Methods and Materials for Minimizing Posterior Capsule Opacification of Intraocular Lens

127400 A2 ||||||||||||||||||||||||||||||||||||||||||ll||||||||||||||||||||||||||||||||||||||||||||||||||| (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization A International Bureau '‘ ||||||||||||||ll||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (10) International Publication Number WO 2007/127 400 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every (43) International Publication Date 8 November 2007 (08.11.2007) A6IF 2/16 (2006.01) kind of national protection available ): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (21) International Application Number: CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, PCT/US2007/010292 FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, (22) International Filing Date: 28 April 2007 (28.04.2007) LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, R0, (25) Filing Language, English RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 26 P bli t‘ L : E 1' h ( ) u ca Ion anguage ng IS (84) Designated States (unless otherwise indicated for every kind of regional protection available ): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (30) Priority Data: 60/745,941 28 April 2006 (28.04.2006) US 60/745,944 28 April 2006 (28.04.2006) US (71) Applicant (for all designated States except US ): IN- NOVIA, LLC [US/US]; 12415 SW 136 Avenue, Unit 3, Miami, FL 33186 (US). Published: (72) Inventor? and — without international search report and to be republished (75) Inventor/Applicant (for US only): PINCHUK, Leonard ttpert reeetpt of that report [US/US]; 13704 SW. 92nd Court, Miami, FL 33176 (US). For two—letter codes and other abbreviations, refer to the ”Guid— (74) Agent: GORDON, David P.; Gordon & Jacobson, P.C., 60 ance Notes on Codes and Abbreviations " appearing at the begin- Long Ridge Road, Suite 407, Stamford, CT 06902 (US). ning of each regular issue of the PCT Gazette. (54) Title: METHODS AND MATERIALS FOR MINIMIZING POSTERIOR CAPSULE OPACIFICATION OF INTRAOCU— LAR LENS R (57) Abstract: Polymeric materials and methods that realize a gel—type intraocular lens that is formed in situ within the lens capsule 3 of the eye. The polymeric material of the intraocular lens includes reactive end groups that effectively bond with lens capsule walls, 3 thus eliminating space between the intraocular lens and the lens capsule walls and significantly reducing the proliferation of lens (‘S epithelial cells which can cause unwanted posterior capsule opacification. In another aspect, various polymers are provided that can be polymerized in the lens capsule with the ability to bond an intraocular lens implant to the posterior capsule of the eye such that there is no space available between the intraocular lens implant and the lens capsule for lens epithelial cells to proliferate and thereby g significantly reducing posterior capsule opacification. WO 2007/127400 PCT/US2007/010292 METHODS AND MATERIALS FOR MINIMIZING POSTERIOR CAPSULE OPACIFICATION OF INTRAOCULAR LENS BACKGROUND OF THE INVENTION 1. .Field of the Invention [0001] This invention relates broadly to artificial lens implants for the eye. 2. State of the Art [0002] One focus of research in cataract surgery is the replacement of the natural crystalline lens of the eye with a gel-type intraocular lens (IOL) that can adjust with contraction and relaxation of the muscles of the eye. The muscles of the eye that control this adjustment are called the zonules. The ideal gel-type replacement intraocular lens is often referred to as a phako—ersatz lens and it differs from the currently used pseudo-phakic lens in that it can theoretically accommodate over 8 diopters of change, whereas the current generation of pseudo-phakic lenses can accommodate at most 2-3 diopters. An example of a commercially—avaiIable pseudo-phakic lens is marketed under the trade name Crystalensm, which move slightly forwards or backwards due to pressure built up in the posterior chamber of the eye. [0003] ' The natural crystalline lens is a ge1—like material that sits within the lens capsule of the eye and when the lens capsule is stretched by the zonules, the gel changes its thickness and therefore its focal point thereby allowing focusing at different distances. The phako—ersatz lens must therefore be a gel or viscous liquid (hereinafter referred to as a “gel”) with a relatively fast response time. Children have the ability to accommodate over 15 diopters. People over the age of 45 can generally accommodate between 1 to 3 diopters due to the stiffening of the lens which occurs with age. People over 50 generally accommodate less than 2 diopters. This lack of accommodation is called presbyopia. [0004] It is also desirable that the gel be placed in the eye through a small opening. It is more preferable that the gel be injected in the eye through a needle or cannula as a liquid and then converted into a gel by a polymerization reaction (usually initiated by light). Although there are gels that approach these capabilities, such as silicone-based 3013. there h3VC 136611 WO 2007/127400 PCT/US2007/010292 some extraneous limitations that have prevented their success in the field. One of these limitations has been the well-known problem of posterior capsule opacification (PCO). [0005] When the natural lens is removed from the lens capsule, lens epithelial cells (LECS) begin to multiply and spread on the posterior capsule and effectively render the posterior capsule opaque, which results in impaired vision. The LEC's also spread on the anterior wall. However, due to the large opening in the anterior capsule (the capsulorrhexus), there is no wall for them to spread onto. The occurrence of PCO is relatively high in traditional IOL implantations where the LECS spread between the IOL and the lens capsule. There have been lOL designs where the sharpness of the corners of the lens prevents cellular migration under the lens; however, recent literature suggests that these geometrical features simply retard the progression of PCO. PCO occurs in approximately 40% of IOL recipients within two years of receiving a synthetic lens. The usual treatment for PCO is laser ablation of the posterior capsule where a laser is used to vaporize the posterior capsule and the cells that adhere to it. However, when a gel is present in the capsule, as required for a phako-ersatz-type procedure, the posterior wall cannot be ablated as the gelled lens will extrude out of the capsule. Further the phako—ersat_z gel does not have sharp corners to prevent LEC migration. Therefore, the presence of PCO has been a major limiting factor in achieving the phalco-ersatz lens. Thus, there is a need for a better material to form a phako-ersatz lens that significantly reduces PCO. SUMMARY OF THE INVENTION [0006] It is therefore an object of the invention to provide an artificial intraocular lens of a gcl—type polymeric material that significantly reduces PCO. [0007] It is another object of the invention to provide such an intraocular lens that chemically bonds to the walls of the lens capsule of the eye in order to limit the invasion of lens epithelial cells between the intraocular lens and the lens capsule and thus significantly _ reduces PCO. [0008] It is yet another object of the invention to provide such an intraocular lens which is synthesized in—situ by injecting a polymer fluid into the lens capsule, the polymer fluid transformed into a gel-type intraocular lens by a polymerization reaction that takes place in the lens capsule of the eye. WO 2007/127400 PCT/US2007/010292 [0009] It is still another object of the invention to provide such an intraocular lens wherein the polymer fluid that is injected into the lens capsule is a multi-part polymer including a pre- polymer and an initiator that are transformed into a gel-type intraocular lens by a polymerization reaction that takes place in the lens capsule of the eye. [0010] It is yet another object of the invention to provide such an intraocular lens wherein the in situ polymerization reaction that forms the gel—type intraocular lens is initiated (and/or accelerated) by moisture within the lens capsule and/or proteins of the lens capsule of the eye. [0011] It is another object of the invention to provide such an intraocular lens that can adjust with contraction and relaxation of the muscles of the eye, i.e., a phako—ersatz lens. [0012] It is yet another object of the invention to provide polymeric material suitable for injection into the eye to realize such an intraocular lens. [0013] In accord with these objects, which will be discussed in detail below, polymeric materials and methods are disclosed that realize a gel-type intraocular lens that is formed in situ within the lens capsule of the eye. The polymeric material that realizes the intraocular lens includes reactive end groups that effectively bond with lens capsule walls, thus eliminating. space between the intraocular lens and the lens capsule walls and significantly reducing the proliferation of lens epithelial cells which can cause unwanted posterior capsule opacification. The polymeric material of the present invention can include i) a prepolymer of polyisobutylene with isocyanate end groups, ii) polyurethanes and polyurethaneureas, iii) cpoxides, iv) cyanoacrylates, v) proteinacious polymers, and vi) carbohydrates or polysaccharides as described below in more detail. [0014] In another aspect of the invention, various polymers are provided that can be polymerized in the lens capsule with the ability to covalently bond an IOL to the posterior capsule of the eye such that there is no space available between the IOL implant and the lens capsule for the LECs to proliferate and thereby significantly reducing PCO. [0015] Additional objects and advantages of the invention will become apparent to those skilled in the art of ocular implants upon reference to the detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS WO 2007/127400 PCT/US2007/010292 [0016] In accordance with the present invention, a polymeric material is provided that includes end groups that react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. The nucleophiles of the lens capsule walls can include hydroxyl groups, amine groups, and sulfur groups. If in non—fluid form, the polymeric material can be placed in a fluid form suitable for injection into the lens capsule of the eye. A small capsulorrhexus (preferably of less than 2mm in diameter) is made in the anterior section of the lens capsule and the natural lens removed by phako emulsification and the like. A miniature diaphragm valve can be placed over the capsulorrhexus and secured in place. The polymeric fluid is injected into the lens capsule of the eye where the polymeric material undergoes a polymerization reaction in situ at the site of the lens capsule. As part of the polymerization reaction, the reactive end groups of the polymeric material react to form the gel-type intraocular lens. Simultaneous to polymerization reaction, the reactive end groups also react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. The end result is a gel-type intraocular lens that is chemically bound to the lens capsule walls of the eye. The chemical bond between the gel-type intraocular lens and the lens capsule walls limits the invasion of lens epithelial cells therebetween and thus significantly reduces PCO. The polymeric material of the present invention can include i) a prepolymer of polyisobutylene with isocyanate end groups, ii) polyurethanes and polyurethaneureas, iii) epoxides, iv) cyanoacrylates, v) proteinacious polymers, and vi) carbohydrates or polysaccharides as described below in more detail. Prepolymer of polyisobutylene with isocyanate end groups [001 7] In accordance with the present invention, a prepolymer of polyisobutylene with isocyanate end groups is provided. The prepolymer can be bifunctional and linear or multifunctional and starred. The isocyanate-terminated prepolymer can be loaded into the first barrel of a two barrel syringe. A reactive co-polymer is loaded into the second barrel of the two barrel syringe. An exemplary reactive co-polymer is a prepolymer of polyisobutylene with hydroxyl or amine end groups. The syringe is preferably realized from polypropylene and is free of air, moisture and any other nucleophile. The isocyanate—terminated prepolymer and the reactive co-polymer are preferably clear with a refractive index between 1.40 and 1.53. The streams from the two barrels of the syringe are merged in a static mixer located on the exit of the syringe. The mixture produced at the exit of the syringe, which is typically a viscous fluid, is injected into the lens capsule through the cansulorrhexus in the anterior section as WO 2007/127400 PCT/US2007/010292 described above. The isocyanate-terminated prepolymer will react with the reactive co- polymer within the lens capsule to form a gel-type intraocular lens. Simultaneous to this polymerization reaction, the reactive isocyanates of the prepolymer component chemically react with the nucleophiles (amine groups) of the lens capsule walls, thereby forming a chemical bond between the gel—type intraocular lens and the lens capsule walls by formation of urea linkage. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. The reaction between the isocyanates of the prepolymer component and the nucleophiles (amine groups) of the lens capsule walls does not produce a byproduct that can otherwise be toxic to the eye. The resultant polymer of the gel—type intraocular lens is preferably clear with a refractive index between 1.40 and 1.53. In the preferred embodiment, the gel-type intraocular lens accommodates with contraction and relaxation of the muscles of the eye and thus operates as a phako-ersatz lens. ‘ [0018] Altematively, the isocyanate-terminated prepolymer and the reactive co-polymer can be premixed prior to loading into a syringe and the contents injected into the lens capsule. In this embodiment, slow reacting components must be used to enable flow through the syringe prior to polymerization. Polyurethanes and Polyurethaneureas [001 9] Polyurethanes and polyurethaneureas are typically comprised of at least two components: an isocyanate-terminated prepolymer and a multinucleophilic co-polymer. An example of a polyurethane is the combination of a multiisocyanate such as the reaction product of a branched polytetramethylene macroglycol reacted with methylene bisphenyl diisocyanate (MDI) to provide a prepolymer that is isocyanate terminated. The multinucleophilic co- polymer can be the same macroglycol, such as polytetramethylene glycol that is terminated with hydroxyl groups. The hydroxyl groups of the multinucleophilic co-polymer react with the isocyanate groups of the multiisocyanate to produce a‘high molecular weight polyether urethane. This polyether urethane can be tailored to provide specific properties by adding chain extenders to the nucleophilic component of the polymer system, such as ethylene glycol and the like. Some polyurethanes are more stable than others in the body. U.S. Patent No. 5,133,742, the details of which are herein incorporated by reference in its entirety, describes methods for increasing the biostability of these polymers. WO 2007/127400 PCT/US2007/010292 [0020] In accordance with the present invention, a low molecular weight isocyanate- terminated prepolymer can be ‘synthesized and loaded into the first barrel of a two barrel syringe. A hydroxyl—terminated co-polymer is loaded into the second barrel of the two barrel syringe. The streams from the two barrels of the syringe are merged in a static mixer (e.g., baffles) located on the exit of the syringe. The mixture produced at the exit of the syringe, which is typically a viscous fluid, is injected into the lens capsule through the capsulorrhexus in the anterior section as described above. The isocyanate-terminated prepolymer and the hydroxl—terminated co-polymer are preferably clear with a refractive index between 1.40 and 1.53. The isocyanate-terminated prepolymer will react with the hydroxyl-terminated co- polymer within the lens capsule to form a gel-type intraocular lens. Simultaneous to this polymerization reaction, the reactive isocyanates of the prepolymer component chemically react with the nucleophiles of the lens capsule walls, thereby forming a chemical bond between the gel—type intraocular lens and the lens capsule walls. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. The resulting gel-type intraocular lens is preferably clear with a refractive index between 1.40 and 1.53. In the preferred embodiment, the gel—type intraocular lens accommodates with contraction and relaxation of the muscles of the eye. and thus operates as a phako-ersatz lens. [0021] Alternatively, the isocyanate—terminated prepolymer and the hydroxyl-terminated co-polymer can be premixed prior to loading into a syringe and the contents injected into the lens capsule. In this embodiment, slow reacting components must be used to enable flow through the syringe prior to polymerization. [0022] An exemplary hydroxyl-terminated co-polymer that can be used in this capacity is a polyisobutylene (PIB) diol as it will provide a rubbery polyurethane—based gel that is biostable. Other hydroxyl-terminated co-polymers are perfluropolyethyleneglycol polytetramethyleneglycol, poly(hcxamethylene carbonate)diol, and the like. Preferably the macroglycol is biostable and has an index of refraction between 1.40 and 1.53. Y Epoxies [0023] Epoxies function in a manner similar to polyurethanes but include an epoxide- terminated prepolymer (rather than the isocyanate~terminate prepolymer) and a multinucleophilic co-polymer. The epoxide-terminated prepolymer and the multinucleophilic WO 2007/127400 PCT/US2007/010292 co-polymer are mixed and the resulting mixture is injected into the lens capsule through the capsulorrhexus in the anterior section as described above. The epoxide-terminated prepolymer will react with the multinucleophilic.co—polymer within the lens capsule to form a gel—type intraocular lens. Simultaneous to this polymerization reaction, the reactive epoxide groups of the prepolymer component chemically react with the nucleophiles of the lens capsule walls, thereby forming a chemical bond between the gel-type intraocular lens and the lens capsule walls. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. In the preferred embodiment, the gel-type intraocular lens accommodates with contraction and relaxation of the muscles of the eye and thus operates as a phako-ersatz lens. [0024] Suitable epoxies include glycidyl-terminated polytetramethylene glycol, glycidyl- terminated polyisobutylene, glycidyl terminated perfluroethyleneoxide, and the like. [0025] In an exemplary embodiment, two barrels of a syringe are loaded with an epoxide- terminated prepolymer (Part A) and a nucleophile reactant (Part B), respectively. The streams from the two barrels of the syringe are merged in a static mixer located on the exit of the J syringe. The mixture produced at the exit of the syringe, which is typically a viscous fluid, is injected into the lens capsule for in situ polymerization into a gel over a few minutes. Such polymerization forms a gel-type intraocular lens. Simultaneous to this polymerization ’ reaction, the reactive epoxides of the prepolymer component (part A) will chemically react with the nucleophiles of the lens capsule walls, thereby forming a chemical bond between the gel—type intraocular lens and the lens capsule walls. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. The epoxide—terminated prepolymer and the nucleophile reactant as well as the resulting gel-type intraocular lens are preferably clear with a refractive index between 1.40 and 1.53. In the preferred embodiment, the gel—type intraocular lens accommodates with contraction and relaxation of the muscles of the eye and thus operates as a phako—ersatz lens. [0026] Alternatively, the epoxide—terminated prepolymer and the multinucleophilic co- polymer epoxy can be premixed prior to loading into a syringe and the contents injected into the lens capsule. In this embodiment, a slow reacting epoxy, such as the 5 minute epoxies, must be used to enable flow through the syringe prior to polymerization. WO 2007/127400 PCT/US2007/010292 C anoac lates CA [0027] In accordance with the invention, a polymeric material with cyanoacrylate end groups is provided that readily transforms to a soft rubbery gel (e.g., shore A=20) in the lens capsule upon contact with moisture and/or proteins within the lens capsule to form a gel-type intraocular lens. Simultaneous to this polymerization reaction, the reactive cyanoacrylate groups chemically react with the nucleophiles of the lens capsule walls, thereby forming a chemical bond between the gel-type intraocular lens and the lens capsule walls. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. The cyanoacrylate—terminated polymer as well as the resulting gel—type intraocular lens are preferably clear with a refractive index between 1.40 and 1.53. .In the preferred embodiment, the gel—type intraocular lens accommodates with contraction and relaxation of the muscles of the eye and thus operates as a phako-ersatz lens. [0028] Suitable cyanoacrylate (CA) terminated materials that yield soft rubber—like gels upon contact with moisture and/or proteins within the lens capsule include: i) 3—arm star cyanoacrylate (CA)—telechelic PIB [®(PIB-CA)3]; ii) CA-PDMS—CA where PDMS is poly(climethyl siloxane); iii) CA-PEG-CA where PEG is polyethylene glycol; and iv) CA-PEG-b-PDMS—b—PEG—CA. A liquid form cyanoacrylate-based material (such as liquid CA-PDMS—CA) can be used as such (in bulk). Preferably, it is loaded into a syringe and injected into the lens capsule from the syringe. Alternatively, a non-fluid form cyanoacrylate—based material (such as crystalline PEG—based material) is preferably dissolved in a suitable solvent (such as DMSO, a non-protic, biocompatible FDA approved solvent) to render the prepolymer injectable. The cyanoacrylation method seems to be of general applicability and can be used for the cyanoac lation of a reat variety of hydroxide-containing molecules. 1")’ 8 [0029] Aromatic silicone cyanoacrylates can also be used which have a higher refractive index. A PlB—based cyanoacrylate material can also be used. Such material has an even higher refractive index. WO 2007/127400 PCT/US2007/010292 [0030] A table of other potential cyanoacrylate—based materials follows below. An initiator component (e.g., N,N—dimethyl-p-toluidine in n-C51-1,4) can also be mixed with a cyanoacrylate-based material to ensure completeness of the reaction that forms the gel-type intraocular lens. The F n number in the chart below represents the functionality number of the polymer material and relates to the number of end groups per mole of the polymer material. WO 2007/127400 PCT/US2007/010292 ll) too soft to measure even by Shore A I08‘/o in hexanes light brown. big'h|y viscous. not injeetable by N.N—dimethyl— p-toluidine in "'C6Hu egg yolk crosslinks (hard to separate egg yolk and oi mer N,N-d'Lmethyi- crosslinks during storage p-toluidine in within 2-3 days, n-C6H;4 sol fraction 5% in THF crosslintu upon contact with initiator sol fraction 15% in THF viscosity liquid, flows freely, injectable by too sofi to measure even by Shore A crosslinks during storage within 2-3 days, sol fraction 10% in THF light brown, low viscosity liquid, flows freely, injectable by syringe N,N-dimethyl- p-toluidinc in I1-CaHu crosslinks (hard to separate egg yolk and egg yolk polymer) glass surface crosslinks during storage (moisture) within 2-3 days, sticks to lassware 2000 too soft to measure even by Shore A brown solid soluble in DMSO. solution syringible, crosslinks upon contact with moisture, crosslinks during storage in less thanlhr, becomes rubbery upon DMSO addition. solubility limit in DMSO: 50wt% erosslinks experiment to be repeated with F,.-2.0 triblock l010% (in water) 612% (in DMSO) glass surface (moisture) THF extracted product: too soil to measure even by Shore A light brown, low viscosity liquid, flows freely, injectablc by s rin e N.N-dimethyl- p-toluidine in THF WO 2007/127400 PCT/US2007/010292 11 Proteinacious polymers and carbohydrates or polysaccharides [0031] Proteinacious polymers can also be used in this invention. Here, slurries of collagen, elastin, and/or other peptides can be mixed with one or more cross-linking agents (such as formaldehyde, gluteraldehyde, carbodiimide and the like) and injected into the lens capsule through the capsulorrhexus in the anterior section as described above. The cross- linking agent reacts with the proteinacious polymer to form a gel-type intraocular lens. Simultaneous to this cross—linking reaction, the cross-linking agent chemically reacts with the nucleophiles of the lens capsule walls, thereby forming a chemical bond between the gel-type intraocular lens and the lens capsule walls. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. The proteinacious polymer and the cross— linking agent(s) as well as the resulting gel-type intraocular lens are preferably clear with a refractive index between 1.40 and 1.53. In the preferred embodiment, the gel-type intraocular lens accommodates with contraction and relaxation of the muscles of the eye and thus operates as a phako-ersatz lens. [0032] Similarly, carbohydrate or polysaccharide gel-like materials can be used for this purpose. Such gel like materials can include alginate, pectin, carrageenan, gellan, starch and the like. The gel like materials are mixed with one or more cross—linking agents (such as multivalent cations including calcium chloride, barium chloride and the like; more permanent cross—linking agents can also be used including the epoxides and the multiisocyanates as described above). This mixture is injected into the lens capsule through the capsulorrhexus in the anterior section as described above. The cross-linking agent reacts with the gel-like material to form a gel-type intraocular lens. Simultaneous to this cross—linking reaction, the cross-linking agent chemically reacts with the nucleophiles of the lens capsule walls, thereby forming a chemical bond between the gel-type intraocular lens and the lens capsule walls. Such chemical bonding eliminates spaces where lens epithelial cells can migrate and cause PCO. The carbohydrate or polysaccharide gel-like materials and the cross—linking agent(s) as well as the resulting gel-type intraocular lens are preferably clear with a refractive index between 1.40 -and 1.53. In the preferred embodiment, the gel-type intraocular lens accommodates with contraction and relaxation of thelmuscles of the eye and thus operates as a phako-ersatz lens. WO 2007/127400 PCT/US2007/010292 12 [0033] In another aspect of the invention, a polymeric adhesive is provided that is synthesized in the lens capsule. The polymeric adhesive reacts with or otherwise adheres to an IOL implant and also reacts with the nucleophiles of the posterior capsule. The polymer adhesive bonds the IOL implant to the posterior capsule, thereby eliminating space between the IOL implant and the posterior capsule where cells can migrate and thus significantly reducing PCO. [0034] In one embodiment, a thin layer of polymeric adhesive material is spread over the posterior capsule. The IOL implant is placed in contact with the thin layer of polymeric adhesive material. The thin polymeric adhesive material reacts with or otherwise adheres to the IOL implant and reacts with the nucleophiles of the posterior capsule to effectively bond the IOL. implant to the posterior capsule, thereby eliminating space between the IOL implant and the posterior capsule where cells can migrate. PCO is thereby significantly reduced. [0035] in another embodiment, the polymeric adhesive material is encapsulated in one or more breakable microcapsules and placed on the IOL implant. Subsequent breakage of the microcapsule(s) dispenses the polymeric adhesive material onto the posterior capsule. The polymeric adhesive material is synthesized in the lens capsule and reacts with the IOL implant and with the nucleophiles of the posterior capsule to effectively bond the IOL implant to the posterior capsule, thereby eliminating space between the IOL implant and the posterior capsule where cells can migrate. PCO is thereby significantly reduced. [0036] Examples of the nucleophiles that exist on the posterior capsule include hydroxyl groups, amine groups, acid groups, sulfur groups and the like. Polymers that have the ability to react with the nucleophiles of the posterior capsule to thereby bind the IOL implant to the posterior capsule include i) a prepolymer of polyisobutylene with isocyanate end groups, ii) polyurethanes and polyurethaneureas, iii) epoxides, iv) cyanoacrylates, v) proteinacious polymers, vi) carbohydrates or polysaccharides, and v) silicon rubber with reactive end groups as described below in more detail. Prepolymer of polyisobutylene with isocyanate end groups [0037] In accordance with the present invention, a prepolymer of polyisobutylene with isocyanate end groups is provided. The prepolymer can be bifunctional and linear or multifunctional and starred. The isocyanate-terminated‘prepolymer can be loaded into the first WO 2007/127400 PCT/US2007/010292 13 barrel of a two barrel syringe. A reactive co~polymer is loaded into the second barrel of the two barrel syringe. An exemplary reactive co~polymer is a prepolymer of polyisobutylene with hydroxyl or amine end groups. The syringe is preferably realized from polypropylene and is free of air, moisture and any other nucleophile. The isocyanate-terminated prepolymer and the reactive co-polymer are preferably clear with a refractive index between 1.40 and 1.53. The streams from the two barrels of the syringe are merged in a static mixer located on the exit of the syringe. The mixture produced at the exit of the syringe, which is typically a viscous fluid, is injected through the capsulorrhexus such that it covers the posterior capsule. The IOL implant is positioned in the lens capsule in Contact with the mixture. Other mechanisms (e.g., breakable microcapsules) can be used to locate the mixture between the posterior capsule and the IOL implant. Within the lens capsule, the isocyanate-terminated prepolymer will react with the reactive co-polymer to form a gel-type adhesive film. Simultaneous to this polymerization reaction, the reactive isocyanates of the prepolymer component chemically react with the nucleophiles (amine groups) of the posterior capsule, thereby forming a chemical bond between the gel—type adhesive film and the posterior capsule by formation of urea linkage. Such chemical bonding permanently adheres the IOL implant to the posterior capsule and eliminates spaces where lens epithelial cells can migrate and cause PCO. The reaction between the isocyanates of the prepolymer component and the nucleophiles (amine groups) of the posterior capsule does not produce a byproduct that can otherwise be toxic to the eye. The resultant polymer of the gel—type adhesive film is preferably clear with a refractive index between 1.40 and 1.53. [0038] Alternatively, the isocyanate-terminated prepolymer and the reactive co-polymer can be premixed prior to leading into a syringe and the contents injected through the capsulorrhexus such that it covers the posterior capsule. In this embodiment, slow reacting components must be used to enable flow through the syringe prior to polymerization. Polyurethanes and Polyurethaneureas [0039] Polyurethanes and polyurethaneureas are typically comprised of at least two components: an isocyanate-terminated prepolymer and a multinucleophilic co-polymer. An example of a polyurethane is the combination of a multiisocyanate such as the reaction product of a branched polytetramethylene macroglycol reacted with methylene bisphenyl diisocyanate (MDI) to provide a prepolymer that is isocyanate terminated. The multinucleophilic co- WO 2007/127400 PCT/US2007/010292 14 polymer can be the same macroglycol, such as polytetramethylene glycol that is terminated with hydroxyl groups. The hydroxyl groups of the multinucleophilic co-polymer react with the isocyanate groups of the multiisocyanate to produce a high molecular weight polyether urethane. This polyether urethane can be tailored to provide specific properties by adding chain extenders to the nucleophilic component of the polymer system, such as ethylene glycol and the like. Some polyurethanes are more stable than others in the body. U.S. Patent No. 5,133,742, the details of which are herein incorporated by reference in its entirety, describes methods for increasing the biostability of these polymers. [0040] In accordance with the present invention,'a low molecular weight isocyanate- terminated prepolymer can be synthesized and loaded into the first barrel of a two barrel syringe. A hydroxyl-terminated co-polymer is loaded into the second barrel of the two barrel syringe. The streams from the two barrels of the syringe are merged in a static mixer (e. g., baffles) located on the exit of the syringe. The mixture produced at the exit of the syringe, which is typically a viscous fluid, is injected through the capsulorrhexus such that it covers the posterior capsule. The IOL implant is positioned in the lens capsule in contact with the mixture. Other mechanisms (e.g., breakable microcapsules) can be used to locate the mixture between the posterior capsule and the IOL implant. Within the lens capsule, the isocyanate- terminated prepolymer will react with the hydroxyl~terminated co-polymer to form a gel-type adhesive film. Simultaneous to this polymerization reaction, the reactive isocyanates of the prepolymer component chemically react with the nucleophiles of the posterior capsule, thereby forming a chemical bond between the gel-type adhesive film and the posterior capsule. Such chemical bonding permanently adheres the IOL implant to the posterior capsule and eliminates spaces where lens epithelial cells can migrate and cause PCO. The resulting gel-type adhesive film is preferably clear with a refractive index between 1.40 and 1.53. [0041] Alternatively, the isocyanate—terminated prepolymer and the hydroxyl-terminated co-polymer can be premixed prior to loading into a syringe and the contents injected through the capsulorrhexus such that it covers the posterior capsule. In this embodiment, slow reacting components must be used to enable flow through the syringe prior to polymerization. [0042] An exemplary hydroxyl-terminated co-polymer that can be used in this capacity is a polyisobutylene (PIB) diol as it will provide a rubbery polyurethane-based gel that is biostable, Other hydroxyl-terminated co-polymers are perfluropolyethyleneglycol WO 2007/127400 PCT/US2007/010292 15 polytetramethyleneglycol, poly(hexamethylene carbonate)diol, and the like. Preferably the macroglycol is biostable and has an index of refraction between 1.40 and 1.53. Epoxies [0043] Epoxies function in a manner similar to polyurethanes but include an epoxide- terminated prepolymer (rather than the isocyanate-terrninate prepolymer) and a multinucleophilic co-polymer. The epoxide—terminated prepolymer and the multinucleophilic co-polymer are mixed and the resulting mixture is injected through the capsulorrhexus such that it covers the posterior capsule. The IOL implant is positioned in the lens capsule in contact with the mixture. Other mechanism can be used to locate the mixture between the posterior capsule and the IOL implant. Within the lens capsule, the epoxide—terminated prepolymer will react with the multinucleophilic co-polymer to form a gel—type adhesive film. Simultaneous to this polymerization reaction, the reactive epoxide groups of the prepolymer component chemically react with the nucleophiles of the posterior capsule, thereby forming a chemical bond between the gel-type adhesive film and the posterior capsule. Such chemical bonding permanently adheres the IOL implant to the posterior capsule and eliminates spaces where lens epithelial cells carliimigrate and cause PCO. The resulting gel—type adhesive film is preferably clear with a refractive index between 1.40 and 1.53. [0044] Alternatively, the epoxide-terminated prepolymer and the multinucleophilic co- polymer epoxy can be premixed prior to loading into a syringe and the contents injected through the capsulorrhexus such that it covers the posterior capsule. In this embodiment, a slow reacting epoxy, such as the 5 minute epoxies, must be used to enable flow through the syringe prior to polymerization. [0045] Suitable epoxies include glycidyl—terminated polytetramethylene glycol, glycidyl- terminated polyisobutylene, glycidyl terminated perfluroethyleneoxide, and the like. Cyanoacrylates (CA) [0046] In accordance with the invention, a polymeric material with cyanoacrylate end groups is provided that readily transforms to a soft rubbery gel (e.g., shore A=20) in the lens capsule upon contact with moisture and/or proteins within the lens capsule to form a gel-type adhesive film. Simultaneous to this polymerization reaction, the reactive cyanoacrylate groups WO 2007/127400 PCT/US2007/010292 16 chemically react with the nucleophiles of the posterior capsule, thereby forming a chemical bond between the gel-type adhesive film and the posterior capsule. Such chemical bonding permanently adheres an IOL implant to the posterior capsule and eliminates spaces where lens epithelial cells can migrate and cause PCO. The cyanoacrylate-terminated polymer as well as the resulting gel—type adhesive film are preferably clear with a refractive index between 1.40 and 1.53. [0047] Suitable cyanoacrylate (CA) terminated materials that yield soft rubber-like gels upon Contact with moisture and/or proteins within the lens capsule include: i) 3—arm star cyanoacrylate (CA)-telechelic PIB [®(PlB-CA)3]; ii) CA—PDMS-CA where PDMS is poly(dimethyl siloxane); iii) CA—PEG-CA where PEG is polyethylene glycol; and iv) CA—PEG-b-PDMS-b-PEG-CA. A liquid form cyanoacrylate-based material (such as liquid CA—PDMS-CA) can be used as such (in bulk). Preferably, it is loaded into a syringe and injected into the lens capsule from the syringe. Alternatively, a non—fluid form cyanoacrylate-based material (such as crystalline PEG—based material) is preferably dissolved in a suitable solvent (such as DMSO, a non-protic, biocompatible FDA approved solvent) to render the prepolymer injectable. The cyanoacrylation method seems to be of general applicability and can be used for the cyanoacrylation of a great variety of hydroxide-containing molecules. [0048] Aromatic silicone cyanoacrylatcs can also be used which have a higher refractive index. A PIB-based cyanoacrylate material can also be used. Such material has an even higher refractive index. [0049] A table of other potential cyanoacrylate-based materials is provided above. An initiator component (e.g., N,N-dimethyl-p-toluidine in n—C5H.4) can also be mixed with a cyanoacrylate-based material to ensure completeness of the reaction that forms the gel-type adhesive material. The Fn number in the chart below represents the functionality number of the polymer material and relates to the number of end groups per mole of the polymer material. WO 2007/127400 PCT/US2007/010292 17 [0050] In an exemplary embodiment, the CA-terminated material is applied as a thin layer to the posterior capsule. The IOL implant is placed in contact with the thin CA-terminated material. Upon contact with moisture and/or proteins within the lens capsule, the CA- terminated material undergoes a polymerization reaction that forms a gel-type adhesive film. Simultaneous to the polymerization reaction, the CA-terminated material reacts with the IOL implant and reacts with the nucleophiles of the posterior capsule to effectively bond the IOL implant to the posterior capsule, thereby eliminating space between the IOL implant and the posterior capsule where cells can migrate and thus significantly reducing PCO. [0051] In another embodiment, the CA-based material is encapsulated in one or more breakable microcapsules and placed on the IOL implant and/or on the posterior capsule. The IOL implant is placed such that microcapsules are disposed between the IOL implant and the posterior capsule. Subsequent breakage of the microcapsule(s) dispenses the polymeric adhesive material onto the posterior capsule. The polymeric adhesive material is synthesized in the lens capsule. The polymeric adhesive material reacts with the IOL implant and reacts with the nucleophiles of the posterior capsule to effectively bond the IOL implant to the posterior capsule, thereby eliminating space between the IOL implant and the posterior capsule where cells can migrate and thus significantly reducing PCO. WO 2007/127400 PCT/US2007/010292 18 Proteinacious polymers and carbohydrates or polysaccharides [0052] Proteinacious polymers can also be used in this invention. Here, slurries of collagen, elastin, and/or other peptides can be mixed with one or more cross~linking agents (such as formaldehyde, gluteraldehyde, carbodiimide and the like) and applied as a thin layer to the posterior capsule. The IOL implant is placed in contact with this thin layer. Other mechanisms (e. g., breakable microcapsules) can be used to locate the mixture between the posterior capsule and the IOL implant. Within the lens capsule, the cross-linking agent reacts with the proteinacious polymer to fonn a gel-type adhesive film. Simultaneous to this cross- linking reaction, the cross-linking agent chemically reacts with the nucleophiles of the posterior capsule, thereby forming a chemical bond between the gel-type adhesive film and the posterior capsule. Such chemical bonding effectively bonds the IOL implant to the posterior capsule and eliminates spaces where lens epithelial cells can migrate and cause PCO. The proteinacious polymer and the cross-linking agent(s) as well as the resulting gel-type adhesive film are preferably clear with a refractive index between 1.40 and l.53. [0053] Similarly, carbohydrate or polysaccharide gel—like materials can be used for this purpose. Such gel like materials can include alginate, pectin,‘ carrageenan, gellan, starch and the like. The gel like materials are mixed with one or more cross-linking agents (such as multivalent cations including calcium chloride, barium. chloride and the like; more permanent cross-linking agents can also be used including the epoxides and the multiisocyanates as described above). This mixture is applied as a thin layer to the posterior capsule. The IOL implant is placed in contact with this thin layer. Other mechanisms (e.g., breakable microcapsules) can be used to locate the mixture between the posterior capsule and the IOL implant. Within the lens capsule, the cross-linking agent reacts with the gel—like material to form a gel~type adhesive film. Simultaneous to this cross-linking reaction, the cross-linking agent chemically reacts with the nucleophiles of the posterior capsule, thereby fonning a chemical bond between the gel-type adhesive film and the posterior capsule. Such chemical bonding effectively bonds the IOL implant to the posterior capsule and eliminates spaces where lens epithelial cells can migrate and cause PCO. The carbohydrate or polysaccharide gel—like materials and the cross-linking agent(s) as well as the resulting gel-type adhesive film are preferably clear with a refractive index between 1.40 and 1.53. WO 2007/127400 PCT/US2007/010292 19 Silicone Rubber with Reactive End Groups [0054] Prepolymers of silicone rubber can be made with reactive end groups (e.g., methoxy, ethoxy, acetoxy, hydrogen, chlorine and others) that can both initiate polymerization and react with tissue at the same time to effectively gel and bond the IOL implant to the posterior capsule. It is important that the reactive end group be non-toxic to the posterior capsule. [0055] ln an exemplary embodiment, the silicon-based material is applied as a thin layer to the posterior capsule. The IOL implant is placed in contact with the thin silcon-based adhesive layer. Simultaneous to the polymerization reaction, the adhesive layer reacts with the IOL implant and with the nucleophiles of the posterior capsule reactive to effectively bond the IOL implant to the posterior capsule, thereby eliminating space between the IOL implant and the posterior capsule where cells can migrate and thus significantly reducing PCO. [0056] In another embodiment, the silicon-based material is encapsulated in one or more breakable microcapsules and placed on the IOL implant and/or on the posterior capsule. The IOL implant is placed such that microcapsules are disposed between the IOL implant and the posterior capsule. Subsequent breakage of the microcapsule(s) dispenses the polymeric adhesive material onto the posterior capsule. The polymeric adhesive material is synthesized in the lens capsule, and also reacts with the IOL implant and reacts with the nucleophiles of the posterior capsule to effectively bond the IOL implant to the posterior capsule, thereby eliminating spaces between the IOL implant and the posterior capsule where cells can migrate and thus significantly reducing PCO. [0057] Although the polymeric adhesive material described herein employs a polymerization reaction to the nucleophiles (e.g., hydroxyl groups) of the posterior capsule to effectively bind thereto, this polymerization reaction can be initiated and continued with small amounts of water. Use of a Tacky polymer [0058] In another embodiment, a tacky adhesive is placed on the IOL and the lens is pressed against the lens capsule. Here there is no physical bond between the lens and the IOL, rather they are coupled by hydrophobic interactions. WO 2007/127400 PCT/US2007/010292 20 [0059] There are certain polymers that are both tacky and hydrophobic in nature and can be used to adhere an IOL to the lens capsule. Exemplary polymers include polybutadiene, polyisoprene or polyisobutylene polymers of molecular weight less than 100,000 Daltons; preferably between 500 and 30,000 Daltons. These polymers can be syringed onto the posterior or anterior walls of the lens capsule and an lOL pressed against it to effectively bond the IOL to the wall of the lens capsule. Although these bonds are non-reactive, the hydrophobic and tacky nature of the polymer will hold the IOL in place and provide a boundary which will prevent cells from migrating between the IOL and the lens capsule. [0060] In another embodiment of the invention, an IOL can be bonded to the posterior wall of the lens capsule or the anterior wall of the lens capsule or alternatively, two IOLs can be used where one is attached to the posterior capsule and another to the anterior capsule. In this manner, the lenses are able to move closer or further apart from each other depending upon the pressure in the vitreous humour or upon the tension exerted on the lens capsule by the zonules. In this manner, the lenses behave like a telescope and will allow focusing of an image on the retina. In this manner, the eye is capable of accommodating. The adhesive provides both a means ofsupporting the lOLs as well as preventing epithelial cells from spreading between the lens capsule and the IOL. [0061] There have been described and illustrated herein several embodiments of polymeric material that can be injected into the lens capsule of the eye to form a gel-type intraocular lens in situ. The polymeric material includes reactive end groups that react to form the ge1—type intraocular lens within the lens capsule of the eye. The reactive end groups of the polymeric material also react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. For example, mixtures of the polymer materials described herein with similar end groups can be used to realize the gel-type intraocular lens in situ. Moreover, the aforementioned polymers may be used in conjunction with a lens capsule where the capsulorrhexis is closed with a patch. [0062] In another aspect, there have been described and illustrated herein several embodiments of a polymeric adhesive material for bonding an intraocular lens implant to the WO 2007/127400 PCT/US2007/010292 21 posterior capsule of the eye in a manner that minimizes posterior or anterior capsule opacification. [0063] While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. It will therefore be appreciated by those skilled in the art that yet other modifications could be made to the provided invention without deviating from its spirit and scope as claimed herein. WO 2007/127400 PCT/US2007/010292 22 WHAT ISCLAIMED IS: l. A method for forming an intraocular lens within a lens capsule of an eye, said method comprising: injecting a polymeric material within the lens capsule, the polymeric material including reactive end groups that react with the nucleophiles of walls of the lens capsule to effectively bond to the walls of the lens capsule. 2. A method according to claim 1, wherein: the nucleophiles of the lens capsule walls include at least one of hydroxyl groups, amine groups, and sulfur groups. 3. A method according to claim 1, wherein: the polymeric material reacts within the lens capsule to form a gel—type intraocular lens therein, and the chemical bond between the gel-type intraocular lens and the lens capsule walls limits the invasion of lens epithelial cells therebetween and thus significantly reduces PCO. 4. A method according to claim 1, wherein: the polymeric material comprises an isocyanate~terminated prepolymer having isocyanate groups that react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 5. A method according to claim 1, wherein: the isocyanate~terminate prepolymer comprises one of a polyurethane and polyisobutylene. 6. A method according to claim 5, wherein: the polymeric material further comprises one of a hydroxyl-terminated copolymer and an amine—terminated copolymer. 7. A method according to claim 1, wherein: the polymeric material comprises an epoxide-terrninated prepolymer having epoxide groups that react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 8. A method according to claim 1, wherein: said polymeric material comprises a cyanoacrylate-terminated polymer. 9. A method according to claim 8, wherein: said cyanoacrylate-terminated polymer is selected from the group including 3-arm star cyanoacrylate-telechelic polyisobutylene [@(polyisobutylene - cyanoacrylate)3], cyanoacrylate-poly(dimethyl siloxane)-cyanoacrylate, cyanoacrylate—polyethylene glycol- WO 2007/127400 PCT/US2007/010292 23 cyanoacrylate, cyanoacrylate— polyethylene glyco1—b—poly(dimethyl siloxane)—b-polyethylene glycol-cyanoacrylate, aromatic silicone cyanoacrylate, and polyisobutylene-based cyanoacrylate. . 10. A method according to claim 8, wherein: said cyanoacrylate—terminated polymer transforms to a gel upon contact with at least one of moisture and proteins within the lens capsule. 1 1. A method according to claim 1, wherein: said polymeric material comprises at least one proteinacious polymer and at least one cross-linking agent, said cross-linking agent reacting with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 12. A method according to claim 1 1, wherein: said proteinacious polymer comprises at least one of collagen, elastin, and another peptide. 13. A method according to claim 1 1, wherein: said cross-linking agent comprises at least one of formaldehyde, gluteraldehyde, carbodiimide and the like. 14. A method according to claim 1, wherein: said polymeric material comprises at least on carbohydrate or polysaccharide material and at least one cross-linking agent, said cross-linking agent reacting with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 15. A method according to claim 14, wherein: the at least on carbohydrate or polysaccharide material comprises at least one of alginate, pectin, carrageenan, gellan, starch and the like. 16. A method according to claim 14, wherein: said cross-linking agent comprises multivalent cations. 17. A method according to claim 14, wherein: said cross-linking agent comprises at least one of calcium chloride, barium chloride and the like. 18. A method according to claim 14, wherein: said cross-linking agent comprises one of an epoxide group and an isocyanate group. 19. A method according to claim 1, wherein: said polymeric material comprises an initiator that initiates a polymerization reaction that forms the gel within the lens capsule. WO 2007/127400 PCT/US2007/010292 24 20. A method according to claim 1, wherein: said polymeric material includes material selected from the group consisting of: an isocyanate-terminated prepolymer, an epoxide-terminated prepolymer, a cyanoacrylate— terminated polymer, at least one proteinacious polymer, a carbohydrate, a polysaccharide and mixtures thereof. 21. A material for forming an intraocular lens within a lens capsule of an eye, said material comprising: polymeric material including reactive end groups that react with the nucleophiles of walls of the lens capsule to effectively bond to the walls of the lens capsule. 22. A material according to claim 21, wherein: the nucleophiles of the lens capsule walls include at least one of hydroxyl groups, amine groups, and sulfur groups. 23. A material according to claim 21, wherein: the polymeric material reacts within the lens capsule to form a gel—type intraocular lens therein, and the chemical bond between the gel-type intraocular lens and the lens capsule walls limits the invasion of lens epithelial cells therebetween and thus significantly reduces PCO. 24. A material according to claim 21, wherein: the polymeric material comprises an isocyanate-tenninated prepolymer having isocyanate groups that react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 25. A material according to claim 21, wherein: the isocyanate—terminate prepolymer comprises one of a polyurethane and polyisobutylene. 26. A material according to claim 25, wherein: the polymeric material further comprises one of a hydroxyl-terminated copolymer and an amine—terminated copolymer. 27. A material according to claim 21, wherein: the polymeric material comprises an epoxide-terrninated prepolymer having epoxide groups that react with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 28. A material according to claim 21, wherein: said polymeric material comprises a cyanoacrylate—terminated polymer. WO 2007/127400 PCT/US2007/010292 25 29. A material according to claim 28, wherein: said cyanoacrylate—terminated polymer is selected from the group including 3-arm star cyanoacrylate—telechelic polyisobutylene [0(polyisobutylene — cyanoacrylate)3], cyanoacrylate—poly(dimethyl siloxane)-cyanoacrylate, cyanoacrylate-polyethylene glycol- cyanoacrylate, cyanoacrylate- polyethylene glycol—b-poly(dimethyl siloxane)-b-polyethylene glycol-cyanoacrylate, aromatic silicone cyanoacrylate, and polyisobutylene-based cyanoacrylate. 30. A material according to claim 28, wherein: said cyanoacrylate-terminated polymer transforms to a gel upon contact with at least one of moisture and proteins within the lens capsule. 31. A material according to claim 21, wherein: said polymeric material comprises at least one proteinacious polymer and at least one cross-linking agent, said cross—linking agent reacting with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 32. A material according to claim 31, wherein: said proteinacious polymer comprises at least one of collagen, elastin, and another peptide. 33. A material according to claim 31, wherein: said cross—linking agent comprises at least one of formaldehyde, gluteraldehyde, carbodiimide and the like. 34. A material according to claim 21, wherein: said polymeric material comprises at least on carbohydrate or polysaccharide material and at least one cross-linking agent, said cross-linking agent reacting with the nucleophiles of the lens capsule walls to effectively bond to the lens capsule walls. 35. A material according to claim 34, wherein: the at least on carbohydrate or polysaccharide material comprises at least one of alginate, pectin, carrageenan, gellan, starch and the like. 36. A material according to claim 34, wherein: said cross~linking agent comprises multivalent cations. 37. A material according to claim 34, wherein: ' said cross-linking agent comprises at least one of calcium chloride, barium chloride and the like. WO 2007/127400 PCT/US2007/010292 26 38. A material according to claim 34, wherein: said cross-linking agent comprises one of an epoxide group and an isocyanate group. 39. A method according to claim.2I, wherein: . said polymeric material comprises an initiator that initiates a polymerization reaction that forms the gel within the lens capsule. 40. A method according to claim 21, wherein: said polymeric material includes material selected from the group consisting of: an isocyanate—terminated prepolymer, an epoxide-terminated prepolymer, a cyanoacrylate- terminated polymer, at least one proteinacious polymer, a carbohydrate, a polysaccharide and mixtures thereof. 4]. A gel-type intraocular lens formed with the polymeric material of claim 1. 42. A gel—type intraocular lens formed with the method of claim 21. 43. An adhesive for bonding an intraocular lens implant to a capsulary wall of the eye, the adhesive comprising: a polymeric material that is injectable into the lens capsule for reactive polymerization into a gel therein, and said polymeric material being reactable with the intraocular lens and being reactable with nucleophiles of the capsulary wall to effectively bond the intraocular lens implant to the capsulary wall in a manner that reduces space between the intraocular lens implant and the capsulary wall. 44. An adhesive according to claim 43, wherein: said polymeric material comprises at least one of i) polyisobutylene with isocyanate end groups, ii) a polyurethane, ii) a polyurethaneurea, iii) an epoxide, iv) a cyanoacrylate, v) a silicone rubber with reactive end groups, vi) a proteinacious polymer, vii) a carbohydrate, and viii) a polysaccharides. 45. An adhesive according to claim 44, wherein: said polymeric material comprises a polyurethane having a multiisocyanate component and a multinucleophilic co-polymer component. 46. An adhesive according to claim 44, wherein: said polymeric material comprises one of a hydroxyl-terminated co-polymer and an amine—terminate copolymer. 47. An adhesive according to claim 44, wherein: said polymeric material comprises an epoxide terminated prepolymer combined with a mmlennhile reactant WO 2007/127400 PCT/US2007/010292 27 48. An adhesive according to claim 44, wherein: said polymeric material comprises at least one cyanoacrylate-based material that yields a soft rubber-like gel upon contact with the wet proteins of the lens capsule. 49. An adhesive according to claim 48, wherein: said at least one cyanoacrylate-based material is selected from the group including i) 3- arm star cyanoacrylate (CA)-telechelic PIB [®(PIB-CA)3], ii) CA-PDMS—CA where PDMS is poly(dimethyl siloxane), iii) CA—PEG-CA where PEG is polyethylene glycol, iv) CA—PEG—b— PDMS-b-PEG-CA, v) an aromatic silicone cyanoacrylate, and vi) a PIB—based cyanoacrylate, and vi) any combination of the above. 50. An adhesive according to claim 44, wherein: said polymeric material includes a silicone rubber with reactive end groups selected from the group including i) methoxy groups, ii) ethoxy groups, iii) acetoxy groups, iv) hydrogen groups, v) chlorine groups, and vi) any combination of the above. 51. An adhesive according to claim 43, wherein: F said intraocular lens is an accommodating intraocular lens. 52. A method comprising: inserting an intraocular lens implant into the lens capsule of the eye; and interposing a polymeric adhesive material between the intraocular lens implant and a capsulary wall, said polymeric adhesive material reacting with the intraocular lens and reacting with nucleophiles of the capsulary wall to bond the intraocular lens implant to the capsulary wall in a manner that reduces space between the intraocular lens implant and the capsulary wall. 53. A method according to claim 52, wherein: . said polymeric adhesive material comprises at least one of i) polyisobutylene with isocyanate end groups, ii) a polyurethane, ii) a polyurethaneurea, iii) an epoxide, iv) a cyanoacrylate, v) a silicone rubber with reactive end groups, vi) a proteinacious polymer, vii) a carbohydrate, and viii) a polysaccharides. 54. A method according to claim 52, wherein: said polymeric adhesive material comprises a polyurethane having a multiisocyanate component and a multinucleophilic co-polymer component. 55. A method according to claim 52, wherein: said polymeric adhesive material comprises at least one of a hydroxyl-terminated co- polymer and an amine—terminated copolymer. WO 2007/127400 PCT/US2007/010292 28 56. A method according to claim 52, wherein: said polymeric adhesive material comprises an epoxide-terminated prepolymer combined with a nucleophile reactant. ’ 57. Aimethod according to claim 52, wherein: said polymeric adhesive material‘ comprises at least one cyanoacrylate-terminated material that yields a soft rubber-like gel upon contact with the wet proteins of the lens capsule. 58. A method according to claim 57, wherein: said at least one cyanoacrylate-terminated material is selected from the group including i) 3—arm star cyanoacrylate (CA)-telechelic PIB [®(PIB-CA)3], ii) CA—PDMS-CA where PDMS is poly(dimethyl siloxane), iii) CA-PEG—CA where PEG is polyethylene glycol, iv) CA-PEG-b-PDMS-b—PEG-CA, v) an aromatic silicone cyanoacrylate, and vi) a PlB—based cyanoacrylate, and vi) any combination of the above. 59. A method according to claim 52, wherein: said polymeric adhesive material includes a silicone rubber with reactive end groups selected from the group including i) methoxy groups, ii) ethoxy groups, iii) acetoxy groups, iv) hydrogen groups, v) chlorine groups, and vi) any combination of the above. 60. A method according to claim 52, wherein: said polymeric adhesive material reactively polymerizes within the lens capsule of the eye. . 61. A method according to claim 52, wherein: said polymeric adhesive material is applied as a thin layer to the capsulary wall. 62. A method according to claim 52, wherein: said polymeric adhesive material is encapsulated in one or more breakable microcapsules that are interposed between the intraocular lens implant and the capsulary wall and then broken to dispense the polymeric adhesive material therebetween. 63. A method according to claim 52, wherein: said capsulary wall comprises a posterior capsule wall. 64. A method according to claim 52, wherein: said intraocular lens implant is an accommodating intraocular lens implant. WO 2007/127400 PCT/US2007/010292 29 65. A method according to claim 64, wherein: said intraocular lens implant includes first and second intraocular lens implant, wherein the first intraocular lens is bonded to an anterior capsule wall by the polymeric adhesive material in a manner that reduces space between the first intraocular lens implant and the anterior capsule wall, and wherein the second intraocular lens is bonded to a posterior capsule wall by the polymeric adhesive material in a manner that reduces space between the intraocular lens implant and the posterior capsule wall. ll 66. An adhesive for bonding an intraocular lens implant to a capsulary wall of the eye, the adhesive comprising: a polymeric material that is injectable into the lens capsule, the polymer being tacky and hydrophobic in nature for adhering an intraocular lens implant to the capsulary wall via hydrophobic interactions. 67. An adhesive according to claim 66, wherein: the polymeric material includes a material selected from the group consisting of polybutadiene, polyisoprene, polyisobutylene, and mixtures thereof. (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization A International Bureau (43) International Publication Date 8 November 2007 (08.11.2007) (51) International Patent Classification: A6lF 2/16 (2006.01) (21) International Application Number: PCT/US2007/010292 (22) International Filing Date: 28 April 2007 (28.04.2007) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 60/745,941 60/745,944 28 April 2006 (28.04.2006) 28 April 2006 (28.04.2006) US US (71) Applicant (for all designated States except US ): IN- NOVIA, LLC [US/US]; 12415 SW 136 Avenue, Unit 3, Miami, FL 33186 (US). (72) Inventor; and (75) Inventor/Applicant (for US only): PINCHUK, Leonard [US/US]; 13704 SW. 92nd Court, Miami, FL 33176 (US). (74) Agent: GORDON, David P.; Gordon & Jacobson, P.C., 60 Long Ridge Road, Suite 407, Stamford, CT 06902 (US). LAR LENS 127400 A3 ||||||||||||||||||||||||||||||||||||||||||ll||||||||||||||||||||||||||||||||||||||||||||||||||| (81) (34) (88) '‘ ||||||||||||||ll||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| (10) International Publication Number W0 2007/127 400 A3 Designated States (unless otherwise indicated, for every kind of national protection available ): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Designated States (unless otherwise indicated, for every kind of regional protection available ): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Published: with international search report Date of publication of the international search report: 29 May 2008 (54) Title: METHODS AND MATERIALS FOR MINIMIZING POSTERIOR CAPSULE OPACIFICATION OF INTRAOCU— R (57) Abstract: Polymeric materials and methods that realize a gel—type intraocular lens that is formed in situ within the lens capsule 3 of the eye. The polymeric material of the intraocular lens includes reactive end groups that effectively bond with lens capsule walls, 3 thus eliminating space between the intraocular lens and the lens capsule walls and significantly reducing the proliferation of lens (‘S epithelial cells which can cause unwanted posterior capsule opacification. In another aspect, various polymers are provided that can be polymerized in the lens capsule with the ability to bond an intraocular lens implant to the posterior capsule of the eye such that 3 Significantly reducing posterior capsule opacification. there is no space available between the intraocular lens implant and the lens capsule for lens epithelial cells to proliferate and thereby INTERNATIONAL SEARCH REPORT ‘“‘°"“"‘°““' “""“°““°“ ”°‘ PCT/US07/10292 A. CLASSIFICATION OF SUBJECT MATTER IPC: A6lF 2/16( 2006.01) USPC: 623/6.56 According to Intemational Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S. : 623/6.56,6.59, 6.62; 523/118; 424/427 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the intemational search (name of data base and, where practicable, search terms used) EAST BRS search terms: tissue with adhesive with ($4saccharide$3 or carbohydrate) C. DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X US 4,740,534 A (MATSUDA et al) 26 April 1988 (26.04.1988), see the abstract, column 4, 21-23, 28-30, 39, 40, lines 12-49 and column 4, line 64 to column 5, line 5. and 42 X EP 1106189 A2 (MATSUDA et al) 13 June 2001 (13-06.2001), see the abstract. 21-23, 34, 35, 39, 40, and 42 X US 6,629,947 B1 (SAHATJIAN et al) 07 October 2003 (07.10.2003), see the abstract and 21-23, 34-37, 40 and 42 colurrm 3, line 54 to column 4, line 19. El Further documents are listed in the continuation of Box C. D See patent family annex. Special categories of cited documents: later document published alter the international filing date or priority date and not in conflict with the application but cited to understand the document defining the general state of the art which is not considered to be of principle or theory underlying the invention particular relevance document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone earlier application or patent published on or afier the intemational filing date document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or other special reason (as specified) document referring to an oral disclosure, use, exhibition or other means document published prior to the international filing date but later than the document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is combined with one or more other such documents, such combination being obvious to a person skilled in the an document member of the same patent family priority date claimed Date of the actual completion of the intemational search Date of mailing of the intemational search report 28 January 2008 (28.01.2008) _ _: Name and mailing address of the ISA/US Authorilfid Office!‘ . . I Mail Stop PCT, Ann. ISA/US Paul B_ Prebmc Wafi Commissioner for Patents R0" 3°“ '4” Telephone No. (571) 272-4758 Alexandria, Virginia 22313-1450 Facsimile No. (571) 273-3201 Form PCT/ISA/210 (second sheet) (April 2005) Intemational application No. INTERNATIONAL SEARCH REPORT PCT/US07/10292 Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This intemational search report has not been established in respect of certain claims under Article l7(2)(a) for the following reasons: 1. E Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Claims Nos.: because they relate to parts of the intemational application that do not comply with the prescribed requirements to such an extent that no meaningfiil intemational search can be carried out, specifically: Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). This Intemational Searching Authority found multiple inventions in this intemational application, as follows: Please See Continuation Sheet As all required additional search fees were timely paid by the applicant, this intemational search report covers all searchable claims. As all searchable claims could be searched without efibrt justifying additional fees, this Authority did not invite payment of any additional fees. 3. As only some of the required additional search fees were timely paid by the applicant, this intemational search report covers only those claims for which fees were paid, specifically claims Nos.: 21-23,28-30,34-37,39,40 and 42 E] No required azlditional search fees were timely paid by the applicant. Consequently, this intemational search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest G The additional search fees were accompanied by the applicant’s protest and, where applicable, the payment of a protest fee. G The additional search fees were accompanied by the applicant’s protest but the applicable protest fee was not paid within the time limit specified in the invitation. Fonn PCT/ISA/210 (continuation of fust sheet(2)) (April 2005) No protest accompanied the payment of additional search fees. Intemational application No. INTERNATIONAL SEARCH REPORT pcr/U307/10292 BOX III. OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING The intemational search authority has found 12 inventions in the Intemational Application as set forth below: This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1. In order for all inventions to be examined, the appropriate additional examination fees must be paid. Group I, claim(s) 1-20 and 41, drawn to a method of forming an intraocular lens. Group II, claim(s) 21-40 and 42, drawn to a material for fonning an intraocular lens. Group III, claim(s) 43-51, 66, and 67, drawn to an adhesive material. Group IV, claim(s) 52-65, drawn to a method of using an adhesive material in the eye. This application contains claims directed to more than one species of me generic invention. These species are deemed to lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1. In order for more than one species to be examined, the appropriate additional examination fees must be paid. The species are as follows: A. cyanoacrylate-terminated polymer (claims 8-10, 20, 28-30,40, 48, 49, 57, and 58) B. proteinaceous polymer (claims 11-13, 20, 31-32, and 40) C. carbohydrate or polysaccharide tenninated polymer (claims 14-18, 20, 24, 34-37, and 40) D. epoxide-terminated polymer (claims 7, 20, 27, 38, 40, 47, and 56). E. hydroxyl-terminated copolymer (claims 6, 25, 26, 46, and 55) F. amine-terminated copolymer (claims 6, 25, 26, 45, and 55) G. silicone rubber (claims 50 and 59). H. unsaturated adhesive polymer (claim 67) I. isocyanate-terminated polymer (claims 4-6, 20, 24, 25, 26, 38, 40, 45, and 54) The claims are deemed to correspond to the species listed above in the following manner: A. cyanoacrylate-terminated polymer (claims 8-10, 20, 28-30,40, 48, 49, 57, and 58) B. proteinaceous polymer (claims 11-13, 20, 31-32, and 40) C. carbohydrate or polysaccharide terminated polymer (claims 14-18, 20, 24, 34-37 and 40) D. epoxide-terminated polymer (claims 7, 20, 27, 38, 40, 47, and 56). E. hydroxyl-tenninated copolymer (claims 6, 25, 26, 46, and 55) F. amine-terminated copolymer (claims 6, 25, 26, 45, and 55) G. silicone rubber (claims 50 and 59). H. unsaturated adhesive polymer (claim 67 on I“IllI ‘I nolu‘ .n ‘- Form PCT/ISA/210 (extra sheet) (April 2005) Intemational application No. INTERNATIONAL SEARCH REPORT pcr/uso7/10292 The following c|aim(s) are generic: 1-3, 19, 21, 22, 23, 39, 41, 42, 43, 44, 51-53, 60-66. The intemation search authority does not comply with the requirement for unity of invention (Rules 13.1, 13.2, and 13.3) as indicated below: The inventions listed as Groups I to IV do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons: They lack a special technical feature. The common technical feature is a polymeric material that can react with the nucleophiles of the walls of a lens capsule. However, the EP 1364663, US 5391590, WO 01/89435, and US 6747090 demonstrate that this technical feature was known to the art. Therefore, there is no corresponding special technical feature as required for unity of invention. The species listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, the species lack the same or corresponding special technical features for the following reasons: The same prior art as set forth in the preceding paragraph demonstrates that the particular species claimed lack special technical features. Form PCT/ISA/210 (extra sheet) (April 2005)