WO2013040047A1 - Biopolymer films and methods of making and using same - Google Patents

Abstract

The present invention provides for silk-derived devices (e.g., films, lenses, etc.) for insertion in an eye and methods for correcting vision of a patient. The films are placed within or on the retracting components of the eye (e.g., as corneal inlays or corneal onlays), or can be applied to the surface of another ocular device (e.g., an intraocular lens). The silk films are designed to provide optimized light transmission and refraction, thus allowing for effective distance, intermediate and/or near vision correction. The correction may be permanent, if it remains satisfactory, or may he reversed by removing the present device from the eye.

Description

Biopolvmer Films and Methods of Making and Using Same

Cross Reference to Related Applications

This application claims priority to U.S. Provisional Application No. 61/533,596 (filed on September 12, 2011) and International Application No. PCT/US2012/041288 (filed on June 7, 2012), the disclosures of which are incorporated herein by reference in their entirety.

Field of the Invention

The present invention relates to silk-derived devices for application to an eye. particular, the present invention relates to silk fibroin films and methods for vision correction.

Background of the Invention

Presbyopia is a condition in which, with age, the eye loses its ability to focus, making it difficult to see near objects. Currently presbyopia is mainly treated optically with the use of bifocal or multifocal spectacles, bifocal or multifocal contact lenses and intraocular lenses (IOLs) that contain multifocality or emulate the physiological accommodative mechanism of the younger eye. However, spectacles, contact lenses and intraocular lenses may cause inconvenience and/or complications. Surgically, the present presbyopic corneal procedures include monovision laser in situ keratomileusis (LASIK), photorefractive keratectomy, conductive keratoplasty, and presbyopic LASIK. None of these procedures has gained general acceptance because some have disadvantages, such as poor predictability, regression, limited effectiveness, and irreversibility; others are in their infancy. Seyeddain et al., Small-aperture corneal inlay for the correction of presbyopia: 3-vear follow-up. J. Cataract Refract. Surp. 2012: 38:35-45. Therefore, better treatments for presbyopia are still in demand.

Silk films are currently being developed for use in ophthalmology due to their biocompatibility, tunable properties and transparency. Lawrence et al, Silk film biomaterials for cornea tissue engineering, Biomaterials. 2009; 30(7): 1299-308. Harkin et al., Silk fibroin in ocular tissue reconstruction, Biomaterials. 2011 , 32, 10, 2445-2458. Chirila et al., Bombyx mori silk fibroin membranes as potential substrata for epithelial constructs used in the management of ocular surface disorders, Tissue Engineering Part A, 2008; 14(7): 1203-11. Vepari et al., Silk as a biomaterial, Progress in Polymer Science. 2007; 32(8-9):991-1007. Airman et al., Silk-based biomaterials, Biomaterials. 2003; 24(3):401-16. Lawrence et al., Bioactive silk protein biomaterial systems for optical devices. Biomacromolecules. 2008; 9(4):1214-20. Specifically, recent work has focused on developing silk ilms for use in ocular surface repair and corneal tissue engineering applications. Jin et al., Water-Stable Silk Films with Reduced β-Sheet Content. Advanced Functional Materials. 2005: 15(8):1241-1247.

Silk generally is a filamentous product secreted by a silkworm or spider.

Silkworm silk fibers are constituted from core fibrous proteins (fibroins), which are held together by glue-like proteins (sericins). Chirila et al. Bombyx mori Silk Fibroin Membranes as Potential Substrata for Epithelial Constructs Used in the Management of Ocular Surface Disorders, Tissue Engineering. Part A, Volume 14. Number 7, 2008, 1203-1211. Shear et al., A Devonian spinneret: early evidence of spiders and silk use, Science. 1989; 246(4929):479. Shao et al., Materials: Surprising strength of silkworm silk, Nature. 2002;418(6899):741. Silk proteins are characterized by a highly repetitive primary sequence that leads to significant homogeneity in secondary structure, i.e., β- sheets in the case of many silks. These types of proteins usually exhibit important mechanical properties, biocompatibility and biodegradability. Silk proteins provide an important set of material options in the fields of tissue regeneration, biomaterials, tissue engineering and drug delivery. Airman et al., Silk-based biomaterials, Biomaterials. 2003; 24(3):401-16. Kluge et al., Spider silks and their applications, Trends in Biotechnology. 2008; 26(5):244-51. Options for genetic manipulations to tailor sequence further facilitate to exploit these natural proteins for biomedical applications. Foo et al., Adv. Drug Deliver. Rev. 2002, 54, 1131-1 143; Dinerman et al., J. Control- Release. 2002, 82, 277-287; Megeed et al., Adv. Drug Deliver. Rev. 2002, 54, 1075- 1091; Petrini et al.. J. Mater. Sci-Mater. M. 2001, 12, 849-853; Altaian et al.,

Biomaterials. 2002, 23, 4131-4141; Panilaitis et al., Biomaterials. 2003, 24, 3079-3085. Rockwood et al., Materials fabrication from Bombyx mori silk fibroin, Nature Protocols. 201 1, 22; 6(10):1612-31. Jin et al., Mechanism of silk processing in insects and spiders, Nature. 2003; 424(6952): 1057-61. Lawrence et al., Processing methods to control silk fibroin film biomaterial features, Journal of Materials Science. 2008; 43(21):6967-85. Chen et al., Conformation transition of silk fibroin induced by blending chitosan, Journal of Polymer Science. Part B: Polymer Physics, 1997; 35(14):2293-6.

Specifically, silk films offer a wide platform for biomaterial innovation due to their highly controlled material properties, ease of fabrication, biocompatible nature, and potential for chemical modification. Lawrence et al, Bioactive silk protein biomaterial systems for optical devices, Biomacromolecules. 2008; 9(4):1214-20. Lawrence et al., Silk Film Culture System for in vitro Analysis and Biomaterial Design. JoVE. 2012 (62):e3646. Meinel et al., The inflammatory responses to silk films in vitro and in vivo. Biomaterials. 2005; 26(2): 147-55. Omenetto et al., A new route for silk, Nature Photonics. 2008; 2(11):641-3.

One useful material property of silk films is their ability to produce topographic features on the micrometer and nanometer scale. Lawrence et al, Bioactive silk protein biomaterial systems for optical devices. Biomacromolecules. 2008: 9(4):1214-20. This topography can be designed to produce diffractive optical elements, which can be used to alter light refraction through the material. Omenetto et al., A new route for silk, Nature Photonics. 2008; 2(11):641-3. In this regard, biopolymer films composed of silk and/or other naturally derived materials can be surface patterned and then implanted into the eye to correct vision.

Summary

The present invention provides for a device for applying into an eye of a patient to correct vision, comprising from about 50% (w/w) to about 100% (w/w) or from about 80% (w/w) to 100% (w/w) fibroin and having an optical portion, wherein the optical portion has a thickness ranging from about 100 nm to about 20 μm, from about 1 μm to about 10 μm, about 5 μm, or about 10 μm. The optical portion may be a film. The device may comprise a lens, a microlens array, a diffractive optic, an optical grating, a hologram, a pattern generator, a beam reshaper, diffraction gratings, photonic crystals, a Fresnel lens, a non-Fresnel type lens, a waveguide or a diffractive optical element. The device can be applied to the surface of an intraocular lens, an intracomeal lens, a contact lens or a lens of spectacles.

The present invention also provides for a method for correcting vision of a patient having an ocular condition, the method comprising the steps of:

a) providing a device comprising from about 50% (w/w) to about 100% (w/w) or from about 80% (w/w) to 100% (w/w) fibroin and having an optical portion, wherein the optical portion has a thickness ranging from about 100 nm to about 20 μιτι, from about 1 μm to about 10 μm, about 5 μm, or about 10 μm;

b) forming an incision in an eye of the patient; and

c) inserting the device in the eye.

In step (b), the incision may form a corneal flap or corneal pocket.

The ocular conditions that can be treated using the present devices and methods include presbyopia, astigmatism, myopia, hyperopia, macular degeneration or combination thereof.

The device may be applied on the cornea, implanted in the cornea, implanted in the anterior chamber of the eye, implanted behind the iris, implanted in the posterior chamber of the eye, or implanted in the capsule of the crystalline lens. In step (c), the device may be implanted underneath an epithelium sheet of the cornea, beneath the cornea's Bowman membrane, in the corneal stroma, behind the corneal stroma, or on top of the corneal stroma.

The surface of the device may comprise a pattern or may be smooth. The pattern may comprise a diffractive optical element, including, e.g., holographic gratings. The diffractive optical element may have from about 1 to about 10,000 features per millimeter.

The optical portion of the device may have a biconvex, plano-convex, convex- concave, meniscus, plano-concave or biconcave optical profile. The optical portion may have a diopter power ranging from about +20 to about -40. The optical portion may be single-focal, bifocal or multifocal.

The device may contain a plurality of pores. The device may comprise a pharmacologically and or biologically active agent, such as an antibiotic.

Brief Description of the Drawings

Figure 1. Silk film casting process where (A) the silk solution is produced, (B) cast upon a patterned silicone rubber (PDMS) surface, and the processed (C) and removed from the surface to provide a patterned silk films optic.

Figure 2. (A) Post-casting silk film optic used for in vivo experiments. Confocal microscopy imaging of the silk film autofluorescent signal allowed for visualization of both the (B) pores structures and patterned silk film surface topography, and (C) cross- sectional area of silk film surface topography.

Figure 3 is a schematic diagram of silk inlay design showing in (A) cross-section and (B) en face. Various cross-sectional designs can be envisioned to customize for material handling and mechanical needs, where (A: 1-3) the side walls can be incorporated with various sloping geometries or (A:4) no side walls at all. (B) The silk inlay will have a central region containing the optical element with an optional handling ring of built material to the device periphery.

Figure 4. In vivo assessment of silk film material placed within the mouse corneal stroma tissue as assessed over a 49-week period. The upper panels indicate the corneal stroma was free from defects and the lower panels show the presence of the silk film material through autofluorescent imaging over the entire course of the study.

Figure 5. Histological images of the mouse cornea using H&E staining (A) before surgery, (B) 6-weeks after surgery, and (C) 49-weeks after surgery revealing the absence of inflammatory cells and silk film integration with the host tissue.

Figure 6. Schematic of silk film inlay procedure in which the cornea has a circular flap incision produce in the corneal stroma. The film is then laid into the corneal tissue stromal region, and then the flap is returned and sutured close. Figure 7. (A) Slit lamp image of the rabbit cornea 6-weeks post silk film optic implantation demonstrating the high degree of tissue transparency and lack of inflammatory responses. Silk film material stability was also assessed where (B) differential interference contrast (DIC) microscopy was used to assess silk film (B) surface and (C) feature cross-sectional areas. (D) Scanning electron microscopy (SEM) indicated the patterned silk topography maintained robust feature edges indicating a high degree of material stability after 8-weeks post implantation.

Figure 8. Histological sections of cornea samples stained with H&E. (A) The silk film optic can be seen in cross-section and has been separated from the tissue during processing, however patterned ridges can be seen on the adjacent corneal tissue that match the silk film surface ridged topography as indicated by the white error. This demonstrates that both tissue integration and material stability is apparent. (B) Control cornea cross-section without implant.

Figure 9 shows slit lamp photograph of rabbit cornea at 6 weeks post implantation with a (A) 5 μm and (B) 20 μm thick silk film inlay, where (B) the cornea shows signs of adema and hazing for the thicker device. Respective histology sections show that the 5 μm- thick silk film integrating well with the surrounding cornea tissue (C), while the 20 μm- thick silk film showed signs of inflammatory cells indicating a lack of tissue integration (D).

Detailed Description of the Invention

The present invention provides for silk-derived devices (e.g., films, lenses, etc.) for insertion in an eye and methods for correcting vision of a patient. The films are placed within or on the refracting components of the eye (e.g., as corneal inlays or corneal onlays), or can be applied to the surface of another ocular device (e.g., an intraocular lens). The silk films are designed to provide optimized light transmission and refraction, thus achieving effective near, intermediate and/or distance visual acuity. The correction may be permanent, if it remains satisfactory, or may be reversed by removing the present device from the eye.

The present device contains silk proteins such as fibroin, and is produced by processing silk cocoons into a water-based solution (i.e., a dissolved silk), which is then cast into a film or fabricated as a lens. The present device may be surface-patterned, e.g., having a defined surface topography resulting in desired refractive properties to correct vision.

Conditions that may be treated by the present devices and methods include, but are not limited to, presbyopia, astigmatism, myopia, hyperopia, or combination thereof. The present devices and methods may also be used to treat macular degeneration, e.g., by directing light rays to unaffected portions of the retina, thereby improving the vision of the patient. In combination with a LASIK (laser-assisted in situ keratomileusis), procedure, the present devices may be deployed to eliminate the effects of abrasions, aberrations, and divots in the cornea. Another use of the present devices is to improve vision by reducing or enhancing light of a certain wavelength or in a given spectrum, such as blocking ultraviolet radiation to reduce glare. U.S. Patent Publication Nos. 20060134170, 20070092550 and 20110208300. Gil et al., Response of human corneal fibroblasts on silk film surface patterns, Macromol Biosci 10(6): 664-73. Sashina et al., Study of a Possibility of Applying the Films of the Silk Fibroin and Its Mixtures with Synthetic Polymers for Creating the Materials of Contact Lenses, Russian Journal of Applied Chemistry. 2009, Vol. 82, No. 5, pp. 898-904.

The present devices may be customized for a patient to provide optical characteristics specifically targeted to correct a visual defect of the patient. The present devices may also be provided as an off-the-shelf unit with pre-determined optical characteristics. To suit specific needs, the properties of the devices can be adjusted, such as thickness, optical characteristics, geometrical size, degradation rate, transparency, etc.

The present device may consist of, or consist essentially of, an optical portion. Alternatively, the present device may comprise an optical portion and a non-optical portion. The optical portion has optical power, while the non-optic portion has no, minimal or low optical power.

Besides silk fibroin, other suitable biopolymers can also be used to produce the present devices. Non-limiting examples of the biopolymers include collagen, chitosan, fibrin, or other polymers from a natural source.

In one embodiment, the present invention provides for a device for applying into an eye of a patient to correct vision, comprising about 50% (w/w) to about 100% (w/w) fibroin and having an optical portion, wherein the optical portion has a thickness ranging from about 100 nm to about 20 μm.

In another embodiment, the present invention provides for a method for correcting vision of a patient having an ocular condition, the method comprising the steps of: a) providing a device comprising about 50% (w/w) to about 100% (w/w) fibroin and having an optical portion, wherein the optical portion has a thickness ranging from about 100 nm to about 20 μm;

b) forming an incision in an eye of the patient; and

c) inserting the device in the eye.

The present device or its optical portion may contain fibroin, fibroin-related protein, modified fibroin protein, or a fragment or variant thereof. Fibroin can be obtained from a solution containing a dissolved silk. Silk can be a silkworm silk, e.g., from domesticated silkworm Bombyx mori, a spider silk, e.g. from Nephila clavipes. Other sources of silk include, but are not limited to, other strains of Bombycidae including Antheraea pernyi, Antheraea yamamai, Antheraea mylitta, Antheraea assania, and Philosamia cynthia ricini, as well as silk producing members of the families Saturnidae, Thaumetopoeidae. Lucas et al. Adv. Protein Chem. 13: 107-242 Π958Ί. In general, silks can be produced by certain species in the class Insecia, including the order Lepidoptera (butterflies), and by species in the class Arachnida, including the order Araneae (spiders).

The starting material for fibroin may be cocoons, cocoon filaments, raw silk, silk fabrics, silk yarn, degummed silk, any other partially cleaned silk, etc. This may also include short fragments of raw or sericin-depleted silk.

Silks may also be from a recombinant source, such as silks from genetically engineered cells (e.g., bacteria, yeast, insect or mammalian cells), silks from transgenic plants and animals, silks from cultured cells, silks from cloned full or partial sequences of native silk genes, and silks from synthetic genes encoding silk or silk-like sequences. See, for example, WO 97/08315 and U.S. Patent No. 5,245,012.

The silk protein (e.g., fibroin) in the present device or its optical portion may range from about 10% (w/w) to about 100% (w/w), from about 20% (w/w) to about 95% (w/w), from about 30% (w/w) to about 90% (w/w), from about 40% (w/w) to about 85% (w/w), from about 50% (w/w) to about 80% (w/w), from about 50% (w/w) to about 90% (w/w), from about 60% (w/w) to about 99% (w/w), from about 70% (w/w) to about 99% (w/w), from about 80% (w/w) to about 99% (w/w), from about 50% (w/w) to about 100% (w/w), from about 60% (w/w) to about 100% (w/w), from about 70% (w/w) to about 100% (w/w), from about 80% (w/w) to about 100% (w/w), from about 90% (w/w) to about 99% (w/w), or from about 80% (w/w) to about 90% (w/w). Higher or lower silk protein content may also be possible.

The water content in the present device or its optical portion may range from about 0 % (w/w) to about 60 % (w/w), from about 0.5 % (w/w) to about 50 % (w/w), from about 1 % (w/w) to about 40 % (w/w), from about 1 % (w/w) to about 30 % (w/w), from about 1 % (w/w) to about 20 % (w/w), from about 1 % (w/w) to about 15 % (w/w), from about 1 % (w/w) to about 12 % (w/w), from about 2 % (w/w) to about 10 % (w/w), from about 3 % (w/w) to about 9 % (w/w), from about 4 % (w/w) to about 8 % (w/w), from about 5 % (w/w) to about 7 % (w/w), from about 6 % (w/w) to about 12 % (w/w), from about 5 % (w/w) to about 10 % (w/w),or from about 5 % (w/w) to about 15 % (w/w). Higher or lower water content may also be possible.

In certain embodiments, the silk used for preparation of the present device or its optical portion is substantially depleted of its sericin content (i.e., less than about 4% (w/w) residual sericin in the final extracted silk). Alternatively, higher concentrations of residual sericin may be left on the silk following extraction or the extraction step may be omitted. In aspects of this embodiment, the sericin-depleted silk fibroin has, e.g., less than about 1% (w/w), less than about 2% (w/w), less than about 3% (w/w), less than about 4% (w/w), less than about 5% (w/w), less than about 10% (w/w), less than about 15% (w/w), about 1% (w/w) to about 2% (w/w), about 1% (w/w) to about 3% (w/w), or about 1% (w/w) to about 4% (w/w) residual sericin.

Reagents that may be used to remove sericin from silk include, but are not limited to, urea solutions, hot water, enzyme solutions (e.g., papain, etc.). Mechanical methods may also be used to remove sericin from silk fibroin. They include, but are not limited to, ultrasound, abrasive scrubbing and fluid flow.

For example, to remove sericin, B. mori cocoons are boiled in an aqueous solution, for example, for about 10 minutes to about 5 hours, for about 15 minutes to about 3 hours, for about 20 minutes to about 1 hour, or for about 30 minutes. Shorter or longer boiling time periods are also possible. The aqueous solution can be any suitable solution facilitating the removal of sericin, such as Na2C(½ in the concentration of about 0.02M. The cocoons are rinsed, for example, with water to extract the sericin proteins.

After sericin is removed, the resulting silk can then be solubilized using a dissolution agent (e.g., a chaotropic agent) to produce a dissolved silk containing fibroin. The dissolution agent may be an aqueous salt solution. Salts useful for this purpose include, but are not limited to, lithium bromide, lithium thiocyanate, calcium nitrate, calcium chloride, cupri-ethylenediamine, sodium thiocyanate, lithium thiocyanate, magnesium nitrate or other magnesium salts, zinc chloride, sodium thiocyanate, other lithium and calcium halides, other ionic species, urea or other chemicals capable of solubilizing silk. For example, the extracted silk is dissolved in about 9 M - about 12 M LiBr solution. The dissolution agent can be in any suitable solvent, including, but not limited to, aqueous solutions, alcohol solutions, l,l,l,3,3,3-hexafluoro-2-propanol, hexafluoroacetone, and l-butyl-3-methylimidazolimn. These solvents may also be modified through adjustment of pH by addition of acidic of basic compounds.

When the dissolution agent contains a salt, the salt can subsequently be removed by, for example, dialysis. In one embodiment, the silk solution is dialyzed in water for about 2 hours to about 72 hours, or about 6 hours to about 48 hours. For example, a dialysis cassette with a molecular weight cutoff of 3500 Da may be used. Shorter or longer dialysis time periods are also possible. The dialysis membrane can be, for example, cellulose membranes or any other semi-permeable membrane. Any suitable dialysis system may be used. The apparatus used for dialysis can be cassettes, tubing, or any other system.

Alternatively, the dissolution agent can be organic solvents. Such methods have been described in, for example, Li et al., J. Appl. Poly Sci. 2001, 79, 2192-2199; Min, et al. Sen'I Gakkaishi 1997, 54, 85-92; Nazarov et al., Biomacromolecules 2004 May- June; 5(3):718-26. U.S. Patent No. 8,178,656. The dissolution agent may alternatively be an acid solution (e.g., formic acid, hydrochloric acid, etc.).

During the dissolution process, various parameters may be modified, including, but not limited to, solvent type, silk concentration, temperature, pressure, and addition of mechanical disruptive forces. Mechanical mixing methods employed may also vary, including, for example, agitation, mixing, and sonication.

If necessary, the silk solution may be concentrated by dialyzing against a hygroscopic polymer, for example, polyethylene glycol (PEG), polyethylene oxide, or amylose. The PEG may be of a molecular weight of 8,000-10,000 g/mol and has a concentration of 25-50%. The dialysis may be about 2 hours to about 12 hours. See, for example, PCT application PCT US/04/11199. It is also possible to change the buffer phase in the dialysis system, altering water purity or adding hygroscopic polymers to simultaneously remove ions and water from the initial silk solution.

Insoluble debris may be removed from the silk solution at any stage by centrifugation or filtration.

The resultant dissolved silk may have a silk protein (e.g., fibroin) concentration ranging from about 1% (w/v) to about 50% (w/v). It may be possible to expand this range to include higher or lower fractions of dissolved silk.

The silk solution used to prepare the present device (e.g., a film) or its optical portion may contain fibroin having a concentration ranging from about 0.1% (w/v) to about 50% (w/v), ranging from about 0.1% (w/v) to about 25% (w/v), from about 0.1% (w/v) to about 20% (w/v), from about 1% (w/v) to about 50% (w/v), from about 5% (w/v) to about 50% (w/v), from about 1% (w/v) to about 30% (w/v), from about 1% (w/v) to about 5% (w/v), from about 1% (w/v) to about 10% (w/v), from about 1% (w/v) to about 15% (w/v), from about 1% (w/v) to about 20% (w/v), from about 1% (w/v) to about 25% (w/v), from about 1% (w/v) to about 30% (w/v), from about 5% (w/v) to about 10% (w/v), from about 5% (w/v) to about 15% (w/v), from about 5% (w/v) to about 20% (w/v), from about 5% (w/v) to about 25% (w/v), from about 5% (w/v) to about 30% (w/v), from about 10% (w/v) to about 15% (w/v), from about 10% (w/v) to about 20% (w/v), from about 10% (w/v) to about 25% (w/v), from about 10% (w/v) to about 30% (w/v), about 1 % (w/v), about 2% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v), about 9% (w/v), about 10% (w/v), about 12% (w/v), about 15% (w/v), about 18% (w/v), about 20% (w/v), about 21% (w/v), about 25% (w/v), about 30% (w/v), at least about 1% (w/v), at least about 2% (w/v), at least about 3% (w/v), at least about 4% (w/v), at least about 5% (w/v), at least about 6% (w/v), at least about 7% (w/v), at least about 8% (w/v), at least about 9% (w/v), at least about 10% (w/v), at least about 12% (w/v), at least about 15% (w/v), at least about 18% (w/v), at least about 20% (w/v), at least about 25% (w/v), or at least about 30% (w/v). A silk solution (or a solution of another natural biopolymer, or mixture thereof) can be fabricated into a variety of different forms, such as films, lenses, hydrogels, fibers, mats, scaffolds, etc. Therefore, the present device or its optical portion may comprise a film, a lens, a hydrogel, a fiber, a mat, a scaffold, etc.

A film can be produced by drying an aqueous solution of fibroin on a supporting surface, e.g., a hydrophobic surface. The film may be fabricated by applying the fibroin solution onto a substrate by spin-coating or casting. The solution is dried until a film is formed. Wang et al., Langmuir 21. 11335-11341 (2005). Jiang et al. Adv. Func. Mater. 17, 2229-2237 (2007).The rate and temperature at which the fibroin solution is dried can vary which may affect both the morphology and properties of the films (e.g., thickness, surface hydrophilicity, mechanical properties and degradation properties). The supporting surface can be, for example, part of a mold. The supporting surface can comprise, for example, polydimethylsiloxane (PDMS), silicone, or any other suitable material. The film is then left to dry until some or all the solvent has evaporated to give solid fibroin silk films. The drying step can take place in air, on the bench or in a laminar flow hood. The drying process can be about 6 hours to about 72 hours, about 12 hours to about 48 hours, about 24 hours to about 48 hours, or 24 hours or 48 hours. After drying, the film is removed from the supporting surface, for example, by using a surgical blade or forceps. See, for example PCT application PCT US/04/11199.

The film may be prepared using the following method: (a) providing a supporting surface; (b) casting a silk fibroin solution onto the supporting surface; (c) drying the supporting surface until a film forms; and (d) removing the film from the supporting surface.

The present device (e.g., film, lens, etc.) or its optical portion may have a thickness ranging from about 100 nm to about 1 mm, from about 500 nm to about 900 μm, from about 1 μm to about 800 μm, from about 1 μm to about 500 μm, from about 1 μm to about 10 μm, from about 1 μm to about 8 μm, from about 1 μm to about 6 μm, from about 1 μm to about 4 μm, from about 1 μm to about 2 μm, about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, from about 1 μm to about 20 μm, from about 10 μm to about 20 μm, from about 20 μm to about 30 μm, from about 10 μm to about 200 μm, from about 10 μm to about 100 μm, from about 30 μm to about 50 μm, from about 50 μm to about 200 μm, from about 75 μm to about 200 μm, from about 50 μm to about 100 μm, from about 60 μm to about 240 μm, from about 100 μm to about 200 μm, from about 75 μm to about 150 μm, from about 100 μm to about 150 μm, from about 60 μm to about 120 μm, from about 80 μm to about 120 μm, from about 10 nm to about 900 nm, from about 10 nm to about 800 nm, from about 20 nm to about 600 nm, from about 500 nm to about 900 nm, from about 100 nm to about 300 nm, from about 100 nm to about 20 μm, from about 400 nm to about 10 μm, or from about 10 nm to about 100 nm.

Different thicknesses can be obtained by varying volume of the solution casted, the protein concentration in the solution, the number of layers, etc. The thickness of the present device or its optical portion may be constant across the body of the device, or may vary from one portion to another. For example, the thickness of the inner portion may differ from that of the outer periphery.

The present device or its optical portion may have a convex cross-sectional profile, or a concave cross-sectional profile. Other cross-sectional profiles are also possible. The present device or its optical portion may have any suitable optical profile, including, but not limited to, planar, biconvex, plano-convex, convex-concave, meniscus, plano-concave or biconcave.

The present device (or its optical portion) may be of any shape. In one embodiment, the present device (or its optical portion) is circular with a diameter ranging from about 0.1 mm to about 15 mm, from about 0.5 mm to about 10 mm, from about 1 mm to about 8 mm, from about 1 mm to about 7 mm, from about 2 mm to about 6 mm, from about 3 mm to about 5 mm, or from about 4 mm to about 9 mm. The surface of the present device or its optical portion may be smooth, or may be patterned to provide areas of varying light refraction and/or transmission. For example, the surface may have an optical partem, which contributes to vision correction.

Topographic features on the micrometer and nanometer scale can be produced on the present device. Lawrence et al., Bioactive silk protein biomaterial systems for optical devices. Biomacromolecules. 2008: 9(4): 1214-20. This topography can be designed to produce diffractive optical elements, which can be used to alter light refraction through the material. Omenetto et al., A new route for silk, Nature Photonics. 2008; 2(11):641-3. The device may be patterned on one surface or on two surfaces.

The surface of the device or its optical portion may comprise a pattern. The resolution of the pattern may range from about 0.001 nm to about 5 mm, from about 0.01 nm to about 1 mm, from about 1 nm to about 900 μm, from about 10 nm to about 500 μm, from about 20 nm to about 100 μm, from about 30 nm to about 50 μm, from about 40 nm to about 10 μm, from about 50 nm to about 1 μm, from about 100 nm to about 900 nm, from about 200 nm to about 500 nm, from about 10 nm to about 50 nm, from about 1 nm to about 20 nm, or from about 10 nm to about 50 nm. Higher or lower resolutions are also encompassed by the present invention. The pattern may contain an optical element, such as a diffractive optical element. The optical element may comprise holographic gratings. The optical element may comprise features of uniform or varying geometries, ranging from about 1 to about 10,000 features per millimeter, from about 100 to about 5,000 features per millimeter, from about 200 to about 4,000 features per millimeter, from about 300 to about 4,000 features per millimeter, from about 400 to about 3,000 features per millimeter, from about 500 to about 3,000 features per millimeter, from about 600 to 3,600 features per millimeter, or from about 1 ,000 to about 2,000 features per millimeter.

In one embodiment, the silk solution (or other polymer solution) is poured onto a patterned supporting surface or substrate to enable conformal replication of substrate features. Because of the capacity of silk to faithfully conform to micrometer and nanometer features while maintaining smooth sidewalls and plateaus, compositions comprising silk fibroin can be used to prepare sophisticated optical elements with high resolution. Perry et al, Adv. Mater. 20, 3070-3072 (2008). Gupta et al, Langmuir, 23, 1315-1319 (2007).

In certain embodiments, structures with a periodicity and feature size on the order of the dimensions of the wavelength of incident light can be achieved. For example, silk diffraction gratings can be prepared by replicating holographic gratings with features ranging from about 1 to about 10,000 grooves per millimeter, from about 100 to about 5,000 grooves per millimeter, from about 200 to about 4,000 grooves per millimeter, from about 300 to about 4,000 grooves per millimeter, from about 400 to about 3,000 grooves per millimeter, from about 500 to about 3,000 grooves per millimeter, from about 600 to 3,600 grooves per millimeter, or from about 1,000 to about 2,000 grooves per millimeter. Lawrence et al., Biomacromolecules. 9, 1214-1220 (2008). In one embodiment, the silk diffraction gratings have an optical performance comparable to ordinary transmission gratings. Nanopatterning of subwavelength features can also be achieved by silk replication of aperiodic structures.

The present device or its optical portion may be prepared by casting a solution containing fibroin on a supporting surface. The supporting surface may have a diffractive optical pattern, which is designed to correct a refractive error or other visual aberration. A surface-patterned device of the present invention may be prepared as the following: Step a: preparing a molding and/or casting surface, the supporting surface may have ruled and/or holographic diffraction gratings or other geometrical features with desired grooves/mm or features/mm spacing; Step b: preparing a biopolymer solution (e.g., a silk solution) (Figure 1 A); Step c: applying the biopolymer solution to the molding surface (Figure IB); Step d: drying or molding the film (Figure 1C); Step e: processing the dried and/or cured film. Lawrence et al. Silk film biomaterials for cornea tissue engineering. Biomaterials. 2009. 30(7): 1299-1308.

In one embodiment, a patterned silicone rubber surface is first made by casting PDMS solution on a silicon mold surface. Xia et al., Soft lithography, Annu. Rev. Mater. So. 1998, 28: 153-84. After the PDMS mold is cured, a silk solution containing about 0.0001 to about 1 % (w/v) PEO and about 0.1 to about 25 % (w/v) silk fibroin is then cast upon the patterned silicone rubber surface. The silk film is dried, and then processed to decrease the water solubility of the film (i.e. water-anneal processing and or solvent bath incubation) (Figure 2A). The film surface and cross-section can be visualized by imaging silk's autofluorescence, which can be excited in the UV range. Z-stack images can then be reconstructed to view the film surface and cross-sectional area (Figure 2B-C). The processed film is soaked in a water and/or solvent bath for about 1 second to about 1 month, about 10 minutes to about 1 week, about 30 minutes to about 3 days, about 1 hour to about 1 day, about 2 hours to about 10 hours to induce pore formation (Figure 2B). The film is then sterilized using a variety of methods (i.e. dry heat sterilization, steam sterilization, EtOH bath, liquid C02 processing, etc.). Lawrence et al., Silk film biomaterials for cornea tissue engineering, Biomaterials. 2009; 30(7): 1299-308. Harkin et al., Silk fibroin in ocular tissue reconstruction, Biomaterials. 2011, 32, 10, 2445-2458.

The surface pattern may include any desired pattern. The surface patterning technique are known in the art, including, for example, photolithographic, ion etching, or similar microfabrication and nanofabrication techniques, ink jet printing of patterns, dip pen nanolithography patterns, microcontact printing or soft lithographic techniques. Lawrence et al., Bioactive silk protein biomaterial systems for optical devices,

Biomacromolecules. 2008, 9(4): 1214-20. Lawrence et al., Processing methods to control silk fibroin film biomaterial features, Journal of Materials Science. 2008; 43(21):6967- 85. Wilran et al, P.N.A.S.. 98. 13660-64 (2001). Bettinger et al, Adv. Mat. 19, 2847-50 (2007). PCT/US/07/83620. PCT/US2008/082487. Topographic patterning on the surface of silk film combined with silk film's optical transparent clarity may provide high resolution surface features that are not only suitable for bio-optical device such as an optical grating, a lens, a microlens array (WO 08/127,404), but also suitable for tissue engineered construct (WO 08/106,485).

The present device or its optical portion may comprise complex surfaces and patterns to correct higher order aberrations detected by wavefront sensing. Myrowitz et al., A comparison of wavefront-optimized and wavefront-guided Ablations, Curr. Opin. Ophthalmol. 20:247-250. Franzco et al, Wavefront's role in corneal refractive surgery, Clinical and Experimental Ophthalmology. 2005; 33: 199-209.

In another embodiment, the surface of the present device or its optical portion may be treated physically or chemically (such as by etching) to alter the refractive and/or transmissive properties of the device or its optical portion. In certain embodiments, the film is prepared using a spin casting process. The method may comprise the following steps: (a) providing a supporting surface; (b) casting a silk fibroin solution onto the supporting surface; (c) spinning the supporting surface until a film forms; and (d) removing the film from the supporting surface.

The supporting surface may be concave, convex or flat. The supporting surface may be smooth or patterned. In certain embodiments, the supporting surface is a mold having a concave inner surface. The supporting surface may be spun at a fixed rate, for example, ranging from about 100 to about 800 rotations per minute (RPM), from about 200 RPM to about 600 RPM, from about 300 RPM to about 500 RPM, from about 400 RPM to about 600 RPM, or about 500 RPM. The supporting surface may also be spun at varied rates.

Pressurized air may be flown through the supporting surface. The flow rate of the pressurized air may range from about 5 PSI to about 200 PSI, from about 10 PSI to about 150 PSI, from about 20 PSI to about 100 PSI, from about 20 PSI to about 60 PSI, or about 40 PSI.

The film may be flat or curved in shape. The film may be used as a single layer, or more than one layer stacking together, for example, about 2 to about 10 layers, about 3 to about 8 layers, about 4 to about 6 layers, about 2 to about 5 layers, or about 2 to about 3 layers.

The present invention further provides for a method for coating a surface of a substrate with a silk composition comprising: providing a substrate; coating the substrate with a silk solution; and drying the substrate until a film forms. The substrate may be a medical device. Also provided in the present invention is a method of embedding at least one active agent in a silk film, comprising: (a) blending a silk fibroin solution with at least one active agent; (b) casting the silk solution onto a film-supporting surface; and (c) drying the film.

Without further processing (i.e., annealing), films produced from silk fibroin are highly soluble in water, possibly because of dominating random coil protein structures. The structures of the protein can be transformed from random coil to β-sheet by further processing. This structural transition decreases aqueous solubility and increases degradation time. The processing treatments include, but are not limited to, heating (Hu et al., Macromolecules. 41, 3939-48 (2008)), mechanical stretching (e.g., the film can be drawn or stretched mono-axially or biaxially) (Jin et al., Nature. 424: 1057-61 (2003)), immersion in polar organic solvents (e.g, methanol, propanol) (Canetti et al.,

Biopolvmers— Peptide Sci. 28:1613-24 (1989)), and curing in water or water vapor (Jin et al., Water-Stable Silk Films with Reduced β-Sheet Content, Advanced Functional Materials. 2005;15(8):1241-1247). Lawrence et al., Effect of Hydration on Silk Film Material Properties. Macromolecular Bioscience. 2010 Apr. 8; 10(4):393— 403.

For water processing (i.e., water-annealing), the film may be placed in a vacuum in the presence of water vapor. The film is then dried, e.g., in a laminar flow hood or on the bench. The vacuum can range from about 0 to about 100% vacuum, from about 10% to about 90% vacuum, from about 20% to about 80% vacuum, from about 30% to about 70% vacuum, from about 40% to about 60% vacuum; from about 0 to about 760 Torr, from about 40 Torr to about 700 Torr, from about 70 Torr to about 600 Torr, from about 100 Torr to about 500 Torr, or from about 300 Torr to about 400 Torr. The relative humidity may range from about 0 to about 100%, from about 10% to about 90%, from about 20% to about 80%, from about 30% to about 70%, from about 40% to about 60%, from about 40% to about 85%, from about 30% to about 55%, from about 60% to about 90%, or from about 50% to about 80%. The temperature can range from about 4°C to 99°C, from about 4°C to about 80°C, from about 10°C to about 60°C, from about 15°C to about 50°C, from about 20°C to about 40°C, about 20°C, about 25°C, or about 30°C. The water processing time can range from about 0 minute to about 48 hours, from about 10 minutes to about 36 hours, from about 30 minutes to about 24 hours, from about 20 minutes to about 40 minutes, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 3 hours to about 8 hours, or from about 4 hours to about 6 hours.

For heat processing, the temperature and or duration of the heating can be adjusted. The temperature may range from about 60°C to about 300°C, from about 80°C to about 250°C, from about 100°C to about 200°C, from about 150°C to about 180°C, from about 160°C to about 170°C, about 150°C, or about 180°C. Higher or lower temperatures are also possible. The heat processing time may range from about 10 minutes to about 10 hours, from about 30 minutes to about 8 hours, from about 1 hour to about 6 hours, from about 1 hour to about 4 hours, from about 2 hours to about 3 hours, or from about 1 hour to about 2 hours. Longer or shorter processing time periods are also possible. In one embodiment, a dry heat environment (e.g., a dry heat sterilizing oven) is used. In another embodiment, steam heating is used. Additionally, heat-annealing may have the added benefit of sterilizing the material while simultaneously processing the silk composition to increase dissolution time.

The present device or its optical portion can comprise any of the suitable optical elements, including, but not limited to, lenses, microlens arrays, diffractive optics, optical grating, holograms, pattern generators, beam reshapers, diffraction gratings, photonic crystals, Fresnel lenses, non-Fresnel type lenses, waveguides and diffractive optical elements. Schwiegerling, Intraocular Lenses, Handbook of Optics, Vol. 3, chapter 21.

In one embodiment, the present devices modify the optical power of the cornea by changing the shape of the anterior corneal surface or by creating a lens with a different or same refractive index of the corneal stroma. The present device or its optical portion may have a single focal length (single- focal) or may be bifocal or multifocal. For example, a multifocal lens can have variations in either refractive index or lens shape, or both. The focal length of such lens is not constant, but varies across the expanse of the lens. Such multifocality may be used to compensate for presbyopia, by causing one portion of the light incoming to the eye to be focused if the source is far away, while another portion of the light is focused when the source is close (as when reading). In one embodiment, reading and other close work are accomplished through the central zone of the device, and distance vision is achieved through the peripheral zone of the device. In another embodiment, varying focal length of toric surfaces of the lens can be used to correct astigmatism. The present invention may be practiced using multifocal lenses to simultaneously correct or compensate various combinations of defects including myopia, hyperopia, astigmatism and presbyopia. U.S. Patent No. 7,207,998.

Multifocality may be accomplished using a Fresnel lens, or using a non-Fresnel lens having a varying refractive shape and/or a varying refractive index. For example, the refractive index of the present device or its optical portion may be changed in annular rings from outer annular ring to central portion. It will be understood by those skilled in the art that the actual choice of refractive contour depends upon the defects of the eye to be corrected.

The present device or its optical portion provides desired focal modifications when disposed within the eye. The present device or its optical portion may have an asymmetric, radially and/or axially varying focus. For example, the present device or its optical portion may employ annular changes in the index of refraction of the lens material, and/or changes in refractive shape which may be annular or not, to affect variations in focal length.

The present device or its optical portion may have a desired amount of optical power. Optical power may be provided by configuring one or both surfaces of the device with curvature. In one embodiment, the anterior and posterior surfaces of the present devices or its optical portion are provided with different degrees of curvature. In this embodiment, the device or its optical portion has varying thickness from the outer periphery to the center region. In another embodiment, one of the anterior surface and the posterior surface of the present device or its optical portion is substantially planar. In yet another embodiment, both of the anterior and posterior surfaces are substantially planar. U.S. Patent No. 7,455,691.

The present device (or the optical portion hereof) may have a diopter power or value ranging from about +20 to about -40, from about +20 to about -20, from about 0 to about 5, from about +15 to about -30, from about +10 to about -25, from about +10 to about -20, from about +5 to about -15, from about +5 to about -10, from about +5 to about -5, from about +3 to about -3, from about +3 to about +1, or from about -1 to about -3.

For visible light, the refractive index of the present device or its optical portion may range from about 1 to about 2, from about 1.3 to about 1.7, or about 1.5. Higher or lower refractive indexes are also possible.

The present device or its optical portion may exhibit optical properties such as transparency and translucency. Lawrence et al., Bioactive silk protein biomaterial systems for optical devices. Biomacromolecules. 2008:9(4^'>:1214-20y In some embodiments, the present device or its optical portion is optically transparent. The device or its optical portion transmits, e.g., about 75% of the light, about 80% of the light, about 85% of the light, about 90% of the light, about 95% of the light, or about 100% of the light, at least 75% of the light, at least 80% of the light, at least 85% of the light, at least 90% of the light, at least 95% of the light, about 75% to about 100% of the light, about 80% to about 100% of the light, about 85% to about 100% of the light, about 90% to about 100% of the light, or about 95% to about 100% of the light.

In certain embodiments, the present device or its optical portion is optically opaque. In aspects of this embodiment, the device or its optical portion transmits, e.g., about 5% of the light, about 10% of the light, about 15% of the light, about 20% of the light, about 25% of the light, about 30% of the light, about 35% of the light, about 40% of the light, about 45% of the light, about 50% of the light, about 55% of the light, about 60% of the light, about 65% of the light, or about 70% of the light, at most 5% of the light, at most 10% of the light, at most 15% of the light, at most 20% of the light, at most 25% of the light, at most 30% of the light, at most 35% of the light, at most 40% of the light, at most 45% of the light, at most 50% of the light, at most 55% of the light, at most 60% of the light, at most 65% of the light, at most 70% of the light, at most 75% of the light, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, about 5% to about 50%, about 5% to about 55%, about 5% to about 60%, about 5% to about 65%, about 5% to about 70%, about 5% to about 75%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, about 15% to about 60%, about 15% to about 65%, about 15% to about 70%, about 15% to about 75%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 55%, about 25% to about 60%, about 25% to about 65%, about 25% to about 70%, or about 25% to about 75% of the light.

In another embodiment, the present device or its optical portion is optically translucent. In aspects of this embodiment, the device or its optical portion diffusely transmits, e.g., about 75% of the light, about 80% of the light, about 85% of the light, about 90% of the light, about 95% of the light, about 100% of the light, at least 75% of the light, at least 80% of the light, at least 85% of the light, at least 90% of the light, or at least 95% of the light, about 75% to about 100% of the light, about 80% to about 100% of the light, about 85% to about 100% of the light, about 90% to about 100% of the light, or about 95% to about 100% of the light.

The present device or its optical portion may have various cross-sectional designs. For example, the device or its optical portion may have side walls with various sloping geometries (Figure 3, panel A: 1-3) or may have no side walls (Figure 3, panel A: 4).

In one embodiment, the present device consists of, or consists essentially of, an optical portion. The present device may comprise an optical portion and a non-optical portion. The optical portion has optical power, while the non-optic portion has no, minimal or low optical power. Optical portion may be positioned at a central or inner location of the device, or may be positioned at an outer location of the device. Optical portion may have various shapes, such as circular or oval. In one embodiment, the present device comprises an optical portion for refraction and a haptic portion for supporting the device in the eye. The haptic portion may be grasped by a surgeon during insertion of the device in an eye of a patient, and may allow improved maneuverability during positioning of the device in the eye. The haptic portion may deform or fold during insertion of the device in the eye. In another embodiment, the present device has a central region containing the optical portion with an optional peripheral, non-optical handling ring (Figure 3, panel B).

The body of the device may be configured to conform to the curvature of the native anatomy of the region of the eye in which it is to be applied. For example, where the device is to be coupled with an ocular structure that has curvature, the body of the device may be provided with a degree of curvature that corresponds to the anatomical curvature.

The present device can also be used in combination with other ocular devices, including, but not limited to, lenses (e.g., contact lenses, intraocular lenses, intracorneal lenses, a lens of spectacles, etc.). For example, the present film is applied to the surface of another implantable device, such as an intraocular lens, or an intracorneal lens, to enhance refractive ability. Non-limiting examples of such devices that can be used in combination with the present devices can be found in U.S. Patent No. 7,455,691. The present device may also be used as a coating on a substrate (e.g., another ocular device). A silk film may be wrapped or shaped around the substrate.

The present device may be used in combination with other procedures to correct refractive error. In one embodiment, the device is used along with LASI or PRK (photoref active keratectomy) to correct presbyopia, myopia, hyperopia or astigmatism or on a patient who has had LASIK or PRK. In another embodiment, the present device is used on a patient who has a phakic intraocular lens or a standard monofocal intraocular lens after a cataract surgery. The present device can be implanted in eyes operated with LASIK, and in post-cataract patients.

The present device or its optical portion can permit sufficient gas diffusion and nutrient and fluid (e.g., water) flow across the device. For example, the present device allows adequate oxygenation of internal eye tissues, and/or passage of aqueous humor. In one embodiment, the use of the present device within a certain time period does not result in corneal melting or additional clinical pathologies. Specifically, in this embodiment, the present device is permeable enough to allow sufficient nutrient flow through the cornea because corneal nutrients come from the aqueous humor. An interruption of this flow after intracorneal inlay implantation could cause corneal thinning, loss of transparency and, finally, corneal epithelial and stromal decompensation and melting.

The present device or its optical portion may or may not contain a plurality of pores, openings, channels, other suitable structures, or combinations thereof. These structures may be present in a portion of the device, or may be located throughout the body of the device. In one embodiment, these structures do not generate diffraction patterns or otherwise interfere with the vision correcting effects of the present devices.

In one embodiment, the present device or its optical portion is able to maintain greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 95%, or greater than about 98%, of the natural flow of at least one nutrient (e.g., glucose and other metabolic substances) between the two spaces separated by the present device.

The present device or its optical portion may contain a plurality of pores. The pores may have a diameter or mean (or average) diameter ranging from about 0.1 um to about 200 μm, about 0.1 μm to about 200 μm, about 0.5 μm to about 100 μm, about 0.5 um to about 80 μm, about 0.5 μm to about 60 μm, about 1 μm to about 50 μm, about 5 um to about 30 μm, about 15 μm to about 25 μm, about 0.5 μm to about 5 μm, about 0.5 um to about 10 μm, about 10 μm to about 1 mm, about 200 μm to about 800 μm, about 300 μm to about 700 μm, about 50 μm to about 200 μm, about 10 nm to about 500 nm, about 20 nm to about 400 nm, about 30 nm to about 300 nm, or about 50 nm to about 200 nm.

The pores may pass through the entire cross-section of the device or its optical portion, or may pass only partially through the cross-section of the device or its optical portion. To introduce pores, fibroin solutions may be casted in the presence of more hydrophilic polymers, such as poly(ethylene oxide) (PEO). PEO with different molecular weights may be used. In one embodiment, a mixture of silk fibroin (e.g., 1%) and polyethylene oxide (PEO, e.g., 0.05%) solutions is prepared to induce pore formation within the silk film matrix. The solution is cast on a flat PDMS substrate to produce a film. After casting, silk films are water-annealed and then placed into a water bath for 24 hours to leach out the PEO phase. Lawrence et al. Silk film biomaterials for cornea tissue engineering. Biomaterials. 2009 March ; 30(7): 1299-1308. In another embodiment, to produce porous silk films, PEO (Mv = 900,000) are mixed with 1% silk solution to produce mixtures with the following PEO concentrations: 0, 0.05, 0.10, 0.15, 0.20, and 0.25 w/v%, respectively. Films are then cast using the mixtures. An additional film with no PEO is also cast to produce a nonporous film. After water-annealing, the films are then placed into a water bath for PEO leaching over a 24-hour time period at ambient temperature conditions. Lawrence et al., Processing methods to control silk fibroin film biomaterial features, Journal of Materials Science. 2008; 43(21):6967-85.

Other suitable materials may also be used to create pores through phase separation. Non-limiting examples of techniques include track etching.

The present compositions and devices may also comprise biological dopants, non- limiting examples of which include enzymes, proteins, peptides, dyes and small compounds. In one embodiment, the present compositions and devices may act as a biosensor (e.g., to monitor biological activity while being positioned in the eye). Demura et al., Biotechnol. Bioene. 33, 598-603 (1989). Demura et al., J. Biotechnol. 10, 113— 120 (1989). Wu et al.. Anal. Chim. Acta. 558. 179-186 (2006). Zhang. Biotechnol. Adv. 16, 961-971 (1998). In one embodiment, the dopant is mixed with the silk fibroin solution before the mixture is casted on a holographic diffraction-grating master mold. Omenetto et al., A new route for silk, Nature Photonics. 2008; 2(11):641-3.

The tensile strength of the present device or its optical portion may range from about 1 MPa to about 500 MPa, about 50 MPa to about 400 MPa, about 1 MPa to about 200 MPa, from about 5 MPa to about 150 MPa, from about 10 MPa to about 100 MPa, from about 20 MPa to about 80 MPa, from about 30 MPa to about 60 MPa, from about 10 MPa to about 50 MPa.

Elongation at break of the present device or its optical portion may range from about 1% to about 300%, from about 2% to about 200%, from about 5% to about 150%, from about 10% to about 100%, from about 10% to about 60%, from about 10% to about 30%.

The tensile modulus (or Young's modulus) of the present device or its optical portion may range from about 0.1 GPa to about 5 GPa, about 1 MPa to about 30 MPa, about 10 MPa to about 50 MPa, about 25 MPa to about 75 MPa, about 50 MPa to about 100 MPa, about 100 MPa to about 300 MPa, about 200 MPa to about 400 MPa, about 300 MPa to about 500 MPa, about 100 MPa to about 500 MPa, about 250 MPa to about 750 MPa, about 500 MPa to about 1 GPa, about 1 GPa to about 30 GPa, about 1 GPa to about 10 GPa, about 10 GPa to about 30 GPa, about 1 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa, about 750 MPa, about 1 GPa, about 5 GPa, about 10 GPa, about 15 GPa, about 20 GPa, about 25 GPa, about 30 GPa, at least about 1 MPa, at least about 10 MPa, at least about 20 MPa, at least about 30 MPa, at least about 40 MPa, at least about 50 MPa, at least about 60 MPa, at least about 70 MPa, at least about 80 MPa, at least about 90 MPa, at least about 100 MPa, at least about 200 MPa, at least about 300 MPa, at least about 400 MPa, at least about 500 MPa, at least about 750 MPa, at least about 1 GPa, at least about 5 GPa, at least about 10 GPa, at least about 15 GPa, at least about 20 GPa, at least about 25 GPa, or at least about 30 GPa.

The shear modulus of the present device or its optical portion may range from about 1 MPa to about 30 MPa, about 10 MPa to about 50 MPa, about 25 MPa to about 75 MPa, about 50 MPa to about 100 MPa, about 100 MPa to about 300 MPa, about 200 MPa to about 400 MPa, about 300 MPa to about 500 MPa, about 100 MPa to about 500 MPa, about 250 MPa to about 750 MPa, about 500 MPa to about 1 GPa, about 1 GPa to about 30 GPa, about 10 GPa to about 30 GPa, about 1 MPa, about 10 MPa, about 20 MPa, about 30 MPa, about 40 MPa, about 50 MPa, about 60 MPa, about 70 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 200 MPa, about 300 MPa, about 400 MPa, about 500 MPa, about 750 MPa, about 1 GPa, about 5 GPa, about 10 GPa, about 15 GPa, about 20 GPa, about 25 GPa, or about 30 GPa, at least 1 MPa, at least 10 MPa, at least 20 MPa, at least about 30 MPa, at least about 40 MPa, at least about 50 MPa, at least about 60 MPa, at least about 70 MPa, at least about 80 MPa, at least about 90 MPa, at least about 100 MPa, at least about 200 MPa, at least about 300 MPa, at least about 400 MPa, at least about 500 MPa, at least about 750 MPa, at least about 1 GPa, at least about 5 GPa, at least about 10 GPa, at least about 15 GPa, at least about 20 GPa, at least about 25 GPa, or at least about 30 GPa.

The bulk modulus of the present device or its optical portion may range from about 5 GPa to about 50 GPa, about 5 GPa to about 100 GPa, about 10 GPa to about 50 GPa, about 10 GPa to about 100 GPa, or about 50 GPa to about 100 GPa, about 5 GPa, about 6 GPa, about 7 GPa, about 8 GPa, about 9 GPa, about 10 GPa, about 15 GPa, about 20 GPa, about 25 GPa, about 30 GPa, about 35 GPa, about 40 GPa, about 45 GPa, about 50 GPa, about 60 GPa, about 70 GPa, about 80 GPa, about 90 GPa, about 100 GPa, at least about 5 GPa, at least about 6 GPa, at least about 7 GPa, at least about 8 GPa, at least about 9 GPa, at least about 10 GPa, at least about 15 GPa, at least about 20 GPa, at least about 25 GPa, at least about 30 GPa, at least about 35 GPa, at least about 40 GPa, at least about 45 GPa, at least about 50 GPa, at least about 60 GPa, at least about 70 GPa, at least about 80 GPa, at least about 90 GPa, or at least about 100 GPa.

The present device or its optical portion may exhibit cohesiveness. In one embodiment, the device or its optical portion may exhibit strong cohesive attraction, on par with water. In another embodiment, the device or its optical portion exhibits low cohesive attraction. In yet another embodiment, the device or its optical portion exhibits sufficient cohesive attraction to remain localized to a site of administration. In still another embodiment, the device or its optical portion exhibits sufficient cohesive attraction to retain its shape. In a further embodiment, the device or its optical portion exhibits sufficient cohesive attraction to retain its shape and functionality.

The present device may contain one or more other biocompatible polymers (synthetic or natural), non-limiting examples of which include, polyethylene oxide (PEO) (U.S. Pat. No. 6,302,848), polyethylene glycol (PEG) (U.S. Pat. No. 6,395,734), collagen (U.S. Pat. No. 6,127,143), fibronectin (U.S. Pat. No. 5,263,992), keratin (U.S. Pat. No.

6,379,690), polyaspartic acid (U.S. Pat. No. 5,015,476), polylysine (U.S. Pat. No.

4,806,355), alginate (U.S. Pat. No. 6,372,244), chitosan (U.S. Pat. No. 6,310,188), chitin

(U.S. Pat. No. 5,093,489), elastin, glycosaminoclycans, polysaccharides, polyallylamine, cellulose, poly(caprolactone-co-D,L-lactide), S-carboxymethyl keratin, poly(vinyl alcohol) (PVA), hyaluronic acid (U.S. Pat. No. 387,413), pectin (U.S. Pat. No.

6,325,810), polycaprolactone (U.S. Pat. No. 6,337,198), polylactic acid or its copolymers

(U.S. Pat. No. 6,267,776), polyglycolic acid or its copolymers (U.S. Pat. No. 5,576,881), polyhydroxyalkanoates (U.S. Pat. No. 6,245,537), dextrans (U.S. Pat. No. 5,902,800), polyanhydrides (U.S. Pat. No. 5,270,419), a cyclodextrin component, polyethylene, polystyrene, polymethylmethylcryalte, polyurethanes, and other biocompatible polymers.

See, Liang & Hirabayashi, 45 J. Appl. Polymer Sci. 1937-43 (1992); Arai et al., 84 J.

Appl. Polymer Sci. 1963-70 (2002); Kitagawa & Yabuki, 80 J. Appl. Polymer Sci. 928-

34 (2001); Noishiki et al., 86 J. Appl. Polymer Sci. 3425-29 (2002); Kesenci et al., 12 J. Biomats. Sci. Polymer Ed. 337-51 (2001); Lee et al, 9 J. Biomats. Sci. Polymer Ed. 905-

14 (1998); Tsukada et al., 32 J. Polymer Sci. B, 243-48 (1994); Gotoh et al., 38 Polymer

487-90 (1997); Jin et al., 5 Biomacromols. 71 1-17 (2004).

In certain embodiments, silk films are produced by casting a solution that contains fibroin and about 0.0001% (w/v) to about 10 % (w/v), about 0.001% (w/v) to about 5 % (w/v), about 0.01% (w/v) to about 2 % (w/v), about 0.1% (w/v) to about 1 % (w/v), about

0.5% (w/v) to about 1 % (w/v) PEO. Lawrence et al, Silk film biomaterials for cornea tissue engineering, Biomaterials. 2009; 30(7): 1299-308. Harkin et al., Silk fibroin in ocular tissue reconstruction, Biomaterials. 2011, 32, 10, 2445-2458.

The present device may comprise a biocompatible material, such as silicone, hydrogel, urethane, acrylic, or other suitable biocompatible material. U.S. Patent No.

5,217,491.

The present device or its optical portion may further contain at least one pharmaceutically and/or biologically active agent. The pharmaceutically and/or biologically active agent may possess any desirable properties to suit specific needs. For example, the active agent can enhance proliferation and/or differentiation of cells. The present compositions with at least one active agent may facilitate tissue repair, tissue ingrowth, tissue regeneration, tissue/organ replacement, etc. The present device may also be used to deliver an active agent. U.S. Patent No. 8,071 ,722.

Non-limiting examples of the pharmaceutically and/or biologically active agents include proteins, peptides, nucleic acids (e.g., DNA, RNA, siRNA, shRNA, antisense RNA, plasmids, etc.), carbohydrates, glycoproteins, lipoproteins, modified RNA/protein composites, cells, nucleic acid analogues, nucleotides, oligonucleotides, peptide nucleic acids, aptamers, viruses, small molecules, and combinations thereof.

Other non-limiting examples of the active agents include anti-infectives such as antibiotics, antimicrobial compounds and antiviral agents; chemotherapeutic agents (i.e. anticancer agents); antibodies or fragments or portions thereof; hormones; hormone antagonists; growth factors and fragments and variants thereof; recombinant growth factors; growth factor inhibitor; cytokines; enzymes; toxins; prodrugs; anti-rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones (e.g., steroids); pharmacological materials; vitamins; sedatives; hypnotics; prostaglandins; radiopharmaceuticals; anti-thrombotics; anti-metabolics; growth promoters;

anticoagulants; antimitotics; and thrombolytic drugs.

The active agent may also be cell attachment mediators, such as collagen, elastin, fibronectin, vitronectin, laminin, integrins, selectins, cadherins, proteoglycans, or peptides containing known integrin binding domains. The active agent may include "RGD" integrin binding sequence, or variations thereof; ligands; and substances that enhance or exclude particular varieties of cellular or tissue ingrowth. Schafmer et al., Cell Mol. Life Sci.. 2003, January; 60(1):119-32; Hersel et al. Biomaterials. 2003, November; 24(24):4385-415.

The silk protein, e.g., fibroin, of the present invention may be modified to include desired functional groups (e.g., RGD sequences). Fibroin can be functionalized through, e.g., the lysine residue or tyrosine residue. Chimeric molecules in which fibroin sequences are combined with those found in ECM molecules may also be prepared through genetic engineering.

The amount of the active agent will depend on the particular agent being employed and medical condition being treated. Typically, the amount of active agent represents about 0.001% (w/w) to about 70% (w/w), about 0.001% (w/w) to about 50% (w/w), about 0.001% (w/w) to about 20% (w/w) by weight of the material. Upon contacting with a body fluid, the active agent may or may not be released. The present device may also contain one or more other pharmaceutically acceptable components, such as diluents, carriers, excipients, stabilizers, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.

The active agent can be introduced at any point(s) throughout the production process for the present device. For example, an active agent may be added to an aqueous solution of a silk protein. The solution is then processed to form a silk-derived device (e.g., a film). Alternatively, the active agent may be loaded into or coated onto the device after it is prepared. The coating can be applied through absorption or chemical bonding. The active agent may be present as a liquid, a finely divided solid, or any other appropriate physical form before being embedded into or coated onto the present compositions. When the active agent is at least one cell, the cells could be seeded on the surface of the present device, or blended into the dissolved silk.

Besides films, the above-described dissolved silk (or a polymer solution) may also be fabricated into other forms, such as, lenses, hydrogels, threads, fibers, foam, meshes, matrixes, three-dimensional scaffolds, tablets, filling material, tablet coating, microparticles, rods, nanoparticles, mats, etc. Methods for generating such are known in the art. See, e.g. U.S. Patent No. 7,635,755, Airman, et al., Biomaterials 24:401, 2003; PCT Publications WO 2004/000915 and WO 2004/001103; and PCT Application No's PCT/US/04/1 1 199 and PCT/US04/00255, which are herein incorporated by reference.

Hydrogels can be prepared by methods known in the art, see for example PCT application PCT/US/04/11199. The sol-gel transition of the concentrated silk fibroin solution can be modified by changes in silk fibroin concentration, temperature, salt concentrations (e.g. CaCb, NaCl, and KC1), pH, hydrophilic polymers, and the like. Before the sol-gel transition, the concentrated aqueous silk solution can be placed in a mold or form. The resulting hydrogel can then be cut into any shape, using, for example, a laser. U.S. Patent Publication No. 20110008406.

Fibers may be produced using, for example, wet spinning or electrospinning. Alternatively, a fiber can be pulled directly from a concentrated solution. Scaffolds can be produced from aqueous fibroin solutions via a variety of techniques including freeze drying, salt leaching or electrospinning.

The present device can be fabricated by any other suitable method, including, for example, fiber spinning, electrospinning, solvent casting, injection molding, thermoforming, extrusion, sheet extrusion, blown film extrusion, compression molding, and the like. U.S. Patent No. 8,173,163.

The different formats of the present devices may or may not be processed using water, heat, etc. as described herein.

The present invention also provides for a method for correcting vision of a patient, comprising providing a device of the present invention; forming an incision in an eye of the patient; and inserting the device in the eye.

In one embodiment, the present invention provides a method for correcting vision of a patient comprising providing the present device; forming an incision in a cornea of the patient; and inserting the present device in the cornea. In another embodiment, the present device help reshape the cornea to change the tissue refractive capability or tissue structure.

The present device may be applied to the eye in any manner and in any location. For example, the present device may be provided as an implant in the cornea (also referred to as a corneal inlay), where it is positioned between the layers of the cornea. In certain embodiments, the present device may be implanted underneath an epithelium sheet of the cornea, beneath the cornea's Bowman membrane, in the corneal stroma, behind the corneal stroma, or on top of the corneal stroma. The present device may be positioned in the anterior chamber of the eye, behind the iris, in the posterior chamber of the eye, anteriorly spaced from the crystalline lens, within the capsule of crystalline lens, etc. The present device may be used as a contact lens placed on the surface of the eyeball. Alternatively, the present device may be incorporated in a patient's crystalline lens or an artificial intraocular lens. The present device can also be applied on or in other regions of the eye. U.S. Patent No. 8,079,706. Lawrence et al., Bioactive silk protein biomaterial systems for optical devices, Biomacromolecules. 2008; 9(4): 1214-1220.

The present device can be applied into an eye through a minimally invasive surgery. For example, an intralamellar pocket or flap is first formed within the cornea stroma in which a desired tissue size or thickness is cut using a surgical blade, microkeratome device, or femtosecond laser cutting tool. The present device is then placed within the pocket or laid within the flap, which is then sutured, glued, or left closed. The incision is allowed to heal over a period of time. An antibiotic, anti- inflammatory, and/or pain medication may be used as needed.

In one embodiment, a method of treating a patient is provided. A corneal flap is lifted to expose an intracomeal surface. Then the present device is positioned on the intracomeal surface. The flap is closed to cover at least a portion of the implant. For example, when used as a corneal implant, a surgeon cuts (e.g., using a laser) and peels away a flap of the corneal epithelium. The present device is then inserted and the flap is placed back in its original position where, over time, it heals.

Any suitable tool or technique may be used to lift the corneal flap to expose a surface in the cornea. For example, a blade (e.g., a microkeratome), a laser (e.g., femtosecond laser) or an electrosurgical tool could be used to form a corneal flap. A corneal flap may be formed by methods similar to those used during LASIK (laser- assisted in-situ keratomileusis) procedures.

In another embodiment, a method of treating a patient is provided. A corneal pocket is created to expose an intracomeal surface. For example, a pocket may be created in the cornea's stroma. Then an implant is positioned on the intracomeal surface. In certain embodiments, to accommodate the present device, a surgeon may need to remove some corneal tissue to provide a pocket that will accommodate the device.

Any suitable tool or technique may be used to create or form the corneal pocket. For example, a blade (e.g., a microkeratome), a laser (e.g., femtosecond laser), or an electrosurgical tool could be used to create or form a pocket in the cornea. Alternatively, a corneal pocket may be formed manually by the surgeon using hand-held instruments. A corneal pocket may be formed by tunneling in the cornea, for example, using a microkeratome having an oscillating metal blade. A comeal-pocket keratome device is disclosed in U.S. Pat. Nos. 6,599,305 and 7,207,998, the disclosures of which are incorporated by reference herein in their entirety.

In one embodiment, the present device is inserted underneath an epithelium sheet of the cornea. A surgeon first removes the epithelium sheet. The epithelium sheet may be rolled back. Then, the surgeon creates a depression in a Bowman's membrane corresponding to the visual axis of the eye. The depression should be of sufficient depth and width to both expose the top layer of the stroma and to accommodate the present device. The present device is then placed in the depression. The depression may not be necessary when the size of the present device is small and/or the device is of sufficient thinness. Last, the epithelium sheet is placed over the present device. Over time, the epithelium sheet will grow and adhere to the top layer of the stroma, as well as the present device. As needed, a contact lens may be placed over the incised cornea to protect the present device.

In another embodiment, the present device is inserted beneath a Bowman's layer of the cornea. The surgeon first hinges open the Bowman's layer. Then, the surgeon creates a depression in a top layer of a stroma corresponding to the visual axis of the eye. The depression should be of sufficient depth and width to accommodate the present device. The depression may not be necessary when the size of the present device is small and/or the device is of sufficient thinness. Then, the present device is placed in the depression. Last, the Bowman's layer is placed over the present device. Over time, the epithelium sheet will grow over the incised area of the Bowman's layer. As needed, a contact lens may be placed over the incised cornea to protect the present device.

In yet another embodiment, the present device may be threaded into a channel created in the top layer of the stroma of the cornea. In this method, a curved channeling tool creates a channel in the top layer of the stroma, the channel being in a plane parallel to the surface of the cornea. The channel is formed in a position corresponding to the visual axis of the eye. The channeling tool either pierces the surface of the cornea, or is inserted via a small superficial radial incision. Alternatively, a laser focusing an ablative beam may create the channel in the top layer of the stroma. The present device is then positioned in the channel. In another embodiment, a method of treating a patient comprises the following steps. A stromal surface is exposed. An implant is positioned on the stromal surface. At least a portion of the implant is covered.

The present device may be injected in the eye and affixed in the anterior chamber to structures in front of the iris (anterior chamber lens) or behind the iris (posterior chamber lens).

The present device may be added to a patient with a crystalline lens (phakic implantation), in a patient with an intraocular lens (pseudophakic implantation), in a patient with no lens (aphakic implantation or secondary implantation), or in exchange for an existing intraocular lens (exchange implantation).

With respect to patients with an existing intraocular lens the present device can be placed at any location in the eye apart from the intraocular lens, or on the anterior or posterior surfaces, or within the intraocular lens. The present device can be placed on the intraocular lens before or after implantation.

The present device could be applied to phakic (anterior or posterior chamber) intraocular lens, anterior chamber intraocular lens in pseudophakic patients, or posterior chamber intraocular lens in pseudophakic patients.

In one embodiment, the present device is fitted between two contact lenses. For example, a contact lens is placed in a patient's eye. Next, the present device is placed on the contact lens. Then a second contact lens is placed over the present device. The second contact lens holds the device in a substantially constant position.

The present device may be inserted in the eye using an injector, as is known in the art. In one embodiment, the device is supplied preloaded onto a delivery device, and is slid into place in the center of the pupil. Then the corneal flap is folded back covering the device.

The present devices and methods may be used to change the optical power of the cornea due to refractive error, to change the toricity of the cornea to correct astigmatism, and/or to add multifocality to the cornea through optics (refractive or diffractive).

The present devices and methods may be used to change power of the intraocular lens due to refractive error, change the toricity of the intraocular lens to correct astigmatism, and or add multifocality to the intraocular lens through optics (refractive or diffractive).

An array of aberrations in the eye can be measured using wavefront sensing techniques and these are used to make more suitable optics when doing laser vision correction with an excimer laser. These higher order aberrations of the eye may be corrected using the present devices and methods, with the wavefront correction or standard correction made on the cornea-applied silk film (or intraocular lens applied silk film) through casting or through use of an excimer laser. Myrowitz et al., A comparison of wavefront-optimized and wavefront-guided Ablations, Curr. Opin. Ophthalmol. 20:247-250. Franzco et al., Wavefront' s role in corneal refractive surgery, Clinical and Experimental Ophthalmology. 2005; 33: 199-209. The present devices can also be wavefront optimized in the presence or absence of wavefront data. In one embodiment, the present silk films for corneal use (or intraocular use) may be wavefront optimized. Methods for applying the present devices to the patient can use the patient's vision to locate the patient's line of sight while the present device is being applied to the eye so that the device may be properly aligned with the line of sight. Prior to application of the present device, the iris may be dilated to enlarge the pupil of the eye.

The present device may be deformed before or during insertion in an eye of a patient. The present device may return to its original size and configuration after insertion in the eye.

In one embodiment, there is provided a method for inserting the present device in an eye of a patient, wherein the method comprises deforming the present device from an extended configuration to a deformed configuration; forming an incision in the eye; introducing the present device, in the deformed configuration, into the eye via the incision; and positioning the present device, an extended configuration, in the eye.

The present devices may adopt a deformed configuration, such as a folded configuration, a rolled configuration, or a partly rolled and partly folded configuration. The present device may be temporarily and reversibly deformed into a deformed or compact configuration prior to applying to the eye. In some embodiments of the invention, the present device may be deformed during passage through a small incision in a procedure for insertion in an eye of a patient.

For example, the present device may be adapted to be deformed by rolling or folding for insertion into the eye of a patient via an incision in the eye.

After implantation or application, the optical properties of the present device or its optical option may be changed in situ using a laser.

The present invention provides for devices and methods to correct defects of vision permanently or reversibly. The correction may be permanent, if it remains satisfactory, or may be reversed by removing the present device from the eye. Removal of the present device may be achieved by simply making an additional incision in the cornea, lifting the flap and removing the device. Alternatively, ablation techniques may be used to remove the device, e.g., through either disintegrating the material or enabling faster biodegradation of the material. In one embodiment, the present device is removed by laser or by surgical explantation (e.g., by peeling of lens or removing from other location).

The present device or its optical portion may be degradable or bioabsorbable. The present device or its optical portion may not be degradable or bioabsorbable. For example, if the present device needs to be retrieved from the eye at a later stage, the degradation time of the device can be controlled. Wang et al., Biomaterials, 29, 1054- 1064 (2008).

In the embodiments where the present device or its optical portion is degradable, the degradation properties may vary. As used herein, the terms "degradation time", "dissolution time" and "residence time" are interchangeable, and refer to the period of time it takes for greater than 95% (w/w) of the device or its optical portion to be degraded upon contacting with a body fluid in a subject (e.g., a patient). The degradation time of the present device or its optical portion may range from about 1 week to about 5 years, from about 2 weeks to about 4 years, from about 1 month to about 3 years, from about 2 months to about 2 years, from about 6 months to 1 year, from about 1 minute to about 24 hours, from about 10 minute to about 20 hours, from about 30 minutes to about 18 hours, from about 1 hour to about 16 hours, from about 1 hour to about 24 hours, from about 2 hours to about 20 hours, from about 3 hours to about 18 hours, from about 4 hours to about 16 hours, from about 5 hours to about 14 hours, from about 6 hours to about 12 hours, from about 8 hours to about 10 hours, from about 10 hours to about 24 hours, about 10 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, from about 1 minute to about 12 months, from about 30 minutes to about 10 months, from about 1 hour to about 6 months, from about 2 hours to about 4 months, from about 3 hours to about 3 months, from about 4 hours to about 1 month, from about 5 hours to about 3 weeks, from about 6 hours to about 2 weeks, from about 7 hours to about 1 week, from about 8 hours to about 5 days, from about 9 hours to about 3 days, or from about 10 hours to about 2 days.

Upon contacting with a body fluid, less than about 20% (w/w) of the device or its optical portion degrades after about 1 minute, and greater than about 80% (w/w) of the device or its optical portion degrades after about 24 hours; less than about 20% (w/w) of the device or its optical portion degrades after about 2 hours, and greater than about 80% (w/w) of the device or its optical portion degrades after about 20 hours; less than about 10% (w/w) of the device or its optical portion degrades after about 1 minute, and greater than about 90% (w/w) of the device or its optical portion degrades after about 24 hour; less than about 20% (w/w) of the device or its optical portion degrades after about 1 minute, greater than about 80% (w/w) of the device or its optical portion degrades after about 10 hours; less than about 20% (w/w) of the device or its optical portion degrades after about 1 minute, greater than about 90% (w/w) of the device or its optical portion degrades after about 10 hours; less than about 10% (w/w) of the device or its optical portion degrades after about 1 minute, greater than about 90% (w/w) of the device or its optical portion degrades after about 10 hours; less than about 20% (w/w) of the device or its optical portion degrades after about 1 hour, greater than about 80% (w/w) of the device or its optical portion degrades after about 10 hours; or less than about 10% (w/w) of the device or its optical portion degrades after about 1 hour, greater than about 90% (w/w) of the device or its optical portion degrades after about 10 hours.

The degradation time of the present device or its optical portion may also be measured in water or an aqueous solution at temperatures ranging from about 20°C to about 40°C, from about 22°C to about 37°C, from about 25°C to about 37°C, about 25°C, or about 37°C. The degradation of the present device or its optical portion may be measured by any suitable methods that can determine the protein level, e.g., UV absorbance, Bradford protein assay, Lowry protein assay, Bicinchoninic acid assay (BCA protein assay), Biuret protein assay, Ninhydrin protein assay, Amido black protein assay or any other suitable methods.

The silk protein(s) and peptide(s) in the present device or its optical portion may contain the β-sheet, ct-helix, random coil, and/or unordered structure.

The silk protein(s) in the present device may have β-sheet conformation ranging from about 0% to about 90%, from about 1% to about 80%, about 5% to about 70%, about 10% to about 60%, about 20% to about 50%, about 30% to about 40%, about 0% to about 30%, about 1% to about 25%, about 2% to about 20%, about 5% to about 15%, about 8% to about 10%, about 3% to about 12%, about 4% to about 22%, about 10% to about 30%, about 20% to about 40%, about 30% to about 50%, about 40% to about 60%, about 50% to about 70%, about 60% to about 80%, about 10% to about 40%, about 30% to about 60%, about 50% to about 80%, about 40% to about 80%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.

The silk protein(s) in the present device may have o-helix conformation ranging from about 0% to about 90%, from about 1% to about 80%, about 5% to about 70%, about 10% to about 60%, about 20% to about 50%, about 30% to about 40%, about 10% to about 30%, about 20% to about 40%, about 30% to about 50%, about 40% to about 60%, about 50% to about 70%, about 60% to about 80%, about 10% to about 40%, about 30% to about 60%, about 50% to about 80%, about 40% to about 80%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.

The silk protein(s) in the present device may have random coil conformation ranging about 1% to about 80%, about 5% to about 70%, about 10% to about 60%, about 20% to about 50%, about 30% to about 40%, about 10% to about 30%, about 20% to about 40%, about 30% to about 50%, about 40% to about 60%, about 50% to about 70%, about 60% to about 80%, about 10% to about 40%, about 30% to about 60%, about 50% to about 80%, about 40% to about 80%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%.

Fourier transform infrared spectroscopy (FTIR) may be used to study secondary structure in silk film materials. For example, peaks near 1650-cm^-1 and 1550-cm^-1 may represent β-sheet and α-helix content respectively. Protein structure may also be measured by x-ray diffraction (XRD), circular dichroism or any other suitable methods.

The present devices and methods may be used in humans, or in animals such as, dogs, cats, horses, monkeys, pigs, cows, or any other mammals. The present compositions may also be used in other subjects, such as mice, rabbits, etc. U.S. Patent No. 7,842,780.

The present device may be sterilized using conventional sterilization process such as radiation based sterilization (i.e. gamma-ray), chemical based sterilization (ethylene oxide), autoclaving, or other appropriate procedures. After sterilization the biomaterials may be packaged in an appropriate sterilize moisture resistant package for shipment and use in hospitals and other health care facilities.

EXAMPLES

The Examples below are illustrative of compositions and methods of the present invention and are not to be construed as limiting.

Example 1 Preparing curved silk films

Silk Solution Preparation

Bombyx mori cocoons were boiled for 30 min in an aqueous solution of 0.02 M Na₂CO₃, and then rinsed thoroughly with water to extract the sericin proteins, using methods previously reported. Jin et al., Adv. Funct. Mater.. 2005, 15 (8), 1241. The solution was then dissolved in 9.3 M LiBr solution at room temperature, yielding a 20% (w/v) solution. This solution was dialyzed in water using a dialysis cassette with a molecular cutoff weight of 3500 Da for 48 h.

Silk Film Preparation

To produce a curved silk film bandage, a spin casting process was developed. A prototype spin casting device was built in which a curved silicone rubber mold could be mounted onto 1 of 4 spindles that were connected to a variable speed motor through a power transfer belt system. To produce the films, silk solution was pipetted into the curved molds and then spun at a fixed rate for a 1.5-hour period until the solution dried. In addition, the curved film drying time was expedited by controlling the spindle environment through controlled compressed air through the system.

The dried curved film was removed by bending the silicone rubber mold and air- lifting the curved film from the casting surface with forceps. The films that emerged were both curved in shape and highly transparent. The process was found to be highly reproducible and controlled by optimizing the spin cast process parameters (e.g., air flow, RPM, and silk concentration).

To reduce silk solution drying time, the casting chamber was also vented with pressurized air. It was shown that the introduction of air-flow reduced drying time from 180 minutes down to 90 minutes (50% reduction). The addition of the pressurized air affected silk film bandage thickness. The effect of the pressurized air on drying rate was negligible in that as long as vented air was flowing through the system drying time was decreased. The higher flow rates of 60 and 80 PSI produced thinner silk film bandage thickness profiles when compared to 40 PSI.

The rotation speed (rotations per minute, RPM) of the mold also affected silk film thickness. 187, 297, 424, 500 and 600 RPM rotation settings were tested.

Example 2 Heat processing of film

A silk film can be water-annealed to decrease its water solubility. As an alternative to water-annealing, the use of heat-annealing was explored. Heat-annealing is the use of a dry heat environment (i.e. dry heat sterilizing oven) to induce protein secondary structure changes over time, which was shown to increase silk bandage dissolution time qualitatively. Additionally, heat-annealing has the added benefit of sterilizing the material while simultaneously processing the silk bandage to increase dissolution time, thus simplifying the manufacturing process by combing two processing steps together. It was found that silk film dissolution time could be readily varied using a window of FDA recommended sterilization temperature (150°C to 180°C) and time ranges (1 hour to 2 hours). Silk film dissolution could be quantified using the bicinchoninic acid (BCA) protein content assay. The processed silk film bandages were placed in 1 mL of water, dissolved for 15 minutes, and then sampled for protein content. Assay results indicated that there is an estimated 10% reduction in total protein dissolution between 80°C and 160°C, with a 25% reduction in dissolution between 160°C and 180°C. Results for the assay indicated that silk film bandage dissolution could be readily modified based on the length of heat-annealing time with the largest change in dissolution represented at 180°C.

Example 3 In vivo testing of silk films in mouse model

The device was tested in vivo to determine both the material stability and biocompatibility in a mouse cornea model.

Production of silk solution

Bombyx mori silkworm cocoons (Tajima Shoji Co., Yokohama, Japan) were cut into thirds and then boiled for 40 minutes in 0.02M Na₂CO₃ (Sigma-Aldrich) to extract the glue-like sericin proteins from the structural fibroin proteins as previously described. Lawrence et al., Silk film biomaterials for cornea tissue engineering. Biomaterials. 2009; 30(7): 1299-308. The fibroin extract was then rinsed three times in dH₂O for 20 minutes per wash then dried overnight. The rinsed fibroin extract was then dissolved in 9.3M LiBr solution at room temperature, and placed covered in a 60°C oven for 4 hours. The solution was dialyzed in water for 48 hours (MWCO 3,500, Pierce, Inc.). The dialyzed silk solution was centrifuged twice at 13,000 g, and the supernatant collected and stored at 4°C. The final concentration of aqueous silk solution was 8 wt./vol.%, as determined by gravimetric analysis.

Preparation of PDMS casting surfaces

Polydimethylsiloxane (PDMS) substrates of 0.5 to 1.0 mm thickness were produced by pouring 5 mL of a 1 : 10 casting catalyst/potting solution (Momentive, Inc., Albany, NY) onto a plastic 90-mm petri dish surface. The cast PDMS solution was then degassed for 2 hours under vacuum, and then cured in an oven at 60°C overnight. The following day the cured PDMS was removed from the silicon substrate and then punched to form round 14-mm circles. The PDMS substrates were placed cast side up and dust/debris was cleared by using clear tape. The surfaces were further cleaned with 70% ethanol, three dH₂O rinses, and then allowed to air dry in a clean environment.

Silk film casting and sterilization

Silk films measuring 80 μm in thickness were created by casting 8% silk fibroin solution upon the round PDMS surface. After casting the silk solution, films were covered and allowed to dry for 24 hours to form the patterned silk film surface. Silk film samples were then water-annealed (WA) for different time periods by placing the samples in water filled chambers at a 10-psi vacuum and 85% relative humidity. Jin et al., Water Stable Silk Films with Reduced β-Sheet Content. Advanced Functional Materials. 2005; 15(8):1241-7. Hu et al., Regulation of Silk Material Structure by Temperature- Controlled Water Vapor Annealing, Biomacromolecules. 2011 May 9; 12(5): 1686-96.

Surgical procedure

For mouse studies, a micro-pocket incision was produced in the mouse cornea stroma region about half the thickness of the total tissue thickness. A 20 μm-thick silk film was produced which possessed an equilateral triangle geometry measuring 2 mm per side length. This shape and thickness was used to allow for optimal placement within the corneal stromal micro-pocket. A total of 6 mice were used for the experiments and followed up to 49 weeks (Figure 4). After placing the film within the micro-pocket, antibiotics were added 3 times a day for 1 week to prevent infection. Results

Results indicated that the mouse cornea remained transparent in nature over the entire study (Figure 4, upper panels), and that the material remained embedded within the cornea as highlighted by fluorescent imaging (Figure 4, lower panels). The corneas appeared to heal without infection and the mice vision did not appear impacted based on behavioral observations.

Animals were sacrificed at various time points, the eye balls were excised, and the tissue was mounted for histological sectioning in paraffin. Hemotoxylin and eosin (H&E) staining revealed that no corneal inflammation or scarring was present at the various time points of the study (Figure 5). Histology further confirmed that the cornea maintained viability, while showing biomaterial tissue integration (Figure 5, panel B). In addition, the surrounding corneal tissue appeared largely unaffected by the presence of the silk film after 49-weeks (Figure 5, panel C).

Example 4 In vivo testing of silk films in rabbit model

The mouse animal model has limitations due to the small size of the corneal tissue region. Therefore a more physiologically advanced and larger rabbit corneal model was used to study the effect of silk film implantation on the cornea.

Silk film optics were produced as described above with 6 mm diameters and a 3 μm film thickness. The films were water-annealed for 5-hours to produce highly insoluble silk films. The films were then sterilized by placing them into a dry heat oven at 150°C for 2.5 hours as indicated by standard FDA guidelines for medical device sterilization.

The surgical procedure was performed on 8 rabbits in which an 8.5 mm trephine incision was produced, and then a corneal flap was manually created using a surgical blade and scissors (Figure 6). The flap was lifted and a silk film was placed flat on the stroma tissue bed. The flap was replaced over the silk film and sutured close using 10-0 nylon sutures. The animals were given an anti-inflammatory three times a day for 3 days post procedure. In addition, antibiotics and steroids were administered three times a day for 1 week. The silk film and corneal healing were observed with slit lamp photography. At each of 4- week, 8-week, 12-week and 36-week post-procedure time points, two rabbits were sacrificed. The corneas were removed for histological preparation in paraffin wax, and portions of the tissue were whole mounted for imaging with differential inference contrast (DIC) microscopy. Whole mounted tissue samples were then prepared for scanning electron microscopy (SEM) imaging by dehydrating the tissue in serial ethanol baths with a final dehydrating treatment in hexamethyldisiloxane (HMDS) for 2 minutes. The dried samples were then coated with a layer of palladium. Results

Results indicated that the corneas remained transparent and free from tissue inflammation or angiogenesis post implantation. The cornea incision healed within the first week as indicated by fluorescein imaging, and the rabbit behavior seemed to be normal when compared to surgical procedure controls with no implants. Using the slit lamp photography, it was observed that the implanted silk film remained embedded within the corneal stroma after 6 weeks post-implantation (Figure 7, panel A).

Examination of the silk film with DIC and SEM imaging indicated that the surface topography of the silk film appeared unaffected while implanted in the stromal matrix (Figure 7, panels B-D). This suggested that the material stability of the silk films is high within the corneal stromal matrix. In addition, there was no inflammation or subsequent blood vessel formation for both treated and untreated controls, which indicates the material is biocompatible and not stimulating a foreign body response.

Excised rabbit corneas were prepared for histological sectioning in paraffin, and then stained with H&E. Imaging of the tissue sections indicated that the rabbit cornea was free of inflammatory cells and integrated with the silk film optic (Figure 8, panel A). In addition, no blood vessel formation could be detected indicating that the material is not angiogenic. During sectioning, the corneal tissue appeared to separate from the patterned silk film surface as indicated by similar features located on the adjacent stromal tissue. This indicates that the silk is integrating with the surrounding corneal tissue while maintaining material stability. Controlled corneas appeared similar in tissue architecture to the silk treated corneas (Figure 8, panel B). Conclusion

In summary, the above experiment demonstrates that a silk film optic can be successfully produced and implanted into a variety of animal models. The material is both highly biocompatible and stable within the corneal environment.

Example 5 Silk film implanted as corneal inlay in rabbit model

The purpose of this study was to evaluate the biocompatibility and degradation of silk fibroin film in rabbit corneal stromal layers.

Methods

Patterned silk fibroin film with different thickness (3, 5, 10 and 20 μm) was implanted into rabbit corneal anterior stromal and followed up to 6 months. Postoperative ocular inflammation, neutrophil infiltration, corneal wound healing, neovascularization, infection and integrity of silk film were examined under slit lamp microscope. In vivo corneal architecture was examined by optical coherence tomography. Rabbits were sacrificed at 1 , 3 and 6 months post-op respectively. H&E staining of corneal sections was performed to examine the corneal structure, inflammatory response and silk film degradation.

Histology: excised rabbit corneas were prepared for hemotoxylin and eosin

(H&E) staining. Samples were paraffinized, and then sectioned into 7-um thick slices. The sections were deparaffinized with two changes of Histoclear solution (National Diagnostics, Atlanta, GA), and then serial rehydrated in serial ethanol dilutions. Samples were stained in hemotoxylin and differentiated in 1% acid alcohol, and then blued in 0.2% ammonia water. Samples were counterstained in eosin solution, serially dehydrate with Ethanol dilutions, and mounted with DPX mounting medium.

Experiment #1: porous & nonporous silk films, 3 and 5 μη\ thickness

The surgical procedure was performed on 7 New Zealand white rabbits. The implants included silk films 6mm in diameter, and 3 μιτι and 5 μm in thickness. Among the silk films, 3 were porous and the other 3 non-porous. The experimental design was as follows:

Surgical procedure

Topical proparacaine was applied to the right eye. A speculum was placed to maintain the eyelids open. A trephine with 8 mm in diameter was used to demarcate the cornea in the right eye. A corneal incision was made at 9 o'clock with a diamond blade, and stromal dissection was carried out with a crescent surgical blade. After the corneal flap with 1/3 of corneal thickness was created, a piece of silk film was implanted under the corneal flap. 10-0 nylon sutures were placed to fix the flap in place. For control group, no silk film was implanted. Corneal incision was closed using 10-0 nylon sutures. The knots were buried and topical moxifloxacin antibiotic drops were applied. Rabbits were closely monitored for evidence of distress or infection.

Post-op care included analgesic drug metacam po. for 3 days, and topical eyedrops, prednisolone eye drops and moxifloxacin eye drops, tid. for 1 week. Corneal sutures were removed 2 weeks post-op.

Preliminary results

Silk films with 3 μm or 5 μm thickness were easy to handle and transfer during the surgery. Corneal re-epithelialization was completed within 1 week post-op with minimal inflammatory response. Silk film was transparent and intact up to 6 months follow-up. Both OCT and histological staining of corneal tissue showed that silk film was well integrated and tolerated by host cornea stroma without obvious inflammatory cell infiltration and degradation which was demonstrated by the maintenance surface pattern. No significant difference was found between porous and non-porous films regarding the corneal gross and microscopic structure. Experiment #2: nonporous silk films with 5, 10 and 20 m thickness

The surgical procedure was performed on 6 New Zealand white rabbits. Implants included silk films 6 mm in diameter and S, 10 and 20 μm in thickness.

The experimental design was as follows:

Surgical procedure

Topical proparacaine was applied to the right eye. A speculum was placed to maintain the eyelids open. A trephine with 8 mm in diameter was used to demarcate the cornea in the right eye. A corneal incision was made at 9 o'clock with a diamond blade, and stromal dissection was carried out with a crescent surgical blade. After the corneal flap with 1/3 of corneal thickness was created, a piece of silk film was implanted under the corneal flap. 10-0 nylon sutures were placed to fix the flap in place. The knots were buried and topical moxifloxacin antibiotic drops were applied. Rabbits were closely monitored for evidence of distress or infection.

Post-op care included analgesic drug metacam po. for 3 days; topical eyedrops, prednisolone eye drops and moxifloxacin eye drops, tid. for 1 week. Corneal sutures were removed 2 weeks post-op. Preliminary results

Eyes with 20 μm silk film implanted showed intense ocular inflammation, corneal flap edema, opacity and melting, neutrophil infiltration and superior superficial neovascularization (Figure 9, panels B and D). In contrast, eyes with 10 and 5 μm silk film implanted showed fast re-epithelialization, quiet ocular surface, and transparent cornea and silk film (Figure 9, panels A and C, and data not shown). No inflammation and neovascularization was observed during the 1 month follow up. 2 rabbits with 20 μm silk film implantation were sacrificed and corneal tissues were harvested for histological analysis. The other 4 rabbits were sacrificed at 3 months for histological study.

Example 6 Corneal inlay to correct presbyopia in patients

The experiment will be designed as a 3 -year prospective nonrandomized noncomparative study to evaluate the safety and efficacy of the silk corneal inlay in emmetropic presbyopic patients. Seyeddain et al., Small-aperture corneal inlay for the correction of presbyopia: 3-year follow-up, J. Cataract Refract. Surg. 2012; 38:35-45. Doran et al., Corneal Inlays for Presbyopia Move Closer to Approval, Evenet. March 2010, 25 - 26. VERITY et al., Outcomes of PermaVision Intracomeal Implants for the Correction of Hyperopia, Am. J. Ophthalmol. 2009; 147:973-977. Mulet et al., Hydrogel Intracomeal Inlays for theCorrection of Hyperopia, Ophthalmology. 2009;1 16:1455- 1460. Alio et al., Intracomeal Inlay Complicated by Intrastromal Epithelial Opacification, Arch. Ophthalmol. 2004:122:1441-1446.

Patients

Key requirements for participation in the study will include a preoperative uncorrected near visual acuity (U VA) between 20/40 (Jaeger [J] 5) and 20/100 (J10/J11) in the surgical eye, uncorrected distance visual acuity (UDVA) of at least 20/20 in both eyes, cycloplegic refraction of G0.50 diopter (D), minimum central corneal thickness (CCT) of 500 mm or more, endothelial cell density (ECD) in the surgical eye of 2000 cells/mm² if 45 to 49 years of age or of 1800 cells/mm² or more if 50 to 55 years of age, corneal power from 41.00 to 47.00 D in all meridians measured by keratometry, and stable refraction (manifest refraction within G0.50 D sphere) 12 months before corneal inlay implantation.

Key exclusion criteria will be previous ocular surgery, anterior or posterior segment disease or degeneration, and immunosuppressive disorders. In addition, patients using systemic medications with significant ocular side effects or patients with latent hyperopia (difference of more than 1.00 D between manifest refraction and cycloplegic refraction) will be excluded. Corneal Inlay will be prepared as described above. The device will be implanted in the nondominant eye.

Surgical Technique

In brief, a superior hinged flap will be created in the nondominant eye with a 60 kHz Intralase femtosecond laser (Abbott Medical Optics) (8 μm x 8 μm spot/line separation, 0.9 μ,Ι/pulse, 9.0 mm intended diameter). The intended depth from the corneal surface will be 170 μm. With the patient fixating on the excimer laser microscope's single light source, the corneal inlay will be centered on the stromal bed, with the first Purkinje reflex in the center of the inner diameter of the inlay. Then, the flap will be carefully repositioned.

Outcome Parameters

Postoperative follow-up examinations will be scheduled at 1 day, 1 week, and 1, 3, 6, 9, 12, 18, 24, 30 and 36 months. The primary outcome parameters will be manifest refraction, visual acuity, contrast sensitivity, visual fields, subjective patient satisfaction and symptoms, and intraoperative and postoperative adverse events and complications. Postoperative centration of the inlay will be determined by direct ophthalmoscopy, looking for the relationship of the inlay center to the first Purkinje reflex on the cornea.

Manifest Refraction and Visual Acuity

Manifest refraction and visual acuity will be assessed preoperatively and postoperatively from 1 week onward. Visual acuity measurements will include monocular and binocular UDVA, corrected distance visual acuity (CDVA) at a simulated far distance of 20 feet, UNVA at 16 inches, and uncorrected intermediate visual acuity (UIVA) at 32 inches. All visual acuity measurements will be performed with the Optec 6500P Vision Tester (Stereo Optical Co., Inc.) by recording the number of logarithmic Early Treatment of Diabetic Retinopathy Study targets identified correctly and deriving the corresponding Snellen equivalent.

Contrast Sensitivity and Visual Field Contrast sensitivity and visual field tests will be performed preoperatively and postoperatively at 12, 24 and 36 months. Contrast sensitivity will be tested with best distance correction using an Optec 65 OOP Vision Tester and Functional Acuity Contrast Test. The surgical eye will be tested first under photopic conditions (85 candelas

[cd]/m²); after dark adaptation for 10 minutes, mesopic (3 cd m²) contrast sensitivity testing will be performed in the surgical eye and then binocularly. Mesopic contrast sensitivity will be tested in the surgical eye with a glare source of 28 lux. Testing will be performed at 1.5, 3, 6, 12, and 18 cycles per degree.

Visual fields will be tested with best near correction using the Humphrey Instruments Field Analyzer (model 750, Carl Zeiss Meditec AG). A test will be repeated if more than 2 of 14 fixation losses are recorded. The maximum allowable false-positive or false- negative error for each test will be 3%. The mean deviation and pattern standard deviation (SD) of the visual field indices will be determined and compared between preoperatively and postoperatively.

Patient Satisfaction

A subjective questionnaire to assess outcomes in the clinical trial will be developed. Patients will be asked to rate their near, intermediate, and distance vision; level of dependence on spectacles; visual symptoms, such as light sensitivity, pain/burning, dryness, glare, halos, blurry vision, and night vision; and overall satisfaction with the procedure. Patients will be asked to rate distance, intermediate, and near vision performance on a visual analog scale from 0 (no difficulty at all) to 10 (extreme difficulty).

The scope of the present invention is not limited by what has been specifically and described hereinabove. Those skilled in the art will recognize that there are suitable alternatives to the depicted examples of materials, configurations, constructions and dimensions. Numerous references, including patents and various publications, are cited and discussed in the description of this invention. The citation and discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any reference is prior art to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety. Variations, modifications and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and scope of the invention. While certain embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the spirit and scope of the invention. The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not as a limitation.

Claims

What is claimed is:

1. A device for applying into an eye of a patient to correct vision, comprising from about 50% (w/w) to about 100% (w/w) fibroin and having an optical portion, wherein the optical portion has a thickness ranging from about 100 nm to about 20 μm .

2. The device of claim 1 , wherein the optical portion is a film.

3. The device of claim 1 , wherein the device comprises a lens, a microlens array, a diffractive optic, an optical grating, a hologram, a pattern generator, a beam reshaper, diffraction gratings, photonic crystals, a Fresnel lens, a non-Fresnel type lens, a waveguide or a diffractive optical element.

4. The device of claim 1 , wherein the surface of the device comprises a pattern.

5. The device of claim 4, wherein the pattern comprises a diffractive optical element.

6. The device of claim 5, wherein the diffractive optical element comprises

holographic gratings.

7. The device of claim 5, wherein the diffractive optical element comprises from about 1 to about 10,000 features per millimeter.

8. The device of claim 1 , wherein the surface of the device is smooth.

9. The device of claim 1 , wherein the optical portion has a biconvex, plano-convex, convex-concave, meniscus, plano-concave or biconcave optical profile.

10. The device of claim 1 , wherein the optical portion has a diopter power ranging from about +20 to about -40.

11. The device of claim 1, wherein the optical portion is single-focal, bifocal or

multifocal.

12. The device of claim 1, wherein the optical portion has a thickness ranging from about i μm to about 10 μm .

13. The device of claim 12, wherein the optical portion has a thickness of about 5 μm .

14. The device of claim 12, wherein the optical portion has a thickness of about 10 μm .

15. The device of claim 1, wherein the device is applied to the surface of an

intraocular lens, an intracorneal lens, a contact lens or a lens of spectacles.

16. The device of claim 1 , wherein fibroin is obtained from silkworm silk, spider silk or genetically engineered silk.

17. The device of claim 16, wherein the silkworm silk is obtained from Bombyx

mori.

18. The device of claim 16, wherein the spider silk is obtained from Nephila clavipes.

19. The device of claim 1, wherein fibroin is in an amount ranging from about 80%

(w/w) to 100% (w/w).

20. The device of claim 1, further comprising a plurality of pores.

21. The device of claim 1, further comprising a pharmacologically and/or biologically active agent.

22. the device of claim 21, wherein the pharmacologically or biologically active agent is an antibiotic.

23. A method for correcting vision of a patient having an ocular condition, the

method comprising the steps of: a) providing a device comprising from about 50% (w/w) to about 100% (w/w) fibroin and having an optical portion, wherein the optical portion has a thickness ranging from about 100 nm to about 20 μηι;

b) forming an incision in an eye of the patient; and

c) inserting the device in the eye.

24. The method of claim 23, wherein the ocular condition is chosen from presbyopia, astigmatism, myopia, hyperopia, macular degeneration or combination thereof.

25. The method of claim 23, wherein in step (c), the device is applied on the cornea, implanted in the cornea, implanted in the anterior chamber of the eye, implanted behind the iris, implanted in the posterior chamber of the eye, or implanted in the capsule of the crystalline lens.

26. The method of claim 23, wherein in step (c), the device is implanted underneath an epithelium sheet of the cornea, beneath the cornea's Bowman membrane, in the corneal stroma, behind the corneal str oma, or on top of the corneal stroma.

27. The method of claim 23, wherein in step (b), the incision forms a corneal flap or corneal pocket.

28. The method of claim 23, wherein the optical portion is a film.

29. The method of claim 23, wherein the device comprises a lens, a microlens array, a diffractive optic, an optical grating, a hologram, a pattern generator, a beam reshaper, diffraction gratings, photonic crystals, a Fresnel lens, a non-Fresnel type lens, a waveguide or a diffractive optical element.

30. The method of claim 23, wherein the surface of the device comprises a pattern.

31. The method of claim 30, wherein the pattern comprises a diffractive optical

element.

32. The method of claim 23, wherein the optical portion has a biconvex, plano- convex, convex-concave, meniscus, plano-concave or biconcave optical profile.

33. The method of claim 23, wherein the optical portion has a diopter power ranging from about +20 to about -40.

34. The method of claim 23, wherein the optical portion is single-focal, bifocal or multifocal.

35. The device of claim 23, wherein the optical portion has a thickness ranging from about 1 μm to about 10 μm.

36. The method of claim 35, wherein the optical portion has a thickness of about 5 μm.

37. The method of claim 35, wherein the optical portion has a thickness of about 10 μm.

38. The method of claim 23, wherein in step (c) the device is applied to the surface of an intraocular lens or an intracomeal lens in the eye.

39. The method of claim 23, wherein the silk fibroin is obtained from silkworm silk, spider silk or genetically engineered silk.

40. The method of claim 39, wherein the silkworm silk is obtained from Bombyx mori.

41. The method of claim 39, wherein the spider silk is obtained from Nephila

clavipes.