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
  • 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.
• ocular implants such as intraocular lenses (IOL) , etc.
• IOL intraocular lenses
• Most ocular implants are constructed of hydrophobia polymethylmethacrylate (PMMA) polymers because of their superior optical qualities, resistance to biodegradation, etc. It has been found, however, that PMMA surfaces adhere to endothelial cells upon even casual contact and that separation of the surface therefrom results in a tearing away of the endothelial tissue adhered to the polymer surface. Similar adhesive interactions with other ocular tissues, i.e., the iris, can also cause adverse tissue damage.
• 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. otolaryngol., Vol.
• Ocular implant surfaces have been coated with various hydrophilic polymer solutions or temporary soluble coatings such as methylcellulose, polyvinylpyrrolidone [Katz et al, supra, and Knight et al, Chem. Abs., Vol. 92:203547f (1980)] to reduce the degree of adhesion between the implant surfaces and endothelial tissue cells. While offering some temporary protection, these methods have not proven entirely satisfactory since such coatings complicate surgery, do not adhere adequately to the implant surfaces, become dislodged or deteriorate after implantation, dissolve away rapidly during or soon after surgery or may produce adverse post-operative complications. Moreover, it is difficult to control the thicknesses and uniformity of such coatings.
• N-vinyl-pyrrolidone N-vinyl-pyrrolidone
• HEMA 2-hydroxyethylmethacrylate
• PHEMA HEMA
• ocular implants constructed of materials including polymethylmethacrylate (PMMA) and of other process conditions and parameters which produce thin gamma irradiation induced graft PVP, P(NVP-HEMA), or PHEMA coatings on the surfaces of ocular articles constructed of materials including polypropylene (PP) , polyvinylidene fluoride (PVDF) , polycarbonate (PC) and silicone (PSi) .
• PP polypropylene
• PVDF polyvinylidene fluoride
• PC polycarbonate
• PSi silicone
• the coatings increase the hydrophilicity of the implant surface and minimize adhesion between the surface and sensitive ocular tissues such as corneal endothelium or iris thereby minimizing tissue damage and post-operative complications occasioned by contact between the implant surface and ocular tissue.
• 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: a) monomer concentration in the range of from about 0.5 to about 50%, by weight; b) total gamma dose in the range of from about 0.01 to about 0.50 Mrad; c) gamma dose rate in the range of from about 10 to about 2500 rads/minute; and d) maintaining the molecular weight of the polymer in solution in the range of from about 250,000 to about 5,000,000.
• the method may also be carried out under one or more of the following conditions: e) substantially excluding free oxygen from the aqueous graft polymerization solution; f) maintaining the thickness of the PVP or
• P(NVP-HEMA) surface graft in the range of from about lOOA to about 150 microns; g) including a free radical scavenger in the aqueous graft polymerization solution; and h) including in the aqueous graft polymerization solution a swelling solvent for PMMA or other polymer substrate surface.
• PSi to form optimum PVP or P(NVP-HEMA) surface grafts thereon may also be carried out under specific combinations of the process parameters as indicated above for PMMA but also under conditions which involve excluding free oxygen from the polymerization solution for preferred surface modification of these ocular implant polymer substrates.
• the present invention is predicated on the discovery that, in order to produce the hydrophilic coatings on the surfaces of ocular implants according to the method described in U.S. Patent No. 4,806,382, the "maintenance of the molecular weight of the polymer in solution in the range of from about 250,000 to about 5,000,000" is not a critical condition.
• 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 o.ooi 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.
• 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 polymeri ⁇ zation may be inhibited significantly without sacrificing efficient surface graft polymerization and the resulting solution polymer molecular weight may thereby be relatively low (i.e., as low as 5,000-10,000) .
• Yalon et al (supra) and Knight et al (supra) disclose gamma-irradiation coatings on PMMA using N-vinylpyrrolidone (NVP) and 2-hydroxyethylmethacrylate (HEMA) and indicate poor dynamic (abrasive) protection of endothelium for these coatings.
• NDP N-vinylpyrrolidone
• HEMA 2-hydroxyethylmethacrylate
• Dissolvable coatings of polyvinyl-alcohol (PVA) were regarded as optimal for intraocular lenses (IOLs) by Knight et al, supra, and commercial development of a PVA-coated IOL was attempted with unsatisfactory clinical results.
• the literature generally discloses conditions which produce distortion and degradation of the substrate due to the use of high gamma-radiation dose (>l Mrad) and non-aqueous solvent media, and yield thick, cloudy, non-uniform coatings (e.g., Chapiro, Radiation Chemistry of Polymeric Systems, John Wiley and Sons, Inc., New York (1962); Henglein et al, Angew. Chem., Vol. 15, p. 461 (1958). b) Long-term biocompatibility in vivo. c) Low contact angle (high wettability) for water or underwater air bubble (less than about 30*).
• Non-adherent to tissue (adhesive force to endothelium less than about 150 mg/cm 2 ) .
• Non-damaging to endothelium (less than ca. 20% damage for in vitro contact tests) .
• Measurable graft coating by ESCA or FTIR analysis.
• 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.
• 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.
• the surface modifica ⁇ tion 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 preventing solution gelation at high monomer concentrations.
• Monomer concentration Increasing 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
• PVP viscosity mol. wt. ( ) increases from 560,000 to 2,700,000 and the PMMA graft C . decreases from 29' to 21" at 0.1 Mrad and 309 rads/min.
• 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.
• Wt. The mol. wt. may vary widely depending upon process conditions, monomers and radical inhibitors used. Effective grafting with low CA. may therefore be achieved with even low mol. wt. solution polymer ( y as low as 5000-10,000 or less) . However, solution polymer M greater than 5,000,000 or gels which form during grafting are generally impractical because of washing problems.
• e) 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.l Mrad) . Oxygen degassing also has a large effect on PVP M plain and % conversion of monomer.
• 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 o.l to 5 microns.
• swelling solvents such as ethyl acetate
• polymer grafts on PMMA of 100 microns or more can be prepared.
• thicker ••spongy" coatings of 20-100 microns.
• 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 concentrations) in slowing the onset of solution gelation during grafting. However, under practical grafting conditions, this may result in lower mol. wts., high concentrations of unreacted monomer and broad mol. wt. distributions. Use of metal salts may also be objectionable where maximum biocompatibility is critical.
• 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. These conditions use high monomer concentrations (up to 50%) and thicker grafted are obtained using ethyl acetate as a swelling solvent (0.5-5%).
• 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 polymerization. Penetration of monomers into the substrate increases graft coating thickness and enhances bonding to the surface. 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.
• the PVP, 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.
• 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 dimethyla inostyrene 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.
• basic or amino-functional monomers e.g., vinylpyridines, aminostyrenes, aminoacrylates or aminomethacrylates such as dimethylaminomethylmethacrylate or dimethyla inostyrene
• 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.
• This system is generally preferred to (1) .
• 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.
• EXAMPLE 1 This example illustrates the important effects which result from varying the above-discussed process conditions and polymerization parameters for gamma-irradiated polymer graft surface modification of PMMA with PVP.
• PMMA slab samples were washed twice each by soap solution and distilled water using a sonicator. After complete drying, the samples were put into NVP solutions in glass vials. The samples were then T-irradiated at various conditions. After r-irradiation, the surface modified PMMA samples were rinsed several times with H 2 0 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 ( ) or gel permeation chromatography (M w ) .
• M w gel permeation chromatography
• 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 r-grafting with NVP at different solution concentra ⁇ tions 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). Hydrophilicity at 10% monomer appears to be favored somewhat by the lower dose rate (CA. 18* vs. 25*). Polar organic solvents or aqueous-polar organic solvent mixtures may be useful for hydrophilic monomer graft polymerization.
• organic solvents Typical of such 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.
• EXAMPLE 2 This example illustrates the effect of swelling solvents on the surface modification process.
• ethyl acetate ethyl acetate
• aqueous monomer solutions for hydrophilic gamma grafts on PMMA as the substrate, for example, addition of the swelling solvent, ethyl acetate (EtOAc) , to aqueous monomer solutions is advantageous to achieve more efficient diffusion of monomer into the PMMA surface.
• EtOAc ethyl acetate
• a homogenous reaction medium can be achieved in the presence of a monomer such as NVP.
• the thickness of the graft polymer surface modification can be increased by higher ethyl acetate concentrations and by longer diffusion times prior to irradiation; i.e., the time of pre-swelling.
• gamma radiation doses 0.10 - 0.15 Mrad are suitable to achieve significant amounts of grafting.
• 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.
• the PMMA substrate was immersed in aqueous monomer-solvent solutions and exposed to gamma radiation.
• 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.
• samples were removed from the gamma polymer solution and washed several times with distilled water and in deionized water with agitation, some samples were weighed hydrated after blotting with filter paper to remove surface water and then dried for 24 hours in a vacuum desiccator.
• the polymerization solutions ranged from clear viscous solutions to gels. The following parameters were measured.
• percent hydration W w - W j x 100
• 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.
• Captive air bubble and n-octane contact angles were measured for the radiation grafted PMMA surfaces to estimate the hydrophilicity of modified surfaces.
• static contact angles were measured on a Rame-Hart contact angle goniometer. At least five measurements on different surface regions of each sample were made.
• IR/ATR surface analysis of the grafted and 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 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.
• Measurement of percent swelling of PMMA samples in NVP-ethyl acetate-H 2 0 (1:1:8) vs. time shows that swelling of about 6% is attained after 12 hours.
• the thickness of the grafted layer could be controlled by changing the time allowed for diffusion prior to irradiation, thus controlling the thickness of the grafted zone.
• Table 11 shows the graft behavior after 24 hours of pre-swelling of PMMA in 1:9 ethyl acetate: water containing 15% of NVP. Comparing this data with Table 10 (no swelling time) , it is clear that the % graft is significantly higher for pre-swelling PMMA. At a given ethyl acetate concentration, this difference is generally more pronounced at lower monomer concentrations, e.g., 5% monomer compared to 15% monomer.
• 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
• ethyl acetate a monomer concentration
• Variation of the ethyl acetate concentration being a swelling agent, affects graft yield.
• Table 12 summarizes the observations made by varying the concentration of ethyl acetate while keeping other factors constant showing that the percent grafting does increase with higher ethyl acetate concentrations.
• 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.
• the presence of the PVP surface graft was confirmed by gravimetric, contact angle, ATR-IR and ESCA measurements.
• NVP aqueous solution As follows: (a) polymerization in presence of oxygen (air) ; (b) polymerization in absence of oxygen using argon degassing; and
• a method used for determining unreacted NVP after irradiation was as follows: 5 ml of the gamma irradiated NVP solution was extracted using 50 1 acetonitrile. NVP is soluble in acetonitrile, but PVP is not. The PVP precipitate was centrifuged and the supernatant solution was analyzed for NVP. The NVP monomer solution (10% NVP/aqueous) was used as a control. 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.
• 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 non-degassed oxygen (air) containing solutions. However, 46%, 61% and 63% conversion to PVP occurred for the AR-purged, 1FT and 3FT samples, respectively. Even at 0.10 Mrad, samples irradiated in air showed only 90% conversion (10% unreacted NVP monomer) compared to virtually complete conversion (99%) for oxygen degassed systems. This is important for biological implants where unreacted monomers can cause serious adverse toxicological behavior. To demonstrate more efficient grafting of PVP on
• 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.
• EXAMPLE 5 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 improved hydrophilic gamma graft surfaces, prepared under preferred process conditions, exhibit much lower adhesion; below 150 mg/cm 2 and often less than 100 mg/cm 2 . This is accompanied by a major reduction in endothelium cell damage as measured by SEM; from about 50-80% damage for PMMA or silicone to 20% or less for surfaces gamma grafted under preferred process conditions of this invention.
• 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 l The method of Example l 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 17*.
• a 7% NVP/HEMA solution (5:2) gave a surface with C . 23", and a 2.5% HEMA solution gave a surface with C.A. 18".
• EXAMPLE 7 This example demonstrates the graft copolymeriza ⁇ tion of anionic or cationic monomers with the hydro ⁇ philic monomers of this invention using ionic monomers with NVP.
• the method of Example l 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 18-22* and endothelium adhesion was about one half or less that of unmodified PMMA indicating formation of a good hydrophilic graft coating.
• styrene sulfonic acid was also used to produce anionic grafts with NVP on PMMA according to the method of Example l. using an SSA:NVP ratio of 1:2 (33% SSA) and total monomer concentration of 30% at 0.15 Mrad and about 700 rads/min. dose rate, hydrophilic grafts with 30-40' CA. were prepared.
• Styrene sulfonic acid sodium salt 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.
• This example demonstrates the hydrophilic monomer surface grafting of polypropylene (PP) and the importance of oxygen degassing for effective surface modification.
• Hydrophilic surface grafts on polypropylene are not readily prepared by gamma irradiation of aqueous NVP in the presence of oxygen, under conditions of Example l, even at gamma doses >0.l Mrad and monomer concentra ⁇ tions >10%, little surface hydrophilicity and little reduction in CA. occurs.
• contact angles were about 15*.
• Very hydrophilic PP grafts which are also mechanically stable by a mechanical abrasion test are thereby readily prepared using oxygen degassed process conditions. This is especially important for gamma graft surface modification of IOLs with PMMA optics and PP haptics.
• 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. 19*.
• silicone (PSi) does not gamma graft with NVP as readily as PMMA, PSi surfaces were modified using oxygen degassed 10% NVP solutions. Irradiation to 0.05 Mrad at 93 rad/min yields C.A. of about 45* indicating significant surface hydrophilicity. Higher doses, swelling solvents, higher monomer concentrations and different hydrophilic monomers can produce improved hydrophilicity. For example, gamma grafting of NVP/HEMA (10:1) at 0.10 Mrad and 157 rad/min even without oxygen degassing yields grafts with 30* C .
• PVDF Polyvinylidene fluoride
• NVP polyvinylidene fluoride
• NVP polyvinylidene fluoride
• EtOAc-water systems Hydrophilic grafts, with C.A. about 30*, 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. 17*.
• NVP monomer is also an effective swelling solvent for PVDF, allowing pre- radiation swelling time is favorable for producing improved grafts. For example, C.A. as low as 14* 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 combina ⁇ tions 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 surfaces. 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 sum- marizes some lens/haptic combinations with preferred mutual grafting conditions for obtaining improved PVP grafts. PMMA/PP and PMMA/PVDF
• 157 rad/min, 0.05 Mrad and 10% aqueous NVP solutions efficient hydrophilic grafting occurs on both polymers yielding contact angles of 19* and 15', respectively.
• PVDF and PC are both grafted under the same conditions which graft PC/PP and PMMA/PP combinations; e.g., 157 rad/min, 0.05 Mrad, 10% degassed NVP. Since PVDF swells in NVP, gamma grafting with prior swelling time can result in improved binding of PVP to the PVDF. Conditions are thereby afforded for simultaneous hydrophilic polymer grafting to IOLs or other ocular implants which are made of two or more polymers as indicated above. See Table 16.
• Intraocular lenses were surface modified using several conditions described in the above examples and implanted in rabbit eyes for periods of up to one year to demonstrate the good bioacceptance of hydrophilic gamma polymerization surface modified 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 and one-piece flexible haptic PMMA IOLs were implanted in the posterior chambers of New Zealand white rabbits.
• Process conditions for IOL surface modifications include:
• PMMA/PP a 10% degassed NVP, low dose rate (LDR)**,
• PMMA/PVDF a 10% degassed NVP, LDR,
• EXAMPLE 14 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 condi ⁇ tions 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

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