NON-INVASIVE VISION CORRECTION with FEMTOSECOND LASERS Wayne H

Home , Contact lens, Monocle

Technology and Innovation, Vol. 20, pp. 385-398, 2019 ISSN 1949-821 • E-ISSN 1949-825X http:// Printed in the USA. All rights reserved. dx.doi.org/10.21300/20.4.2019.385 Copyright © 2019 National Academy of Inventors. www.technologyandinnovation.org

INVENTING A NEW WAY TO SEE CLEARLY: NON-INVASIVE VISION CORRECTION WITH FEMTOSECOND LASERS Wayne H. Knox 1The Institute of Optics, University of Rochester, Rochester, NY, USA 2Clerio Vision, Inc., Rochester, NY, USA

Ever since the first documented use of spectacles for vision correction around the mid-1200s, we have been looking for better ways to correct human vision. A wide range of technologies have been developed to correct vision, including eyeglasses that now can help mitigate presbyopia, more comfortable contact lenses that can be used for extended times, intraocular lenses for treating cataracts, and, most recently, LASIK surgery for cutting and reshaping the human cornea directly. All of these are invasive to certain degrees, and it is desirable to develop less invasive forms of vision correction. We have developed an alternative approach to vision correction involving directly changing the index of refraction of ophthalmic materials by femtosecond laser micromachining. We discuss metrology, wavefront, and human visual testing results in hydrogel materials that are commonly used for contact lenses and intraocular lenses, as well as fully scaled vision correctors written directly into the cornea stroma layer in live eyes. This new technique has been developed to be non-invasive and has a significant accompanying patent portfolio. We describe the research and development efforts, which started in 2003, leading to this new approach to vision correction that we refer to as LIRIC: Light Induced Refractive Index Change.

Key words: Technology; Innovation; Vision correction; Lasers; Patents

INTRODUCTION received in battle, and reportedly for melting wax tab- Ever since the first humans gazed upon the earth, lets that early tax bills were written upon. Therefore, we have been looking for better ways to correct our it was known that by imparting a specific curvature vision to be as sharp as it can be. The invention of onto a transparent substance, light could be made to transparent glasses around 5000 BC made possible focus. In the case of the burning glasses, the purpose the invention of the refractive lens. Even before that, was to concentrate sunlight to start a fire. However, early inventors surely noticed that even a water drop- it was realized that when looking through these early let could magnify an image of a leaf because of the lenses, under certain conditions, they could actually curved surface that forms due to the water menis- improve the vision of a person with fuzzy vision. cus. Also, polished spheres of naturally found crystals The first known painting of a human wearing read- were used as burning glasses as early as 300 BC in ing spectacles is shown in Figure 1. It is a painting the sunlight for starting fires, cauterizing wounds of the Cardinal Ugo Di Provenza (1). Although the

______

Accepted: November 1, 2018. Address correspondence to Wayne H. Knox, University of Rochester, The Institute of Optics, 275 Hutchison Rd., Rochester, NY, 14627, USA. Tel: +1 (585) 273-5520. E-mail: [email protected]

385 386 KNOX painting, painted by Tomasso Di Modena, is dated when needed. Figure 2, entitled “Living Made Easy,” to about AD 1352, it is known that the Cardinal died shows a somewhat fanciful invention that provides around the year AD 1250. It is worth pointing out several forms of accommodation (2). On the right, that the existence of uniform quality highly transpar- attached to a revolving hat frame are a pair of spec- ent glass is necessary, but not sufficient, to actually tacles, a snuff box, a reading monocle, and a cigar. improve human vision as shown in this figure. On the device to the left, a hearing aid is included. The text at the bottom says, “Revolving Hat, Which by a slight touch presents its Wearer with, Eye-Glass, Cegar, Scent-Box, Spectacles, Hearing Trumpet, etc. etc., without the intolerable trouble of holding them. London, Pub.d by T. McLean…1830.”

Figure 2. Multi-purpose rotating hat device invented ca. 1830. Figure 1. Earliest indication of use of reading glasses ca. AD https://wellcomecollection.org/‌works/‌xpztc4cg?query=revolv- 1250. Photo credit: https://‌commons.wikimedia.org/wiki/ ing%20hat. CC-BY attribution - Two men wearing revolving top File:Tommaso_da_modena,_ritratti_di_domenicani_(Ugo_di_ hats with several attachments for optical aids and tobacco etc. Provenza)_1352_150cm,_treviso,_ex_convento_di_san_nicco- Coloured etching. Credit: Science Museum, London. l%C3%B2,_sala_del_capitolo.jpg. And so, we ask the question: Is vision correc- The aforementioned glass material must be pol- tion invasive? Clearly, the need to wear eyeglasses is ished carefully to avoid creating scratches, voids, and quite invasive for some people. Eyeglasses are com- other imperfections that can scatter light, and, fur- monly lost, broken, scratched, bent, blown off in thermore, the shape of the curved glass lenses must windstorms, misplaced, difficult for some people to be controlled rather precisely in order to produce a obtain, and otherwise “intolerable trouble,” to use spectacle lens that provides the necessary optical cor- the words of the 1830 inventors. In a 2014 issue of rection. If the applied correction is too large or too National Geographic magazine, the Kayapo people small, the vision will actually be made worse, and then of the Amazon were described as Defenders of the the spectacles will not be worn. Since the Cardinal Amazon (3). In this article, a photo of the powerful looks to be of advanced age in the painting, we may chief Pukatire is presented, and he is wearing body presume that he had at least a condition called pres- paints made of fruits, nuts, and charcoal as well as byopia, wherein the ability of an eye to accommodate glasses (Figure 3). In many parts of the modern world, to focus for up-close work typically reduces above eyeglasses are difficult to come by, and eye clinics are age 40. A person with normal distance vision does few and far between. In some developing countries, not always want to wear reading glasses, and reading women actually do not want to wear glasses because glasses for close-up work are commonly misplaced they fear that they will be seen as unattractive and be and considered inconvenient. Throughout history, unable to get married. Truck drivers in remote loca- many inventions were developed in order to make it tions drive without wearing proper driving glasses, more convenient to have vision correctors available causing hazardous conditions. Therefore, there is NON-INVASIVE VISION CORRECTION 387 plenty of motivation to try to find less invasive forms take them out, resulting in damaging eye conditions. of vision correction. Infections can be caused by unsanitary solutions or handling practices. Therefore, although very suc- cessful for most patients, we cannot consider contact lenses to be non-invasive vision correction; nonethe- less, the global market for contact lenses is currently about $10 billion.

Figure 4. Modern contact lenses, photo credit CC BY-SA 3.0, https://commons.wikimedia.org/‌w/index.php?curid=514486.

Figure 3. Chief Pukatire of the Amazon Kayapo tribe. Photo PRK and LASIK by Martin Schoeller, used with permission from the photogra- pher, www.martinschoeller.com, originally published in National Efforts to directly change the shape of the human Geographic in January 2014. eye were dreamed of for many years in hopes to obtain new ways to permanently correct the human vision FORMS OF VISION CORRECTION condition. When the laser (U.S. Patent 2,929,922) was Contact Lenses invented around 1960, it was thought that it could As we discussed in the introduction, eyeglasses provide new ways to modify the shape of the eye. are common forms of vision correction. Contact PRK, or photorefractive keratectomy, was developed lenses have a long historical development (4), but by Dr. Steven Trokel in 1987, using an ultraviolet it is commonly accepted that roughly around 1950, excimer laser to change the shape of the cornea. In early contact lenses made by Prof. Dr. L. Heine Keil the quest to develop a less invasive form of vision in Germany began to be available. Contact lenses correction that produced less modification of the have significantly evolved over the years into a major outer epithelial layer of the cornea than PRK, a rev- industry, with many different kinds of contact lenses olutionary new kind of vision correction treatment now available. The newest contact lenses, which have was developed: laser-assisted in situ keratomilieusis, a high water content, are so comfortable that they can now known as LASIK. A very long historical devel- hardly be felt when properly placed on the eye (Figure opment is available (5), but here we simply note that 4). For many, contact lenses are an acceptable solu- since the 1950s, it was known that any technique that tion to vision correction; however, just like with any changes the curvature of the human cornea could sig- medical devices, there are limitations. Some people nificantly change the refractive power of the eye since become allergic to the contact lenses and/or contact roughly 2/3 of the refracting power of the human eye lens solutions and have to stop wearing them. It has comes from the cornea surface in air. The other 1/3 been reported that some people have forgotten to comes from the internal lens. Early forms of LASIK, 388 KNOX such as that developed by IntraLase, used a rapidly index of the materials around the same time in 1996 vibrating razor blade (microkeratome) to cut a flap to 2001 (8). Having been introduced to ophthalmic in the cornea open, and then, once the flap was lifted materials such as hydrogels in 2003, the author began out of the way, the ultraviolet excimer laser could be studying the femtosecond laser micromachining pro- used to ablate (vaporize) thin layers of cornea tissue. cesses in them to see if they could be locally modified The corneal flap was then put back in place, and the by femtosecond laser exposure to produce substantial refractive correction was complete. The procedures refractive index variations. Figure 6 shows a com- were widely adopted despite difficulties with the flap parison of different laser-material interactions that depth location and other issues related to the use of are of interest. In Figure 6A, a laser beam is strongly the microkeratome to cut the flap. In 1999, a new absorbed in the material; therefore, all of the energy technique was demonstrated to cut the corneal flap. is deposited on the surface of the material. At the University of Michigan, Tibor Juhasz and his group demonstrated that a corneal flap could be cut using a tightly focused femtosecond laser (6). Figure 5 shows a schematic representation of the cutting of a corneal flap using a femtosecond laser. The femtosecond laser procedure for LASIK surgery was very successfully adopted by the industry, and currently more than 10 million LASIK procedures have been completed in the U.S. and roughly 40 million in the world (5). Yet, can we consider LASIK to be a non-invasive vision correction? The flap cutting procedure, whether done with the microkeratome or the fem- Figure 6. Comparison of different focusing conditions for mate- tosecond laser, is still a tissue cutting procedure that rial processing. can result in complications (7,8). Quite remarkably, of those needing some form of refractive correction, This case would be good for LASIK ablation using only about 2% have had LASIK surgery to date, leav- a 193 nm wavelength excimer laser since the require- ing the rest of the 98% looking for something perhaps ment for LASIK cornea ablation is to remove by less invasive. vaporization thin layers of cornea stromal tissue on Whereas the initial work by Juhasz et al. reported a shot-by-shot basis. The ultraviolet laser beam is in 1999 was directed toward tissue cutting, it had also moved around the cornea in a controlled fashion to been demonstrated that, using femtosecond lasers, produce the new cornea shape. In Figure 6B, a laser optical glasses could be modified without inducing beam is weakly focused into a transparent material, significant damage to locally change the refractive and then the material changes are made primarily

Figure 5. Schematic representation of corneal flap cutting using a laser adapted fromhttps:// ‌en.wikipedia.org/wiki/LASIK. NON-INVASIVE VISION CORRECTION 389 inside the material over a large volume. This kind of can be modified locally using femtosecond lasers and condition is used for certain types of microprocess- then ultimately engineered to provide new kinds of ing, such as lens sectioning in cataract surgery (9). refractive correctors. In Figure 6C, it is shown that when conditions are established in which refractive LIRIC, OR LASER INDUCED REFRACTIVE INDEX index is locally modified, then simply by scanning CORRECTION the focused laser beam, or even by moving the sample, a specified pattern of modified refractive index In Figure 6C, a very different condition is shown, profile can be created, and that is the fundamental wherein a laser beam is tightly focused with a high basis for a new way to do refractive device fabrica- numerical aperture lens to a very small spot. When tion, ultimately in a non-invasive manner. this is done in the transparency region of a material, we can obtain very different results compared to both conditions shown in Figures 6A and 6B. As had been shown by Davis et. al (8) and others, this condition makes use of the fact that, while a transparent material may have very little absorption at the laser wavelength, if we use a laser with a high enough intensity, we can induce absorption through a process known as multiphoton absorption. In that case, a material that absorbs only ultraviolet light, such as common glass, and may be transparent to near infrared laser light at, say, 1035 nm wavelength, may Figure 7. Elementary femtosecond micromachining setup for flat hydrated samples. absorb a number of infrared photons simultaneously, resulting in substantial deposition of energy. The Figure 7 shows a very simple form of experiment region of energy deposition can be quite small, lead- that was first reported by the author in 2006 (10). A ing to micron-sized or even sub-micron sized features flat sample of ophthalmic hydrogel is sandwiched in various materials. Starting in 2003, the author stud- between thin glass plates and immersed in a water- ied the response of various ophthalmic materials to based ophthalmic solution. A femtosecond laser femtosecond laser excitation under many conditions. beam is focused with a microscope objective typ- One common material of interest is the ophthalmic ically a distance of 100 to 200 microns under the hydrogel. A hydrogel is a gel that is made up of var- surface of the sample. The sample is raster-scanned ious mixtures of hydrophobic (do not attract water) back and forth in order to create a uniform series of and hydrophilic (attract water) monomer chemical lines of refractive index modification, similar to the elements. Those monomer elements can be mixed way that optical waveguides were first written in glass together with other chemicals that link them together blocks (8). Figure 8 shows the results of the first basic into long molecular chains known as polymers. These experiments, with the left panel showing a phase con- materials can have very diverse optical, mechanical, trast microscope photo of the grating lines and right chemical, biological, therapeutic, and other proper- panel showing a bright field or intensity photograph. ties. The first contact lenses, discussed previously, The fact that the phase photo clearly indicates opti- were made out of polymethyl methacrylate (PMMA) cal phase shift and the bright field indicates nothing when it was discovered that fighter pilots coming back is the expected result when we want to only mod- from World War II had fragments of PMMA wind- ify the refractive index of the material and not the shields embedded in their eyes without displaying any optical transmission. Figure 8B shows a diffraction wound healing effects, indicating that PMMA was pattern that is created when a red laser beam of 632 quite biocompatible with the eye. Many kinds of soft nm wavelength is transmitted through the device. contact lenses have been developed with improved With 1-micron line widths and 5-micron line spac- oxygen permeability and improved user comfort. It ings, the far field diffraction pattern looks much as is of interest to see whether these kinds of materials 390 KNOX we would expect. From an analysis of the intensity refractive index change as a function of the laser distribution of the spots, we can ascertain that the power. Since the writing process is based on non-lin- refractive index change is about 0.06, although a very ear optical absorption, as discussed previously, the wide range of refractive index modification can be writing process has a threshold intensity of minimum written in this manner in the range -0.10 to +0.10. intensity to write a change. Going to higher powers, Those kinds of refractive index modifications allow the refractive index starts changing in a controlled us to easily create powerful custom-designed vision and predictable way until a threshold is reached. The correction devices in a wide range of materials and first appearance of optically induced damage is man- for a wide range of applications. Figure 9 shows the ifest in a randomization of the small-scale structure limitations of the technique. that was written, resulting in randomized localized index fluctuations. Beyond that, going to higher powers will produce gross distortions of the material, and ultimately pyrolytic decomposition, which is a com- plicated word for “burning.” The writing process can be thought of in much the same way as using a mag- nifying glass to focus sunlight onto a piece of wood. If the lens is focused too weakly, there will be no marking. At a certain focusing position, the marking just starts. Then, once the focusing lens starts to move, if it is moved too quickly, the marking will reduce. And, if the lens is moved too slowly, the entire piece of wood will be lit on fire. Figure 9B shows this scan speed dependence schematically. By staying within the boundaries of speed and power to optimize the writing process, the refractive index can be control- lably changed within the orange triangle regions.

Figure 8. Writing simple phase gratings in hydrogels: (a) phase photo and bright field photo and (b) diffraction pattern from the hydrogel phase grating.

Figure 10. Demonstrating astigmatic correction by writing crossed cylinder lenses.

Figure 9. Schematic for refractive index change regions (a) vs power and (b) vs scan speed. Figure 9A shows a schematic diagram of the written NON-INVASIVE VISION CORRECTION 391

Writing Vision Correction Devices with LIRIC The first actual device that we wrote was a cylindrical lens structure written in an ophthalmic hydrogel exhibiting up to -0.9D optical power (11). This simple structure was written at constant laser power by varying the scanning speed, as in Figure 9B. Since the refractive index modified regions are actually very thin layers (less than 5 microns thick), we can stack Figure 11. (a) Our first galvo scanning microscope. (b) and (c) them vertically to create stronger and different kinds Lissajous patterns. of devices. Figure 10 shows a slightly more complex device made by stacking layers in orthogonal direc- tions, forming a structure that is crossed cylindrical lenses. Figure 10A shows an interferogram indicating the parabolic phase fronts that are induced in each cylindrical lens, which become circular in the central overlap area, as expected. Crossed cylindrical lenses are the basis for astigmatic and spherical vision corrections (Figure 10B).

Development of Improved Scanners Figure 12. (a) A representation of an eye with a small spot scanning The simple x-y-z raster scanner that we started with a 6.5 mm zone and (b) a LIRIC checkerboard showing high-resolution writing. had significant limitations in accuracy, speed, control, and resolution; therefore, we started to develop Another important necessary element in writing more complex scanning systems in order to be able complex arbitrary structures was the modeling of to write more sophisticated devices. The first scan- the speed- and intensity-dependence of the refrac- ning microscope that we built in the author’s group tive index modifications. This is needed in order used a high speed galvanometer pair to rapidly scan to translate continuous phase shift designs into a the beam in the focus of a microscope objective with written structure with controllable phase shifts. We a specially designed optical relay lens system (12) have developed several different models for this. (Figure 11A). With this system, we demonstrated Figure 13 shows the writing of a microdevice in a writing arbitrary structures such as Lissajous pat- 150-micron round region (13). This device is writ- terns (Figures 11B and 11C) in ophthalmic hydrogels. ten in ophthalmic hydrogel to generate a pure trefoil, With this scanning microscope system, we demon- which corresponds to the Zernike polynomial Z10. strated high-resolution writing of various structures. The optical phase shifts induced are extracted from Figure 12 shows a representation of a human eye Mach-Zehnder interferometry. Figure 13A shows with a scanning spot covering a 6.5 mm wide circu- the extracted phase shifts from a three-layer thick lar zone in a raster scan. Compared to LASIK, LIRIC device, demonstrating the additive phase shift power has much higher spatial resolution since our focused of LIRIC in thin layers. In Figure 13B, we show the beam is only a few microns in diameter. LASIK abla- theoretically expected phase profile for a pure Z10 tion beams vary from about 0.45 mm to 6.5 mm in Zernike polynomial. Figure 13C shows the extracted diameter. Figure 12B shows a checkerboard made to decomposition of all Zernike polynomials for the show the high spatial resolution of LIRIC. device shown in Figure 13C. The ability to write arbitrary Zernike polynomials demonstrates the ability to design and write customized refractive correctors. It is worth pointing out that there is no purpose what- soever for trefoil in any vision correction; however, 392 KNOX if we can write any one single Zernike, then we can measurements (14), as shown in Figure 15. Figure write them all, and then we can write any linear com- 15A shows the Raman scattering spectra obtained bination of them and achieve arbitrary correction. from the modified regions of a HEMA-based hydrogel as a function of the applied laser power for one particular material formulation “labeled material C.” Figure 15B shows the corresponding Raman spectra of the same material with higher levels of two photon absorber and activator molecules, leading to much larger refractive index change and correspondingly larger increase in the Raman water signals. This con- firms the hypothesis shown in Figure 14.

Figure 13. (a) The extracted phase shift for a pure trefoil device, (b) theory, and (c) Zernike decomposition showing nearly pure trefoil. Reprinted from Montano et. al (13) with permission of the Optical Society of America, copyright 2017.

Polymer Materials Science and LIRIC The materials science aspects in this work are quite extensive and interesting. For the purposes of the Figure 14. Schematic representation of a Hema monomer: (a) present article, we provide a simplified picture to hydrated HEMA polymer before LIRIC and (b) HEMA poly- illustrate one important feature. Polymers are made mer after LIRIC. up of many smaller molecules known as monomers. Figure 14 shows a representation of a monomer of Poly(2-hydroxy-ethyl-methacrylate), or PHEMA. When prepared with cross-linking molecules, the polymer matrix swells with water until an equilibrium is reached (Figure 14A). After LIRIC, the localized deposition of laser energy in the form of multiphoton absorption causes a localized depolymerization of parts of the polymer chain. The depolymerization fragments (known as n-mers) then diffuse out, allowing more water to move into the locally mod- Figure 15. Raman scattering measurements of HEMA hydrogel ified regions. In the particular case of this material, as more refractive change is written by increasing laser power. the result is a locally decreased index of refraction Reprinted from Montano et. al (14) with permission of the Optical due to the fact that the water has an index of refrac- Society of America, copyright 2017. tion of 1.33 and the dehydrated polymer index of refraction is about 1.51. The equilibrium water content is roughly 58% for this kind of material. We have confirmed this hypothesis with Raman scattering NON-INVASIVE VISION CORRECTION 393

Real Vision Correction Devices and Figure 18B shows the image obtained while the system images through the written Fresnel lens, indi- The optical phase shifting layers written with the cating high imaging quality. We also measured the LIRIC technique are quite thin, measuring in the Modulation Transfer Function curves and studied range of 3 to 5 microns. As a result, and also as the visual performance when the device is imaged a result of the fundamental materials modification onto a human test subject (16). limits, the amount of phase shift that can be written is limited. In some cases, we can only write 0.1 or 0.2 waves of phase shift in a single layer. In other cases, with optimized materials, we can write up to 4 to 6 waves of phase shift. For the writing of real vision correctors, in some cases we would have to write significantly larger phase shifts than that. In a very important discovery, Augustin-Jean Fresnel recognized that very large glass lenses could be made much thinner and lighter, particularly where they were needed for lighthouses, by stepping the material and taking out the thick parts of the lens that were not needed. They were first used in lighthouses in 1823 (Figure 16A). So, it turns out that although we are not interested in making really large Figure 16. (a) A large lighthouse glass Fresnel lens and (b) a sche- lenses for lighthouses, we are interested in making matic diagram for a thin layer LIRIC Fresnel lens. Photo credit for 16(a) is https://commons.wikimedia.org/wiki/File:‌Fresnel_‌Lens_‌ very thin vison correcting devices using a limited at_Point_Arena_Lighthouse_Museum.jpg. amount of available phase shift per layer. In some cases, we can write a vision corrector with a single layer, and in some cases, we need to write a few layers overlapped. Figure 16B shows a design for a phase-wrapped Fresnel lens to be written in a single layer (13). A nominally parabolic phase front is interrupted each time the optical phase increases by 2p, resulting in a flat Fresnel lens. Using the system shown in Figure 11, with very small field of view, we wrote a Fresnel lens consisting of 1,400 conjoined segments into a commercially available HEMA-based contact lens material (15) with peak phase shift near one wave measured at a wavelength of 543 nm. The written stitched devices were 6 mm in diameter but measured over 5.8 mm to avoid edge measurement artifacts (Figure 17). Faint straight lines Figure 17. A section of Fresnel lens written in 1,400 rectangular segments. Reprinted from Montano et. al (15) with permission are visible from small registration errors at the edge of the Optical Society of America, copyright 2018. of each rectangular region, and bright curved lines are visible when the 2p phase wraps that comprise Scaled-up Vision Correction Devices the Fresnel lens structure are quite visible. We per- formed an extensive set of vision and image quality Although the prototype device written with the analysis steps on this Fresnel lens. Figure 18 shows small field galvanometer scanner provided very the image quality obtained while imaging a standard good visual performance, clearly it is not desirable Air Force resolution target (15). Figure 18A shows to have to stitch together as many as 1,400 tiny lens- the system performance in imaging the test target, lets in order to create a 6.5 mm diameter device. With 394 KNOX this in mind, we built a scaled-up system that could as the human eye. The straight stitching lines are write a 6.5 mm diameter lens with only six stitched faintly visible, as is the faint reflection from the segments. This research system is shown in early Fresnel lens stepped regions. This approach leads construction phase in Figure 19 in the laboratory of us to a new way to fabricate contact lenses that have the author. It consists of a femtosecond laser system, very new and exciting kinds of visual benefits, which beam handling system, intensity controls, dispersion are too difficult or even impossible to fabricate with compensators, relay optics, high speed galvanometer conventional technologies, such as molding and dia- scanners, and a beam delivery system with applana- mond tooling. tion capability so that the system can write prototype devices in flat hydrogel samples, contact lenses, intraocular lenses, and also directly into live eyes.

Figure 18. Test target images (a) with no LIRIC lens and (b) LIRIC -1.5D lens inserted.

Adjustable Intraocular Lenses The original project motivation was to develop a technology for refractive in vivo adjustments of intraocular lenses. As we age, it is common for the human lens to develop scattering properties, resulting in Figure 19. Laboratory scaling system for writing LIRIC lenses cloudy vision. This causes increasing problems with with little stitching at faster speeds. nighttime driving, reading, and other vision-inten- sive tasks. The normal remedy for this is to remove Custom Contact Lenses with Reduced Stitching the cataractous lens and replace it with a new poly- Using this scaled-up writing system, we wrote mer lens that fits into the intact lens capsule. During LIRIC corrections into commercial contact lenses the lens placement process, the lenses may not fit pre- (Johnson and Johnson Acuvue 2). Since the result- cisely into the lens capsule where intended. Figure ing phase modification pattern is completely clear, 21A shows an intraocular lens that is intended for it is quite difficult to see the written patterns. Figure implantation. 20 shows a photograph of the written device when placed onto a glass ball of roughly the same diameter NON-INVASIVE VISION CORRECTION 395

implanted into a rabbit eye (18). Some significant challenges remain to be solved before this procedure can be applied to live humans. However, the technology looks very promising.

Directly Writing into Cornea As previously discussed, it is a goal to develop a truly non-invasive form of refractive correction that could be applied directly to live eyes. Existing commercial forms of refractive surgery, such as PRK, LASIK, and Small Incision Lenticule Extraction (SMILE), all involve cutting or vaporization of tissue. Would the same kinds of LIRIC techniques discussed previously also work in the cornea? The cornea con- Figure 21. (a) An intraocular lens, (b) a Medicem intraocular lens sists of several layers, with the thickest being the with LIRIC Fresnel pattern inscribed, and (c) the induced wave- stroma, which is made mostly of collagen (~90%). front in (c), nearly spherical. Photo credit for (a) Greenteamochees We found that when we applied our tightly focused - Solidworks, CC BY 3.0, https://commons.wikimedia.org/w/index. femtosecond laser technology directly to the cornea, php?curid=20336409, and (b) and (c) reprinted from the March 2018 edition of Laser Focus World, copyright 2019 by PennWell. under the right conditions, we can obtain significant optical phase shifts, corresponding to refractive index These lenses exhibit a central lens portion that changes up to +0.037 (19), and we named this tech- replaces the normal human lens but also show ‘legs’ nique IRIS, which stands for intra-tissue refractive or haptics that protrude away from the lens. The pur- index surgery. Figure 22A shows a phase contrast pose of the haptics is to position the lens in the correct microscope photograph of a piece of cat cornea that position, resulting in the desired visual correction has had grating lines written into it with 10 microns outcome. Many different designs of haptics have been spacing. We can clearly see areas of induced optical tried; however, in the end, it is commonly observed phase shift. Looking down into a single written line that the visual correction can be in error by as much with the transmission electron microscope (TEM), as +0.5 diopters, which is clinically significant, due we can see that in the focus region of the laser, the to placement and movement errors. It is desirable collagen fibrils that are normally about 40 nm on end to develop a technology that can adjust, or literally are intermixed with the extracellular matrix in the re-write the correction, into an intraocular lens par- region of the focus, forming a somewhat uniform ticularly after the lens has been implanted into an eye. gray area on the TEM photo. By scanning dense pat- A first step in this consists of writing a high-quality terns of lines in the cornea, we can achieve relatively correction into an intraocular lens outside the eye. uniform areas of optical phase shift in cornea, just We have demonstrated writing such a corrector into as in the case of the ophthalmic hydrogels. We have a commercial intraocular lens (Medicem, Inc.) and proposed some detailed mechanisms for the ultra- measured the resultant wavefront correction, which structural changes that we have induced in the cornea was extremely close to what was intended (17). Again, (20). We have studied the biological changes in the the written phase pattern is nearly invisible, making cornea tissue using histology techniques. Figure 23A it difficult to photograph; however, in Figure 21B, shows an end-on section of cat cornea that has been we show a faint reflection from the Fresnel lens seg- stained with DAPI (4’,6-diamidino-2-phenylindole) ments inside the intraocular lens. Figure 21C shows to indicate live keratocytes as blue (about 10% of the the measured wavefront of the correction, which stroma tissue) and TUNEL (Terminal deoxynucleo- was nearly perfectly spherical as intended. Another tidyl transferase dUTP nick end labeling) to indicate group has tested the feasibility of writing a refrac- dying keratocytes undergoing apoptosis as red. Also tive correction into an intraocular lens after it was visible in green is the tissue autofluorescence that may 396 KNOX indicate some increased amount of tissue cross-link- 17 months later. ing. Three layers were written with about 20 microns We then applied all of the previous knowledge and inter-layer separation. The layers were written about experience to the case of a live cat to see if we could 150 microns below the surface of the epithelium, write refractive correctors in live eyes. Figure 24A which is the thin bright blue region at the top. We shows a Fresnel lens structure of 6 mm diameter find that some keratocytes are killed by the fem- written into a live cat eye in a photo taken imme- tosecond micromachining process but only within diately after the writing. A scattering array of very the focus region. No cell death is indicated above small bubbles is visible immediately after applana- or below the focus regions, indicating good axial tion is removed; however, it clears generally within 30 localization, as expected for a non-linear (two-pho- minutes. The resulting Fresnel lens refractive patterns ton) absorption process. In Figure 23B, a similarly remain after the bubbles clear, but it is very difficult to treated tissue section was stained in the same way 17 photograph. Figure 24B shows the same eye photo- months after writing, and it is observed that essen- graphed one week later, showing a nice, clear pattern tially all of the keratocytes have been eliminated from inscribed. We have been tracking the induced refrac- the writing zone. It appears that the writing process tive effects written in cat and rabbit eyes over several that intermixed part of the stromal tissue caused years, and, currently, the results indicate that refrac- some long-lived effects in the biology of the cornea. tive effects persist for at least two years (22). This is important in determining the longevity of the vision correction effects that could result from the written changes. We have seen similar changes in porcine (pig), leporine (rabbit), feline (cat), and cadaver (human) cornea tissue; therefore, the technology appears to be largely independent of the tissue species.

Application of LIRIC in Humans The research results presented so far are quite promising for a wide range of hydrogel materials Figure 22. (a) A Phase contrast photo of grating lines in cat cornea as well as direct writing in cornea. For applications and (b) a transmission electron microscope photo of focus region. in humans, several steps are necessary. For custom contact lenses, we are currently conducting human clinical trials to test the visual performance of a new kind of customized contact lens. For intraocular lenses, we are optimizing materials for LIRIC efficiency and developing an in vivo procedure. For directly writing LIRIC into live humans, we are plan- ning new clinical trials. These results will be reported in the future. We have developed a human clinical prototype instrument with our commercial partner, Starfish Medical in Vancouver BC. Figure 25 shows a photo of the instrument in development. Figure 23. Histology of cat cornea (a) right after writing and (b) NON-INVASIVE VISION CORRECTION 397

distinction of this new approach to vision correction, as applied to the case of corneal refractive correction, is simply the absence of a corneal flap cut. The procedure can be implemented without the use of surgical masks since it is not a surgical procedure. Despite the large amount of work that has gone into this technology, it is clear that much is still to be learned, and many limits have not even been reached yet; therefore, the future of these approaches looks bright and sharp.

Figure 25. Prototype system for First in Human study developed ACKNOWLEDGMENTS with Starfish Medical. Wayne H. Knox is co-founder and chief science officer at Clerio Vision, where he holds founder’s SUMMARY AND CONCLUSIONS equity but has no fiduciary or management respon- This article reviewed a large body of work per- sibility. This research has been supported by Bausch formed over a fifteen-year period. This work has led and Lomb, the National Science Foundation Phase to new approaches in vision correction. It is hoped 1 and 2 STTR programs, the New York State CEIS that these advances will benefit many in society, mak- Program, and a research grant from Clerio Vision. ing for safer, faster, better, and eventually cheaper The author thanks the many collaborators and grad- refractive corrections that can be applied in small uate students who have contributed to this work over increments if required. Eyeglasses are not efficient the years. when applied in small corrections since a patient would need to buy a whole new pair for each cor- REFERENCES rection. In the case of LASIK, it is not desirable to 1. Da Modena T. Hugo of Saint-Cher open up the corneal flap and re-do a small correction. [image]. [accessed 2019 Jan 20]. https:// For intraocular lenses, it is not generally possible to commons.‌wikimedia.‌org/wiki/‌File:Tommaso_ take the intraocular lens out and replace it once the da_modena,_ritratti_di_domenicani_‌(Ugo_ capsule has shrunk around it. Also, LASIK is not indi- di_Provenza)_‌1352_150cm,_treviso,_ex_con- cated for young people, which is unfortunate precisely vento_di_san_niccol%C3%B2,_sala_del_cap- because their vision is changing so rapidly, and that itolo.jpg. is also when they lose their glasses most often. It is 2. A Humorous Image of Two Men Wearing hoped that smaller and simpler delivery systems can Revolving Top Hats [image]. [accessed 2019 be engineered and delivered to developing country Jan 20]. https://commons.‌wikimedia.org/wiki/ locations, where the lack of LASIK flap cutting dislo- File:A_humorous_image_of_two_men_wear- cation and potential infections, problems with dust, ing_‌revolving_top_hats_Wellcome_V0015848. etc. would be minimized with a flap-cutting-free tech- jpg https://commons.wikimedia.org/wiki/. nology. Current methods of presbyopia correction 3. Schoeller M. Pukatire [image]. National are problematic, with progressive eyeglasses diffi- Geographic. [accessed 2019 Jan 20]. https:// cult to tolerate and multi-focal intraocular lenses also www.nationalgeographic.com/‌ magazine/2014/01/‌ difficult to use. Those who choose multi-focal intra- kayapo-courage/. ocular lenses are really stuck with them once they 4. Contactlenzen Confortissimo [image]. are implanted. Current contact lenses can be eas- [accessed 2019 Jan 20]. https://commons.wiki- ily exchanged for those with different prescriptions; media.‌ org/‌ ‌ w/‌index.php?‌curid=514486. however, many people cannot tolerate them, and 5. Wikipedia. LASIK. [2019 Apr 13; 2019 Jan 20]. excellent presbyopia correctors have not been avail- https://en.wikipedia.org/wiki/LASIK. able in contact lenses. Perhaps the most important 398 KNOX

6. Juhasz T, Loesel F, Kurtz R, Horvath C, Bille 17. Zheleznyak L, Gandara-Montano GA, MacRae J, Mourou G. Corneal refractive surgery with S, Huxlin KR, Ellis JD, Yoon G, Knox WH. First femtosecond lasers. IEEE J Select Topics demonstration of human visual performance Quantum Electron. 1999;5(4):902–910. through refractive-index modified ophthalmic 7. Lasik Complications. [accessed 2019 Jan 20]. devices written in hydrogels. Invest Ophthalmol http://lasikcomplications.com/. Vis Sci. 2017;58(8):1274. 8. Moshirfar M, Gardiner J, Schlessinger J. Laser 18. Petrak V, Stoy VA, Dudič M, Gandara-Montano in situ keratomileusis flap complications using GA, Knox WH, Johannsmeier S, Heineman mechanical microkeratome versus femtosec- D, Ripken T, Stodůlka P. Bioanalogic hydro- ond laser: retrospective comparison. J Cataract gels as special materials for implantable lenses Refract Surg. 2010;36(11):1925-1933. post-operatively adjustable by femtosecond 9. Davis KM, Miura K, Sugimoto N, Hirao K. lasers. American Academy of Ophthalmology Writing waveguides in glass with a femtosec- Annual Meeting; 2017 Nov 11-14; New Orleans ond laser. Opt Lett. 1996;21(21):1729–1731. (LA). 10. My Alcon. Lensx Laser. Fort Worth (TX): Alcon. 19. Sahler R, Bille J, Enright S, Chhoeung S, Chan [accessed 2019 Jan 20]. https://www.myalcon.‌ K. Creation of a refractive lens within an exist- com/products/surgical/lensx-laser/. ing intraocular lens using a femtosecond laser, 11. Ding L, Blackwell R, Kumzler J, Knox WH. J Cataract Refract Surg. 2016;42(8):1207–1215. Large refractive index change in silicone-based 20. Xu L, Knox WH, DeMagistris M, Wang N, and non-silicone based hydrogel polymers Huxlin KR. Noninvasive intratissue refrac- induced by femtosecond laser micromachin- tive index shaping (IRIS) of the cornea ing. Opt Express. 2006;14(24):11901–11909. with blue femtosecond laser light. IOVS. 12. Xu L, Knox WH. Lateral gradient index micro- 2011;52:8148-8155. lenses written in ophthalmic hydrogel polymers 21. Wozniak K, Elkins N, Brooks D, Savage D, by femtosecond laser micromachining. Opt DeMagestris M, MacRae S, Hindman H, Ellis Mater Express. 2011;1(8):1416-1424. J, Knox WH, Huxlin KR. Differential impact 13. Xu L. Femtosecond laser processing of oph- of LIRIC and femto-LASIK on keratocyte via- thalmic materials and ocular tissues: a novel bility in cat cornea. IOVS. 2016;57(12):4889. approach for non-invasive vision correction Meeting Abstract. [dissertation]. [Rochester (NY]: University of 22. MacRae S, Brooks D, Wozniak K, Gearhart Rochester, The Institute of Optics; 2013. S, Savage D, Ellis J, Knox WH, Huxlin K. 14. Gandara-Montano GA, Ivansky A, Savage DE, Ablation-free corneal refractive correction via Ellis JD, Knox WH. Femtosecond laser writ- ultrafast femtosecond laser induced refractive ing of freeform gradient index microlenses index modification. American Academy of in hydrogel-based contact lenses. Opt Mater Ophthalmology Annual Meeting; 2017 Nov Express. 2015;5(10):2257-2271. 11-14; New Orleans (LA). 15. Gandara-Montano GA, Stoy V, Dudic M, Petrak V, Haskovcova K, Knox WH. Large optical phase shifts in hydrogels written with femtosecond laser pulses: elucidating the role of localized water concentration changes. Opt Mater Express. 2017;7(9):3162–3180. 16. Gandara-Montano GA, Zheleznyak L, Knox WH. Optical quality of hydrogel ophthalmic devices created with femtosecond laser induced refractive index modification. Opt Mater Express. 2018;8(2):295-313.