CA2179061A1 - Polyethylene oxide coated intraocular lens - Google Patents
Polyethylene oxide coated intraocular lensInfo
- Publication number
- CA2179061A1 CA2179061A1 CA002179061A CA2179061A CA2179061A1 CA 2179061 A1 CA2179061 A1 CA 2179061A1 CA 002179061 A CA002179061 A CA 002179061A CA 2179061 A CA2179061 A CA 2179061A CA 2179061 A1 CA2179061 A1 CA 2179061A1
- Authority
- CA
- Canada
- Prior art keywords
- lens
- amine
- intraocular lens
- coating
- polyethylene oxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
- 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
- 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
- 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
Abstract
An intraocular lens having improved biocompatibility is coated with polyethylene oxide through covalent bonding, preferably using a plasma-deposited amine layer. The lens is then sterilized with ethylene oxide and extracted with water.
Description
W0951~6475 2 1 7 9 0 6 1 PCT/US94/146~i0 .
POLY~TI~YL~N~ OXIDE COATED INTRAn~AI?T~AR LENS
This invention was made with ~uv~ t support under Grant No. G~ 4011 awarded by the National Institutes of Health. The United States Guv t has certain rights in the invention Backc~round of the Invention This invention relates to intr~AculAr lenses and more particularly, relates to intraocular lenses which have been coated with polyethylene oxide in a manner 5which improves hic , otibility.
Backc~round Art IntrAo~ Ar lenses (IOL) are well known in the field of ophthalmology. An intr~ llAr lens, when surgically implanted in the eye, can be used to replace a natural lens which has been diseased by cataracts. Such lenses c~n also be placed in the eye to ,An~ate for ref ractive errors . The optical portion of such lenses may be f ormed of various materials . One type of lens is the so-called hard lens made of a polymethylmethacrylate (~qA) . Hard plastic lenses have Ay,Apl l_nt optical characteristics and good ~~~Ahinin~ and polishing qualities. A second class of lenses~include the flexible sLlicone lenses, but which are susceptible to discoloration. A third category of lenses comprises the soft (non-silicone type) lenses which are generally called hydrogel lenses. Soft lenses are usually made from polyHED~A. A fourth category of lenses includes soft acrylate lenses.
Wo 95116475 2 1 7 9 0 6 1 PCr/Uss4/l46so .
The implantation of intraocular lenses is recognized as a substantial surgical advantage, part;rlllArly in the treatment of cataracts. However, some problems still exist in their use since implantation of an intr~c~llAr lens may cause damage to the corneal endothelium, inf lammatory responses within the anterior or posterior segment of the eye, as well as other problems. When an intrAn~lllAr lens is inserted into the eye, the ^hAnic~
of insertion may lead to adhesion to the lens of delicate intraocular tissues and damage to these structures ensues either immediately or over long periods. Nhen in position, the lenses may cause adhesions and damage intraocular tissues which may require removal and rPrl A~ t of the lens . The lenses may also adsorb protein and become "fouled."
It is recognized in the art that lenses may be coated with a coating material . Thus, U . S . Patent No .
4,170,043 discloses intraocular lenses coated with a film that dissolves slowly in water. This helps prevent endothelial dam~ge upon implantation of the IOL. The coating dissolves within about 24 hours af ter implantation .
U.S. Patent No. 4,731,080 discloses a coated intraocular lens, wherein the lens is coated with a non-smudging, biologically compatible hydrophobic crosslin3ced 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. In this ,UlUU~ ULt~, which may be used on an intraocular lens, a first biocompatible material, pref erably having pendant carboxylic acid or amine groups, is covalently grafted to the surface of a substrate polymer core by radio frequency plasma induction. A second biocompatible material then may be grafted to the first biocompatible Wo 95/16475 2 1 7 9 0 ~ ~ p,~ S94/l4C50 .
material using a cross-linking agent. This patent does not suggest that a polyethylene oxide coating could be applied in this way.
A series of patents disclose contact lenses which are coated by vnrious materi~ls includLng polyethylene oxide. 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 r~i~rlAs~ coating a contact lens by grafting polyoxyethylene thereto. However, contact lenses and intraocular lenses are different products each with its different problems, so solutions to problems of contact lenses cannot be extrapolated into solving problems with intraocular lenses.
A problem remains in the art to provide coated intraocular lenses which have improved biocompatibility.
The present invention meets this need by providing polyethylene oxide coated intraocular lenses wherein the polyethylene oxide coating is ~pplied through covalent bonding .
SummarV of the Invention It is accordingly one ob~ect of the present invention to provide an intraocular lens having improved biocompatibility .
It is a still further ob~ect of the invention to provide an intraocular lens having improved h; ~ , -tibility which is achieved by applying a polyethylene oxide coating to the lens surface through covalent bonding.
An even further object of the invention is to provide an intraocular lens wherein the biocompatibility of the lens is improved by applying a polyethylene oxide coating to the lens through amine covale ~t bonding .
Wo 95/16475 2 1 7 9 0 6 1 PCrNss4/146so .
other ob~ects and advantages of the present invention will become apparent as the description thereof proceeds.
In satisfaction of the foregoing ob~ects and advantages, the present invention provides an in~rAnr--lAr lens having ; uv~d hi r ~ tibility, said lens being coated with a polyethylene oxide through amine covalent bonding. The polyethylene oxide is covalently bound at the lens surface by the process steps comprising:
1 ) creating an active surface on said lens by plasma deposition;
POLY~TI~YL~N~ OXIDE COATED INTRAn~AI?T~AR LENS
This invention was made with ~uv~ t support under Grant No. G~ 4011 awarded by the National Institutes of Health. The United States Guv t has certain rights in the invention Backc~round of the Invention This invention relates to intr~AculAr lenses and more particularly, relates to intraocular lenses which have been coated with polyethylene oxide in a manner 5which improves hic , otibility.
Backc~round Art IntrAo~ Ar lenses (IOL) are well known in the field of ophthalmology. An intr~ llAr lens, when surgically implanted in the eye, can be used to replace a natural lens which has been diseased by cataracts. Such lenses c~n also be placed in the eye to ,An~ate for ref ractive errors . The optical portion of such lenses may be f ormed of various materials . One type of lens is the so-called hard lens made of a polymethylmethacrylate (~qA) . Hard plastic lenses have Ay,Apl l_nt optical characteristics and good ~~~Ahinin~ and polishing qualities. A second class of lenses~include the flexible sLlicone lenses, but which are susceptible to discoloration. A third category of lenses comprises the soft (non-silicone type) lenses which are generally called hydrogel lenses. Soft lenses are usually made from polyHED~A. A fourth category of lenses includes soft acrylate lenses.
Wo 95116475 2 1 7 9 0 6 1 PCr/Uss4/l46so .
The implantation of intraocular lenses is recognized as a substantial surgical advantage, part;rlllArly in the treatment of cataracts. However, some problems still exist in their use since implantation of an intr~c~llAr lens may cause damage to the corneal endothelium, inf lammatory responses within the anterior or posterior segment of the eye, as well as other problems. When an intrAn~lllAr lens is inserted into the eye, the ^hAnic~
of insertion may lead to adhesion to the lens of delicate intraocular tissues and damage to these structures ensues either immediately or over long periods. Nhen in position, the lenses may cause adhesions and damage intraocular tissues which may require removal and rPrl A~ t of the lens . The lenses may also adsorb protein and become "fouled."
It is recognized in the art that lenses may be coated with a coating material . Thus, U . S . Patent No .
4,170,043 discloses intraocular lenses coated with a film that dissolves slowly in water. This helps prevent endothelial dam~ge upon implantation of the IOL. The coating dissolves within about 24 hours af ter implantation .
U.S. Patent No. 4,731,080 discloses a coated intraocular lens, wherein the lens is coated with a non-smudging, biologically compatible hydrophobic crosslin3ced 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. In this ,UlUU~ ULt~, which may be used on an intraocular lens, a first biocompatible material, pref erably having pendant carboxylic acid or amine groups, is covalently grafted to the surface of a substrate polymer core by radio frequency plasma induction. A second biocompatible material then may be grafted to the first biocompatible Wo 95/16475 2 1 7 9 0 ~ ~ p,~ S94/l4C50 .
material using a cross-linking agent. This patent does not suggest that a polyethylene oxide coating could be applied in this way.
A series of patents disclose contact lenses which are coated by vnrious materi~ls includLng polyethylene oxide. 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 r~i~rlAs~ coating a contact lens by grafting polyoxyethylene thereto. However, contact lenses and intraocular lenses are different products each with its different problems, so solutions to problems of contact lenses cannot be extrapolated into solving problems with intraocular lenses.
A problem remains in the art to provide coated intraocular lenses which have improved biocompatibility.
The present invention meets this need by providing polyethylene oxide coated intraocular lenses wherein the polyethylene oxide coating is ~pplied through covalent bonding .
SummarV of the Invention It is accordingly one ob~ect of the present invention to provide an intraocular lens having improved biocompatibility .
It is a still further ob~ect of the invention to provide an intraocular lens having improved h; ~ , -tibility which is achieved by applying a polyethylene oxide coating to the lens surface through covalent bonding.
An even further object of the invention is to provide an intraocular lens wherein the biocompatibility of the lens is improved by applying a polyethylene oxide coating to the lens through amine covale ~t bonding .
Wo 95/16475 2 1 7 9 0 6 1 PCrNss4/146so .
other ob~ects and advantages of the present invention will become apparent as the description thereof proceeds.
In satisfaction of the foregoing ob~ects and advantages, the present invention provides an in~rAnr--lAr lens having ; uv~d hi r ~ tibility, said lens being coated with a polyethylene oxide through amine covalent bonding. The polyethylene oxide is covalently bound at the lens surface by the process steps comprising:
1 ) creating an active surface on said lens by plasma deposition;
2 ) reacting the active lens surface with a polyethylene oxide through covalent bonding;
and 3) stAhili7in~ the resultant coating.
r)escriPtion of the Invention The present invention relates to coated intraocular lenses. The intraocular lenses may be formed from any of the well known hard lenses formed from polymers including those formed from polymethylmeth-acrylate (PN~SA) or acrylic lenses. Such lenses are well known in the art.
The invention includes coating of soft acrylate lenses, such as those disclosed in cop~'n~i i n~ U . S . Patent ~pplication Seria1 No. 08/076,378. In one r-mho~i t, the lens is formed from a copolymer with an elongation of at least 15096 wherein the copolymer is formed from two ~, the f irst 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.9;. An ultraviolet Ahfiorhing material such WO95116475 0 6 ~ p~ S94114650 as 2- ( 3 ' -methallyl ' -2-hydroxy-5 ' -methyl-phenyl ) benzotriazole may also be included. The invention is applicable to all lens styles. The disclosures of the prior patents discusaed above are hereby incorporated into this disclosure with respect to the disclosure and discussion of various types of intraocular lenses to which this invention is ~rPl i rAh1 ~ .
~rrrlr~ing to this invention, the biocompatibility of such lenses is substantially improved by coating the lenses with a polyethylene oxide coating. The expression "hif -tible" means that the resultant intraocular lens coated with a polyethylene oxide f ilm is more biologically compatible with the eye than known lenses when inserted into the eye. In particular, the lS biocompatibility of the lens is improved by the discovery that intraocular lenses coated with polyethylene oxide arcnrr~ i n~ to this invention have improved resistance to protein adsorption. This results in a lens which is ''non-fouling" and resistant to cell deposition and therefore, more biocompatible than known lenses.
The lenses are coated with a polyethylene oxide in a special manner as d~rri hF~d herein to obtain covalent bonding to the lens surf ace through an active int~ te layer. It has been discovered that the use of covalent bonding through an int~ 'i ~te layer makes the polyethylene oxide coating, more adherent to the lens surface, and provides for a uniform continuous coating which has improved resistance to protein adsorption and cell deposition.
According to this invention, the lens is first provided with an active coating or layer on the lens surface to create an active primary amine layer. A
preferred procedure is to create an active layer on the lens by plasma deposition of a polymer coating containing -Wo 95116475 PCr/USs4/146so a primary amine. ~owever, equivalent active inr~ ';Ate layers may be used.
The primary amine layer is preferably formed by contacting the lens with an allyl amine or a lower alkyl amine of the formula RN~I2, wherein R is an alkyl or allyl group of about 3-12 carbon atoms. Preferably the alkyl or allyl amine is one of int~ iAte chain-length wherein R is an alkyl group of 5-8 carbons, and most preferably, is n-heptyl amine.
The alkyl or allyl amine may be applied to the lens 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 on the lens surface. 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 dis_iosures of which are incorporated by ref erence .
~cor-l i n~ to thi3 invention, plasma deposition of the primary amine layer on the lens is generally carried out in two steps. First, the lens is placed in an electrical glow discharge apparatus, wherein a gaseous ~tmosphere is provided, te.g., argon), and then the gaseous atmosphere is subjected to an electrical glow discharge to clean the surface. The gas is then removed.
In the second step, 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 form an ultrathin coating of about 5-300 angstroms on the surf ace of the lens .
After the surface of the lens is treated with the amine, the lens surface containing the amine layer is then reacted with a polyethylene oxide. The polyethylene oxide should have terminal groups or caps which are reactive with the amine coating. Aldehyde terminated polyethylene oxides are especially preferred. Through 2l79o6l wo95/16475 Pcr/uS94/14650 this reaction of the polyethylene oxide and the amine attached to the lens surf ace in the presence of a reducing agent, a stable polyethylene oxide coating will be attached to the lens surf ace through the resultant covalent bonding. Such polyethylene oxides are known in the art, e.g. from the publication by ~arris, "Polymer Preprints", 32, 154 (lg91).
The alkyl or allyl amine is applied by plasma deposition as indicated above. In a preferred plucedu~ ~, the intraocular lens is first etched prior to amine deposition for best results. Preferably, etching of the surface is conducted by contact with argon. An argon flow rate in the range of 60-120 cm3/min, and a chamber pressure of 200-300 mTorr i9 satisfactory. In conducting the deposition, the intraocular lens is placed in a holder and centered in a plasma chamber with the desired argon flow rate to argon etch prior to amine deposition.
A container f or the amine is connected to the plasma chamber unit. The plasma chamber is then evacuated to its baseline pressure and, while under the argon ~low rate, is ignited for a short period, for example, 60N for six minutes. After the argon etch, 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. After the plasma is extinguished, 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 container such as a sealed microcentrifuge tube.
A polyethylene oxide (PEO), e.g., aldehyde capped polyethylene oxide, is dissolved in a buffer solution in a concentration in the range of 5-50 mg/ml and is preferably purified to remove any particulates. This 21 7qO61 Wo gsll6475 PCT/US94/146~0 solution is then added to each microcentrifuge tube containing the amine-plasma coated intraocular lens.
St~hi l; 7Ation of the coating on the lens is then carried out by treating the lens with an alkali metal borohydride dissolved in a buffer in a concentration of 10-50 mg/ml.
Reduction of the PEO amine bond with the alkali metal bUL~}~yL~lide will provide a stable PEO coating of about 5-500 Angstroms, prefera}~ly 100-300 Angstroms. ~ixing of the solution is preferably done by inverting the tube6.
The resulting samples are then heated at a low temperature, for example, 25-50C for about ten to thirty hours . In a preferred ~ L'Lt:LIULr', stAhi 1 i 7A~tion is repeated and the lenses are again heated. Each lens is then washed in deionized water and the water removed.
A preferred polyethylene oxide utilized in the present invention is an aldehyde-terminated polyethylene oxide which has a molecular weight in the range of 200 to lO0,000, preferably 1500-10,000. Such aldehyde-capped polyethylene oxides are known in the art, e.g., Harris, "Polymer Preprints", 32, 154 (1991). However, any polyethylene oxide having reactive t~rmi nA 1 groups may also be used in the invention.
The preferred stAhili7in~ agent is an alkali metal borohydride, most preferably sodium or potassium cy~nnh~.L~.~yLl~Lide of the formula NaCNBH3, a commercially available material.
An import,~nt aspect of the invention concerns st~ri l i 7ation of the coated lenses after preparation.
The lenses may be st~ri 1 i 7e~l using standard ethylene oxide st~ri 1 i 7A~tion and aeration to remove residual ethylene oxide. St~ri l i 7Ation with ethylene oxide L~ contact with 10-209~ ethylene oxide in a flllnrirll~ solvent for 1-4 hours at 10-40 psi and 40-60C., prefer~bly after preconditioning in a humid atmosphere.
35 However, according to this invention, it has been WO 9S/1647S 6 I~/usg4n46so discuv~L~:d that aqueous extraction rather than aeration ûf the residual ethylene oxide following st~ri 1 i 7Ation minimi70c loss of protein and cell rf~ Rinn ability of the polyethylene oxide coating. Aqueous extr~ction comprises contact of the lens with 1-3 ml of sterile water per lens while heating at a t~ eL~.Lu~e of about 25-60C. for 3-9 days. Theoretically, it appears the aqueous extraction prevents the polyethylene oxide chain from inverting. Also, since the water contains less oxygen than air, cleavage of the polyethylene oxide molec:ules may be reduced. It has been found that aqueous extraction ~ffir~ionr-y also increases with temperatures ranges from 35 to 60C and time from 3 to 14 days.
Residual ethylene oxide levels as low 6 ppm can be achieved. Further, the residual levels of epichlorohydrin and ethylene glycol which are byproducts of ethylene oxi~ extracted with water, are very low, i.e. less than 10 ppm and 50 ppm respectively. This is below industry 5tAn~ r~ so that extraction vials with water or buffers, for example, BSS, may also be used for final packaging.
The resulting intrAncl~1Ar lens will have the indicated i ~,v~d biocompatibility i n~ i n~ increased reistance to protein adsorption which makes the lens non-fouling and resistant to cell deposition.
The following examples are presented to illustrate the invention but the invention is not to be limited thereto. Parts are by weight unless otherwise indicated.
l~A~LI;: 1:
A. Surf ace Amination PN~LA IOLs (6mm, plano-convex, single piece or monoflex - PMMA or polypropylene haptics) are each placed in a butterfly lens holder and the lens holder then positioned in a cleaned glass-rack. The glass rack is Wo 95/l647s PCrNSs4/146~0 .
placed onto a larger glas ~ rack centered in the plasma chamber .
n-Heptylamine ~5.0g) is placed in a 250mL round bottom flask. The flask is connected via a rubber stopper to a metering-valve located at the front of the plasma chamber unit. With the needle valve to the heptylamine flask closed, the plasma chamber is evacuated to its baseline pressure of ~pproximately 13 mTorr. This condition is maintained for thirty minutes.
The IOLs are argon-etched prior to n-heptyl~mine deposition. At an argon flow rate of 90 cm3/min and a chamber ~L.~:iu-el of 250 mTorr, a plasma is ignited at 60W
f or 8iX minutes . Af ter the argon etch, the plasma chamber i9 evacuated to its baseline L)L~::SI:IUL_.
n-Heptylamine vapor is introduced into the chamber of the plasma unit. Vacuum pump speed is lowered and the chamber is allowed to equilibrate for ten minutes. The plasma i5 ignited and a thickness monitor is activated to record deposition. The plasma is maintained until a thickness monitor reading o~ 190 Any~iLLl - is achieved.
After the plasma is extinguished, the chamber conditions are maintained f or two minutes . Following this, the vacuum pump speed is returned to maximum and maintained for ten minutes. The chamber is brought u~? to ai ~heLic conditions by back-filling with argon. The s~mples are removed from their respective holders and each placed in a microcentrif uge tube containing PEO
solution .
wo95116475 11 2 1 7906 1 p~ S94/14650 B. PEO T 1 j 7s~tion Phosphate/Sulphate buffer: 7 . 838 grams Potassium Sulphate ( K2SO4 ) 0. 060 grams Sodium phosphate dibasic ( Na2HPO4 ) ~p10nizr~c~ Water to final volume of 100 mL
Heatiny is required to dissolve the K2SO4. Final pH
range 8 . 5-9 ~ 0 .
Nethoxy end-capped, dithiolaldehyde derivatized PEO
of molecular weight 5000 (designated MPEG5~;S2CHO), which can be made according to the procedure set forth in Harris et al., "Polymer Preprints", 32, 154 (1991), is dissolved in buffer at a concentration of 10 mg/mL. The solution is filtered through a fritted glass filter ( coarse ) to remove any particulates . IPEG5XS2CHO
solution (900 uL) is added to each microcentrifuge tube containing plasma-coated IOL. Sodium cyanoborohydride (NaCNBH3) is dissolved in the buffer at a concentration of 20 mg/mL. 10011L of this solution is added to each microcentrifuge tube containing plasma-coated IOL. Each solution is gently mixed by inverting the tubes ten times. The NaCNBH3 solution is hydrolytically unstable and should be prepared ~ust prior to its addition to the reaction solution.
The samples are then heated at 35C overnight (16-18 hours ) . The treatment with NaCNBH3 is repeated, and the samples heated at 35C for another four hours. Each IOL
sample is washed by consecutive dip-rinsing in three beakers containing 140 mL of deionized water. Each IOL
is then placed in 3mL rlr~i~ni7r~ water and sonicated for five minutes. This wash water is then replaced by fresh n i 7r~rl water and sonication repeated . This last sonication step is repeated. (Three sonications in total). Each IOL is removed from wash solution, the Wo 95/16475 2 1 7 9 0 6 1 PCT/US94/14650 excess water removed from the sample IOL, and then repackaged .
R~r~MPLE 2:
Biointeraction Studie8:
A. Protein Adsor~tion A6 fihrinngPn play6 a ~i~nific~nt role in the biocompatibility of implanted device6 in~ t-iing in~rancl-lAr len6es, its adsorption from single protein and multi-protein solutions was investigated. EIuman fihrinngen radiol~h~ with ~25Iodine was used to determine the amounts of adsorbed protein on the IOL
surface. Prior to exposure to protein solutions the IOL
s~tmples (without haptics) were incubated at 37C, for one hour in BSS (RAl~nced Salt Solution). In the single protein ~rr~ri L each IOL was incubated at 37C for one hour in a BSS solution containing 5 llg/mL of l25I-fibrinogen. For the multi-protein experiment IOLs were exposed to 1:5:16 mixtures of ~25I-fibrinogen, IgG and albumin at 37C for one hour. Fibrinogen concentrations at 125 ~tg~mL (Multi-protein A) and 62.5 ,~Lg~mL (Nulti-protein B ) were investigated . These protein concentrations were chosen to simulate post-operative human aqueous humor levels.
The protein adsorption re6ults are reported as fractions of the amount adsorbed on uncoated PMNA IOL
controls; and are ,i, rized in Table 1. The results of the single protein study lndicated that the heptylamine-plasma pre-coat marginally increased the amount of adsorbed f ;hrinngen over uncoated P~SA controls while the PEO coating reduced it by about 85~; PNNA adsorbed 158 +
30 ng/cm2 fibrinogen. Similar levels of reduction were observed when PEO coated IOLs were exposed to higher protein concentrations in the simulated post-operative aqueous humor. The presence of albumin and IgG appeared _ -Wo 9s/l647s 7 9 ~ 6pLnTS94J14650 .
not to significantly affect the amount of P~iqnrhr~d f i hri nngen .
Table 1: F~hrinngr~n Adsorption Co-~L~ ffl- SL=yl~ pro:~L~ ~ulel-p~o~L= A~ Hulri-p~ L= 3 (=oi~ulL~d)~ ~=oir~lLi~-d) (=oiRl lLi~d) d~p~y~ ' F 1 10 + 0.09 1 53 + 0 37 ---____ (= - 2~) (= - 2) PE0 0 13 + 0 09 0 11 + 0.06 0 10 + 0 05 (= - 2~) (= - Il) ~n - ~) ~Amount i~r~qr~rh~rl nnrr~li7er1 against that oi PMMA
controls .
~Fibrinogen ~125~Lg/mL), IgG (625 llg/mL) and Albumin (2 10 mg/mL) ~Fibrinogen (62.5 ~g/mL), IgG (312.5 llg/mL) and Albumin ( 1 mg /mL ) B . T _ _ ld Staininq To visualize the pattern of ~ qnrhPd f i hri nngen on IOL surfaces and to draw some inferences about the uniformity of PEO coating, a method involving antibodies linked with gold was utilized. IOL surfaces were first exposed to solutions of f i hri nngen ( single protein adsorption ) and then incubated in the presence of rabbit anti-human fihrinngen antibody. The samples were subsequently reacted with goat anti-rabbit IgG-gold complex, i ~lified with silver particles and observed under a light microscope ~100-400 X ---~nifice,tions). A
uniform coating of gold-silver was observed on both PMMA
and heptylamine-plasma coated surfaces while PEO surfaces appeared to be free of gold indicating little or no adsorbed protein.
- C. Cell interactions (i) Human Macror~haqe Activation: Surface induced - 30 release of hydrogen peroxide from human macrophages was used to model the inf lammatory response to PEO coated Wo 95/16475 PCrlUSs4/14650 .
IOLs . As adsorbed protein can inf luence the extent of activation, the samples were pre-exposed to simulated post-surgical aqueous humor solution under experimental conditions similar to those described for the multi-protein adsorption study. The foLlowing methods describe how cultured human macrophages were seeded onto the IOL
optic surface in serum-free culture medium for 2 hours at 37 C, followed by incubation in a phenol red-horseradish peroxidase solution for l hour at 37C. After removing and making this solution AlkZ~l ino~ the peroxide concentration was deto~minod at 630 nm. The results were reported as nntT-lizo-i values (against P~A) and ~ummari~ed in Table 2. The results indicated that the PEO coating significantly reduced acute macrophage activation on P~A IOLs.
Table 2: Human ~acropha~e Interactions.
Surf ace HzO2 Production ~ normalized P~A l.00 + 0.l9 (n = 5) PEO 0 . 20 + 0 . l0 (n = 7) ( ii ) Rabbit Lens EPithelial Cell Interaction: Along with repelling proteins from the surface of an implant, another function of immobilized PEO is to prevent the attachment and growth of cells (macrophages, neutrophils, epithelial cells, fibroblasts, etc. ) which can ultimately lead to device failure. To quantify the potential of adhesion and growth of celLs on the PEO coating an assay nvolving the incorporation of 3H-thymidine into the DNA
of mitotic rabbit lens epithelial cells (LEC) was utilized. It should be noted that this assay was not intended as a method for assessing the ability of the PEO
coating to prevent posterior capsule opacification.
Briefly, the assay involved seeding cultured LEC onto the optic surfz~ce of both coated and uncoated IOLs in culture medium containing 596 serum and 3H-thymidine, followed by incubation for 2 days at 37C. The cells were then fixed in 2~ glutaraldehyde and their levels of radioactivity detPrmi nF.rl .
To investigate the role of protein adsorption on the growth of LEC, the assay was performed on bare surfaces as well as those pre-exposed to simulated post-surgical aqueous humor. As shown in Table 3, the PEO coating was unable to support the .9~1hl~c ~ ~n and growth of LEC
ilLe~e. Live of whether proteins were pre-adsorbed to the surf ace . Examination of the surf aces by phase-contrast light microscopy revealed only a few round cells on the PEO surface, while a fully confluent layer of spread cells was observed on P~A and tissue-culture polystyrene controls. Rounded cells result from their inability to attach and spread on substrate surface. In the confluent layer the cells attained their natural polygonal morphology. It was interesting to note that pre-adsorption of protein to PN~A resulted in significantly more cell growth on the surface.
Table 3: Rabbit Lens EPithelial Cell Interactions Surface Normalized cell ~rowth PMNA 1 . 00 + O . 032 (n = 5)~
PEO* 0 . 010 + 0 . 005 (n = 5) PEO 0 . 021 + 0 . 028 (n = 5) - * pre-exposed to simulated post-surgical aqueous humor ** n is number test samples.
~IO 95ll6475 2 1 7 9 0 6 1 PCr/US94114650 .
EXA!iPLE 3 Sterilization Studies The polyethylene oxide coated IOLs were sterilized with 12% ethylene oxide (in Freon) ~or two hours at 22-24 psi and 46C, after a one hour preconditioning in a 60%
relative humidity atmosphere. Each stPri 1 i 7c~sl lens was then tr2nsferred to 3 mls of sterile water and heated at 60C ~or 7 days. The lenses were then stored ~at RT) in this solution until used.
Results of a f 1 hr; nngPn adsorption assay, shown in table, indicated that aqueous extraction restores the efficacy of the coating.
RESULTS
Table: Nnrr~l i ze~ Fibrinogen Adsorption 15 EO Sterilized O~ly EO Sterilized and EO Sterilized ~
Aerated Aqueous Extracted 0.35 + 0.20 0.6 + 0.14 0.18 + 0.09 n = 9 n = 8 n = 5 Amount of fihrin~gPn P~i~orhe~ on each lens was nnrr~ 1 i 7P~i against that on PMMA control .
* Following stPrili7Jltion aerate for 8.5 days at 49C~
2C under atmospheric lJL~SaUL~.
The invention has been r~P~rrl he-l herein with reference to certain preferred . ' 'i ts; however, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.
and 3) stAhili7in~ the resultant coating.
r)escriPtion of the Invention The present invention relates to coated intraocular lenses. The intraocular lenses may be formed from any of the well known hard lenses formed from polymers including those formed from polymethylmeth-acrylate (PN~SA) or acrylic lenses. Such lenses are well known in the art.
The invention includes coating of soft acrylate lenses, such as those disclosed in cop~'n~i i n~ U . S . Patent ~pplication Seria1 No. 08/076,378. In one r-mho~i t, the lens is formed from a copolymer with an elongation of at least 15096 wherein the copolymer is formed from two ~, the f irst 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.9;. An ultraviolet Ahfiorhing material such WO95116475 0 6 ~ p~ S94114650 as 2- ( 3 ' -methallyl ' -2-hydroxy-5 ' -methyl-phenyl ) benzotriazole may also be included. The invention is applicable to all lens styles. The disclosures of the prior patents discusaed above are hereby incorporated into this disclosure with respect to the disclosure and discussion of various types of intraocular lenses to which this invention is ~rPl i rAh1 ~ .
~rrrlr~ing to this invention, the biocompatibility of such lenses is substantially improved by coating the lenses with a polyethylene oxide coating. The expression "hif -tible" means that the resultant intraocular lens coated with a polyethylene oxide f ilm is more biologically compatible with the eye than known lenses when inserted into the eye. In particular, the lS biocompatibility of the lens is improved by the discovery that intraocular lenses coated with polyethylene oxide arcnrr~ i n~ to this invention have improved resistance to protein adsorption. This results in a lens which is ''non-fouling" and resistant to cell deposition and therefore, more biocompatible than known lenses.
The lenses are coated with a polyethylene oxide in a special manner as d~rri hF~d herein to obtain covalent bonding to the lens surf ace through an active int~ te layer. It has been discovered that the use of covalent bonding through an int~ 'i ~te layer makes the polyethylene oxide coating, more adherent to the lens surface, and provides for a uniform continuous coating which has improved resistance to protein adsorption and cell deposition.
According to this invention, the lens is first provided with an active coating or layer on the lens surface to create an active primary amine layer. A
preferred procedure is to create an active layer on the lens by plasma deposition of a polymer coating containing -Wo 95116475 PCr/USs4/146so a primary amine. ~owever, equivalent active inr~ ';Ate layers may be used.
The primary amine layer is preferably formed by contacting the lens with an allyl amine or a lower alkyl amine of the formula RN~I2, wherein R is an alkyl or allyl group of about 3-12 carbon atoms. Preferably the alkyl or allyl amine is one of int~ iAte chain-length wherein R is an alkyl group of 5-8 carbons, and most preferably, is n-heptyl amine.
The alkyl or allyl amine may be applied to the lens 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 on the lens surface. 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 dis_iosures of which are incorporated by ref erence .
~cor-l i n~ to thi3 invention, plasma deposition of the primary amine layer on the lens is generally carried out in two steps. First, the lens is placed in an electrical glow discharge apparatus, wherein a gaseous ~tmosphere is provided, te.g., argon), and then the gaseous atmosphere is subjected to an electrical glow discharge to clean the surface. The gas is then removed.
In the second step, 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 form an ultrathin coating of about 5-300 angstroms on the surf ace of the lens .
After the surface of the lens is treated with the amine, the lens surface containing the amine layer is then reacted with a polyethylene oxide. The polyethylene oxide should have terminal groups or caps which are reactive with the amine coating. Aldehyde terminated polyethylene oxides are especially preferred. Through 2l79o6l wo95/16475 Pcr/uS94/14650 this reaction of the polyethylene oxide and the amine attached to the lens surf ace in the presence of a reducing agent, a stable polyethylene oxide coating will be attached to the lens surf ace through the resultant covalent bonding. Such polyethylene oxides are known in the art, e.g. from the publication by ~arris, "Polymer Preprints", 32, 154 (lg91).
The alkyl or allyl amine is applied by plasma deposition as indicated above. In a preferred plucedu~ ~, the intraocular lens is first etched prior to amine deposition for best results. Preferably, etching of the surface is conducted by contact with argon. An argon flow rate in the range of 60-120 cm3/min, and a chamber pressure of 200-300 mTorr i9 satisfactory. In conducting the deposition, the intraocular lens is placed in a holder and centered in a plasma chamber with the desired argon flow rate to argon etch prior to amine deposition.
A container f or the amine is connected to the plasma chamber unit. The plasma chamber is then evacuated to its baseline pressure and, while under the argon ~low rate, is ignited for a short period, for example, 60N for six minutes. After the argon etch, 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. After the plasma is extinguished, 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 container such as a sealed microcentrifuge tube.
A polyethylene oxide (PEO), e.g., aldehyde capped polyethylene oxide, is dissolved in a buffer solution in a concentration in the range of 5-50 mg/ml and is preferably purified to remove any particulates. This 21 7qO61 Wo gsll6475 PCT/US94/146~0 solution is then added to each microcentrifuge tube containing the amine-plasma coated intraocular lens.
St~hi l; 7Ation of the coating on the lens is then carried out by treating the lens with an alkali metal borohydride dissolved in a buffer in a concentration of 10-50 mg/ml.
Reduction of the PEO amine bond with the alkali metal bUL~}~yL~lide will provide a stable PEO coating of about 5-500 Angstroms, prefera}~ly 100-300 Angstroms. ~ixing of the solution is preferably done by inverting the tube6.
The resulting samples are then heated at a low temperature, for example, 25-50C for about ten to thirty hours . In a preferred ~ L'Lt:LIULr', stAhi 1 i 7A~tion is repeated and the lenses are again heated. Each lens is then washed in deionized water and the water removed.
A preferred polyethylene oxide utilized in the present invention is an aldehyde-terminated polyethylene oxide which has a molecular weight in the range of 200 to lO0,000, preferably 1500-10,000. Such aldehyde-capped polyethylene oxides are known in the art, e.g., Harris, "Polymer Preprints", 32, 154 (1991). However, any polyethylene oxide having reactive t~rmi nA 1 groups may also be used in the invention.
The preferred stAhili7in~ agent is an alkali metal borohydride, most preferably sodium or potassium cy~nnh~.L~.~yLl~Lide of the formula NaCNBH3, a commercially available material.
An import,~nt aspect of the invention concerns st~ri l i 7ation of the coated lenses after preparation.
The lenses may be st~ri 1 i 7e~l using standard ethylene oxide st~ri 1 i 7A~tion and aeration to remove residual ethylene oxide. St~ri l i 7Ation with ethylene oxide L~ contact with 10-209~ ethylene oxide in a flllnrirll~ solvent for 1-4 hours at 10-40 psi and 40-60C., prefer~bly after preconditioning in a humid atmosphere.
35 However, according to this invention, it has been WO 9S/1647S 6 I~/usg4n46so discuv~L~:d that aqueous extraction rather than aeration ûf the residual ethylene oxide following st~ri 1 i 7Ation minimi70c loss of protein and cell rf~ Rinn ability of the polyethylene oxide coating. Aqueous extr~ction comprises contact of the lens with 1-3 ml of sterile water per lens while heating at a t~ eL~.Lu~e of about 25-60C. for 3-9 days. Theoretically, it appears the aqueous extraction prevents the polyethylene oxide chain from inverting. Also, since the water contains less oxygen than air, cleavage of the polyethylene oxide molec:ules may be reduced. It has been found that aqueous extraction ~ffir~ionr-y also increases with temperatures ranges from 35 to 60C and time from 3 to 14 days.
Residual ethylene oxide levels as low 6 ppm can be achieved. Further, the residual levels of epichlorohydrin and ethylene glycol which are byproducts of ethylene oxi~ extracted with water, are very low, i.e. less than 10 ppm and 50 ppm respectively. This is below industry 5tAn~ r~ so that extraction vials with water or buffers, for example, BSS, may also be used for final packaging.
The resulting intrAncl~1Ar lens will have the indicated i ~,v~d biocompatibility i n~ i n~ increased reistance to protein adsorption which makes the lens non-fouling and resistant to cell deposition.
The following examples are presented to illustrate the invention but the invention is not to be limited thereto. Parts are by weight unless otherwise indicated.
l~A~LI;: 1:
A. Surf ace Amination PN~LA IOLs (6mm, plano-convex, single piece or monoflex - PMMA or polypropylene haptics) are each placed in a butterfly lens holder and the lens holder then positioned in a cleaned glass-rack. The glass rack is Wo 95/l647s PCrNSs4/146~0 .
placed onto a larger glas ~ rack centered in the plasma chamber .
n-Heptylamine ~5.0g) is placed in a 250mL round bottom flask. The flask is connected via a rubber stopper to a metering-valve located at the front of the plasma chamber unit. With the needle valve to the heptylamine flask closed, the plasma chamber is evacuated to its baseline pressure of ~pproximately 13 mTorr. This condition is maintained for thirty minutes.
The IOLs are argon-etched prior to n-heptyl~mine deposition. At an argon flow rate of 90 cm3/min and a chamber ~L.~:iu-el of 250 mTorr, a plasma is ignited at 60W
f or 8iX minutes . Af ter the argon etch, the plasma chamber i9 evacuated to its baseline L)L~::SI:IUL_.
n-Heptylamine vapor is introduced into the chamber of the plasma unit. Vacuum pump speed is lowered and the chamber is allowed to equilibrate for ten minutes. The plasma i5 ignited and a thickness monitor is activated to record deposition. The plasma is maintained until a thickness monitor reading o~ 190 Any~iLLl - is achieved.
After the plasma is extinguished, the chamber conditions are maintained f or two minutes . Following this, the vacuum pump speed is returned to maximum and maintained for ten minutes. The chamber is brought u~? to ai ~heLic conditions by back-filling with argon. The s~mples are removed from their respective holders and each placed in a microcentrif uge tube containing PEO
solution .
wo95116475 11 2 1 7906 1 p~ S94/14650 B. PEO T 1 j 7s~tion Phosphate/Sulphate buffer: 7 . 838 grams Potassium Sulphate ( K2SO4 ) 0. 060 grams Sodium phosphate dibasic ( Na2HPO4 ) ~p10nizr~c~ Water to final volume of 100 mL
Heatiny is required to dissolve the K2SO4. Final pH
range 8 . 5-9 ~ 0 .
Nethoxy end-capped, dithiolaldehyde derivatized PEO
of molecular weight 5000 (designated MPEG5~;S2CHO), which can be made according to the procedure set forth in Harris et al., "Polymer Preprints", 32, 154 (1991), is dissolved in buffer at a concentration of 10 mg/mL. The solution is filtered through a fritted glass filter ( coarse ) to remove any particulates . IPEG5XS2CHO
solution (900 uL) is added to each microcentrifuge tube containing plasma-coated IOL. Sodium cyanoborohydride (NaCNBH3) is dissolved in the buffer at a concentration of 20 mg/mL. 10011L of this solution is added to each microcentrifuge tube containing plasma-coated IOL. Each solution is gently mixed by inverting the tubes ten times. The NaCNBH3 solution is hydrolytically unstable and should be prepared ~ust prior to its addition to the reaction solution.
The samples are then heated at 35C overnight (16-18 hours ) . The treatment with NaCNBH3 is repeated, and the samples heated at 35C for another four hours. Each IOL
sample is washed by consecutive dip-rinsing in three beakers containing 140 mL of deionized water. Each IOL
is then placed in 3mL rlr~i~ni7r~ water and sonicated for five minutes. This wash water is then replaced by fresh n i 7r~rl water and sonication repeated . This last sonication step is repeated. (Three sonications in total). Each IOL is removed from wash solution, the Wo 95/16475 2 1 7 9 0 6 1 PCT/US94/14650 excess water removed from the sample IOL, and then repackaged .
R~r~MPLE 2:
Biointeraction Studie8:
A. Protein Adsor~tion A6 fihrinngPn play6 a ~i~nific~nt role in the biocompatibility of implanted device6 in~ t-iing in~rancl-lAr len6es, its adsorption from single protein and multi-protein solutions was investigated. EIuman fihrinngen radiol~h~ with ~25Iodine was used to determine the amounts of adsorbed protein on the IOL
surface. Prior to exposure to protein solutions the IOL
s~tmples (without haptics) were incubated at 37C, for one hour in BSS (RAl~nced Salt Solution). In the single protein ~rr~ri L each IOL was incubated at 37C for one hour in a BSS solution containing 5 llg/mL of l25I-fibrinogen. For the multi-protein experiment IOLs were exposed to 1:5:16 mixtures of ~25I-fibrinogen, IgG and albumin at 37C for one hour. Fibrinogen concentrations at 125 ~tg~mL (Multi-protein A) and 62.5 ,~Lg~mL (Nulti-protein B ) were investigated . These protein concentrations were chosen to simulate post-operative human aqueous humor levels.
The protein adsorption re6ults are reported as fractions of the amount adsorbed on uncoated PMNA IOL
controls; and are ,i, rized in Table 1. The results of the single protein study lndicated that the heptylamine-plasma pre-coat marginally increased the amount of adsorbed f ;hrinngen over uncoated P~SA controls while the PEO coating reduced it by about 85~; PNNA adsorbed 158 +
30 ng/cm2 fibrinogen. Similar levels of reduction were observed when PEO coated IOLs were exposed to higher protein concentrations in the simulated post-operative aqueous humor. The presence of albumin and IgG appeared _ -Wo 9s/l647s 7 9 ~ 6pLnTS94J14650 .
not to significantly affect the amount of P~iqnrhr~d f i hri nngen .
Table 1: F~hrinngr~n Adsorption Co-~L~ ffl- SL=yl~ pro:~L~ ~ulel-p~o~L= A~ Hulri-p~ L= 3 (=oi~ulL~d)~ ~=oir~lLi~-d) (=oiRl lLi~d) d~p~y~ ' F 1 10 + 0.09 1 53 + 0 37 ---____ (= - 2~) (= - 2) PE0 0 13 + 0 09 0 11 + 0.06 0 10 + 0 05 (= - 2~) (= - Il) ~n - ~) ~Amount i~r~qr~rh~rl nnrr~li7er1 against that oi PMMA
controls .
~Fibrinogen ~125~Lg/mL), IgG (625 llg/mL) and Albumin (2 10 mg/mL) ~Fibrinogen (62.5 ~g/mL), IgG (312.5 llg/mL) and Albumin ( 1 mg /mL ) B . T _ _ ld Staininq To visualize the pattern of ~ qnrhPd f i hri nngen on IOL surfaces and to draw some inferences about the uniformity of PEO coating, a method involving antibodies linked with gold was utilized. IOL surfaces were first exposed to solutions of f i hri nngen ( single protein adsorption ) and then incubated in the presence of rabbit anti-human fihrinngen antibody. The samples were subsequently reacted with goat anti-rabbit IgG-gold complex, i ~lified with silver particles and observed under a light microscope ~100-400 X ---~nifice,tions). A
uniform coating of gold-silver was observed on both PMMA
and heptylamine-plasma coated surfaces while PEO surfaces appeared to be free of gold indicating little or no adsorbed protein.
- C. Cell interactions (i) Human Macror~haqe Activation: Surface induced - 30 release of hydrogen peroxide from human macrophages was used to model the inf lammatory response to PEO coated Wo 95/16475 PCrlUSs4/14650 .
IOLs . As adsorbed protein can inf luence the extent of activation, the samples were pre-exposed to simulated post-surgical aqueous humor solution under experimental conditions similar to those described for the multi-protein adsorption study. The foLlowing methods describe how cultured human macrophages were seeded onto the IOL
optic surface in serum-free culture medium for 2 hours at 37 C, followed by incubation in a phenol red-horseradish peroxidase solution for l hour at 37C. After removing and making this solution AlkZ~l ino~ the peroxide concentration was deto~minod at 630 nm. The results were reported as nntT-lizo-i values (against P~A) and ~ummari~ed in Table 2. The results indicated that the PEO coating significantly reduced acute macrophage activation on P~A IOLs.
Table 2: Human ~acropha~e Interactions.
Surf ace HzO2 Production ~ normalized P~A l.00 + 0.l9 (n = 5) PEO 0 . 20 + 0 . l0 (n = 7) ( ii ) Rabbit Lens EPithelial Cell Interaction: Along with repelling proteins from the surface of an implant, another function of immobilized PEO is to prevent the attachment and growth of cells (macrophages, neutrophils, epithelial cells, fibroblasts, etc. ) which can ultimately lead to device failure. To quantify the potential of adhesion and growth of celLs on the PEO coating an assay nvolving the incorporation of 3H-thymidine into the DNA
of mitotic rabbit lens epithelial cells (LEC) was utilized. It should be noted that this assay was not intended as a method for assessing the ability of the PEO
coating to prevent posterior capsule opacification.
Briefly, the assay involved seeding cultured LEC onto the optic surfz~ce of both coated and uncoated IOLs in culture medium containing 596 serum and 3H-thymidine, followed by incubation for 2 days at 37C. The cells were then fixed in 2~ glutaraldehyde and their levels of radioactivity detPrmi nF.rl .
To investigate the role of protein adsorption on the growth of LEC, the assay was performed on bare surfaces as well as those pre-exposed to simulated post-surgical aqueous humor. As shown in Table 3, the PEO coating was unable to support the .9~1hl~c ~ ~n and growth of LEC
ilLe~e. Live of whether proteins were pre-adsorbed to the surf ace . Examination of the surf aces by phase-contrast light microscopy revealed only a few round cells on the PEO surface, while a fully confluent layer of spread cells was observed on P~A and tissue-culture polystyrene controls. Rounded cells result from their inability to attach and spread on substrate surface. In the confluent layer the cells attained their natural polygonal morphology. It was interesting to note that pre-adsorption of protein to PN~A resulted in significantly more cell growth on the surface.
Table 3: Rabbit Lens EPithelial Cell Interactions Surface Normalized cell ~rowth PMNA 1 . 00 + O . 032 (n = 5)~
PEO* 0 . 010 + 0 . 005 (n = 5) PEO 0 . 021 + 0 . 028 (n = 5) - * pre-exposed to simulated post-surgical aqueous humor ** n is number test samples.
~IO 95ll6475 2 1 7 9 0 6 1 PCr/US94114650 .
EXA!iPLE 3 Sterilization Studies The polyethylene oxide coated IOLs were sterilized with 12% ethylene oxide (in Freon) ~or two hours at 22-24 psi and 46C, after a one hour preconditioning in a 60%
relative humidity atmosphere. Each stPri 1 i 7c~sl lens was then tr2nsferred to 3 mls of sterile water and heated at 60C ~or 7 days. The lenses were then stored ~at RT) in this solution until used.
Results of a f 1 hr; nngPn adsorption assay, shown in table, indicated that aqueous extraction restores the efficacy of the coating.
RESULTS
Table: Nnrr~l i ze~ Fibrinogen Adsorption 15 EO Sterilized O~ly EO Sterilized and EO Sterilized ~
Aerated Aqueous Extracted 0.35 + 0.20 0.6 + 0.14 0.18 + 0.09 n = 9 n = 8 n = 5 Amount of fihrin~gPn P~i~orhe~ on each lens was nnrr~ 1 i 7P~i against that on PMMA control .
* Following stPrili7Jltion aerate for 8.5 days at 49C~
2C under atmospheric lJL~SaUL~.
The invention has been r~P~rrl he-l herein with reference to certain preferred . ' 'i ts; however, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.
Claims (24)
1. An intraocular lens having improved biocompatibility, said lens containing a coating of a polyethylene oxide covalently bonded to the lens.
2. An intraocular lens according to claim 1 wherein the improved biocompatibility comprises resistance to protein adsorption when the lens is inserted in the eye, and where the polyethylene oxide coating is about 5-500 Angstroms in thickness.
3. An intraocular lens according to claim 1 wherein the covalent bonding is an amine bond as an intermediate layer on said lens.
4. An intraocular lens according to claim 1 wherein the lens is a PMMA lens.
5. An intraocular lens according to claim 1 wherein the lens is a soft acrylate lens.
6. An intraocular lens according to claim 1 which has been sterilized with ethylene oxide (ETO) and then residual ETO is extracted with water.
7. An intraocular lens having improved biocompatibility, said lens being a PMMA lens coated with polyethylene oxide through amine covalent bonding, wherein an amine coating is formed from plasma deposition of a normal alkyl amine or allyl amine having about 3-12 carbon atoms, and the polyethylene oxide coating attaches to the lens surface by reaction of terminal aldehyde groups with the active primary amine in the groups deposited coating.
8. An intraocular lens according to claim 7 wherein the amine is n-heptyl amine.
9. An intraocular lens according to claim 2 wherein the polyethylene oxide coating is about 100-300 Angstroms in thickness.
10. An intraocular lens having improved biocompatibility, said lens being a soft acrylate lens coated with polyethylene oxide through amine covalent bonding, wherein an amine coating is formed from plasma deposition of a normal alkyl amine or allyl amine having about 3-12 carbon atoms, and the polyethylene oxide coating attaches to the lens surface by reaction of terminal aldehyde groups with the active primary amine groups in the deposited coating.
11. An intraocular lens according to claim 10 wherein the amine is n-heptyl amine.
12. An intraocular lens according to claim 10 wherein the acrylate comprises a copolymer with an elongation of at least 150% wherein said copolymer is comprised of 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.
13. An intraocular lens according to claim 10 wherein the acrylate comprises a copolymer with an elongation of at least 150% comprised of two monomers, the first of which is 2-phenylethyl acrylate, the second of which is 2-phenylethyl methacrylate, and a cross-linking monomer 1,4-butanediol diacrylate.
14. The intraocular lens of claim 10 wherein the first monomer is present at a concentration about 65 wt.%
and the second monomer is present at a concentration of about 30 wt.%.
and the second monomer is present at a concentration of about 30 wt.%.
15. The intraocular lens of claim 10 wherein said cross-linking monomer is 1,4-butanediol diacrylate.
16. The intraocular lens of claim 10 further comprising an ultraviolet absorbing material.
17. The intraocular lens of claim 16 wherein the ultraviolet absorbing material is 2-(3'-methallyl'-2-hydroxy-5'-methyl-phenyl) benzotriazole.
18. An intraocular lens having improved biocompatibility, said lens being coated with polyethylene oxide through amine covalent bonding, wherein an amine coating is formed from plasma deposition of a normal alkyl amine or allyl amine having about 3-12 carbon atoms, and the polyethylene oxide coating attaches to the lens surface by reaction of terminal aldehyde groups with the active primary amine in the groups deposited coating, said lens then being sterilized with ethylene oxide and then extracted with water.
19. An intraocular lens according to claim 6, wherein the amine is n-heptyl amine.
20. A method for the production of an intraocular lens having improved biocompatibility which comprises coating said lens with polyethylene oxide through covalent bonding by the process steps comprising:
1 ) plasma depositing an n-alkyl amine or allyl amine on the lens surf ace to create an active primary amine layer;
2) reacting the amine treated lens having the active primary amine layer with an aldehyde-terminated polyethylene oxide; and 3) Stabilizing the coated lens.
1 ) plasma depositing an n-alkyl amine or allyl amine on the lens surf ace to create an active primary amine layer;
2) reacting the amine treated lens having the active primary amine layer with an aldehyde-terminated polyethylene oxide; and 3) Stabilizing the coated lens.
21. A method according to claim 20 wherein the n-alkyl amine is n-heptyl amine.
22. A method according to claim 20 wherein stabilization is carried out by treating the coated lens with an alkali metal borohydride.
23. A method according to claim 20 wherein the amine PEO coating as a thickness of about 5-500 Angstroms.
24. A method according to claim 20 wherein the coated lens is then sterilized with ethylene oxide and extracted with water to remove unreacted ethylene oxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/166,033 US5618316A (en) | 1993-12-14 | 1993-12-14 | Polyethylene oxide coated intraocular lens |
| US08/166,033 | 1993-12-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2179061A1 true CA2179061A1 (en) | 1995-06-22 |
Family
ID=22601521
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002179061A Abandoned CA2179061A1 (en) | 1993-12-14 | 1994-12-14 | Polyethylene oxide coated intraocular lens |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5618316A (en) |
| EP (1) | EP0734269B1 (en) |
| JP (1) | JP3553954B2 (en) |
| AT (1) | ATE209050T1 (en) |
| AU (1) | AU694474B2 (en) |
| CA (1) | CA2179061A1 (en) |
| DE (1) | DE69429189T2 (en) |
| ES (1) | ES2168353T3 (en) |
| WO (1) | WO1995016475A1 (en) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9403392D0 (en) * | 1994-10-06 | 1994-10-06 | Pharmacia Ab | Intraocular lens materials |
| US5507804A (en) * | 1994-11-16 | 1996-04-16 | Alcon Laboratories, Inc. | Cross-linked polyethylene oxide coatings to improve the biocompatibility of implantable medical devices |
| WO1996014887A1 (en) * | 1994-11-16 | 1996-05-23 | Alcon Laboratories, Inc. | Cross-linked polyethylene oxide coatings to improve the biocompatibility of implantable medical devices |
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-
1993
- 1993-12-14 US US08/166,033 patent/US5618316A/en not_active Expired - Fee Related
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1994
- 1994-12-14 AU AU14402/95A patent/AU694474B2/en not_active Ceased
- 1994-12-14 DE DE69429189T patent/DE69429189T2/en not_active Expired - Fee Related
- 1994-12-14 CA CA002179061A patent/CA2179061A1/en not_active Abandoned
- 1994-12-14 WO PCT/US1994/014650 patent/WO1995016475A1/en active IP Right Grant
- 1994-12-14 EP EP95906016A patent/EP0734269B1/en not_active Expired - Lifetime
- 1994-12-14 AT AT95906016T patent/ATE209050T1/en not_active IP Right Cessation
- 1994-12-14 JP JP51701095A patent/JP3553954B2/en not_active Expired - Fee Related
- 1994-12-14 ES ES95906016T patent/ES2168353T3/en not_active Expired - Lifetime
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|---|---|
| DE69429189T2 (en) | 2002-04-18 |
| AU1440295A (en) | 1995-07-03 |
| US5618316A (en) | 1997-04-08 |
| WO1995016475A1 (en) | 1995-06-22 |
| JPH09506795A (en) | 1997-07-08 |
| EP0734269B1 (en) | 2001-11-21 |
| JP3553954B2 (en) | 2004-08-11 |
| AU694474B2 (en) | 1998-07-23 |
| DE69429189D1 (en) | 2002-01-03 |
| EP0734269A1 (en) | 1996-10-02 |
| ES2168353T3 (en) | 2002-06-16 |
| ATE209050T1 (en) | 2001-12-15 |
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| EEER | Examination request | ||
| FZDE | Discontinued |