Biostable polymer brushes with defined viscous and optical properties for use in novel intraocular lenses - Patent Application 20070233334

Abstract

In one or more embodiments, the invention provides bottlebrush polymers for use with implantable synthetic intraocular lenses, including homopolymers or copolymers of highly reflective methacrylate monomers or polymers, such as monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), 2,2,2-trifluoroethyl methacrylate (TFEMA), oligo(ethylene glycol) methacrylate (OEGMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA), ethylene glycol phenyl ether methacrylate (EGPhEMA), hydroxyethyl methacrylate (HEMA), or combinations thereof, having refractive indices and complex viscosities suitable for use as a filler material for implantable synthetic intraocular lenses.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 191,018, entitled “Biostable Polymer Brushes with Defined Viscosity and Optical Properties for Use in a Novel Intraocular Lens,” filed May 20, 2021, and incorporated herein by reference in its entirety.

[0002] Names of the parties to the joint research agreement This application arises out of work conducted pursuant to a Cooperative Research Agreement between Duke University, Durham, North Carolina, and Adaptilens, LLC, Chestnut Hill, Massachusetts.

[0003] One or more embodiments of the present invention relate to bottle-brush polymers. In certain embodiments, the present invention relates to biostable polymer bottle-brushes with tunable viscosity and optical properties for use in intraocular lenses. [Background technology]

[0004] Polymers are divided into two general classes: thermoplastics and thermosets. Due to the lack of a crosslinked network, thermoplastics can be soluble in good solvents and soften or melt when heated, thus making them reprocessable and remoldable. Thermosets, on the other hand, contain a crosslinked network and are irreversibly cured for high performance applications. Elastomers are a class of materials that contain a lightly crosslinked polymer network that gives elastomers their elasticity. Soft elastomers can be prepared by increasing the molecular weight of the network chains (polymer chains between two junctions / crosslinking points) and decreasing the chain entanglement of the polymer chains. Polymer chains start to create entanglements in the system above a certain molecular weight, called the chain entanglement molecular weight, and these entangled chains become permanently trapped upon crosslinking and then function as topological crosslinks. These chain entanglements can be prevented or delayed by modifying the "volume" of the polymer chain, which can be done by changing the polymer chain architecture from linear to branched or to a form in which the side chains are highly extended and crowded, forcing the backbone into a highly elongated state commonly referred to as a bottle brush.

[0005] Bottle brush polymers (BBPs) are a type of polymer with long and densely grafted side chains. BBPs can be synthesized using different approaches such as grafting to, grafting from, and grafting through approaches. In the grafting to approach, long polymer chains asymmetrically terminated with functional groups can ideally be chemically connected to a polymer backbone with many functional groups on all repeat units that are reactive to the functional groups on the long polymer chain. The grafting from approach ideally requires a polymer backbone with initiator sites on all repeat units. Using small molecule monomers, polymer side chains can typically be grown from the polymer backbone using controlled radical polymerization (CRP) techniques such as atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. Finally, the grafting through approach allows the use of macromonomers with polymerizable units at one chain end and the utilization of different polymerization techniques such as reversible deactivation radical polymerization (RDRP, i.e., ATRP or RAFT) or ring-opening metathesis polymerization (ROMP). While RDRP requires the commonly used styrenic or (meth)acrylic functional groups, ROMP utilizes norbornene-based polymer chain ends to polymerize macromonomers into BBP.

[0006] The different approaches discussed previously resulted in different grafting densities. In general, the grafting to approach results in the lowest grafting density, while the grafting through approach produces the highest grafting density among these three approaches. The difference in grafting density due to the selection of different grafting approaches is due to the steric hindrance generated between the components (i.e., between the polymer backbone-long side chains in the grafting to approach, the growing chains on the polymer backbone in the grafting from approach, and the growing BBP-macromonomer in the grafting through approach). To synthesize a true BBP, the grafting density needs to be high enough to give the BBP rigidity and prevent entanglement. BBPs and bottle brush gels can be distinguished according to the identity of the macromonomer (the side chains play a central role in determining the final properties of the obtained BBP), the degree of polymerization (DP) of the side chains, the backbone DP, the grafting density (the distance between each side chain), and the crosslinking density (in the case of bottle brush gels).

[0007] Recent developments in the technology of certain intraocular lenses (IOLs) and accommodative or adaptive intraocular lenses (A-IOLs) for use in surgery to treat cataracts have led to the development of a suitable refractive index (n rThis has created a need for optically clear biostable polymeric filling materials with a complex viscosity and viscosity. Over time, the lens in the eye becomes stiffer and less flexible, making it more difficult for the eye to focus on nearby objects. This gradual age-related loss of accommodation is called presbyopia. As people get older, the lens thickens and becomes opaque, forming cataracts, causing blurred vision. The standard of care is to undergo cataract surgery to remove the cataract and replace it with an IOL. The current standard lens is a flat monofocal IOL that cannot accommodate both near and far vision, making the patient dependent on glasses. A-IOLs allow patients to see clearly over a range of distances without glasses or contact lenses. A variety of different polymers have been used in IOL refill lenses and other types of A-IOLs with mixed results. Many of these materials require a solvent or other diluting fluid to reach a working viscosity. Both Jean Marie Parel, PhD (Bascom Palmer) and Steven Koopmans, MD (Pharmacia) attempted to restore accommodation by refilling the capsular bag with soft polymers (Hao et al., 2010; Koopmans, 2003 and 2006). Both injected in situ polymerizing materials directly into the capsular bag. Both scientists ended their efforts after in vivo animal studies showed significant complications including ocular inflammation and post-cataract (PCO) (Koopmans, 2014; Hao 2012). Similarly, Nishi's attempt to develop a silicone oil-filled intracapsular balloon failed when severe post-cataracts occurred (Nishi 1997). The Fluid Vision IOL is a hydrophobic acrylic lens with a hollow optic and two hollow haptics filled with silicone oil. When the ciliary muscle contracts, oil shifts from the haptics to the optic, changing the shape of the lens. This IOL is still in Phase II clinical trials, but issues with the lens include patients being slow to focus and inconsistent effective lens position (Young, 2016).

[0008] What is needed in the art is a synthetic route to generate optically clear, biostable polymeric bottle-brushes with tunable viscosity and optical properties that can be used as fluid-like filling materials in IOLs and A-IOLs. Summary of the Invention

[0009] In one or more embodiments, the present invention provides a synthetic route to generate optically clear, biostable bottle-brush polymers with tunable mechanical and optical properties that make them suitable for use as a fluid-like fill material in implantable intraocular lenses for use in treating presbyopia, cataracts, and similar ailments. The method precisely controls the refractive index of the bottle-brush polymers and their mechanical properties necessary for fluid conformance to the lens, while avoiding the use of solvents or other diluting fluids.

[0010] In various embodiments, the present invention uses a RAFT polymerization and grafting through approach to create BBPs for use in intraocular lenses (IOLs). In one or more of these embodiments, the BBPs have low glass transition temperatures (T g ), different refractive indices (n r In some of these embodiments, poly(dimethylsiloxane)-methacrylate (PDMS-MA) and / or oligo(ethylene glycol) methacrylate (OEGMA) are used. PDMS-MA has an n of 1.41 to 142. r On the other hand, oligo(ethylene glycol) methacrylate (OEGMA) has an n of 1.45 to 1.46. r In some embodiments, these two macromonomers can be homopolymerized to give poly(PDMS-MA) and poly(OEGMA), or copolymerized to give poly(DMS-MA-random-OEGMA), all of which are honey-like viscous liquids with complex viscosities ranging from 0.4 to 12 Pa s. They also have low n rand high n r A low molecular weight methacrylate monomer was copolymerized with PDMS-MA and OEGMA to obtain the final n without increasing the viscosity out of the range. r It has also been found that it is possible to adjust n. Thus, in some embodiments, fluorinated methacrylic monomers are copolymerized with PDMS-MA to provide n r In these embodiments, the final n is reduced and the benzyl monomer is copolymerized with OEGMA to reach the upper limit of n. r The range of α is 1.40-1.48. In addition, it has been found that using a similar copolymerization approach, it is possible to incorporate UV absorbing agents into the BBP backbone to filter out UV light.

[0011] In one or more embodiments, the optically clear biostable bottlebrush polymers of the present invention may be used to create an A-IOL having a thin flexible shell and a filling material that includes an optically clear biostable bottlebrush polymer. When the eye's ciliary muscles contract during accommodation, the flexible lens changes shape to increase the lens' power and allow the patient to focus near. When the accommodative muscles relax, the lens resumes its baseline shape, allowing the patient to see at a distance.

[0012] The IOLs described herein are advantageous compared to other devices because they utilize natural accommodation to precisely change the refractive power of the eye without damaging its tissues or circulating aqueous materials. In preferred embodiments, the IOLs are soft and flexible to ensure that the IOL-eye system re-establishes the accommodative mechanism so that the patient's optical system can respond to changes in spatial images and illumination, allowing the lens to be fitted by a simple procedure that can be performed quickly. In addition, the IOLs are localized within the natural capsule to minimize decentration and loss of accommodation, providing functional performance similar to that of the natural eye, and allowing volume adjustment so that the ciliary muscles can control the accommodation of the IOL. As a result, a wider variety of patients with lens diseases may be provided with natural and responsive vision under a wider variety of circumstances, including but not limited to improved accommodation, reduced glare, and durable functionality, utilizing a new system of polymer shells and filling materials to improve the optical performance of the eye and establish a normal visual experience.

[0013] In a first aspect, the present invention is directed to bottlebrush polymers, comprising a homopolymer of a methacrylate macromolecular monomer selected from the group consisting of monomethacryloxypropyl terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), or at least one of PDMS-MA and OEGMA, including, but not limited to, 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA), ethylene glycol phenyl ... and copolymers with at least one methacrylate or acrylate monomer, which may include 2,2,2-trifluoroethyl acrylate (EGPhEMA), hydroxyethyl methacrylate (HEMA), 2,2,2-trifluoroethyl acrylate (TFEA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl acrylate (HDFDA), benzyl acrylate (BzA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof, having one or more end groups derived from a reversible addition-fragmentation chain transfer (RAFT) agent.

[0014] In one or more embodiments, the homopolymer or copolymer comprises the residue of an ultraviolet (UV) light blocking methacrylate monomer. In one or more of these embodiments, the ultraviolet light blocking methacrylate monomer is 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA).

[0015] In one or more embodiments, the bottle brush polymer of the invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention, wherein the bottle brush polymer is formed by RAFT polymerization and is a copolymer of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), comprising about 10 to about 95 mole percent, preferably about 10 to about 90 mole percent, and more preferably about 10 to about 80 mole percent PDMS-MA.

[0016] In one or more embodiments, the bottle brush polymer of the invention includes any one or more of the embodiments referenced above in the first aspect of the invention having a complex viscosity of from about 0.5 to about 30 Pa.s at 37° C. In one or more embodiments, the bottle brush polymer of the invention includes any one or more of the embodiments referenced above in the first aspect of the invention having a refractive index of from about 1.39 to about 1.48, preferably from about 1.40 to about 1.46, and more preferably from about 1.42 to about 1.46.

[0017] In one or more embodiments, the bottle brush polymer of the invention comprises any one or more of the embodiments referenced above in the first aspect of the invention, wherein the RAFT agent is selected from the group consisting of dithiobenzoic acid, trithiocarbonate, and combinations thereof. In one or more embodiments, the bottle brush polymer of the invention comprises any one or more of the embodiments referenced above in the first aspect of the invention, wherein the RAFT agent is selected from the group consisting of: [ka] and combinations thereof, where y is an integer from about 3 to about 11.

[0018] In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] where x is an integer from about 5 to about 10, y is an integer from about 3 to about 11, and a is an integer from about 20 to about 300. In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] where x is an integer from about 5 to about 10, and a is an integer from about 20 to about 300.

[0019] In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from 5 to 10, y is an integer from about 3 to about 11, n is a mole percentage from about 70% to about 95%, and m is a mole percentage from about 5% to about 30%. In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, n is a mole percent from about 5% to about 30%, m is a mole percent from about 70% to about 95%, and n+m=100.

[0020] In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] where y is an integer from about 5 to about 10 and a is an integer from about 20 to about 300. In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, n is a mole percent from about 70% to about 95%, and m is a mole percent from about 5% to about 30%.

[0021] In one or more embodiments, the bottle brush polymer of the present invention comprises any one or more of the above-referenced embodiments of the first aspect of the invention having the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, n is a mole percent from about 70% to about 95%, and m is a mole percent from about 5% to about 30%.

[0022] In one or more embodiments, the bottle brush polymer of the present invention includes any one or more of the above-referenced embodiments of the first aspect of the invention, wherein the bottle brush polymer is optically transparent.

[0023] In a second aspect, the present invention is directed to a filling material for use in an artificial lens comprising one or more optically clear bottle-brush polymers having a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46, and a complex viscosity of about 0.5 to about 50 Pa.s. In some embodiments, the artificial lens is an accommodating intraocular lens (A-IOL) or a presbyopia-correcting IOL.

[0024] In one or more embodiments, the filler material of the invention comprises any one or more of the above-referenced embodiments of the second aspect of the invention, wherein the one or more optically clear bottle brush polymers are selected from the group consisting of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), or a mixture of at least one of PDMS-MA and OEGMA with 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (Bz ... and copolymers with at least one methacrylate or acrylate monomer selected from the group consisting of 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof, having one or more end groups derived from a reversible addition-fragmentation chain transfer (RAFT) agent. In one or more embodiments, the filling material of the present invention comprises any one or more of the above-referenced embodiments of the second aspect of the present invention, wherein the optically clear bottle brush polymer is a copolymer of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), comprising about 10 to about 95 mole percent, preferably about 10 to about 90 mole percent, and more preferably about 10 to about 80 mole percent PDMS-MA.

[0025] In one or more embodiments, the filling material of the invention comprises any one or more of the embodiments referenced above in the second aspect of the invention, wherein the optically clear bottle brush polymer has a complex viscosity of about 0.5 to about 30 Pa.s at 37° C. In one or more embodiments, the filling material of the invention comprises any one or more of the embodiments referenced above in the second aspect of the invention, wherein the optically clear bottle brush polymer has a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46.

[0026] In one or more embodiments, the packing material of the invention comprises any one or more of the embodiments referenced above in the second aspect of the invention, wherein the RAFT agent is selected from dithiobenzoic acid, trithiocarbonate, and combinations thereof. In one or more embodiments, the packing material of the invention comprises any one or more of the embodiments referenced above in the second aspect of the invention, wherein the RAFT agent is selected from dithiobenzoic acid, trithiocarbonate, and combinations thereof. [ka] and combinations thereof, where y is an integer from about 3 to about 11.

[0027] In one or more embodiments, the filling material of the present invention comprises any one or more of the above-referenced embodiments of the second aspect of the invention, wherein the optically clear bottle-brush polymer has the formula: [ka] In the formula, R is [ka] where x is an integer from 5 to 10, and a is an integer from about 20 to about 300.

[0028] In one or more embodiments, the filling material of the present invention comprises any one or more of the above-referenced embodiments of the second aspect of the invention, wherein the optically clear bottle-brush polymer has the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where n is a mole percent of about 5% to about 30%, m is a mole percent of about 70% to about 95%, and y is an integer from about 5 to about 10.

[0029] In a third aspect, the present invention is directed to an intraocular lens comprising a filling medium and a capsule interface configured and dimensioned to be received within the natural ocular capsule and to be filled with the filling medium either prior to insertion into the eye or in situ, the filling material comprising one or more optically clear bottle-brush polymers having a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46, and a complex viscosity of about 0.5 Pa.s to about 50 Pa.s, the capsule interface filled with the filling medium defining a predetermined optical power. In one or more embodiments, the capsule interface filled with the filling medium is an accommodating lens that responds to ciliary muscle movement and accommodates to a changed shape.

[0030] In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the present invention, where the capsule interface and the filling medium define a first refractive power and change their shape in response to the action of the ciliary muscle to define a second refractive power. In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the present invention, where the first and second refractive powers are predetermined by at least the shape and refractive index of the capsule interface and the refractive index of the filling medium, and thus the first and second refractive powers vary depending on the shape and refractive index of the capsule interface and the refractive index of the filling medium.

[0031] In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the surface of the capsule interface is coated with an ophthalmic drug or substance used to prevent the formation of secondary cataracts (PCO).

[0032] In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above referenced embodiments of the third aspect of the invention, where the capsule interface when filled ranges in predetermined dimensions from about 9 mm-11 mm diameter to about 4-6 mm thickness depending on the size of the patient's lens capsule. In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above referenced embodiments of the third aspect of the invention, where it corrects corneal astigmatism by different forces established along different meridians of the polymer capsule interface or by filling media having different refractive indices in different compartments within the intraocular lens.

[0033] In various embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the present invention, wherein the optically clear bottle brush polymer is a homopolymer of a methacrylate macromolecular monomer selected from the group consisting of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), or a mixture of at least one of PDMS-MA and OEGMA with 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAz). and copolymers with at least one methacrylate or acrylate monomer selected from the group consisting of ethylene glycol phenyl ether acrylate (EGPhEMA), hydroxyethyl methacrylate (HEMA), 2,2,2-trifluoroethyl acrylate (TFEA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl acrylate (HDFDA), benzyl acrylate (BzA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof, having one or more end groups derived from a reversible addition-fragmentation chain transfer (RAFT) agent. In one or more embodiments, the intraocular lens of the present invention includes any one or more of the above-referenced embodiments of the third aspect of the present invention, wherein the optically clear bottle-brush polymer is a copolymer of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methyl ether methacrylate (OEGMA), comprising about 10 to about 95 mole percent PDMS-MA.

[0034] In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the optically clear bottle-brush polymer comprises a residue of an ultraviolet (UV) light-blocking methacrylate monomer. In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the ultraviolet (UV) light-blocking methacrylate monomer is 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA).

[0035] In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the embodiments referenced above in the third aspect of the invention, wherein the transparent bottle-brush polymer has a complex viscosity of about 0.5 to about 15 Pa·s. In one or more embodiments, the intraocular lens of the present invention comprises any one or more of the embodiments referenced above in the third aspect of the invention, wherein the optically clear bottle-brush polymer has a refractive index of about 1.43 to about 1.48.

[0036] In one or more embodiments, the intraocular lens of the present invention includes any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the optically clear bottle-brush polymer has the formula: [ka] In the formula, R is [ka] wherein x is an integer from about 5 to about 10, and a is an integer from about 20 to about 300. In various other embodiments, the intraocular lens of the present invention includes any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the optically clear bottle-brush polymer has the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from 5 to 10, n is a mole percent from about 5% to about 30%, and m is a mole percent from about 70% to about 95%.

[0037] In some embodiments, the intraocular lens of the present invention comprises any one or more of the above-referenced embodiments of the third aspect of the invention, wherein the optically clear bottle-brush polymer has the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from 5 to 10, n is a mole percent from about 5% to about 30%, and m is a mole percent from about 70% to about 95%.

[0038] These and other features of the systems and methods of the present invention will become more readily apparent to those skilled in the art from the following detailed description of the preferred embodiments taken in conjunction with the drawings. [Brief description of the drawings]

[0039] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention taken in conjunction with the accompanying drawings.

[0040] [Figure 1] 13 is an image of an optically clear poly(PDMS-MA) bottle-brush polymer after end-group removal. [Diagram 2] FIG. 1 is a schematic diagram of an IOL that includes a thin, flexible shell 2a filled with an optically transparent filling medium 2b. [Diagram 3]FIG. 1 is a schematic diagram of an IOL showing the thin, flexible shell of an IOL 3a inserted into a capsular bag 3f using an inserter / filling device 3b. [Figure 4] 1 is an image of one version of an A-IOL in which the polymeric shell material is of uniform thickness. [Diagram 5] 1H NMR spectrum of poly(PDMS-MA) in CDCl3. [Figure 6] 1H NMR spectrum of poly(OEGMA) in CDCl3. [Figure 7] 1H NMR spectrum of poly(PDMS-MA-co-OEGMA) in CDCl3 (injection ratio: 70 mol% PDMS-MA and 30 mol% OEGMA. Actual composition: 68 mol% PDMS-MA and 32 mol% OEGMA). [Figure 8] 1H NMR spectrum of poly(PDMS-MA-co-OEGMA) in CDCl3 (injection ratio: 90 mol% PDMS-MA and 10 mol% OEGMA. Actual composition: 84 mol% PDMS-MA and 16 mol% OEGMA). [Figure 9] 1H NMR spectrum of poly(PDMS-MA-co-OEGMA) in CDCl3. (Injection ratio: 10 mol% PDMS-MA and 90 mol% OEGMA. Actual composition: 20 mol% PDMS-MA and 80 mol% OEGMA). [Figure 10] 1H NMR spectrum of poly(PDMS-MA-co-BzMA) in CDCl3 (injection ratio: 70 mol% PDMS-MA and 30 mol% BzMA. Actual composition: 58 mol% PDMS-MA and 42 mol% BzMA). [Figure 11] 1H NMR spectrum of poly(PDMS-MA-co-BzMA) in CD2Cl2 (injection ratio: 90 mol% PDMS-MA and 10 mol% BzMA. Actual composition: 80 mol% PDMS-MA and 20 mol% BzMA). [Figure 12]1H NMR spectrum of poly(PDMS-MA-co-EGPhEMA) in CDCl3. (Injection ratio: 70 mol% PDMS-MA and 30 mol% EGPhEMA. Actual composition: 64 mol% PDMS-MA and 36 mol% EGPhEMA). [Figure 13] 1H NMR spectrum of poly(OEGMA-co-EGPhEMA) in CD2Cl2 (injection ratio: 90 mol% PDMS-MA and 10 mol% EGPhEMA. Actual composition: 81 mol% OEGMA and 19 mol% EGPhEMA). [Figure 14] 1H NMR spectrum of poly(PDMS-MA-co-TFEMA) in CDCl3 (injection ratio: 70 mol% PDMS-MA and 30 mol% TFEMA. Actual composition: 66 mol% PDMS-MA and 34 mol% TFEMA). [Figure 15] 1H NMR spectrum of poly(PDMS-MA-co-TFEMA) in CDCl3. (Injection ratio: 50 mol% PDMS-MA and 50 mol% TFEMA. Actual composition: 48 mol% PDMS-MA and 52 mol% TFEMA). [Figure 16] 1H NMR spectrum of poly(PDMS-MA-co-BzTAzMA) in CDCl3. [Figure 17] THF sec traces of poly(PDMS-MA) with three different molecular weights (a: Mn=13,370 g / mol, b: Mn=27,160 g / mol, c: Mn=67,900 g / mol). [Figure 18] Three detector THF sec traces of poly(PDMS-MA). Top trace: refractive index detector, middle trace: 254 nm UV detector, bottom trace: light scattering detector. [Figure 19] 1 is a graph showing complex viscosity measurements of poly(PDMS-MA), POEGMA, and their random copolymers in various ratios at 25° C. [Figure 20]FIG. 13 shows complex viscosity measurements of poly(PDMS-MA), poly(PDMS-MA70-co-BzMA30), and poly(PDMS-MA70-co-EGPhEMA30) at 25° C. [Figure 21] FIG. 13 is a graph showing complex viscosity measurements of poly(PDMS-MA90-co-BzMA10) and poly(OEGMA90-co-EGPhEMA10) at 25° C. [Figure 22] FIG. 1 is a graph showing complex viscosity measurements of poly(PDMS-MA) at various temperatures (Mn, theo = 30,000-40,000 g / mol). [Diagram 23] FIG. 1 is a graph showing complex viscosity measurements of poly(PDMS-MA) at various temperatures (Mn,theo>200,000 g / mol). [Figure 24] 1 is a graph comparing the refractive index (RI) and viscosity of polydimethylsiloxane methacrylate (PDMS-MA), heptadecafluorodecyl methacrylate (HDFDMA), trifluoroethyl methacrylate (TFEMA), oligoethylene glycol methacrylate (OEGMA), benzyl methacrylate (BzMA), and ethylene glycol phenyl ether methacrylate (EGPhEMA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The following is a detailed description of the present disclosure provided to help those skilled in the art to implement the present disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs. The technical terms used in the description of the disclosure herein are only for describing specific embodiments and are not intended to limit the present disclosure.

[0042] In one or more embodiments, the present invention provides a synthetic route to generate biostable polymer bottlebrushes with tunable viscosity and optical properties that make them suitable for use as optically clear filling fluids in intraocular lenses. The method precisely controls the refractive index of the bottlebrush and the viscous properties required for the fluid to conform to the lens, avoiding the use of solvents or other diluting fluids. In some embodiments, RAFT polymerization techniques are used to create transparent BBPs for use in artificial lenses for the treatment of cataracts. In one or more of these embodiments, the low glass transition temperature (T g ), different refractive indices (n r In some of these embodiments, two macromonomers with high refractive index, such as poly(dimethylsiloxane)-methacrylate (PDMS-MA) and / or oligo(ethylene glycol) methacrylate (OEGMA), may be used to form the BBP. PDMS-MA has an n of 1.41 to 142. r On the other hand, oligo(ethylene glycol) methacrylate (OEGMA) has an n of 1.45 to 1.46. r In some embodiments, these two macromonomers can be homopolymerized to give poly(PDMS-MA) and poly(OEGMA), or copolymerized to give poly(DMS-MA-random-OEGMA), all of which are honey-like viscous liquids with complex viscosities ranging from 0.4 to 12 Pa s. They also have low n r and high n r Small molecule monomers were copolymerized with PDMS-MA and OEGMA to obtain the final n without increasing the viscosity out of the range. r It has also been found that it is possible to adjust n. Thus, in some embodiments, fluorinated methacrylic monomers are copolymerized with PDMS-MA to provide n r The benzyl monomer was copolymerized with OEGMA to reduce n r In these embodiments, the final n rThe range of α is 1.40-1.48. Furthermore, using a similar copolymerization approach, it has been found possible to incorporate UV absorbing reagents into the BBP backbone to filter out UV light by meth(acrylating) UV-absorbing dyes containing alcohol or amine groups onto the bottle brush during or at the end of the polymerization reaction.

[0043] The following terms may have the meanings ascribed to them below unless expressly stated otherwise. As used herein, the terms "comprising," "to comprise," and the like do not exclude the presence of additional elements or steps in addition to those recited in a claim. Similarly, the word "a," "an," or "the" preceding an element or feature does not exclude the presence of a plurality of those elements or features, unless the context clearly dictates otherwise.

[0044] The phrase "and / or" as used in the present specification and claims should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjointly present in some cases and disjointly present in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so conjoined. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether or not related to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising", may refer in one embodiment to only A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0045] As used herein, terms such as "comprising," "to comprise," and the like are intended to be open ended and do not exclude the presence of additional elements or steps in addition to those recited in a claim or other sentence. For example, a polymer "comprises" a particular type of bond if that bond is present in the polymer, even though other bonds are also present.

[0046] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error of the device or method used to determine the value, or the variation that exists between samples being measured. Unless otherwise specified or clear from the context, the term "about" means within 10% (i.e., within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less) above or below the reported numerical value (except when such numerical value is above 100% or below 0% of possible values). When used in conjunction with a range or series of values, the term "about" applies to the endpoints of the range or each of the recited values ​​in the series, unless otherwise indicated. As used in this application, the terms "about" and "approximately" are used as equivalents. Unless otherwise clear from the context, all numerical values ​​provided herein in this specification and claims can be modified by the term "about".

[0047] It should also be understood that the ranges provided herein are abbreviations for all values ​​within the range, and furthermore, that the individual range values ​​provided herein can be combined to form additional undisclosed ranges. For example, the range of 1 to 50 is understood to include not only 1 and 50, but any number, combination of numbers, or subranges from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0048] A polymer "comprises" or is "derived from" a recited monomer if that monomer is incorporated into the polymer. Thus, the incorporated monomer that a polymer contains is not the same as the monomer before it was incorporated into the polymer, at least one particular end group of which is incorporated into the polymer backbone. A polymer "comprises" a particular type of bond if that bond is present in the polymer.

[0049] As will be clear, the term "polymer" is used to refer to a macromolecule having a series of repeated monomer units, or more broadly, a material made therefrom. Unless otherwise indicated or otherwise clear from the context, the term "polymer" is intended to be broadly interpreted and encompasses all types of polymers, including, but not limited to, homopolymers, copolymers, block copolymers, random copolymers, and other known polymer types. As used herein, the term "homopolymer" refers to a polymer derived from a single monomer type. As follows, unless otherwise indicated, the term "copolymer" refers to a polymer derived from two, three, or more monomer types, including alternating copolymers, periodic copolymers, random copolymers, statistical copolymers, and block copolymers. Unless otherwise indicated, the term "block copolymer" includes two or more homopolymer or copolymer subunits linked by covalent bonds.

[0050] As used herein, the term "residue" is used generally to refer to a portion of a monomer or other chemical unit that has been incorporated into a polymer or macromolecule. By extension, the terms "residue of a chain transfer agent" and "chain transfer agent residue" are used interchangeably to refer to a portion of a chain transfer agent that has been incorporated into a bottlebrush polymer. Conversely, when a monomer is incorporated into a polymer, the polymer "comprises" or is "derived from" the described monomer. Thus, the incorporated monomer that a polymer comprises is not the same as the monomer prior to its incorporation into the polymer, in which at least certain end groups are incorporated into the polymer backbone. A polymer "comprises" a particular type of bond if that bond is present in the polymer.

[0051] The term "ultraviolet light" is generally used herein to refer to light in the ultraviolet portion of the spectrum, generally having wavelengths from about 10 nm to about 400 nm. Similarly, the term "ultraviolet light blocking" as applied to a polymer or other material refers broadly to a polymer or other material having the ability or capability of blocking or reducing the transmission of ultraviolet light. A polymer is understood to be "transparent" or "see-through" if it is not hazy and an image can be seen through the material. However, a "transparent" or "see-through" polymer may still have a colored "tint", provided that it is not hazy and an image can be seen through the material. The term "optically clear" as applied herein to a polymer refers to a polymer that is "transparent", substantially uncolored, and suitable for use in optical applications.

[0052] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, meaning that they should be read and considered by the reader as part of this text. It is for the sake of brevity only that documents, references, patent applications, or patents cited in this text are not repeated in this text. In case of conflict, the present disclosure, including definitions, controls. All technical and scientific terms used herein have the same meaning.

[0053] Furthermore, any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein. The fact that certain features, elements or components are recited in different dependent claims does not exclude that at least some of these features, elements or components can be used together in combination.

[0054] In a first aspect, the present invention is directed to bottle-brush homopolymers or copolymers for use as fluid-like filling materials in ophthalmic implants consisting of homopolymers or copolymers of one or more high refractive index methacrylate monomers or macromonomers and reversible addition-fragmentation chain transfer (RAFT) agents. The bottle-brush polymers are biocompatible and transparent, preferably optically clear. As mentioned above, all of these high refractive index methacrylate monomers and macromonomers have terminal reactive methacrylate groups capable of RAFT polymerization and sufficient chain length to provide a polymer with a graft density high enough to provide rigidity and prevent chain entanglement.

[0055] In various embodiments, the optically clear bottle brush polymers of the present invention have a relatively low glass transition temperature (T g) (-50°C to about 30°C) and has a number average molecular weight (Mn) of about 10,000 g / mol to 250,000 g / mol. As used herein, the term "methacrylate macromonomer" refers to a polymer having terminal methacrylate functional groups capable of RAFT, atom transfer radical polymerization (ATRP), ring-opening metathesis polymerization (ROMP), and ring-opening polymerization (ROP) polymerization to form bottle-brush or comb polymers. Suitable high refractive index methacrylate macromonomers may include, but are not limited to, monomethacryloxypropyl-terminated polydimethylsiloxane (PDMS-MA) and oligo(ethylene glycol) methacrylate (OEGMA).

[0056] In some embodiments, the transparent bottle brush polymers of the present invention have a number average molecular weight (M n ), and a refractive index (n r ) and a complex viscosity of about 0.5 Pa s to about 15 Pa s. In some other embodiments, the transparent bottle-brush polymers of the present invention have a number molecular weight (M) of about 25,000 g / mol to about 250,000 g / mol. n ), n of about 1.43 to about 1.48 r , and a homopolymer of OEGMA with a complex viscosity of about 0.5 Pa·s to about 15 Pa·s.

[0057] In one or more embodiments, the transparent bottlebrush polymer is a random copolymer of PDMS-MA and OEGMA formed by RAFT polymerization ("poly(PDMS-MA-co-OEGMA)") and comprises about 10 to about 95 mole percent PDMS-MA. In some embodiments, poly(PDMS-MA-co-OEGMA) will comprise about 20 to about 95, in other embodiments about 30 to about 95, in other embodiments about 50 to about 95, in other embodiments about 70 to about 95, in other embodiments about 80 to about 95, in other embodiments about 10 to about 85, in other embodiments about 10 to about 70, in other embodiments about 10 to about 60, in other embodiments about 10 to about 50, and in other embodiments about 10 to about 30 mole percent PDMS-MA repeat units. In some embodiments, poly(PDMS-MA-co-OEGMA) will comprise about 70 to about 95 mole percent PDMS-MA repeat units.

[0058] In one or more embodiments, these poly(PDMS-MA-co-OEGMA) copolymers have a number molecular weight (M) of about 25,000 g / mol to about 250,000 g / mol, as measured by size exclusion chromatography (SEC). n In some embodiments, the poly(PDMS-MA-co-OEGMA) copolymer will have a molecular weight of about 30,000 g / mol to about 250,000 g / mol, in other embodiments about 50,000 g / mol to about 25,000 g / mol, in other embodiments about 100,000 g / mol to about 250,000 g / mol, and in other embodiments about 150,000 g / mol to about 25 and in another embodiment, about 200,000 g / mol to about 250,000 g / mol, in another embodiment, about 25,000 g / mol to about 200,000 g / mol, in another embodiment, about 25,000 g / mol to about 150,000 g / mol, in another embodiment, about 25,000 g / mol to about 100,000 g / mol, and in another embodiment, about 25,000 g / mol to about 50,000 g / mol. n ).

[0059] In some embodiments, these poly(PDMS-MA-co-OEGMA) copolymers have an n r In some embodiments, n r may be from about 1.41 to about 1.48, in other embodiments from about 1.42 to about 1.48, in other embodiments from about 1.45 to about 1.48, in other embodiments from about 1.46 to about 1.48, in other embodiments from about 1.40 to about 1.47, in other embodiments from about 1.40 to about 1.46, in other embodiments from about 1.40 to about 1.45, in other embodiments from about 1.40 to about 1.44, in other embodiments from about 1.40 to about 1.43, and in other embodiments from about 1.40 to about 1.42. In one or more of these embodiments, the poly(PDMS-MA-co-OEGMA) copolymer may have a complex viscosity, as measured by shear rheology, of from about 0.5 Pa·s to about 15 Pa·s.

[0060] In some other embodiments, PDMS-MA and / or OEGMA or other high refractive index methacrylate macromonomers are used to provide low and high n r Copolymerize with small molecule methacrylate or acrylate monomers to achieve the final n without increasing viscosity outside the desired range. rSuitable small molecule methacrylate monomers include, but are not limited to, 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA), ethylene glycol phenyl ether methacrylate (EGPhEMA), hydroxyethyl methacrylate (HMEMA), methyl methacrylate (M ... acrylate (HEMA), 2,2,2-trifluoroethyl acrylate (TFEA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl acrylate (HDFDA), benzyl acrylate (BzA), 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof. In some embodiments, fluorinated methacrylic monomers are copolymerized with PDMS-MA to form n r In some other embodiments, benzyl monomers are copolymerized with OEGMA to reduce the desired n r Reaching the upper end of the range.

[0061] In some other embodiments, the transparent bottlebrush polymers or copolymers of the invention are copolymers of PDMS-MA and benzyl methacrylate (BzMA) formed by RAFT polymerization ("poly(PDMS-MA-co-BzMA)") and contain about 10 to about 90 mole percent PDMS-MA. In some embodiments, the poly(PDMS-MA-co-BzMA) copolymers will contain about 20 to about 90, in other embodiments about 30 to about 90, in other embodiments about 50 to about 90, in other embodiments about 70 to about 90, in other embodiments about 80 to about 90, in other embodiments about 10 to about 85, in other embodiments about 10 to about 70, in other embodiments about 10 to about 60, in other embodiments about 10 to about 50, and in other embodiments about 10 to about 30 mole percent PDMS-MA repeat units.

[0062] In some other embodiments, the transparent bottlebrush polymer is a copolymer of PDMS-MA and ethylene glycol phenyl ether methacrylate (EGPhEMA) formed by RAFT polymerization ("poly(PDMS-MA-co-EGPhEMA)") and contains about 10 to about 90 mole percent PDMS-MA. In some embodiments, the poly(PDMS-MA-co-EGPhEMA) copolymer will contain about 20 to about 90, in other embodiments about 30 to about 90, in other embodiments about 50 to about 90, in other embodiments about 70 to about 90, in other embodiments about 80 to about 90, in other embodiments about 10 to about 85, in other embodiments about 10 to about 70, in other embodiments about 10 to about 60, in other embodiments about 10 to about 50, and in other embodiments about 10 to about 30 mole percent PDMS-MA repeat units.

[0063] In some embodiments, the high refractive index (meth)acrylate macromonomers (e.g., PDMS-MA and OEGMA) and methacrylate monomers (TFEMA, HDFDMA, BzMA, BzTAzMA, EGPhEMA, and HEMA) may have one of the following formulas: [ka] In the formula, x is an integer of about 5 to about 10.

[0064] In some other embodiments, the acrylate monomers (TFEA, HDFDA, BzA, BzTAzA, EGPhEA, HEA) may have one of the following formulas: [ka]

[0065] In particular, in embodiments in which the transparent bottlebrush polymers and copolymers of the present invention are used as a filling material for intraocular lenses (IOLs) or accommodating intraocular lenses (A-IOLs), the viscosity and refractive index (n r ) are important. In various embodiments, the optically clear bottle brush polymers of the present invention will have a complex viscosity of about 0.4 Pa·s to about 15 Pa·s as measured by a rheometer at 37° C. In some embodiments, the optically clear bottle brush polymers of the present invention will have a complex viscosity at 37° C. of 0.5 Pa·s to about 15 Pa·s, in other embodiments of about 0.5 Pa·s to about 13 Pa·s, in other embodiments of about 0.5 Pa·s to about 12 Pa·s, in other embodiments of about 0.5 Pa·s to about 10 Pa·s, in other embodiments of about 0.5 Pa·s to about 8 Pa·s, in other embodiments of about 0.5 Pa·s to about 6 Pa·s, in other embodiments of about 1 Pa·s to about 15 Pa·s, in other embodiments of about 3 Pa·s to about 15 Pa·s, in other embodiments of about 5 Pa·s to about 15 Pa·s, in other embodiments of about 7 Pa·s to about 15 Pa·s, and in other embodiments of about 9 Pa·s to about 15 Pa·s. In some embodiments, the optically clear bottle brush polymers of the present invention will have a complex viscosity of about 0.4 Pa·s to about 50 Pa·s as measured by a rheometer at 37°C.

[0066] In one or more embodiments, the optically clear bottlebrush polymers and copolymers of the invention will have a refractive index of about 1.43 to about 1.48 when measured by a refractometer at 37° C. In some embodiments, the optically clear bottlebrush polymers and copolymers of the invention will have a refractive index of about 1.40 to about 1.48, in other embodiments about 1.42 to about 1.48, in other embodiments about 1.44 to about 1.48, in other embodiments about 1.46 to about 1.48, in other embodiments about 1.40 to about 1.47, in other embodiments about 1.40 to about 1.46, in other embodiments about 1.40 to about 1.45, and in other embodiments about 1.40 to about 1.43 when measured by a refractometer at 37° C. The refractive indexes of some transparent bottlebrush polymers and copolymers according to the invention are shown in Table 1 below. [Table 1]

[0067] It has been found that it is possible to fine-tune the refractive index of the transparent bottle-brush polymers and copolymers of the present invention by varying the stoichiometry and composition based on refractive index measurements.

[0068] The bottle brush polymers of the present invention can be made by any suitable method, but are preferably made using reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. In various embodiments, the bottle brush polymers of the present invention can be formed by RAFT polymerization using one or more suitable RAFT agents and conventional free radical initiators. Exemplary reaction mechanisms are shown in Schemes 1-11 and discussed in more detail below.

[0069] Suitable RAFT agents may include, but are not limited to, dithiobenzoates, trithiocarbonates, and combinations thereof. In some of these embodiments, the RAFT agent may be 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid (chain transfer agent-1, CTA1) or 4-cyano-4-(thiobenzoylthio))pentanoic acid (CTA2). In some embodiments, the RAFT agent may be a dithiobenzoate having the formula: [ka]

[0070] In some other embodiments, the RAFT agent may be a trithiocarbonate having the formula: [ka] wherein y is an integer from 3 to 11. In yet other embodiments, the RAFT agent has the formula: [ka]

[0071] During the RAFT polymerization reaction, the methacrylate macromonomer polymerizes at a location at or near the center of the RAFT agent, splitting the RAFT agent and forming each half of the RAFT agent that forms the end groups of the bottle-brush polymer. In embodiments where the bottle-brush polymer of the invention needs to be optically transparent, one of these end groups can be removed by the addition of an excess of a thermally or chemically activated radical generating compound, such as 2,2'-azobis(2-methylpropionitrile) (AIBN). The resulting polymer is optically transparent, as shown in FIG.

[0072] The optically clear bottle brush polymers of the present invention have a number average molecular weight M of about 25,000 g / mol to about 250,000 g / mol. n In some embodiments, the M of the optically clear bottlebrush polymers of the present invention will haven is about 50,000 g / mol to about 250,000 g / mol, in other embodiments about 100,000 g / mol to about 250,000 g / mol, in other embodiments about 150,000 g / mol to about 250,000 g / mol, in other embodiments about 200,000 g / mol to about 250,000 g / mol, in other embodiments about 25,000 g / mol to about 200,000 g / mol, in other embodiments about 25,000 g / mol to about 150,000 g / mol, in other embodiments about 25,000 g / mol to about 100,000 g / mol, and in other embodiments about 25,000 g / mol to about 50,000 g / mol, as measured by size exclusion chromatography (SEC). n is from about 50,000 g / mol to about 200,000 g / mol as measured by size exclusion chromatography (SEC). n The optically clear bottle brush polymers of the present invention have a number average molecular weight (M) of about 30,000 g / mol to about 500,000 g / mol, preferably about 100,000 g / mol to about 400,000 g / mol, and more preferably about 150,000 g / mol to about 300,000 g / mol, as measured by size exclusion chromatography (SEC). w ).

[0073] In various embodiments, the optically clear bottle brush polymers of the present invention have a glass transition temperature (T) of about -50°C to about 30°C, preferably about -50°C to about 10°C, and more preferably about -50°C to about 10°C, as measured by dynamic mechanical analysis (DMA) or differential scanning calorimetry (DSC). g ).

[0074] In one or more embodiments, the side chain DP of the macromonomer and resulting polymer segment will be from about 5 to about 10. In some embodiments, the PDMS-MA macromonomer will have a side chain DP of from about 5 to about 10. In some other embodiments, the OEGMA macromonomer will have a side chain DP of from about 8 to about 10.

[0075] In one or more embodiments, the bottle brush polymers of the present invention have the formula: [ka] In the formula, R is [ka] where x is an integer from about 5 to about 10, y is an integer from about 3 to about 11, and a is an integer from about 20 to about 300. In some embodiments, x can be an integer from about 6 to about 10, in other embodiments from about 7 to about 10, in other embodiments from about 8 to about 10, in other embodiments from about 5 to about 9, in other embodiments from about 5 to about 8, and in other embodiments from about 5 to about 7. In some embodiments, x is 5. In other embodiments, x is 6.

[0076] In some embodiments, y is an integer from about 4 to about 11, in other embodiments from about 5 to about 11, in other embodiments from about 6 to about 11, in other embodiments from about 8 to about 11, in other embodiments from about 10 to about 11, in other embodiments from about 3 to about 9, in other embodiments from about 3 to about 7, and in other embodiments from about 3 to about 5. In some embodiments, y is 11. In some embodiments, a can be an integer from about 30 to about 300, in other embodiments from about 50 to about 300, in other embodiments from about 100 to about 300, in other embodiments from about 150 to about 300, in other embodiments from about 200 to about 300, in other embodiments from about 20 to about 200, in other embodiments from about 20 to about 100, in other embodiments from about 20 to about 50, and in other embodiments from about 20 to about 30.

[0077] In one or more embodiments, the bottle brush polymers of the present invention have the formula: [ka] In the formula, R is [ka] wherein x is an integer from 5 to 10, and R′ has the formula [ka] where y is an integer from about 3 to about 11, n is a mole percent from about 70% to about 95%, m is a mole percent from about 5% to about 30%, and n+m=100. In various embodiments, x and y can be as indicated above. In some embodiments, y is 11.

[0078] In some embodiments, n is about 75% to about 95%, in other embodiments, about 80% to about 95%, in other embodiments, about 85% to about 95%, in other embodiments, about 90% to about 95%, in other embodiments, about 70% to about 90%, in other embodiments, about 70% to about 85%, in other embodiments, about 70% to about 80%, and in other embodiments, about 70% to about 75%. In various embodiments, m is about 10% to about 30%, in other embodiments, about 15% to about 30%, in other embodiments, about 20% to about 30%, and in other embodiments, about 25% to about 30%.

[0079] In one or more embodiments, the bottle brush polymers of the present invention have the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, y is an integer from about 3 to about 11, n is a mole percent from about 80% to about 90%, m is a mole percent from about 20% to about 10%, and n+m=100. In various embodiments, x and y can be any of the integers set forth above for x and y, and n and m can be any of the mole percents set forth above for n and m.

[0080] In one or more embodiments, the bottle brush polymers of the present invention have the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where n is a mole percent of about 80% to about 0.90%, y is an integer of about 3 to about 11, and x is an integer of about 5 to about 10. In some embodiments, x is 5 or 6.

[0081] In one or more embodiments, the bottle brush polymers of the present invention have the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, y is an integer from about 3 to about 11, n is a mole percent from about 5% to about 30%, m is a mole percent from about 70% to about 95%, and n+m=100. In some embodiments, x is 5 or 6. In some embodiments, y is 11.

[0082] Although the bottle brush polymers of the present invention are all transparent after formation by RAFT polymerization, they are often tinted and not completely optically transparent. However, it has been found that advantageously, removal of the sulfur-containing end groups (residues of the RAFT agent) produces polymers that are optically transparent. (See, e.g., FIG. 1). In one or more embodiments, the bottle brush polymers of the present invention are homopolymers having the formula: [ka] In the formula, R is [ka] where x is an integer from about 5 to about 10, and a is an integer from about 20 to about 300. In some embodiments, x is 5 or 6.

[0083] In some other embodiments, the bottle brush polymer of the present invention is a copolymer having the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, a is an integer from about 5 to about 30, b is an integer from about 70 to about 95, n is a mole percent from about 5% to about 30%, m is a mole percent from about 70% to about 95%, and n+m=100.

[0084] Furthermore, as shown above, it has been found that this copolymerization approach can be used to incorporate UV absorbing reagents into the bottlebrush polymer backbone to filter out UV light by meth(acrylating) a UV absorbing dye containing an alcohol or amine group to the bottlebrush during or at the end of the polymerization reaction. A suitable UV absorbing dye containing an alcohol or amine group is 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA). In one or more embodiments, the present invention is directed to UV light blocking bottlebrush Raft copolymers having the formula: [ka] In the formula, R is [ka] and R′ has the formula [ka] where x is an integer from about 5 to about 10, n is a mole percent from about 90% to about 99%, m is a mole percent from about 1% to about 10%, and n+m=100.

[0085] As indicated above, the bottle brush polymers of the present invention can be made by any suitable method, but are preferably made using reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. The transparent bottle brush polymers of the present invention can be made by other techniques, including, but not limited to, atom transfer radical polymerization (ATRP), ring-opening metathesis polymerization (ROMP), and ring-opening polymerization (ROP).

[0086] In embodiments using RAFT polymerization, one or more high-n r The methacrylate macromonomer, the RAFT agent, and the free radical initiator are combined in a reaction solvent at elevated temperature and under an inert atmosphere to produce the bottlebrush polymer. In various embodiments, one or more high-nr The methacrylate monomers and / or macromonomers, and the RAFT agent can be any of those described above. The initiator can be any free radical initiator known in the art, provided that it is non-toxic and compatible with the reagents being used. Suitable initiators can include, but are not limited to, azo compounds (e.g., 2,2'-azobis(2-methylpropionitrile, AIBN), organic peroxides (e.g., benzoyl peroxide), inorganic peroxides, or combinations thereof.

[0087] Those skilled in the art will be able to select a free radical initiator without undue experimentation. The reaction solvent is not particularly limited, provided that it can dissolve or at least suspend all the reagents. Furthermore, since the solvent must be removed, it is preferable to minimize the amount of solvent used and use only an amount sufficient to dissolve or suspend the other reagents. Suitable solvents include toluene, tetrahydrofuran (THF), hexane, dichloromethane, chloroform, and combinations thereof. Those skilled in the art will be able to select a reaction solvent without undue experimentation. In one or more embodiments, the solvent is toluene.

[0088] In some embodiments, the bottle brush polymers of the invention are homopolymers and the molar ratio of macromonomer to RAFT agent to initiator used is 1-300:1:0.5 equivalents, preferably 1-200:1:0.5 equivalents, and more preferably 1-100:1:0.5 equivalents. In some embodiments, the molar ratio of macromonomer to RAFT agent to RAFT initiator used is 100:1:0.5 equivalents.

[0089] In various embodiments, the reaction temperature is 60° C. to 80° C., preferably 65° C. to 80° C., and more preferably 70° C. to 75° C. In some of these embodiments, the reaction temperature is about 70° C. In one or more embodiments, the reaction time is 6 hours to 24 hours, preferably 9 hours to 20 hours, and more preferably 12 hours to 16 hours. In some of these embodiments, the reaction time is 12 hours to 16 hours.

[0090] A representative reaction mechanism is shown in Scheme 1 below. Scheme 1 Synthesis scheme of poly(PDMS-MA) via RAFT polymerization using CTA1 [ka]

[0091] In some of these embodiments, x is an integer from about 5 to about 10, as shown above. In various embodiments, n is an integer from about 20 to about 300, as shown above. In the reaction shown in Scheme 1, high n r A methacrylate macromonomer (PDMS-MA) is reacted with a RAFT agent (4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid (CTA1)) in toluene using an initiator (2,2'-azobis(2-methylpropionitrile (AIBN)) at about 70 °C for about 12 to about 16 h to form a poly(PDMS-MA) bottlebrush homopolymer.

[0092] In various embodiments, the RAFT polymerization reaction produces a polymer or copolymer having a backbone with a degree of polymerization (DP) as described above. In some embodiments, the polymer or copolymer has a backbone with a DP of about 20 to about 300, preferably about 50 to about 200, and more preferably about 75 to 150.

[0093] The reaction may be quenched using any suitable method, provided that no additional monomer is added to the chain ends. In some embodiments, the reaction may be quenched by opening the reaction to ambient air. In some embodiments, the reaction may be quenched by adding a weak protic acid in a solvent. In one or more embodiments, the solvent may include, but is not limited to, methanol, hexane, heptane, toluene, isopropanol, ethanol, pentane, and combinations thereof. In some of these embodiments, reactions involving macromonomers such as PDMS-MA are quenched by exposure to air and the addition of methanol, hexane, heptane, toluene, isopropanol, ethanol, pentane, and combinations thereof. In some other embodiments, reactions involving hydrophilic macromonomers such as OEGMA are quenched by exposure to air and the addition of hexane, heptane, toluene, isopropanol, ethanol, pentane, and combinations thereof.

[0094] In some other embodiments, controlled radical polymerization (CRP) procedures, including atom transfer radical polymerization and nitroxide-mediated radical polymerization, as well as ring-opening metathesis polymerization, allow for the synthesis of bottlebrush polymers by three different approaches: grafting to, grafting through, and grafting from. Each relies on the use of monomers compatible with the technology. The majority of bottlebrush polymers synthesized by ATRP use copper bromide-based catalysts and the method of the grafting from approach. The side chains are polymerized from macroinitiators with initiating groups on each monomer unit, resulting in densely grafted polymers with relatively high initiation efficiency and narrow molecular weight distribution, without a significant number of inter- / intramolecular coupling reactions and retention of transferable atoms at the side chain ends.

[0095] The resulting bottle brush polymer or copolymer can be collected and purified using any suitable method. One of ordinary skill in the art will be able to collect and purify the bottle brush polymer without undue experimentation. In various embodiments, the bottle brush polymer or copolymer can be collected and purified as shown in the examples below.

[0096] As shown above, the bottle brush polymers formed as shown above are all clear after formation by RAFT polymerization, but they may be tinted and not completely optically transparent. Without wishing to be limited in any way by theory, it is believed that the tinting of these bottle brush polymers results from sulfur-containing end groups (residues of RAFT agents, see CTA1 and CTA2). In any case, it has been found that removal of these sulfur-containing end groups produces optically clear polymers. (See, e.g., FIG. 1).

[0097] In embodiments where the bottle brush polymers of the invention are required to be optically transparent (e.g., for use in intraocular lenses), these end groups may be removed by the addition of an excess of a thermally or chemically activated radical generating compound, such as 2,2'-azobis(2-methylpropionitrile) (AIBN). In one or more embodiments, the thermally or chemically activated radical generating compound is the same compound used to initiate the RAFT polymerization that formed the bottle brush polymer. In some embodiments, the thermally or chemically activated radical generating compound used to remove the RAFT end groups on the bottle brush polymers of the invention is AIBN.

[0098] In one or more of these embodiments, the sulfur-containing terminal residue of the chain transfer agent on the bottlebrush RAFT polymer of the invention is removed at the ω-chain end of the poly(PDMS-MA) bottlebrush RAFT polymer and converted to 2-cyanopropyl 3-(2-phenylpropanediol) via AIBN treatment, as shown in Scheme 2 below. 0 It may be replaced with a radical end-capping group. Scheme 2 [ka]

[0099] The bottle brush polymer shown in Scheme 2 is a homopolymer of PDMS-MA formed using CTA1 as an initiator (see Scheme 1 above), however, the invention is not so limited and the reaction shown in Scheme 2 can also be used with any of the homopolymers and copolymers shown above having sulfur-containing end groups, including those formed with CTA2 as an initiator.

[0100] In these embodiments, the bottle brush polymer is first placed in a sealable flask or other suitable reaction vessel and dissolved in a suitable solvent. The solvent used is not particularly limited, and any solvent for the bottle brush polymer can be used, provided that the solvent does not degrade or react with the bottle brush polymer or other reagents, or otherwise interfere with the reaction shown in Scheme 2 above. One of ordinary skill in the art would be able to select a solvent for the bottle brush polymer without undue experimentation. Suitable solvents may include, but are not limited to, toluene, tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), and combinations thereof. In some embodiments, the solvent is toluene. In some other embodiments, the solvent is THF.

[0101] A thermally or chemically activated radical generating compound is then added in excess to the bottlebrush RAFT polymer solution and the vessel is heated to remove the sulfur-containing end group residues of the chain transfer agent from the ω-chain ends of the bottlebrush RAFT polymer. In the embodiment shown in Scheme 2 above, an excess of AIBN is added to the reaction vessel, which is then sparged with an inert gas, such as nitrogen gas, to avoid oxidation of the thiols on the RAFT agent, and then heated to remove the sulfur-containing end group residues from the ends of the bottlebrush RAFT polymer. In some embodiments, the reaction vessel may be a flask equipped with a TEFLON® coated stir bar and sealed with a rubber septum.

[0102] As will be appreciated by those skilled in the art, the excess AIBN is more than twice the stoichiometric amount of polymer. In some embodiments, AIBN is added in an amount equal to 20 times the equivalent amount of RAFT agent used to synthesize the polymer. Once AIBN is added, the vessel is sealed and sparged with an inert gas, such as nitrogen gas, to avoid oxidation of the thiols on the RAFT agent. The sparging time is not particularly limited, provided that it is sufficient to avoid oxidation of the thiols on the RAFT agent, and of course depends on the flow rate of the inert gas used. In some embodiments, the AIBN / bottlebrush RAFT polymer mixture may be sparged with N2 for 20-30 minutes (>1 mL / min).

[0103] The reaction vessel is then heated to facilitate the reaction, as set forth above. As shown in Scheme 2, heating radicalizes AIBN to produce two 2-cyanopropyl 3 0 radical and nitrogen gas. As can be seen, these two 2-cyanopropyl 3 0 The radical attacks the carbon-sulfur bond that holds the terminal residue of the chain transfer agent to the ω-chain end of the bottlebrush RAFT polymer, thereby removing it from the end of the polymer. 0Due to the presence of the radical, the sulfur-containing compound was removed and replaced with a 2-cyanopropyl end-capping group as shown in Scheme 2.

[0104] The temperature required to radicalize sufficient AIBN depends on the planned reaction time, but the vessel should be heated to a temperature of at least 40° C. to facilitate the reaction, but not above 60° C. In some embodiments, the reaction vessel is heated to the reflux temperature of the reaction mixture. The reaction vessel may be heated by any suitable method, including, but not limited to, an oil bath, a water bath, or an electric heating plate or coil, but the reaction vessel is preferably heated in an oil bath. As will be apparent to one of skill in the art, the higher the reaction temperature, the shorter the reaction time required for the reaction. In some embodiments, the reaction vessel is submerged in an oil bath and heated to 80° C., and the reaction was carried out for 3-4 hours. In some other embodiments, the reaction vessel is submerged in an oil bath and refluxed at 65-70° C. for 5-6 hours.

[0105] After the reaction shown in Scheme 2 is completed, the reaction mixture is dried and purified using any method known in the art for that purpose resulting in an optically clear bottlebrush RAFT polymer. In some embodiments, the reaction mixture may be dried under reduced pressure using a rotovap (typically 80-100 mbar, 35° C.) and the resulting viscous liquid may be washed repeatedly with methanol, redissolved in THF, and passed through a 1 μm PTFE filter. Finally, all volatiles are removed (80-100 mbar, 35° C.) and the resulting clear, colorless, viscous liquid polymer melt is further dried overnight under high vacuum at room temperature.

[0106] In one or more embodiments, the sulfur-containing end group residues of the chain transfer agents on the bottlebrush RAFT polymers of the invention may be removed and replaced with 2-cyanopropyl end-capping groups as described in Examples 12 and 13 below.

[0107] In a second aspect, the present invention is directed to an artificial intraocular lens (IOL) for use in treating cataracts comprising a lens shell having a sealed cavity substantially filled with an optically transparent filler material comprising one or more of the bottlebrush polymers and copolymers described above. In these embodiments, the bottlebrush polymers and copolymers have a refractive index (n) of about 1.40 to about 1.48. r ) and a complex viscosity of about 0.4 Pa·s to about 12 Pa·s. In various embodiments, the optically clear fill material is solvent-free.

[0108] In various embodiments, the artificial lens comprises a flexible lens shell or bag that includes a filler material that includes one or more of the methacrylate-based bottle-brush polymers or copolymers discussed above. As will be understood by those skilled in the art, the lens of the eye is acted upon by the muscles of accommodation, which change the shape of the lens to allow the eye to focus over a range of distances (FIGS. 2, 3). People with young, healthy eyes can focus on nearby objects through a process called accommodation. During accommodation, there is an increase in the refractive power of the crystalline lens of the eye due to an increase in the axial thickness of the lens, an increase in the curvature of the anterior and posterior surfaces of the lens, and a decrease in the lens diameter.

[0109] An IOL according to one or more embodiments of the present invention is shown in Figures 2-4. Referring initially to Figure 2, the IOL may be comprised of a thin flexible shell 2a filled with an optically clear filling medium 2b. In one or more embodiments, the thin shell may be 20 microns to 1 mm thick and may be comprised of a flexible silicone elastomer, hydrophobic acrylic, or other flexible and biocompatible material. In these embodiments, the filling medium is an optically clear biocompatible flexible bottle brush polymer material as described herein. In these embodiments, the refractive index of the filling material is selected to create an IOL with a predetermined power. An inserter device 2c is used to insert the pre-filled IOL into the capsular bag 2f of the eye through a limbal incision 2i. The IOL may be adaptive such that as the accommodation muscles 2d contract, the shape of the IOL changes, thus providing additional diopter power and allowing the eye to focus near. The cornea 2g and iris 2h of the eye are shown as well as the zonular fibers 2e which attach the ciliary muscle 2d to the capsular bag 2f of the eye. The IOL of this embodiment is filled with a filling medium and sealed before the filling medium enters the inserter device, which then inserts the lens into the capsular bag of the eye. It is also contemplated that an entirely preformed IOL of the polymers described herein may be provided without an outer shell.

[0110] Referring now to FIG. 3, the thin flexible shell of the IOL 3a is inserted into the capsular bag 3f with an inserter device 3b. The inserter device 3b is used to inject an optically clear filling medium into the shell through a thin cannula 5c. The shell may have a one-way valve or plug. The shell may be made of a self-sealing material. Alternatively, a sealant may be placed on the shell after insertion of the filling material. Again, the thin shell may be 20 microns to 1 mm thick and is composed of a flexible silicone elastomer, hydrophobic acrylic, or other flexible and biocompatible material. The filling material is an optically clear biocompatible flexible bottle brush polymer material as described above and can be manufactured with a variety of refractive indices as described herein. The refractive index of the filling material is selected to create an IOL with a predetermined power. In these embodiments, the IOL is adaptive because as the accommodative muscles contract, the shape of the IOL changes 3d, thus providing additional diopter power and allowing the eye to focus near. The cornea 3g, iris 3h, and vitreous body 3j of the eye are shown as well as the zonular fibers 3e that attach the ciliary muscle 3d to the capsular bag 3f of the eye. The IOL of this embodiment is inserted into the capsular bag and then filled with a filling medium and sealed within the capsular bag of the eye. Figure 4 is an image of one version of an A-IOL in which the shell material is of uniform thickness.

[0111] According to the Helmholtz theory of accommodation, when the eye focuses on a distant object, the circular ciliary muscle relaxes and the zonules pull on the lens, flattening it. When the eye focuses on a close object, the ciliary muscle contracts and the lens zonules relax. As zonular tension decreases, the lens becomes thicker and more convex. This rounded lens enhances the eye's acuity and allows for close vision. In the Helmholtz theory, the zonules are relaxed during accommodation and are under tension when accommodation ends. (Glasser 2006)

[0112] As shown above, the natural lens loses its elasticity over time, becoming thicker and less flexible, leading to presbyopia. With age, the crystalline lens becomes thicker and more opaque, leading to blurred vision and cataracts. The artificial lens according to the present invention is implanted in the patient's eye to replace the lens that becomes thicker, less flexible and more opaque with age. This A-IOL has a refractive index (n r ) and complex viscosity to allow it to be deformed by the eye muscles to allow the eye to focus. The present disclosure provides a solution for presbyopia and cataracts with an accommodative intraocular lens that can change shape in response to the accommodative muscles and can eliminate the need for glasses and contact lenses by providing clear vision over a range of distances.

[0113] In some embodiments, the artificial lens is an accommodating intraocular lens (A-IOL). In some embodiments, the intraocular lens will not accommodate. In some embodiments, the IOL can be an intraocular lens as described in U.S. Pat. No. 10,278,810, U.S. Patent Application Publication No. 2019 / 0321163A1 (continuation), or International Application No. PCT / US20 / 52316, the disclosures of which are incorporated herein by reference in their entireties. EXAMPLES

[0114] The following examples are provided to more fully illustrate the present invention, but should not be construed as limiting its scope. Furthermore, although some examples may include conclusions regarding the manner in which the present invention may function, the inventors do not intend to be bound by those conclusions, but present them only as possible illustrations. Furthermore, unless indicated by the use of the past tense, the presentation of examples does not imply that an experiment or procedure was or was not performed, or that a result was or was not actually obtained. Although efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature), some experimental error and deviation may exist. Unless otherwise specified, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0115] material Solvents were received from Fisher Scientific as ACS grade and used without further purification unless otherwise stated. 4-Cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid (Chain Transfer Agent #1 (CTA1), 97% HPLC, Sigma-Aldrich, CAS#870196-80-8), 4-Cyano-4-(thiobenzoylthio)pentanoic acid (CTA2, 97%, Strem Chemicals, CAS#201611-92-9), sodium borohydride (NaBH4, 99.99%, Sigma-Aldrich), chloroform-d (CDCl3, 99.8 atom % D, with 0.03% v / v TMS, Sigma-Aldrich), and methylene chloride-d2 (CD2Cl2, 99.8 atom % D, Acros Organics) were used as received. 2,2'-Azobis(2-methylpropionitrile) (AIBN, 98%, Sigma-Aldrich) was recrystallized from MeOH. Monomethacryloxypropyl-terminated PDMS asymmetric (PDMS-MA700, MCR-M07, MW = 600–800 g / mol, Gelest), oligo(ethylene glycol) methyl ether methacrylate (OEGMA, M n= 500 g / mol, Sigma-Aldrich), benzyl methacrylate (BzMA, 96%, Sigma-Aldrich), ethylene glycol phenyl ether methacrylate (EGPhEMA, Sigma-Aldrich), 2,2,2-trifluoroethyl methacrylate (TFEMA, TCI Chemicals), and hydroxypropyl acrylate (HPA, 95%, Sigma-Aldrich) were freshly purified by passage through a short column of basic alumina before use.

[0116] device NMR spectroscopic analyses of samples were collected using a Bruker Advance Neo 500 MHz multinuclear NMR spectrometer. Chemical shifts are reported in ppm (δ) and are referenced to the residual CHCl3 proton resonance at 7.26 ppm in CDCl3 or the CH2Cl2 proton resonance at 5.32 in CD2Cl2. Size exclusion chromatography (SEC) was performed using a HLC-8420GPC, EcoSEC Elite gel permeation chromatography (GPC) system (Tosoh Bioscience, LLC.) equipped with UV and RI detectors, and a TSKgel GMHHR-M mixed-bed sample column (7.8 mm ID × 30 cm, 5 μm). The number average molecular weight (M n ), weight average molecular weight (M w ), and molecular weight distribution

number

[0117] Example 1 RAFT polymerization of PDMS-MA (MW = 600–800 g / mol)-poly(PDMS-MA) bottlebrush (BB) polymers using CTA1 In one set of experiments, poly(PDMS-MA) bottle-brush (BB) polymers (MW = 600–800 g / mol) were generated using RAFT polymerization of PDMS-MA with the RAFT agent CTA1 at four different monomer ([M]) to RAFT agent to initiator ([I]) molar ratios, as shown in Scheme 1 above.

[0118] [M]:[CTA1]:[I]=50:1:0.5 A typical reversible addition-fragmentation chain transfer (RAFT) polymerization was carried out as follows. Purified PDMS-MA700 macromonomer (M, 3.0 mL, ca. 50 equiv.), RAFT agent (CTA1, 33.2 mg, 0.082 mmol, 1 equiv.), AIBN initiator (I, 6.76 mg, 0.041 mmol, 0.5 equiv.), and toluene (1.5–2.0 mL) were added to a Schlenk flask equipped with a Teflon-coated micro stir bar and sealed with a septum. The mixture was sparged with N2 for 5–10 min. The flask was then placed in a preheated oil bath at 70 °C. The polymerization was run for 12–16 h. The flask was opened to air and the polymerization was quenched by adding 10–15 mL of MeOH directly to the flask. The resulting mixture was vortexed, sonicated, and placed in an ice bath for several minutes. The top liquid layer was then decanted and this purification step was repeated 2-4 more times. The final polymer was dissolved in THF, the solution was passed through a 1 μm PTFE filter, all volatiles were removed under reduced pressure using a rotovap (typically 85-90 mbar, 35-40° C.), and the resulting viscous liquid polymer was dried overnight under high vacuum at room temperature. A yellow, clear, viscous liquid polymer melt was obtained (>95% monomer conversion, 1.86 g isolated yield). n,theo約 30,000~40,000g / mol, M n,GPC = 34,220 g / mol, M w,GPC = 38,600 g / mol,

number

[0119] [M]:[CTA]:[I]=20:1:0.5 PDMS-MA700 macromonomer (M, 1.0 mL, ca. 20 equiv.), RAFT agent (CTA1, 33.2 mg, 0.082 mmol, 1 equiv.), AIBN initiator (I, 6.76 mg, 0.041 mmol, 0.5 equiv.), and toluene (1.0 mL) were used (>95% monomer conversion, 0.90 g isolated yield).

[0120] [M]:[CTA]:[I]=100:1:0.5 PDMS-MA700 macromonomer (M, 6.0 mL, ca. 100 equiv.), RAFT agent (CTA1, 33.2 mg, 0.0823 mmol, 1 equiv.), AIBN initiator (I, 6.76 mg, 0.0411 mmol, 0.5 equiv.), and toluene (3.0-4.0 mL) were used (>95% monomer conversion, isolated yield of ca. 4.0 g). [M]:[CTA]:[I]=300:1:0.5 PDMS-MA700 macromonomer (M, 5.5 mL, ca. 300 equiv.), RAFT agent (CTA1, 10.3 mg, 0.0248 mmol, 1 equiv.), AIBN initiator (I, 2.1 mg, 0.0124 mmol, 0.5 equiv.), and toluene (3.0 mL) were used (>95% monomer conversion, ca. 5.0 g isolated yield).

[0121] Example 2 RAFT polymerization of PDMS-MA to form poly(PDMS-MA) bottlebrush (BB) polymers using CTA1 (large scale) [M]:[CTA]:[I]=50:1:0.5 A typical reversible addition-fragmentation chain transfer (RAFT) polymerization was carried out as shown in Scheme 3 below. Scheme 3 [ka]

[0122] This example is similar to Example 1, but carried out on a larger scale. Purified PDMS-MA macromonomer (M, 10 mL, 13.714 mmol, ca. 50 equiv.), RAFT agent (CTA1, 110 mg, 0.274 mmol, 1 equiv.), AIBN initiator (I, 22.91 mg, 0.137 mmol, 0.5 equiv.), and toluene (5 mL) were added to a Schlenk flask equipped with a Teflon-coated micro stir bar and sealed with a septum. The mixture was sparged with N2 for 10-15 min. The flask was then placed in a preheated oil bath at 70 °C. The polymerization was carried out for 12-16 h (>95%% monomer conversion). The flask was opened to air and the polymerization was quenched by adding methanol directly to the flask. The resulting mixture was vortexed, sonicated, and placed in an ice bath for several minutes. The top liquid layer was then decanted and this purification step was repeated 2-4 more times. The final polymer was dissolved in THF, the solution was passed through a 1 μm PTFE filter, all volatiles were removed under reduced pressure using a rotovap (typically 90-100 mbar, 35-40° C.), and the resulting viscous liquid polymer was dried overnight under high vacuum at room temperature. A yellow, clear, viscous liquid polymer melt was obtained. 1 H NMR(400MHz,CDCl3,25°C)δ=3.86(b,2H,-CO2CH2-),2.10-1.72(b,2H,-CH2-),1.61(b,2H,-CO2CH2CH2-),1.38-1. 25(b,4H,-SiCH2CH2CH2CH3),1.11-0.78(b,6H,-CH3),0.60-0.44(b,4H,-SiCH2-),0.16-0.01(b,36H,-Si(CH3)2)

[0123] Example 3 RAFT polymerization of PDMS-MA (MW = 600-800 g / mol)-poly(PDMS-MA) bottlebrush (BB) polymers using CTA2 Poly(PDMS-MA) bottlebrush (BB) polymers (MW = 600–800 g / mol) were produced by RAFT polymerization of PDMS-MA using CTA2 as the RAFT agent with a macromonomer ([M]) to RAFT agent to initiator ([I]) ratio of 50:1:0.5, as shown in Scheme 4 below.

[0124] PDMS-MA700 macromonomer ([M], 0.67 mL, ca. 50 equiv.), RAFT agent ([CTA2], 5.3 mg, 0.0180 mmol, 1 equiv.), initiator ([I], ca. 3 mg, 0.5 equiv.) ([M]:[CTA2]:[I]=50:1:0.5), and toluene (1.0 mL) were used. The reaction was quenched and the polymer was purified as shown in Example 1 above, yielding a pink, clear, viscous liquid polymer melt after purification (>90% monomer conversion). Scheme 4 Synthesis scheme of poly(PDMS-MA) via RAFT polymerization using CTA2 [ka]

[0125] Example 4 OEGMA(M n = 500 g / mol) - RAFT polymerization of poly(OEGMA) bottle-brush polymer Poly(OEGMA) bottle brush polymers were prepared by the reaction of OEGMA(M n = 500 g / mol) via RAFT polymerization ([M]:[CTA]:[I] = 100:1:0.5). Scheme 5 Synthesis scheme of poly(OEGMA) via RAFT polymerization [ka]

[0126] A Schlenk flask equipped with a Teflon-coated micro stir bar was charged with purified OEGMA500 macromonomer (M, 1.13 mL, ca. 100 equiv.), RAFT agent (CTA1, 9.83 mg, 0.0244 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL) and sealed with a septum. The mixture was sparged with N2 for 5-10 min. The flask was then placed in a preheated oil bath at 70 °C. The polymerization was run for 12-16 h. The flask was opened to air and the polymerization was quenched by adding 10-15 mL of hexane directly to the flask. The resulting mixture was vortexed, sonicated, and placed in an ice bath for several minutes. The top liquid layer was then decanted, and this purification step was repeated 2-4 more times. The final polymer was dissolved in THF, the solution was passed through a 1 μm PTFE filter, all volatiles were removed under reduced pressure using a rotovap (typically 85-90 mbar, 35-40 °C), and the resulting viscous liquid polymer was dried under high vacuum at room temperature overnight. A yellow viscous liquid polymer melt was obtained (>95% monomer conversion, isolated yield of 1.1-1.2 g). 1 H NMR (400 MHz, CDCl3, 25°C) δ = 4.05 (b, 2H, -CO2CH2-), 3.73-3.47 (b, 34H, -O(CH2CH2O)-), 3.35 (b, 3H, -OCH3), 2.27-1.57 (b, 2H), 1.10-0.70 (b, 3H). (See Figure 6)

[0127] Example 5 PDMS-MA (MW = 600-800 g / mol) and OEGMA (M n = 500 g / mol)-RAFT copolymerization of poly(PDMS-MA-co-OEGMA) bottlebrush copolymers In these experiments, poly(PDMS-MA-co-OEGMA) bottlebrush copolymers were prepared using PDMS-MA (MW = 600–800 g / mol) and OEGMA (M n= 500 g / mol) by RAFT copolymerization. Scheme 6 Synthesis scheme of poly(PDMS-MA-co-OEGMA) via RAFT polymerization [ka]

[0128] [PDMS-MA]:[OEGMA]:[CTA]:[I]=70:30:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.25 mL, 1.708 mmol, 70 equiv.) and OEGMA500 macromonomer (0.340 mL, 0.732 mmol, 30 equiv.), RAFT agent (CTA1, 9.83 mg, 0.0244 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL) were added and sealed with a septum. The mixture was sparged with N2 for 5-10 min. The flask was then placed in a preheated oil bath at 70 °C. The polymerization was carried out for 12-16 h. The polymerization was quenched by opening the flask to air and adding 10-15 mL of methanol directly to the flask. The resulting mixture was vortexed, sonicated, and placed in an ice bath for several minutes. The top liquid layer was then decanted and this purification step was repeated 2-4 more times. The final polymer was dissolved in THF, the solution was passed through a 1 μm PTFE filter, all volatiles were removed under reduced pressure using a rotovap (typically 85-90 mbar, 35-40° C.), and the resulting viscous liquid polymer was dried overnight under high vacuum at room temperature. A yellow viscous liquid polymer melt was obtained (>95% monomer conversion, actual composition: 1 68 mol % PDMS-MA and 32 mol % OEGMA by H NMR spectroscopy, isolated yield of about 1.5 g. (See FIG. 7).

[0129] [PDMS-MA]:[OEGMA]:[CTA]:[I]=90:10:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.60 mL, 2.196 mmol, 90 equiv.) and OEGMA500 macromonomer (0.110 mL, 0.244 mmol, 10 equiv.), RAFT agent (CTA1, 9.83 mg, 0.0244 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL) were added. The resulting polymer was precipitated using methanol. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 84 mol % PDMS-MA and 16 mol % OEGMA by H NMR spectroscopy, isolated yield of about 1.5 g. (See FIG. 8).

[0130] [PDMS-MA]:[OEGMA]:[CTA]:[I]=10:90:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (0.178 mL, 0.244 mmol, 10 equiv.) and OEGMA500 macromonomer (1.02 mL, 2.196 mmol, 90 equiv.), RAFT agent (CTA1, 9.83 mg, 0.0244 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (0.5 mL) were added. Hexane was used to precipitate the resulting polymer. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 20 mol% PDMS-MA and 80 mol% OEGMA by H NMR spectroscopy, isolated yield of about 1.1 g. (See FIG. 9).

[0131] Example 6 RAFT copolymerization of PDMS-MA (MW = 600–800 g / mol) and BzMA-poly(PDMS-MA-co-BzMA) comb copolymers In some experiments, poly(PDMS-MA-co-BzMA) comb copolymers were formed by RAFT copolymerization of PDMS-MA (MW = 600–800 g / mol) and BzMA at two different PDMS-MA:BzMA:RAFT agent ([CTA]):initiator ([I]) ratios, as shown in Scheme 7 below. Scheme 7 Synthesis scheme of poly(PDMS-MA-co-BzMA) via RAFT polymerization [ka]

[0132] [PDMS-MA]:[BzMA]:[CTA]:[I]=70:30:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.03 mL, 1.38 mmol, 70 equiv.) and BzMA (0.10 mL, 0.59 mmol, 30 equiv.), RAFT agent (CTA1, 6.20 mg, 0.0153 mmol, 1 equiv.), AIBN initiator (I, 1-2 mg, 0.5 equiv.), and toluene (1.0 mL) were used. The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 60 mol % PDMS-MA and 40 mol % BzMA by H NMR spectroscopy, isolated yield of about 0.90 g. (See FIG. 10.)

[0133] [PDMS-MA]:[BzMA]:[CTA]:[I]=90:10:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (2.00 mL, 2.654 mmol, 90 equiv.) and BzMA (0.05 mL, 0.295 mmol, 10 equiv.), RAFT agent (CTA1, 11.91 mg, 0.0295 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.5 equiv.), and toluene (1.0 mL) were used. The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 80 mol % PDMS-MA and 20 mol % BzMA by H NMR spectroscopy, isolated yield of about 1.94 g. (See FIG. 11).

[0134] Example 7 RAFT copolymerization of PDMS-MA (MW = 600–800 g / mol) and EGPhEMA-poly(PDMS-MA-co-EGPhEMA) comb copolymers In these experiments, poly(PDMS-MA-co-EGPhEMA) comb copolymers were formed by RAFT copolymerization of PDMS-MA (MW = 600-800 g / mol) and EGPhEMA in a molar ratio of PDMS-MA to EGPhEMA to Raft agent ([CTA]) to initiator ([I]) of 70:30:1:0.5 ([PDMS-MA]:[EGPhEMA]:[CTA]:[I] = 70:30:1:0.5) (see Figure 12).

[0135] In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.214 mL, 1.734 mmol, 70 equiv.) and EGPhEMA (0.142 mL, 0.743 mmol, 30 equiv.), RAFT agent (CTA1, 10 mg, 0.0248 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.5 equiv.), and toluene (1.0 mL) were used. The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 163 mol % PDMS-MA and 37 mol % EGPhEMA by H NMR spectroscopy, isolated yield of approximately 1.08 g).

[0136] Example 8 OEGMA(M n = 500 g / mol) and RAFT copolymerization of EGPhEMA-poly(OEGMA-co-EGPhEMA) comb copolymers In these experiments, poly(OEGMA-co-EGPhEMA) comb copolymers were prepared using a molar ratio of OEGMA to EGPhEMA to Raft agent ([CTA]) to initiator ([I]) of 90:10:1:0.5 ([OEGMA]:[EGPhEMA]:[CTA]:[I]=90:10:1:0.5) with OEGMA (M n = 500 g / mol) and EGPhEMA via RAFT copolymerization.

[0137] In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified OEGMA500 macromonomer (2.18 mL, 2.356 mmol, 90 equiv.) and EGPhEMA (0.10 mL, 0.262 mmol, 10 equiv.), RAFT agent (CTA1, 10.58 mg, 0.0262 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL) were used. Hexane was used to precipitate the resulting polymer. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 81.5 mol % OEGMA and 18.5 mol % EGPhEMA by H NMR spectroscopy, isolated yield of about 1.49 g. (See FIG. 13). Scheme 8 Synthesis scheme of poly(OEGMA-co-EGPhEMA) via RAFT polymerization [ka]

[0138] Example 9 RAFT copolymerization of PDMS-MA (MW = 600–800 g / mol) and TFEMA-poly(PDMS-MA-co-TFEMA) comb copolymers In these experiments, poly(PDMS-MA-co-TFEMA) comb copolymers were formed by RAFT copolymerization of PDMS-MA (MW = 600-800 g / mol) and TFEMA at two different molar ratios of PDMS-MA to TFEMA to RAFT agent to initiator, as shown in Scheme 9 below. Scheme 9 Synthesis scheme of poly(PDMS-MA-co-TFEMA) via RAFT polymerization [ka]

[0139] [PDMS-MA]:[TFEMA]:[CTA]:[I]=70:30:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.20 mL, 1.639 mmol, 70 equiv.) and TFEMA (0.10 mL, 0.703 mmol, 30 equiv.), RAFT agent (CTA1, 9.45 mg, 0.0234 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL) were used. The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 66 mol % PDMS-MA and 34 mol % TFEMA by H NMR spectroscopy, isolated yield of about 1.10 g. (See FIG. 14).

[0140] [PDMS-MA]:[TFEMA]:[CTA]:[I]=50:50:1:0.5 A Schlenk flask equipped with a Teflon-coated micro stir bar was charged with purified PDMS-MA macromonomer (1.0 mL, 1.371 mmol, 50 equiv.) and TFEMA (0.20 mL, 1.371 mmol, 50 equiv.), RAFT agent (CTA1, 11.07 mg, 0.0274 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL). The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 48 mol % PDMS-MA and 52 mol % TFEMA by H NMR spectroscopy, isolated yield of about 0.82 g. (See FIG. 15).

[0141] Example 10 RAFT copolymerization of PDMS-MA (MW = 600-800 g / mol) and BzTAzMA-poly(PDMS-MA-co-BzTAzMA) comb copolymers In some experiments, poly(PDMS-MA-co-BzTAzMA) comb copolymers were formed by RAFT copolymerization of PDMS-MA (MW = 600–800 g / mol) and BzTAzMA with a PDMS-MA:BzTAzMA:RAFT agent ([CTA]):initiator ([I]) ratio of 90:10:1:0.5, as shown in Scheme 10 below. Scheme 10 Synthesis scheme of poly(PDMS-MA-co-BzTAzMA) via RAFT polymerization [ka]

[0142] [PDMS-MA]:[BzTAzMA]:[CTA]:[I]=90:10:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.0 mL, 1.37 mmol, 90 equiv.) and BzTAzMA (50 mg, 0.152 mmol, 30 equiv.), RAFT agent (CTA1, 6.15 mg, 0.0153 mmol, 1 equiv.), AIBN initiator (I, 1-2 mg, 0.5 equiv.), and toluene (1.5 mL) were used. The reaction was quenched and the resulting copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, isolated yield of about 0.90 g). M n Approximately 60k,

number

[0143] Example 11 RAFT copolymerization of PDMS-MA (MW = 600-800 g / mol) and HDFDMA-poly(PDMS-MA-co-HDFDMA) bottlebrush copolymers In these experiments, poly(PDMS-MA-co-HDFDMA) bottlebrush copolymers were formed by RAFT copolymerization of PDMS-MA (MW = 600-800 g / mol) and HDFDMA at two different molar ratios of PDMS-MA to HDFDMA to RAFT agent to initiator, as shown in Scheme 11 below. Scheme 11 Synthesis scheme of poly(PDMS-MA-co-HDFDMA) via RAFT polymerization [ka]

[0144] [PDMS-MA]:[HDFDMA]:[CTA]:[I]=70:30:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.00 mL, 1.372 mmol, 70 equiv.) and HDFDMA (0.196 mL, 0.588 mmol, 30 equiv.), RAFT agent (CTA1, 7.91 mg, 0.0196 mmol, 1 equiv.), AIBN initiator (I, 1-2 mg, 0.0098 mmol, 0.5 equiv.), and toluene (1.0 mL) were used. The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 66 mol % PDMS-MA and 34 mol % HDFDMA by H NMR spectroscopy, isolated yield of approximately 0.90 g).

[0145] [PDMS-MA]:[HDFDMA]:[CTA]:[I]=80:20:1:0.5 In a Schlenk flask equipped with a Teflon-coated micro stir bar, purified PDMS-MA macromonomer (1.00 mL, 1.372 mmol, 80 equiv.) and HDFDMA (0.114 mL, 0.343 mmol, 30 equiv.), RAFT agent (CTA1, 6.92 mg, 0.0172 mmol, 1 equiv.), AIBN initiator (I, 2-3 mg, 0.0122 mmol, 0.5 equiv.), and toluene (1.0 mL) were used. The reaction was quenched and the copolymer was purified as shown in Example 1 above. A yellow viscous liquid polymer melt was obtained after purification (>95% monomer conversion, actual composition: 1 76 mol % PDMS-MA and 24 mol % HDFDMA by H NMR spectroscopy, isolated yield of approximately 0.80 g).

[0146] Example 12 End-group removal (EGR) of RAFT bottlebrush (BB) polymers via AIBN treatment In these experiments, AIBN was used to remove end groups from RAFT bottlebrush polymers, as shown in Scheme 12 below. Scheme 12 End-group removal of poly(PDMS-MA) bottle-brush RAFT polymers via AIBN treatment [ka]

[0147] First, the polymer was dissolved in toluene (approximately 100-200 mg / mL of solution) and AIBN was added to the flask (20 equivalents relative to the RAFT agent used to synthesize the polymer). The flask was equipped with a Teflon-coated stir bar and sealed with a rubber septum. The resulting mixture was sparged with N2 (>1 mL / min) for 20-30 min. The flask was then submerged in an oil bath and heated to 80 °C, and the reaction was carried out for 3-4 h (the half-life of AIBN at 80 °C, t 1 / 2 (The reaction time is about 90 min). After the reaction, the flask was cooled back to room temperature and another 20 equivalents of AIBN were added to the flask. The mixture was sparged with N2 and heated at 80 °C for another 3-4 h. After a total of three AIBN treatments, the reaction mixture was dried under reduced pressure using a rotovap (typically 80 mbar, 45 °C). The viscous liquid was washed five times with methanol, redissolved in THF and passed through a 1 μm PTFE filter. Finally, all volatiles were removed (90-100 mbar, 35 °C) and the resulting viscous liquid polymer melt was further dried under high vacuum at room temperature overnight.

[0148] Example 13 End-group removal of chain transfer agents at the omega-chain ends of poly(PDMS-MA) bottle-brush RAFT polymers via AIBN treatment As shown in Scheme 2 above, excess AIBN was used to remove the chain transfer agent (CTA) end groups from the polymer. First, the polymer was dissolved in THF (approximately 0.1 g / mL of solution) and AIBN was added to the flask (20 equivalents relative to the CTA used to synthesize the polymer). The flask was equipped with a Teflon-coated stir bar and sealed with a rubber septum. The resulting mixture was sparged with N2 (>1 mL / min) for 20-30 minutes. The flask was then submerged in an oil bath and refluxed at 65-70 °C for 5-6 hours (the half-life of AIBN at 70 °C, t1 / 2 (The drying time is about 5 h). After AIBN treatment, the reaction mixture was dried under reduced pressure using a rotovap (typically 80-100 mbar, 35 °C). The viscous liquid was washed five times with methanol, redissolved in THF and passed through a 1 μm PTFE filter. Finally, all volatiles were removed (80-100 mbar, 35 °C) and the resulting clear, colorless, viscous liquid polymer melt was further dried overnight under high vacuum at room temperature. (Overall isolated yield of 8.3 g, refractive index (n r )=1.429, viscosity=1.05 Pa.s at 25°C, 0.87 Pa.s at 37°C).

[0149] Example 14 THF sec analysis of poly(PDMS-MA) Poly(PDMS-MA) polymers of different molecular weights were analyzed using THF SEC. In the first series of experiments, SEC of three poly(PDMS-MA) polymers was performed using two Agilent PLgel mixed-C columns (105 Å, 7.5×300 mm, 5 μm, part number PL1110-6500) using THF (stabilized with 100 ppm BHT) as the eluent, and the molecular weights were calculated using a Wyatt Dawn EOS multi-angle light scattering (MALS) detector and a Wyatt Optilab DSP interferometer refractometer (RI). The resulting THF SEC was recorded for three different molecular weights of poly(PDMS-MA). (a:M n = 13,370 g / mol, b:M n = 27,160 g / mol, c:M n = 67,900 g / mol) is shown in Figure 17.

[0150] In a second series of experiments, poly(PDMS-MA) polymer samples were analyzed by SEC using an EcoSEC Elite gel permeation chromatography (GPC) system (Tosoh Bioscience, LLC.) equipped with a HLC-8420GPC, UV and RI detectors, and a TSKgel GMHHR-M mixed-bed sample column (7.8 mm ID × 30 cm, 5 μm). The number average molecular weight (Mn ), weight average molecular weight (M w ), and molecular weight distribution

number

[0151] Example 15 Complex Viscosity / RI Analysis The viscosity of pure polymer melts was measured using a TA Instruments Discovery Hybrid Rheometer 3 (DHR 3). Each polymer melt was placed between parallel plates (25 mm diameter) using a 200 μm gap, and data were collected via angular frequency sweeps ranging from 0.1 rad / s to 500 rad / s at 10% strain at 25, 37, 45, and 50° C. Refractive index measurements were performed using a Bellingham & Stanley RFM 340 equipped with a chiller at 25 and 37° C.

[0152] The complex viscosity measurements of poly(PDMS-MA), POEGMA, and their random copolymers at various ratios at 25° C. are shown in FIG. 70 -co-BzMA 30 ), and poly(PDMS-MA 70 -co-EGPhEMA 30 The complex viscosity measurements of poly(PDMS-MA) at 25° C. are shown in FIG. 90 -co-BzMA 10 ) (RI 1.43981 at 37°C) and poly(OEGMA 90 -co-EGPhEMA 10) (RI=1.47694 at 37°C) are shown in Figure 21. Complex viscosity measurements (M n,theo = 30,000-40,000 g / mol) are shown in Figure 22. As expected, the viscosity decreases proportionally with increasing temperature. Complex viscosity measurements (M n,theo >200,000 g / mol) is shown in Figure 23. Finally, Figure 24 is a graph comparing the refractive index (RI) and viscosity of polydimethylsiloxane methacrylate (PDMS-MA), heptadecafluorodecyl methacrylate (HDFDMA), trifluoroethyl methacrylate (TFEMA), oligoethylene glycol methacrylate (OEGMA), benzyl methacrylate (BzMA), and ethylene glycol phenyl ether methacrylate (EGPhEMA).

[0153] References Hao X, Jeffery JL, Wilkie JS, Meijs GF, Clayton AB, Watling JD, Ho A, Fernandez V, Acosta C, Yamamoto H, Aly MGM, Parel JM, Hughes TC (2010) Functionalized polysiloxanes as injectable, in situ curable accommodating intraocular lenses.Biomaterials,31(32):8153-8163.https: / / doi.org / 10.1016 / j.biomaterials.2010.07.065 Koopmans SA,Terwee T,Barkhof J,Haitjema HJ,Kooijman AC(2003)Polymer refilling of presbyopic human lenses in vitro restores the ability to undergo accommodative changes.Investigative Ophthalmology&Visual Science,44(1):250-257.https: / / doi.org / 10.1167 / iovs.02-0256 Koopmans SA,Terwee T,Glasser A,Wendt M,Vilupuru AS,Vilipuru AS,Kooten TG van,Norrby S,Haitjema HJ,Kooijman AC(2006)Accommodative lens refilling in rhesus monkeys.Investigative Ophthalmology&Visual Science,47(7):2976-2984.https: / / doi.org / 10.1167 / iovs.05-1346 Koopmans SA,Terwee T,Hanssen A,Martin H,Langner S,Stachs O,Kooten TG van(2014)Prevention of capsule opacification after accommodating lens refilling:Pilot study of strategies evaluated in a monkey model.Journal of Cataract&Refractive Surgery,40(9):1521-1535.https: / / doi.org / 10.1016 / j.jcrs.2014.02.034 Hao X,Jeffery JL,Le TPT,McFarland G,Johnson G,Mulder RJ,Garrett Q,Manns F,Nankivil D,Arrieta E,Ho A,Parel J-M,Hughes TC(2012)High refractive index polysiloxane as injectable,in situ curable accommodating intraocular lens.Biomaterials,33(23):5659-5671.https: / / doi.org / 10.1016 / j.biomaterials.2012.04.052 Nishi O,Nakai Y,Mizumoto Y,Yamada Y(1997)Capsule opacification after refilling the capsule with an inflatable endocapsular balloon.Journal of Cataract and Refractive Surgery,23(10):1548-1555.https: / / doi.org / 10.1016 / s0886-3350(97)80028-4 Young M,Gamat G(2016)Clinical trial of new accommodating IOL reveals promising results.Eyeworld.https: / / www.eyeworld.org / article-clinical-trial-of-new-accommoda ting-iol-reveals- Glasser,Adrian.“Accommodation:Mechanism and Measurement,”Ophthalmol Clin N Am,19(2006),pp 1-12).

[0154] In view of the above, it should be appreciated that the present invention significantly advances the art by providing optically clear bottle-brush polymers and copolymers that are structurally and functionally improved in several ways, and have tunable viscosity and optical properties for use in intraocular lenses. Although specific embodiments of the present invention have been disclosed in detail herein, it should be understood that the invention is not to be limited thereto, as variations therein will be readily apparent to those skilled in the art. The scope of the present invention should be understood from the claims that follow.

Claims

1. A bottlebrush polymer, which is a homopolymer of a methacrylate polymer monomer selected from the group consisting of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), or at least one of PDMS-MA and OEGMA and 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA), ethylene glycol phenyl ether methacrylate (EGPhEM A) A bottle brush polymer comprising a copolymer with at least one methacrylate or acrylate monomer selected from the group consisting of hydroxyethyl methacrylate (HEMA), 2,2,2-trifluoroethyl acrylate (TFEA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl acrylate (HDFDA), benzyl acrylate (BzA), 2-[3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof, and having one or more terminal groups derived from a reversible addition-cleavage chain transfer (RAFT) agent.

2. The bottle brush polymer according to claim 1, wherein the homopolymer of the copolymer contains a residue of an ultraviolet (UV) light-blocking methacrylate monomer.

3. The bottle brush polymer according to claim 2, wherein the ultraviolet light-blocking methacrylate monomer is 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA).

4. The bottle brush polymer according to claim 1, wherein the bottle brush polymer is a copolymer of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), formed by RAFT polymerization and containing about 10 to about 95 mole percent, preferably about 10 to about 90 mole percent, and more preferably about 10 to about 80 mole percent of PDMS-MA.

5. The bottle brush polymer according to claim 1, having a complex viscosity of approximately 0.5 to approximately 30 Pa·s at 37°C.

6. The bottle brush polymer according to claim 1, having a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46 at 37°C.

7. The bottle brush polymer according to claim 1, wherein the RAFT agent is selected from the group consisting of dithiobenzoic acid, trithiocarbonate, and combinations thereof.

8. The aforementioned RAFT agent, 【Chemistry 1】 The bottle brush polymer according to claim 1, having a formula selected from a combination thereof, wherein y is an integer from about 3 to about 11.

9. The following formula is available: 【Chemistry 2】 In the formula, R is 【Transformation 3】 The bottle brush polymer according to claim 1, wherein x is an integer from about 5 to about 10, y is an integer from about 3 to about 11, and a is an integer from about 20 to about 300.

10. The following formula is available: 【Chemistry 4】 In the formula, R is 【Transformation 5】 The bottle brush polymer according to claim 1, wherein x is an integer from about 5 to about 10, and a is an integer from about 20 to about 300.

11. The following formula is available: 【Transformation 6】 In the formula, R is 【Transformation 7】 It has, and R' is formula 【Transformation 8】 The bottle brush polymer according to claim 1, wherein x is an integer from 5 to 10, y is an integer from about 3 to about 11, n is a mole percent from about 70% to about 95%, and m is a mole percent from about 5% to about 30%.

12. The following formula is available: 【Chemistry 9】 In the formula, R is 【Chemistry 10】 It has, and R' is formula 【Chemistry 11】 The bottle brush polymer according to claim 1, wherein x is an integer from about 5 to about 10, n is a mole percent from about 5% to about 30%, m is a mole percent from about 70% to about 95%, and n + m = 100.

13. The following formula is available: 【Chemistry 12】 In the formula, R is 【Chemistry 13】 The bottle brush polymer according to claim 1, wherein y is an integer from about 5 to about 10, and a is an integer from about 20 to about 300.

14. The following formula is available: 【Chemistry 14】 In the formula, R is 【Chemistry 15】 It has, and R' is formula 【Chemistry 16】 The bottle brush polymer according to claim 2, wherein x is an integer from about 5 to about 10, n is a mole percent from about 70% to about 95%, and m is a mole percent from about 5% to about 30%.

15. The following formula is available: 【Chemistry 17】 In the formula, R is [Chemistry 18] It has, and R' is formula 【Chemistry 19】 The bottle brush polymer according to claim 2, wherein x is an integer from about 5 to about 10, n is a mole percent from about 70% to about 95%, and m is a mole percent from about 5% to about 30%.

16. The bottle brush polymer according to any one of claims 1 to 15, wherein the bottle brush polymer is optically transparent.

17. A filler material for use in artificial lenses, comprising one or more optically transparent bottlebrush polymers having a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46, and a complex viscosity of about 0.5 to about 50 Pa.s.

18. The filling material according to claim 17, wherein the artificial lens is an accommodative intraocular lens (A-IOL) or a presbyopia correcting IOL.

19. The filling material according to claim 17, wherein the one or more optically transparent bottle brush polymers are the bottle brush polymers according to claim 16.

20. The one or more optically transparent bottlebrush polymers are homopolymers of methacrylate polymer monomers selected from the group consisting of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), or at least one of PDMS-MA and OEGMA and 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA), ethylene glycol phenyl ether methacrylate (EG The filler material according to claim 17, which is a copolymer of at least one methacrylate or acrylate monomer selected from the group consisting of PhEMA, hydroxyethyl methacrylate (HEMA), 2,2,2-trifluoroethyl acrylate (TFEA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl acrylate (HDFDA), benzyl acrylate (BzA), 2-[3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof, and has one or more terminal groups derived from a reversible addition-cleavage chain transfer (RAFT) agent.

21. The filling material according to claim 20, wherein the optically transparent bottle brush polymer is a copolymer of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), comprising about 10 to about 95 mole percent, preferably about 10 to about 90 mole percent, and more preferably about 10 to about 80 mole percent of PDMS-MA.

22. The filling material according to claim 17, wherein the optically transparent bottlebrush polymer has a complex viscosity of about 0.5 to about 30 Pa·s at 37°C.

23. The filling material according to claim 17, wherein the optically transparent bottlebrush polymer has a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46 at 37°C.

24. The filler material according to claim 20, wherein the RAFT agent is selected from dithiobenzoic acid, trithiocarbonate, and combinations thereof.

25. The aforementioned RAFT agent, 【Chemistry 20】 The filler material according to claim 20, having a formula selected from a combination thereof, wherein y is an integer between about 3 and about 11.

26. The optically transparent bottle brush polymer, 【Chemistry 21】 In the formula, R is 【Chemistry 22】 The filler material according to claim 17, wherein x is an integer between 5 and 10, and a is an integer between approximately 20 and approximately 300.

27. The optically transparent bottle brush polymer, 【Chemistry 23】 In the formula, R is 【Chemistry 24】 It has, and R' is formula 【Chemistry 25】 The filler material according to claim 17, wherein n is about 5% to about 30% mole percent, m is about 70% to about 95% mole percent, and y is an integer from about 5 to about 10.

28. An intraocular lens comprising a filling medium and a capsule interface configured and dimensionally set to be received within the capsule of a natural eye and to be filled with the filling medium either before insertion into the eye or in situ, wherein the filling material comprises one or more optically transparent bottlebrush polymers having a refractive index of about 1.39 to about 1.48, preferably about 1.40 to about 1.46, and more preferably about 1.42 to about 1.46, and a complex viscosity of about 0.5 Pa.s to about 50 Pa.s, and the capsule interface filled with the filling medium defines a predetermined refractive power.

29. The intraocular lens according to claim 28, wherein the capsule interface filled with the filling medium is an accommodating lens that responds to the movement of the ciliary muscle and adjusts to a changed shape.

30. The intraocular lens according to claim 28, wherein the capsule interface and the filling medium define a first refractive power and, in response to the movement of the ciliary muscle, change their shape to define a second refractive power.

31. The intraocular lens according to claim 28, wherein the first refractive power and the second refractive power are predetermined by at least the shape and refractive index of the capsule interface and the refractive index of the filling medium, and therefore the first refractive power and the second refractive power change according to the shape and refractive index of the capsule interface and the refractive index of the filling medium.

32. The intraocular lens according to claim 28, wherein the surface of the capsule interface is coated with an ophthalmic drug or substance used to prevent the formation of posterior capsule opacification (PCO).

33. The intraocular lens according to claim 28, wherein the capsule interface, when filled, has predetermined dimensions ranging from a diameter of approximately 9 mm to 11 mm to a thickness of approximately 4 to 6 mm, depending on the size of the patient's capsule bag.

34. The intraocular lens according to claim 28, which corrects corneal astigmatism by different forces constructed along different meridians of the polymer capsule interface, or by a filling medium having different refractive indices in different compartments within the intraocular lens.

35. The intraocular lens according to claim 28, wherein the filling medium comprises the filling material described in claim 14.

36. The optically transparent bottlebrush polymer is a homopolymer of a methacrylate polymer monomer selected from the group consisting of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methacrylate (OEGMA), or at least one of PDMS-MA and OEGMA and 2,2,2-trifluoroethyl methacrylate (TFEMA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl methacrylate (HDFDMA), benzyl methacrylate (BzMA), 2-[3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA), ethylene glycol phenyl ether methacrylate (EGPhE An intraocular lens according to claim 28, comprising a copolymer of a methacrylate or acrylate monomer selected from the group consisting of MA), hydroxyethyl methacrylate (HEMA), 2,2,2-trifluoroethyl acrylate (TFEA), 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl acrylate (HDFDA), benzyl acrylate (BzA), 2-[3-(2H-benzotriazole-2-yl)-4-hydroxyphenyl]ethyl acrylate (BzTAzA), ethylene glycol phenyl ether acrylate (EGPhEA), hydroxyethyl acrylate (HEA), and combinations thereof, having one or more terminal groups derived from a reversible addition-cleavage chain transfer (RAFT) agent.

37. The intraocular lens according to claim 36, wherein the optically transparent bottlebrush polymer is a copolymer of monomethacryloxypropyl-terminated polydimethylsiloxane, asymmetric (PDMS-MA), and oligo(ethylene glycol) methyl ether methacrylate (OEGMA), containing about 10 to about 95 mole percent of PDMS-MA.

38. The intraocular lens according to claim 36 or 37, wherein the optically transparent bottlebrush polymer comprises a residue of ultraviolet (UV) light-blocking methacrylate monomer.

39. The intraocular lens according to claim 38, wherein the ultraviolet (UV) light-blocking methacrylate monomer is 2-[3-(2H-benzotriazol-2-yl)-4-hydroxyphenyl]ethyl methacrylate (BzTAzMA).

40. The intraocular lens according to claim 36, wherein the transparent bottlebrush polymer has a complex viscosity of about 0.5 to about 15 Pa·s.

41. The intraocular lens according to claim 36, wherein the optically transparent bottlebrush polymer has a refractive index of about 1.43 to about 1.

48.

42. The optically transparent bottle brush polymer has the following formula: 【Chemistry 26】 In the formula, R is 【Chemistry 27】 The intraocular lens according to claim 28, wherein x is an integer between approximately 5 and approximately 10, and a is an integer between approximately 20 and approximately 300.

43. The optically transparent bottle brush polymer has the following formula: 【Chemistry 28】 In the formula, R is 【Chemistry 29】 It has, and R' is formula 【Transformation 30】 The intraocular lens according to claim 28, wherein x is an integer between 5 and 10, n is about 5% to about 30% mole percent, and m is about 70% to about 95% mole percent.

44. The optically transparent bottle brush polymer has the following formula: 【Chemistry 31】 In the formula, R is 【Chemistry 32】 It has, and R' is formula 【Transformation 33】 The intraocular lens according to claim 28, wherein x is an integer between 5 and 10, n is about 5% to about 30% mole percent, and m is about 70% to about 95% mole percent.

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