WO1992005694A1 - Implants oculaires ameliores et leurs procedes de fabrication - Google Patents

Implants oculaires ameliores et leurs procedes de fabrication Download PDF

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Publication number
WO1992005694A1
WO1992005694A1 PCT/US1991/006729 US9106729W WO9205694A1 WO 1992005694 A1 WO1992005694 A1 WO 1992005694A1 US 9106729 W US9106729 W US 9106729W WO 9205694 A1 WO9205694 A1 WO 9205694A1
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WIPO (PCT)
Prior art keywords
nvp
gamma
hema
range
monomer
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PCT/US1991/006729
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English (en)
Inventor
Eugene P. Goldberg
James W. Burns
G. Sudesh Kumar
David C. Osborn
Jeffrey A. Larson
John W. Sheets
Ali Yahiaoui
Richard Robinson
Original Assignee
University Of Florida
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Priority claimed from US07/592,483 external-priority patent/US5130160A/en
Application filed by University Of Florida filed Critical University Of Florida
Priority to JP3516980A priority Critical patent/JPH06502782A/ja
Publication of WO1992005694A1 publication Critical patent/WO1992005694A1/fr
Priority claimed from PCT/US1994/000060 external-priority patent/WO1995018840A1/fr

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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D7/00—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials
    • B05D7/02—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials to macromolecular substances, e.g. rubber
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
    • G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
    • G02B1/041—Lenses
    • G02B1/043—Contact lenses
    • 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
    • A61F2/1613—Intraocular lenses having special lens configurations, e.g. multipart lenses; having particular optical properties, e.g. pseudo-accommodative lenses, lenses having aberration corrections, diffractive lenses, lenses for variably absorbing electromagnetic radiation, lenses having variable focus
    • A61F2/1648—Multipart lenses
    • 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
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A61F2002/0086—Special surfaces of prostheses, e.g. for improving ingrowth for preferentially controlling or promoting the growth of specific types of cells or tissues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D3/00—Pretreatment of surfaces to which liquids or other fluent materials are to be applied; After-treatment of applied coatings, e.g. intermediate treating of an applied coating preparatory to subsequent applications of liquids or other fluent materials
    • B05D3/06—Pretreatment of surfaces to which liquids or other fluent materials are to be applied; After-treatment of applied coatings, e.g. intermediate treating of an applied coating preparatory to subsequent applications of liquids or other fluent materials by exposure to radiation
    • B05D3/068—Pretreatment of surfaces to which liquids or other fluent materials are to be applied; After-treatment of applied coatings, e.g. intermediate treating of an applied coating preparatory to subsequent applications of liquids or other fluent materials by exposure to radiation using ionising radiations (gamma, X, electrons)

Definitions

  • the present invention relates to ocular implants and methods for improving surfaces thereof.
  • IOL intraocular lenses
  • PMMA polymethylmethacrylate
  • hydrophobia polymers which are used or have been proposed for use in ocular implants (i.e.,
  • polypropylene, polyvinylidene fluoride, polycarbonate, polysiloxane also can adhere to ocular tissue and thereby promote tissue damage. It is well documented in the prior art that a significant disadvantage inherent in PMMA lOLs resides in the fact that any brief, non-traumatic contact between corneal endothelium and PMMA surfaces results in extensive damage to the endothelium. See Bourne et al, Am. J. Ophthalmol., Vol. 81, pp. 482-485 (1976). Forster et al, Trans. Am. Acad. Ophthalmol.
  • Ocular implant surfaces have been coated with various hydrophilic polymer solutions or temporary soluble coatings such as methylcellulose,
  • N-vinyl-pyrrolidone NVP
  • HEMA 2-hydroxyethylmethacrylate
  • PHEMA HEMA
  • PVDF polyvinylidene fluoride
  • PC polycarbonate
  • PSi silicone
  • the coatings produced by the improved method of the invention described in U.S. Patent No. 4,806,382 are thin and reproducibly uniform. Moreover, they are chemically bound to the surface of the ocular implant and, therefore, far more durable and less subject to removal, degradation or deterioration during or following surgery than the coatings produced by prior art methods.
  • the improved gamma-irradiation induced graft polymerization of NVP, HEMA or mixtures of NVP and HEMA on ocular implant surfaces comprising PMMA to form optimum PVP, P(NVP-HEMA) or PHEMA graft polymer surface modifications thereon comprises carrying out the graft polymerization in an aqueous solution under specific combinations of the following conditions:
  • the method may also be carried out under one or more of the following conditions:
  • P(NVP-HEMA) surface graft in the range of from about
  • PSi to form optimum PVP or P(NVP-HEMA) surface grafts thereon may also be carried out under specific
  • the present invention is predicated on the
  • the present invention is further predicated on the discovery that in order to successfully carry out the method described in U.S. Patent No. 4,806,382, the total gamma dose range may be extended to a minimum value of 0.001 Mrad.
  • FIGS. 1-3 depict examples of ocular implants according to the present invention.
  • FIG. 1 depicts a top view of a one-piece intra- ocular lens
  • FIG. 2 depicts a top view of an intraocular lens with fiber haptics which may be made of a different substrate polymer than the optic, and
  • FIG. 3 depicts a top view of a keratoprosthesis.
  • monomer-substrate-process conditions namely: monomer, monomer concentration, total gamma dose and gamma dose rate
  • the molecular weight of the polymer formed in solution cannot be independently varied but will be an output of the process which is dependent upon the values of the above-noted monomer concentration, total gamma dose and gamma dose rate conditions.
  • solution polymerization may be inhibited significantly without
  • N-vinylpyrrolidone N-vinylpyrrolidone (NVP) and 2-hydroxyethylmethacrylate (HEMA) and indicate poor dynamic (abrasive) protection of endothelium for these coatings.
  • HEMA 2-hydroxyethylmethacrylate
  • PVA polyvinyl-alcohol
  • non-aqueous solvent media and yield thick, cloudy, non-uniform coatings (e.g., Chapiro, Radiation
  • Non-adherent to tissue (adhesive force to endothelium less than about 150 mg/cm 2 ).
  • Yalon et al disclose an in vitro technique for measuring endothelium damage. Results for PMMA were used to illustrate the method. Although it was noted that PVP coatings reduced cell damage with less damage at higher monomer concentrations, the conditions for the experiment (i.e., irradiation dose, dose rate, etc.) were not disclosed nor were any of the critical process-product relationships indicated.
  • P(NVP-HEMA) or PHEMA include: % monomer, gamma dose, dose rate, penetration time or swelling time of monomer into the substrate prior to polymerization and oxygen (air) degassing, other optimal process conditions include catalysts, free radical scavengers, polymer swelling solvents and temperature.
  • the solution polymer molecular weight and M.W. distribution, the % conversion and residual monomer, the graft polymer thickness and surface properties, etc., are process results which can change markedly as the process variables change. For example, the surface modification achieved for PVP on polymer surfaces will be different when using 10% monomer and 0.1 Mrad if prepared at low dose rates since low dose rates (slower polymerization) favor higher molecular weights.
  • degassed oxygen-free reaction media result in improved grafts at much lower doses.
  • free radical scavengers such as copper or iron salts or organic reducing agents (i.e., ascorbic acid) also greatly influences other process parameters, generally reducing solution polymer molecular weight and
  • a) Monomer concentration increases polymer mol. wt. in the graft solution and reduces contact angle (C.A.), i.e., renders the surface more hydrophilic.
  • C.A. contact angle
  • M v PVP viscosity mol. wt.
  • monomer concentrations in the range of 0.1-50% are preferred depending on other parameters. Concentrations as low as 0.1 - 0.5% at low dose rates can yield hydrophilic surface grafts with C.A. below 30-40* under conditions of this invention. At monomer concentrations greater than 20-30%, effective grafting without solution polymer gelation requires low doses and use of free radical scavengers.
  • HEMA concentrations of between 0.5% and 10%, by weight, are sufficient.
  • reaction media becomes extremely viscous or form gels which are very difficult to wash and to remove (e.g., about 0.25 Mrad and 10% NVP at 309 rads/min).
  • Electron beam voltages in the range of from about 50 KeV to about 10 MeV may be employed at currents of from about 5 mA to about 100 mA.
  • polymerization i.e., in the range of from about 10 to about 10 8 rads/min or more may be employed.
  • Dose rate Decreasing gamma radiation dose rate generally increases solution PVP M.W., e.g., from 1,150,000 to 5,090,000 at 10% NVP and 0.1 Mrad as dose rate decreases from 1235 to 49 rads/min.
  • the C.A. also goes down at lower dose rates, i.e., from 31o to 15o. As noted above, dose rates of up to 10 8 rads/min or more are practical when employing electron beam
  • Solution Polymer Mol. Wt. The mol. wt. may vary widely depending upon process conditions, monomers and radical inhibitors used. Effective grafting with low C.A. may therefore be achieved with even low mol. wt. solution polymer (M v as low as 5000-10,000 or less). However, solution polymer M v greater than
  • Degassing Removal of oxygen from the graft solutions by vacuum and/or inert gas (e.g., argon purging) has an important effect: lower total doses are required (practical grafting at less than 0.1 Mrad). Oxygen degassing also has a large effect on PVP M w and % conversion of monomer. For example, with degassing, good grafting of PVP on polypropylene (PP) is achieved at 0.05 Mrad and 10% NVP (C.A. 15o). Without
  • Oxygen degassing is critical to hydrophilic surface modification grafting where the
  • substrate polymer is PP, PVDF or PSi. It has been found that graft polymerization is inefficient when using these materials as substrates in the presence of oxygen. Oxygen degassing is also beneficial for PMMA and PC substrates in that much lower radiation doses (0.01-0.15 Mrad) become effective compared with grafting these polymers in the presence of oxygen.
  • Graft thickness Surface grafts less than 100-200 angstroms, although non-adhesive and
  • hydrophilic are useful but may exhibit somewhat less mechanical "softness” or compliant gel-like surfaces than thicker coatings for reduced tissue-contact trauma. Graft coatings greater than ca. 300-500 A (or 0.03 - 0.05 microns) up to 50 microns or more are probably more desirable for many applications as long as they are smooth, uniform, optically clear for optic surfaces, and quickly hydrated.
  • surface grafts which exhibit desired implant properties under preferred process conditions have thicknesses of about 0.1 to 5 microns.
  • swelling solvents such as ethyl acetate
  • polymer grafts on PMMA of 100 microns or more can be prepared.
  • Free-Radical Scavengers Free radical traps, usually reducing agents such as Cu + , Fe +2 ascorbic acid, etc., are known to inhibit radical polymerization in solution and thus be effective (especially at high gamma doses, high dose rates and high monomer
  • graft coatings of PVP, P(NVP-HEMA) or PHEMA have also been defined using ascorbic acid to limit high viscosity and gelation of the graft polymer solution.
  • Swelling solvents The use of substrate polymer solvents in the aqueous monomer grafting solution facilitates swelling and monomer diffusion into the polymer before and during gamma
  • Solvents such as ethyl acetate have been shown to greatly facilitate this process with some substrates such as PMMA.
  • the mixtures may contain up to about 50% by weight of HEMA, based on the weight of the monomer mixture.
  • HEMA radical scavengers and low monomer concentrations should be used to prevent gelation since HEMA enhances the onset of gelation.
  • PVP polyvinyl graft coating
  • P(NVP-HEMA) or PHEMA graft coatings of this invention may be modified by copolymerization with various ionic monomers. Mixtures of hydrophilic and ionic monomers may also be copolymerized therewith. For example, graft copolymerization incorporating vinylsulfonic acid, styrene sulfonic acid,
  • sulfoethylmethacrylate sulfopropylmethacrylate or other vinyl sulfonic acids or vinylcarboxylic acids such as acrylic acid, crotonic acid or methacrylic acid can afford surface modifications which are anionic.
  • graft copolymerization incorporating basic or amino-functional monomers, e.g., vinylpyridines, aminostyrenes, aminoacrylates or aminomethacrylates such as dimethylaminomethylmethacrylate or
  • dimethylaminostyrene afford surface modifications which are cationic. It is also useful to use salts of ionic monomers or to convert ionic grafts to the salt form by post-treatment.
  • Amounts of ionic monomers up to about 50 wt. % of the total monomer weight may be employed, it being understood that the critical process parameters listed above may be maintained.
  • degassed vacuum or inert gas purge, e.g., argon
  • Dose 0.010.15 Mrad (0.05 preferred)
  • % NVP 1-15% (5-10% preferred).
  • This system is generally preferred to (1).
  • gamma polymerization grafts characteristics for gamma polymerization grafts, unless otherwise indicated, are for samples washed with water or water-alcohol at room temperatures or elevated temperatures to remove soluble residual monomer and ungrafted polymer for the improved surface graft processes of this invention.
  • the resulting graft polymers are stable and permanent for long-term use and are not dissolvable by aqueous media.
  • the ocular implants to be graft coated may be also constructed of materials other than PMMA, PP, PVDF, PC or PSi to facilitate their use. It will be understood by those skilled in the art that such materials may also be at least partially graft polymer surface modified so as to improve their properties as implant materials.
  • hydrophilic graft polymer surface modifications of this invention are especially advantageous for intraocular lenses (anterior chamber, posterior chamber and phakic), but are also of great value in affording improved tissue protection and improved
  • biocompatibility for other ocular implants such as corneal inlays, keratoprosthesis, epikeratophakia devices, glaucoma drains, retinal staples, scleral buckles, etc.
  • the surface modified PMMA samples were rinsed several times with H 2 O and evaluated.
  • the polymerized NVP grafting solutions or gels were freeze-dried under a vacuum.
  • the solution PVP samples were evaluated for molecular weight by viscosity measurement (M v ) or gel permeation chromatography (M w ).
  • M v viscosity measurement
  • M w gel permeation chromatography
  • M v PVP was dissolved in distilled water and intrinsic viscosity [ ⁇ ] was measured at 30oC in a capillary viscometer.
  • PVP grafted PMMA samples were evaluated by water drop or underwater air bubble contact angle measure- ments.
  • the bubble technique is regarded as more reliable for very hydrophilic surfaces.
  • air bubble C.A. the grafted PMMA was held horizontally in
  • Table 2 shows the effect of total T-irradiation dose on molecular weight at 309 rads/min. Increasing the total dose gives a higher molecular weight. A polymer gel was formed at a dose of 0.25 Mrad and higher. These results show that a high irradiation dose can cause gelation or cross-linking of the PVP polymer.
  • the molecular weight of PVP increases significantly with increasing concentration of NVP monomer.
  • the contact angle of PMMA was evaluated after ⁇ -grafting with NVP at different solution concentrations at a dose rate of 64 rads/min. These results show that the contact angles of PVP-grafted PMMA decreased with increasing concentration of NVP monomer. This result, at 64 rads/min dose rate is qualitatively similar to results at 309 rads/min (Table 6).
  • Polar organic solvents or aqueous-polar organic solvent mixtures may be useful for hydrophilic monomer graft polymerization.
  • organic solvents are alcohols or ethers such as methanol, ethylene glycol, polyethylene glycols, dioxane, etc.
  • organic solvents act as radical traps or radical chain transfer agents, they must be used at concentrations lower than 50% or with high hydrophilic monomer concentrations (i.e., >25%).
  • methanol has some radical scavenger properties but may be used for PVP gamma grafts on PMMA in water-methanol mixtures up to 50-60% methanol for PVP grafts on PMMA using 0.1 Mrad and 10% monomer (Table 9).
  • Hydrophilic grafts result although radical chain transfer by methanol appears to require low dose rates at 10% monomer. In general these systems yield low viscosity solutions indicative of low molecular weight solution polymer which forms in the presence of radical inhibitors.
  • This example illustrates the effect of swelling solvents on the surface modification process.
  • EtOAc ethyl acetate
  • gamma radiation doses of 0.10 - 0.15 Mrad are suitable to achieve significant amounts of grafting.
  • the NVP-ethyl acetate-water solvent system is also a solvent for PVP and keeps the solution polymer phase homogenous.
  • Embedded grafting of PVP into the PMMA surface is made possible by irradiating the PMMA after exposure for various times to the monomer-swelling solvent-water mixture.
  • NVP monomer was purified by vacuum distillation and stored at 4oC
  • the PMMA substrate was immersed in aqueous monomer-solvent solutions and exposed to gamma radiation. Typically, cleaned
  • substrates were immersed in NVP-ethyl acetate-H 2 mixtures and irradiated in a 600 Curie Co-60 source. The samples were exposed to the monomer solution for various lengths of time. Gamma doses ranging from 0.01 - 0.15 Mrad as measured by Fricke dosimetry were used in this experiment. Dose rates were also varied.
  • W w is the weight of PMMA after equilibration in water (after blotting it dry) and W d is the weight of dry sample (after desiccation). In most cases, the maximum water uptake was reached after 12 hours.
  • ungrafted surfaces was made by using a Perkin-Elmer Model 283B IR Spectrometer using attenuated total reflectance.
  • Radiation doses ranged from 0.01 to 0.15 Mrad and monomer concentrations ranged from 5 to 15%.
  • the NVP-EtOAc-H 2 system swells the surface layers of PMMA and polymerization grafting of monomer molecules in the vicinity of radiation induced radical species near the surface is immediate, under such conditions, more efficient grafting is achieved at lower doses and with deeper penetration of the graft polymer into the solvent swollen surface.
  • Table 11 shows the graft behavior after 24 hours of pre-swelling of PMMA in 1:9 ethyl acetate: water containing 15% of NVP.
  • NVP is the monomer but also acts as a mutual solvent to maintain a homogeneous phase of otherwise poorly miscible solvents, i.e., ethyl acetate and water.
  • ethyl acetate a monomer concentration (e.g., 10%)
  • the NVP-ethyl acetate-water system produces uniform hydrophilic graft polymer surfaces with controllable graft penetration using PMMA as the substrate.
  • the monomer-ethyl acetate-water grafting front gradually penetrates into the substrate and may be controlled by varying the concentration of swelling agent and the time of pre-swelling.
  • a method used for determining unreacted NVP after irradiation was as follows: 5 ml of the gamma
  • NVP analysis was as follows: The 10% by weight aqueous solution was diluted with acetonitrile to appropriate concentrations (0.5 g/ml to 5.0 ⁇ g/ml). The U.V. absorbance was measured for each solution at 323 nm to develop a standard curve of NVP concentration vs. U.V. absorbance. The regression coefficient was 0.99 for this curve.
  • GPC was used for molecular weight measurements and gives M w as well as molecular weight distribution.
  • the % NVP conversion (amount of monomer reacted) is significantly affected by Ar purge deoxygenation and by FT oxygen degassing. At the very low dose of 0.01 Mrad, virtually no polymerization occurs in the
  • polymers i.e., polypropylene, fluorocarbons (e.g., PTFE or PVDF) or silicones
  • the beneficial effect of oxygen degassing can be even greater, oxygen removal may also be used for improved gamma grafting in
  • solution polymer may be of low mol. wt.
  • PVP molecular weight is also greatly affected by oxygen degassing.
  • the Ar-purged and FT samples yield PVP polymers with molecular weights of about 1.6 x 10 6 at only 0.01 Mrad. In sharp contrast, the non-degassed samples do not form high mol. wt. polymer. At 0.05
  • PMMA samples were surface grafted with PVP using gamma irradiation as in Example 1.
  • Ascorbic acid (AscA) was used as a radical inhibitor in these experiments.
  • the irradiation conditions are set forth in Table 15.
  • This example demonstrates the large favorable effect of hydrophilic gamma graft surface modification on reducing tissue adhesion by measuring corneal endothelium adhesion and cell adhesion using fibroblast cells. These are important factors in demonstrating the improved biocompatibility and minimal tissue irritation or damage afforded by the hydrophilic graft surface modifications of this invention.
  • Adhesion force values of about 250-400 mg/cm 2 were measured for PMMA and other hydrophobic polymers evaluated for implants, i.e., silicone, polypropylene, etc.
  • the gamma graft surface modifications of this invention also show a major reduction in cell adhesion as demonstrated by exposure to live cell cultures of chicle embryo fibroblast cells (CEF) or rabbit lens epithelial cells (LE).
  • CEF chicle embryo fibroblast cells
  • LE rabbit lens epithelial cells
  • Grafts prepared at 0.1 Mrad and using 15% NVP, for example showed adherence of only 35% of the number of CEF cells which adhere to PMMA.
  • PHEMA grafts on PMMA exhibited only 38% cell adhesion and 15:1 NVP: HEMA (at 16% total monomer) exhibited only 20% CEF cell adhesion compared to PMMA.
  • This example demonstrates the graft polymerization of HEMA and mixtures of NVP and HEMA on PMMA.
  • Example 1 The method of Example 1 was repeated utilizing a 16% NVP/HEMA (15:1) aqueous solution at about 1300 rads/min and 0.10 Mrad dose.
  • the PVP-PHEMA surface modified PMMA had a C.A. of 17o.
  • This example demonstrates the graft copolymerization of anionic or cationic monomers with the hydrophilic monomers of this invention using ionic monomers with NVP.
  • Example 2 The method of Example 1 was used with PMMA substrate and 15% NVP plus 1-5 wt% of acrylic acid (AA) or crotonic acid (CA) as comonomers at 0.1 Mrad and 1235 rads/min. Contact angles were 18-22o and
  • endothelium adhesion was about one half or less that of unmodified PMMA indicating formation of a good
  • hydrophilic graft coating Similar results can be obtained using dimethylaminoethylacrylate to produce cationic graft coatings, styrene sulfonic acid (SSA) was also used to produce anionic grafts with NVP on PMMA according to the method of Example 1. using an SSA:NVP ratio of 1:2 (33% SSA) and total monomer concentration of 30% at 0.15 Mrad and about 700
  • SSA styrene sulfonic acid
  • hydrophilic grafts with 30-40o C.A. were prepared.
  • Styrene sulfonic acid sodium salt NaSSA was used to prepare highly hydrophilic anionic copolymer grafts with NVP on silicones (PDMS).
  • PDMS samples were cleaned by sonication in ethanol and vacuum dried prior to irradiation in aqueous monomer solutions.
  • Table 16 lists grafting conditions, monomer concentrations and contact angles for graft surfaces prepared at a dose rate of about 700 rads/min.
  • Hydrophilic surface grafts on polypropylene are not readily prepared by gamma irradiation of aqueous NVP in the presence of oxygen, under conditions of Example 1, even at gamma doses >0.1 Mrad and monomer concentrations >10%, little surface hydrophilicity and little reduction in C.A. occurs.
  • contact angles were about 15o.
  • Very hydrophilic PP grafts which are also mechanically stable by a mechanical abrasion test are thereby readily prepared using oxygen degassed process
  • Polycarbonate is a useful engineering plastic for ocular implants. Surface modification of polycarbonate is most readily accomplished using gamma radiation of oxygen degassed aqueous monomer NVP solutions, e.g., grafting conditions of oxygen degassed 10% NVP at 93 rad/min and 0.05 Mrad dose yield C.A. 19o.
  • PVDF Polyvinylidene fluoride
  • NVP NVP
  • Hydrophilic grafts with C.A. about 30o, are prepared at 326 rad/min and 0.20 Mrad.
  • PVDF is preferably grafted using oxygen degassed process conditions. Conditions of 157 rad/min, 0.05 Mrad and 10% aqueous NV produce PVP grafts with C.A. 17o. Since NVP monomer is also an effective swelling solvent for PVDF, allowing preradiation swelling time is favorable for producing improved grafts. For example, C.A. as low as 14o is obtained using 5 hrs. swelling time with 7% NVP, 0.10 Mrad and 94 rads/min.
  • One of the important aspects of this invention is the discovery that certain specific grafting process conditions make it feasible to surface modify combinations of materials to be used as lens/haptic pairs in ocular implants. Surface grafting of an assembled IOL can then take place in a one-step simultaneous grafting procedure yielding improved more biocompatible
  • Lens materials such as PMMA, PC and PSi can thereby be grafted under specific conditions of this invention which also achieve good grafting of haptic fiber materials such as PVDF or PP.
  • Table 16 summarizes some lens/haptic combinations with preferred mutual grafting conditions for obtaining improved PVP grafts.
  • PVDF surface graft studies also indicate the importance of oxygen degassing.
  • PVDF and PC are both grafted under the same
  • Intraocular lenses were surface modified using several conditions described in the above
  • IOL ocular implants prepared by the process conditions of this invention.
  • sinskey-style-037 J-loop lenses PMMA optic/PP haptics
  • PVP sinskey-style-037 J-loop lenses
  • ethylene oxide sterilized and implanted in the anterior chambers
  • one-piece flexible haptic PMMA IOLs were implanted in the posterior chambers of New Zealand white rabbits.
  • Process conditions for IOL surface modifications include:
  • This example illustrates the efficient grafting which can be achieved by the process of this invention at extremely low gamma doses (0.005 Mrad or less) even at very low aqueous monomer concentrations (0.5 wt% or less).
  • PVDF surfaces were surface modified using conditions described in the above examples at the extremely low gamma-radiation doses (0.01 and 0.005 Mrad) and low HEMA monomer concentrations (0.5-2.0%) summarized in
  • the XPS surface analysis clearly shows that efficient surface grafting of PHEMA occurred at 0.005 Mrad.
  • the surface carbon concentration for the graft was about that expected for a PHEMA surface and very little surface fluorine for PVDF was detected.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Physics & Mathematics (AREA)
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  • Epidemiology (AREA)
  • Dermatology (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Graft Or Block Polymers (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
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Abstract

Procédé de modification d'une surface polymère d'implant oculaire (10) par polymérisation induite par rayonnement gamma ou de faisceau d'électrons sur ladite surface de N-vinylpyrrolidone, 2-hydroxyéthylméthacrylate ou d'un mélange de ceux-ci tout en maintenant les conditions suivantes: (a) concentration de monomères situés dans la plage comprise entre environ 0,1 % et environ 50 % en poids; (b) dose de rayonnement gamma total dans la plage comprise entre environ 0, 001 et moins de 0,50 Mrad; et (c) taux de la dose de rayonnement gamma dans la plage comprise entre environ 10 et environ 2500 rads/minute ou taux de la dose de rayonnement du faisceau d'électrons dans la plage comprise entre environ 10 et 108 rads/minute.
PCT/US1991/006729 1990-10-05 1991-09-20 Implants oculaires ameliores et leurs procedes de fabrication WO1992005694A1 (fr)

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JP3516980A JPH06502782A (ja) 1990-10-05 1991-09-20 改良された眼科用インプラントとその製造方法

Applications Claiming Priority (3)

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US592,483 1990-10-05
US07/592,483 US5130160A (en) 1987-04-10 1990-10-05 Ocular implants and methods for their manufacture
PCT/US1994/000060 WO1995018840A1 (fr) 1987-04-10 1994-01-05 Dispositifs medicaux a surface modifiee

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JP (1) JPH06502782A (fr)
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WO (1) WO1992005694A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5603774A (en) * 1993-09-27 1997-02-18 Alcon Laboratories, Inc. Method for reducing tackiness of soft acrylic polymers
US9005281B2 (en) 2009-08-13 2015-04-14 Acufocus, Inc. Masked intraocular implants and lenses
US9138142B2 (en) 2003-05-28 2015-09-22 Acufocus, Inc. Masked intraocular devices
US9204962B2 (en) 2013-03-13 2015-12-08 Acufocus, Inc. In situ adjustable optical mask
US9427922B2 (en) 2013-03-14 2016-08-30 Acufocus, Inc. Process for manufacturing an intraocular lens with an embedded mask
US9545303B2 (en) 2011-12-02 2017-01-17 Acufocus, Inc. Ocular mask having selective spectral transmission

Families Citing this family (11)

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WO1998004605A1 (fr) * 1996-07-29 1998-02-05 Kazunori Kataoka Polymeres modifies dont la molecule contient un segment poly(2-hydroxyethyl(meth)acrylate)
DE60041092D1 (de) * 1999-09-02 2009-01-22 Alcon Inc Kovalent gebundene, hydrophile Beschichtungszusammensetzungen für chirurgische Implantate
CA2381270C (fr) * 1999-09-02 2010-07-20 Alcon Universal, Ltd. Compositions de revetements hydrophiles liees de facon hydrophobe a des implants chirurgicaux
US20050046794A1 (en) 2003-06-17 2005-03-03 Silvestrini Thomas A. Method and apparatus for aligning a mask with the visual axis of an eye
US7976577B2 (en) * 2005-04-14 2011-07-12 Acufocus, Inc. Corneal optic formed of degradation resistant polymer
US10004593B2 (en) 2009-08-13 2018-06-26 Acufocus, Inc. Intraocular lens with elastic mask
EP2464310B1 (fr) 2009-08-13 2019-02-27 CorneaGen Inc. Incrustation de cornée ayant des structures de transport des nutriments
WO2016081493A1 (fr) 2014-11-19 2016-05-26 Acufocus, Inc. Masque cassable pour traiter la presbytie
ES2972581T3 (es) 2015-10-05 2024-06-13 Acufocus Inc Métodos de moldeo de lentes intraoculares
EP3384342B1 (fr) 2015-11-24 2021-08-25 AcuFocus, Inc. Lentille torique intraoculaire à faible ouverture à profondeur de foyer accrue
US11364110B2 (en) 2018-05-09 2022-06-21 Acufocus, Inc. Intraocular implant with removable optic

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US4806382A (en) * 1987-04-10 1989-02-21 University Of Florida Ocular implants and methods for their manufacture
US4897433A (en) * 1986-12-08 1990-01-30 Japan Atomic Energy Research Inst. Process for producing an anti-thrombogenic material by graft polymerization
US4955901A (en) * 1988-05-31 1990-09-11 Canon Kabushiki Kaisha Intraocular implant having coating layer
US5007928A (en) * 1988-05-31 1991-04-16 Canon Kabushiki Kaisha Intraocular implant having coating layer

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US4707380A (en) * 1985-02-04 1987-11-17 Fuji Photo Film Co., Ltd. Process for preparing a magnetic recording medium
US4897433A (en) * 1986-12-08 1990-01-30 Japan Atomic Energy Research Inst. Process for producing an anti-thrombogenic material by graft polymerization
US4806382A (en) * 1987-04-10 1989-02-21 University Of Florida Ocular implants and methods for their manufacture
US4955901A (en) * 1988-05-31 1990-09-11 Canon Kabushiki Kaisha Intraocular implant having coating layer
US5007928A (en) * 1988-05-31 1991-04-16 Canon Kabushiki Kaisha Intraocular implant having coating layer

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5603774A (en) * 1993-09-27 1997-02-18 Alcon Laboratories, Inc. Method for reducing tackiness of soft acrylic polymers
US5882421A (en) * 1993-09-27 1999-03-16 Alcon Laboratories, Inc. Method for reducing taciness of soft acrylic polymers
US9138142B2 (en) 2003-05-28 2015-09-22 Acufocus, Inc. Masked intraocular devices
US9005281B2 (en) 2009-08-13 2015-04-14 Acufocus, Inc. Masked intraocular implants and lenses
US9492272B2 (en) 2009-08-13 2016-11-15 Acufocus, Inc. Masked intraocular implants and lenses
US9545303B2 (en) 2011-12-02 2017-01-17 Acufocus, Inc. Ocular mask having selective spectral transmission
US9204962B2 (en) 2013-03-13 2015-12-08 Acufocus, Inc. In situ adjustable optical mask
US9603704B2 (en) 2013-03-13 2017-03-28 Acufocus, Inc. In situ adjustable optical mask
US10350058B2 (en) 2013-03-13 2019-07-16 Acufocus, Inc. In situ adjustable optical mask
US10939995B2 (en) 2013-03-13 2021-03-09 Acufocus, Inc. In situ adjustable optical mask
US11771552B2 (en) 2013-03-13 2023-10-03 Acufocus, Inc. In situ adjustable optical mask
US9427922B2 (en) 2013-03-14 2016-08-30 Acufocus, Inc. Process for manufacturing an intraocular lens with an embedded mask

Also Published As

Publication number Publication date
CA2052836A1 (fr) 1992-04-06
CA2052836C (fr) 1998-02-03
TW202466B (fr) 1993-03-21
EP0551383A1 (fr) 1993-07-21
EP0551383A4 (en) 1993-11-03
JPH06502782A (ja) 1994-03-31

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