering functionalized end-capped PEO chains to substrate surfaces. Any alternative procedure which tethers a functionalized end-capped PEO chain to substrate surfaces may also be used.
• EtO sterilization comprises contacting the IOL or other device with 5-100% ethylene oxide in a fluorinated solvent for 1-4 hours at 10-40 psi and 40-60 °C, preferably after preconditioning in a humid atmosphere, followed by aeration to remove residual ethylene oxide.
• lOLs or other implantable medical devices coated in the above manner which are sterilized using EtO sterilization lose some of their protein and cell repulsion ability.
• cross-linker method if PEO compounds having more than two functionalized end groups are used, it is not necessary that all of the free functionalized end groups be crosslinked together.
• One or more of the free functionalized ends of a sufficient number of the bound PEO chains are crosslinked with functionalized end groups of other bound PEO chains to decrease the coating's loss of protein and/or cell repulsion ability caused by EtO sterilization procedures.
• Crosslinking can be achieved by reaction of the free end-groups of the bound PEO with a crosslinking agent whose functional groups are reactive toward the bound PEO chain's free end groups.
• the preferred crosslinking agent is a polyether diamine which is based on a predominately polyethylene oxide backbone.
• amine-terminated polyethers with molecular weights in the range 200-10000 are preferred; a molecular weight range of 900-2000 is more preferred.
• the functionalized end-capped PEO tethered to the substrate surface is ⁇ , ⁇ -aldehyde-capped PEO having a molecular weight of about 3400
• the amine-terminated, predominately PEO-backbone polymer should have a molecular weight of at least 900, and preferably about 2000.
• the most preferred crosslinking agent is Jeffamine ED 2001® available from Texaco Chemical Co.
• the crosslinking reaction conditions will depend on the particular functionalized end-capped PEO chains tethered to the substrate surface and the particular crosslinking agent chosen.
• the polyether diamine is dissolved in a buffer in a concentration range of 5-50 mg/ml, preferably at a concentration of about 20 mg/ml.
• the PEO-coated IOL or other device is placed in this solution for a time sufficient for reaction between the tethered PEO chains and the polyether diamine.
• the resulting crosslinks are then stabilized with a buffered solution of alkali metal borohydride, most preferably sodium cyanoborohydride of the formula NaCNBH 3 .
• alkali metal borohydride most preferably sodium cyanoborohydride of the formula NaCNBH 3 .
• the resulting IOL or other device will have the indicated improved biocompatibility including increased resistance to protein adsorption which makes the IOL or other device non-fouling and resistant to cell deposition.
• the PEO chains must be able to achieve a fully extended conformation, through solvent-polymer interaction, and to be able to have free rotation about the single bonds of its backbone, i.e., for the chains to have a "flagella-like" motion, creating a dynamic barrier on the surface of the substrate to which it is immobilized so as to provide maximum resistance against protein adsorption or cell deposition.
• native PEO strands, immobilized through one terminal may become wholly or partially buried beneath the substrate surface during EtO sterilization procedures, thereby losing their ability to resist fouling.
• cross-linking may reduce the flagella-like motion of the PEO strands, it may serve to prevent burial of the PEO strands beneath the substrate surface.
• lOLs made of PMMA or a soft acrylic material held in position by a polyethylene lens holder placed in small glass-rack, are centered in a plasma chamber on a glass rack.
• the rack is positioned with the optic surface oriented parallel to the monomer flow.
• Any plasma chamber capable of holding the device to be coated can be used.
• the plasma chamber was made of a glass cylinder approximately 25 cm in diameter and 55 cm long, wrapped in four quadrants with four copper electrodes (two hot and two ground) each 49 cm x 17cm.
• n-Heptylamine (5g) is placed in a 250 ml round-bottom "flask which is connected to the plasma chamber via a metering-valve. With this valve closed, the plasma chamber is evacuated to its baseline pressure for 30 minutes. Prior to heptylamine deposition, the lOLs are argon-plasma etched. With an argon flow rate of 90 cm 3 / min and a chamber pressure of 250 mTorr, the chamber is equilibrated for ten minutes. A plasma is then ignited at 60 W for 6 minutes. After the argon-plasma is extinguished, the chamber is returned to its baseline pressure.
• heptylamine vapor is evacuated into the chamber.
• the chamber is allowed to equilibrate for ten minutes.
• a plasma is ignited, and the thickness gauge activated to record deposition.
• the plasma is maintained until a thickness of approximately 200 A is achieved.
• the chamber conditions are maintained for 2 minutes.
• the vacuum pump speed is returned to maximum and these conditions are maintained for ten minutes.
• the chamber is then brought up to atmospheric conditions by back-filling with argon and the samples removed from their respective holders. Each is placed in a labeled micro-centrifuge tube.
• Dithiolaldehyde-derivatized PEO which can be synthesized following methods described by Harris et al., US Pat. No. 5,252,714, is dissolved in a 0.0042 M sodium phosphate (dibasic) - 0.45M potassium sulphate buffer (pH 8.5 - 9.0) at a concentration of 10 mg/mL. 900 ⁇ L of this solution is added to each micro-centrifuge tube containing plasma-coated IOL. Sodium cyanoborohydride (NaCNBH 3 ) is dissolved in buffer at a concentration of 20 mg/mL. 100 ⁇ L of this solution is added to each micro-centrifuge tube, and after gentle mixing the samples are heated at 35° C overnight.
• NaCNBH 3 cyanoborohydride
• NaCNBH 3 solution is prepared just prior to its addition to the reaction solution.
• a second treatment with NaCNBH 3 solution is then applied and samples heated at 35° C for another four hours. The samples are then removed from the reaction solution, washed extensively in deionized water, and air dried.
• High-energy method Each sample is mounted in a lens holder and placed in a glass rack. This rack is centered in the plasma chamber used in Step A and the system evacuated to baseline pressure for ten minutes. The chamber is equilibrated for five minutes with argon at 250 mtorr and a flow rate of 90 cm 3 /min. A plasma is ignited at 60 watts for 20 seconds. After the plasma is extinguished, the chamber is maintained at 250 mtorr with argon for five minutes. Each sample is then packaged in a sterilization pouch.
• Cross-linker method Each sample is briefly washed with deionized water and placed in a new micro-centrifuge tube containing 0.05M phosphate buffer (pH 8.0). Samples are equilibrated for approximately 15 minutes. The buffer is then removed and replaced by 900 ⁇ L of crosslinking solution. This solution is prepared by dissolving a diamino PEO in 0.05M phosphate buffer to a final concentration of 20 mg/mL. 100 ⁇ L of NaCNBH 3 solution (20 mg/mL in 0.05M phosphate buffer) is added to the reaction mixture which is gently agitated. Samples are then heated at 35 °C overnight. The treatment with NaCNBH 3 is repeated and the samples are heated for another four hours. Each IOL is spray washed in deionized water, and then sonicated three times each for 5 minutes in approximately 3 mL deionized water. Each is then dried and packaged in a sterilization pouch.
• 0.05M phosphate buffer pH 8.0
• Samples are placed in a sterilization chamber which is then evacuated to about 2 psia. While maintaining this pressure the relative humidity in the chamber is raised to 60% and the temperature to 46 °C. These conditions are maintained for one hour.
• the chamber is then charged with ethylene oxide, 12% in freon, to a final pressure of 22 - 23 psia. After two hours the chamber is evacuated to about 2 psia and then the system is brought up to atmosphere.
• the lens samples are then removed to the aeration chamber and aerated at elevated temperatures for a time sufficient to remove residual EtO levels of less than 25 ppm.

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• 1995
  • 1995-11-16 CA CA002180147A patent/CA2180147A1/en not_active Abandoned
  • 1995-11-16 JP JP8516333A patent/JPH09507784A/ja active Pending
  • 1995-11-16 EP EP95939997A patent/EP0739218A1/en not_active Withdrawn
  • 1995-11-16 WO PCT/US1995/014912 patent/WO1996014887A1/en not_active Application Discontinuation
  • 1995-11-16 AU AU41623/96A patent/AU4162396A/en not_active Abandoned

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