WO2017184717A1

WO2017184717A1 - Systems and methods for cross-linking treatments of an eye

Info

Publication number: WO2017184717A1
Application number: PCT/US2017/028344
Authority: WO
Inventors: Marc D. FRIEMAN
Original assignee: Avedro, Inc.
Priority date: 2016-04-19
Filing date: 2017-04-19
Publication date: 2017-10-26

Abstract

An example system for treating an eye includes a light source configured to emit photoactivating light. The system includes one or more optical elements configured to direct the photoactivating light from the light source towards an eye treated with a photos ensitizer. The system includes a permeable structure configured to be positioned on the eye. The permeable structure is configured to transmit the photoactivating light from the one or more optical elements to the eye. The photoactivating light activates the photosensitizer to generate cross-linking activity in the eye. The permeable structure may applanate the eye. The system may include an oxygen delivery device coupled to an oxygen source, where the permeable structure transmits oxygen from the oxygen delivery device to the eye and the oxygen determines in part the cross-linking activity generated in the eye.

Description

SYSTEMS AND METHODS FOR CROSS-LINKING TREATMENTS OF AN EYE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/324,632, filed April 19, 2016, the contents of which are incorporated entirely herein by reference.

BACKGROUND

Field

[0002] The present disclosure pertains to systems and methods for treating disorders of the eye, and more particularly, to systems and methods for cross-linking treatments of the eye.

Description of Related Art

[0003] Cross-linking treatments may be employed to treat eyes suffering from disorders, such as keratoconus. In particular, keratoconus is a degenerative disorder of the eye in which structural changes within the cornea cause it to weaken and change to an abnormal conical shape. Cross-linking treatments can strengthen and stabilize areas weakened by keratoconus and prevent undesired shape changes.

[0004] Cross-linking treatments may be employed to treat eyes suffering from refractive disorders, such as myopia, hyperopia and astigmatism. In particular, these disorders cause a defocus of the light onto the retina of the eye causing blurred vision. Cross-linking treatments can selectively strengthen and flatten/steepen patterned areas of the cornea creating desired shape changes resulting in improved vision.

[0005] Cross-linking treatments may also be employed after surgical procedures, such as Laser-Assisted in situ Keratomileusis (LASIK) surgery. For instance, a complication known as post-LASIK ectasia may occur due to the thinning and weakening of the cornea caused by LASIK surgery. In post-LASIK ectasia, the cornea experiences progressive steepening (bulging). Accordingly, cross-linking treatments can strengthen and stabilize the structure of the cornea after LASIK surgery and prevent post-LASIK ectasia.

SUMMARY

[0006] According to aspects of the present disclosure, an example system for treating an eye includes a light source configured to emit photoactivating light. The system includes one or more optical elements configured to direct the photoactivating light from the light source towards an eye treated with a photos ensitizer. The system includes a permeable structure configured to be positioned on the eye. The permeable structure is configured to transmit the photoactivating light from the one or more optical elements to the eye. The photoactivating light activates the photos ensitizer to generate cross-linking activity in the eye.

[0007] According to aspects of the present disclosure, an example method for treating an eye includes applying a photosensitizer to an eye. The method includes positioning a permeable structure on the eye. The method includes directing, with one or more optical elements, photoactivating light from a light source towards the eye. The method includes transmitting, through the permeable structure, the photoactivating light from the one or more optical elements to the eye. The photoactivating light activates the photosensitizer to generate cross-linking activity in the eye.

[0008] In the example embodiments, the permeable structure may be configured to applanate the eye.

[0009] The example embodiments may employ an oxygen delivery device coupled to an oxygen source, where the permeable structure is configured to transmit oxygen from the oxygen delivery device to the eye and the oxygen determines in part the cross-linking activity generated in the eye. For instance, the permeable structure may be formed from a gas- permeable polymer.

[0010] In the example embodiments, the permeable structure may be a mesh device including threads defining pores through which the photoactivating light is transmitted to the eye. Additionally, the permeable structure may transmit the photoactivating light according to an illumination pattern that spans an area corresponding to a treatment area for the eye, where the illumination partem includes dark spots distributed across the area of the illumination pattern.

[0011] According to aspects of the present disclosure, another example method for treating an eye includes applying a concentration of photosensitizer to an eye. The method includes applanating the eye with a permeable structure. The method includes directing, with one or more optical elements, photoactivating light from a light source towards the eye according to a partem of pulses and a Gaussian beam waist shape. The method includes transmitting, through the permeable structure, a concentration of oxygen from an oxygen delivery device to the eye. The method includes transmitting, through the permeable structure, the photoactivating light from the one or more optical elements to the eye. The photoactivating light activates the photosensitizer to generate three-dimensional cross-linking activity in the eye. The three-dimensional cross-linking activity is determined by the concentration of photosensitizer, the concentration of oxygen, and the pattern of pulses and the Gaussian beam waist shape of the photoactivating light.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 illustrates an example system that delivers a cross-linking agent and photoactivating light to a cornea of an eye in order to generate cross-linking of corneal collagen, according to aspects of the present disclosure.

[0013] FIG. 2 illustrates an example device for applying cross-linking treatments, according to aspects of the present disclosure.

[0014] FIG. 3 illustrates an example system for cross-linking treatments of a cornea where photoactivating light is applied according to a pattem that promotes corneal healing after the treatment, according to aspects of the present disclosure.

[0015] FIG. 4A illustrates an example irradiance map and a corresponding example cross- linking distribution for a cornea when an illumination pattem with a dark spot having a diameter of 100 μηι is projected onto the surface of the cornea, according to aspects of the present disclosure.

[0016] FIG. 4B illustrates an example irradiance map and a corresponding example cross- linking distribution for a cornea when an illumination pattem with a dark spot having a diameter of 200 μηι is projected onto the surface of the cornea, according to aspects of the present disclosure.

[0017] FIG. 4C illustrates an example irradiance map and a corresponding example cross- linking distribution for a cornea when an illumination pattem with a dark spot having a diameter of 300 μηι is projected onto the surface of the cornea, according to aspects of the present disclosure.

[0018] FIG. 5 illustrates an example system for cross-linking treatments of a cornea where a mesh device is employed, according to aspects of the present disclosure.

[0019] FIG. 6 illustrates an example system for cross-linking treatments of a cornea where a generally permeable structure is employed, according to aspects of the present disclosure.

[0020] While the present disclosure is susceptible to various modifications and alternative forms, a specific embodiment thereof has been shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that it is not intended to limit the present disclosure to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit of the present disclosure. DESCRIPTION

[0021] FIG. 1 illustrates an example treatment system 100 for generating cross-linking of collagen in a cornea 2 of an eye 1. The treatment system 100 includes an applicator 132 for applying a cross-linking agent 130 to the cornea 2. In example embodiments, the applicator 132 may be an eye dropper, syringe, or the like that applies the photosensitizer 130 as drops to the cornea 2. The cross-linking agent 130 may be provided in a formulation that allows the cross-linking agent 130 to pass through the corneal epithelium 2a and to underlying regions in the corneal stroma 2b. Alternatively, the corneal epithelium 2a may be removed or otherwise incised to allow the cross-linking agent 130 to be applied more directly to the underlying tissue.

[0022] The treatment system 100 includes a light source 110 and optical elements 112 for directing light to the cornea 2. The light causes photoactivation of the cross-linking agent 130 to generate cross-linking activity in the cornea 2. For example, the cross-linking agent may include riboflavin and the photoactivating light may be ultraviolet A (UVA) (e.g., 365 nm) light. Alternatively, the photoactivating light may have another wavelength, such as a visible wavelength or near-infrared wavelength. As described further below, corneal cross-linking improves corneal strength by creating chemical bonds within the comeal tissue according to a system of photochemical kinetic reactions. For instance, riboflavin and the photoactivating light are applied to stabilize and/or strengthen corneal tissue to address diseases such as keratoconus or post-LASIK ectasia. Additionally, as described further below, various agents, additives, buffers, etc., may be employed in formulations with the cross-linking agent to enhance cross-linking treatments.

[0023] The treatment system 100 includes one or more controllers 120 that control aspects of the system 100, including the light source 110 and/or the optical elements 112. In an implementation, the cornea 2 can be more broadly treated with the cross-linking agent 130 (e.g., with an eye dropper, syringe, etc.), and the photoactivating light from the light source 110 can be selectively directed to sections of the treated cornea 2 according to a particular pattern.

[0024] The optical elements 112 may include one or more mirrors or lenses for directing and focusing the photoactivating light emitted by the light source 110 to a particular partem on the cornea 2. The optical elements 112 may further include filters for partially blocking wavelengths of light emitted by the light source 110 and for selecting particular wavelengths of light to be directed to the cornea 2 for activating the cross-linking agent 130. In addition, the optical elements 112 may include one or more beam splitters for dividing a beam of light emitted by the light source 110, and may include one or more heat sinks for absorbing light emitted by the light source 110. The optical elements 112 may also accurately and precisely focus the photo-activating light to particular focal planes within the cornea 2, e.g., at a particular depths in the underlying section 2b where cross-linking activity is desired.

[0025] Moreover, specific regimes of the photoactivating light can be modulated to achieve a desired degree of cross-linking in the selected sections of the cornea 2. The one or more controllers 120 may be used to control the operation of the light source 110 and/or the optical elements 112 to precisely deliver the photoactivating light according to any combination of: wavelength, bandwidth, intensity, power, location, depth of penetration, and/or duration of treatment (the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration).

[0026] The parameters for photoactivation of the cross-linking agent 130 can be adjusted, for example, to reduce the amount of time required to achieve the desired cross-linking. In an example implementation, the time can be reduced from minutes to seconds. While some configurations may apply the photoactivating light at an irradiance of 5 mW/cm², larger irradiance of the photoactivating light, e.g., multiples of 5 mW/cm², can be applied to reduce the time required to achieve the desired cross-linking. The total dose of energy absorbed in the cornea 2 can be described as an effective dose, which is an amount of energy absorbed through an area of the corneal epithelium 2a. For example the effective dose for a section of the corneal surface 2A can be, for example, 5 J/cm², or as high as 20 J/cm² or 30 J/cm². The effective dose described can be delivered from a single application of energy, or from repeated applications of energy.

[0027] The optical elements 112 of the treatment system 100 may include a digital micro- mirror device (DMD) to modulate the application of photoactivating light spatially and temporally. Using DMD technology, the photoactivating light from the light source 110 is projected in a precise pixelated spatial partem that is created by microscopically small mirrors laid out in a matrix on a semiconductor chip. Each mirror represents one or more pixels in the pattern of projected light. With the DMD one can perform topography guided cross-linking. The control of the DMD according to topography may employ several different spatial and temporal irradiance and dose profiles. These spatial and temporal dose profiles may be created using continuous wave illumination but may also be modulated via pulsed illumination by pulsing the illumination source under varying frequency and duty cycle regimes as described above. Alternatively, the DMD can modulate different frequencies and duty cycles on a pixel by pixel basis to give ultimate flexibility using continuous wave illumination. Or alternatively, both pulsed illumination and modulated DMD frequency and duty cycle combinations may be combined. This allows for specific amounts of spatially determined corneal cross-linking. This spatially determined cross-linking may be combined with dosimetry, interferometry, optical coherence tomography (OCT), corneal topography, etc. , for pre-treatment planning and/or realtime monitoring and modulation of corneal cross-linking during treatment. Additionally, preclinical patient information may be combined with finite element biomechanical computer modeling to create patient specific pre-treatment plans.

[0028] To control aspects of the delivery of the photoactivating light, embodiments may also employ aspects of multiphoton excitation microscopy. In particular, rather than delivering a single photon of a particular wavelength to the cornea 2, the treatment system 100 may deliver multiple photons of longer wavelengths, i.e., lower energy, that combine to initiate the cross- linking. Advantageously, longer wavelengths are scattered within the cornea 2 to a lesser degree than shorter wavelengths, which allows longer wavelengths of light to penetrate the cornea 2 more efficiently than shorter wavelength light. Shielding effects of incident irradiation at deeper depths within the cornea are also reduced over conventional short wavelength illumination since the absorption of the light by the photos ensitizer is much less at the longer wavelengths. This allows for enhanced control over depth specific cross-linking. For example, in some embodiments, two photons may be employed, where each photon carries approximately half the energy necessary to excite the molecules in the cross-linking agent 130 to generate the photochemical kinetic reactions described further below. When a cross-linking agent molecule simultaneously absorbs both photons, it absorbs enough energy to release reactive radicals in the corneal tissue. Embodiments may also utilize lower energy photons such that a cross-linking agent molecule must simultaneously absorb, for example, three, four, or five, photons to release a reactive radical. The probability of the near-simultaneous absorption of multiple photons is low, so a high flux of excitation photons may be required, and the high flux may be delivered through a femtosecond laser. Further aspects of multiphoton excitation microscopy are described, for instance, in

[0029] A large number of conditions and parameters affect the cross-linking of corneal collagen with the cross-linking agent 130. For example, when the cross-linking agent 130 is riboflavin and the photoactivating light is UVA light, the irradiance and the dose both affect the amount and the rate of cross-linking. The UVA light may be applied continuously (continuous wave (CW)) or as pulsed light, and this selection has an effect on the amount, the rate, and the extent of cross-linking. [0030] If the UVA light is applied as pulsed light, the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration have an effect on the resulting corneal stiffening. Pulsed light illumination can be used to create greater or lesser stiffening of corneal tissue than may be achieved with continuous wave illumination for the same amount or dose of energy delivered. Light pulses of suitable length and frequency may be used to achieve more optimal chemical amplification. For pulsed light treatment, the on/off duty cycle may be between approximately 1000/1 to approximately 1/1000; the irradiance may be between approximately 1 mW/cm² to approximately 1000 mW/cm² average irradiance, and the pulse rate may be between approximately 0.01 HZ to approximately 1000 Hz or between approximately 1000 Hz to approximately 100,000 Hz.

[0031] The treatment system 100 may generate pulsed light by employing a DMD, electronically turning the light source 1 10 on and off, and/or using a mechanical or optoelectronic (e.g., Pockels cells) shutter or mechanical chopper or rotating aperture. Because of the pixel specific modulation capabilities of the DMD and the subsequent stiffness impartment based on the modulated frequency, duty cycle, irradiance and dose delivered to the cornea, complex biomechanical stiffness patterns may be imparted to the cornea to allow for various amounts of refractive correction. These refractive corrections, for example, may involve combinations of myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia and complex corneal refractive surface corrections because of ophthalmic conditions such as keratoconus, pellucid marginal disease, post-Lasik ectasia, and other conditions of corneal biomechanical alteration/degeneration, etc. A specific advantage of the DMD system and method is that it allows for randomized asynchronous pulsed topographic patterning, creating a non-periodic and uniformly appearing illumination which eliminates the possibility for triggering photosensitive epileptic seizures or flicker vertigo for pulsed frequencies between 2 Hz and 84 Hz.

[0032] Although example embodiments may employ stepwise on/off pulsed light functions, it is understood that other functions for applying light to the cornea may be employed to achieve similar effects. For example, light may be applied to the cornea according to a sinusoidal function, sawtooth function, or other complex functions or curves, or any combination of functions or curves. Indeed, it is understood that the function may be substantially stepwise where there may be more gradual transitions between on/off values. In addition, it is understood that irradiance does not have to decrease down to a value of zero during the off cycle, and may be above zero during the off cycle. Desired effects may be achieved by applying light to the cornea according to a curve varying irradiance between two or more values.

[0033] Examples of systems and methods for delivering photoactivating light are described, for example, in U.S. Patent Application Publication No. 2011/0237999, filed March 18, 2011 and titled "Systems and Methods for Applying and Monitoring Eye Therapy," U.S. Patent Application Publication No. 2012/0215155, filed April 3, 2012 and titled "Systems and Methods for Applying and Monitoring Eye Therapy," and U.S. Patent Application Publication No. 2013/0245536, filed March 15, 2013 and titled "Systems and Methods for Corneal Cross- Linking with Pulsed Light," the contents of these applications being incorporated entirely herein by reference.

[0034] The addition of oxygen also affects the amount of corneal stiffening. In human tissue, C content is very low compared to the atmosphere. The rate of cross-linking in the cornea, however, is related to the concentration of O2 when it is irradiated with photoactivating light. Therefore, it may be advantageous to increase or decrease the concentration of O2 actively during irradiation to control the rate of cross-linking until a desired amount of cross- linking is achieved. Oxygen may be applied during the cross-linking treatments in a number of different ways. One approach involves supersaturating the riboflavin with O2. Thus, when the riboflavin is applied to the eye, a higher concentration of O2 is delivered directly into the cornea with the riboflavin and affects the reactions involving O2 when the riboflavin is exposed to the photoactivating light. According to another approach, a steady state of O2 (at a selected concentration) may be maintained at the surface of the cornea to expose the cornea to a selected amount of O2 and cause O2 to enter the cornea. As shown in FIG. 1, for instance, the treatment system 100 also includes an oxygen source 140 and an oxygen delivery device 142 that optionally delivers oxygen at a selected concentration to the cornea 2. Example systems and methods for applying oxygen during cross-linking treatments are described, for example, in U.S. Patent No. 8,574,277, filed October 21, 2010 and titled "Eye Therapy," U.S. Patent Application Publication No. 2013/0060187, filed October 31, 2012 and titled "Systems and Methods for Corneal Cross-Linking with Pulsed Light," the contents of these applications being incorporated entirely herein by reference.

[0035] FIG. 2 illustrates an example treatment device 200 for applying cross-linking treatment to both eyes la, b of a patient. Aspects of the treatment system 100 described above may be incorporated into the treatment device 200. As shown in FIG. 2, the treatment device 200 is configured to be positioned on the patient's face 3 and to fit over both the right eye la and the left eye lb. The treatment device 200 may be kept in position on the patient's face 3 by a strap (not shown) that can be worn around the patient's head. As such, in some aspects, the treatment device 200 may resemble a pair of goggles or a mask. Alternatively, medical tape or the like may be applied to the treatment device 200 and the face 3 to keep the treatment device 200 in position. Alternatively, the treatment device 200 may rest stably on the patient's face 3 without additional support while the patient is lying on his/her back. In some cases, a speculum may be applied to each eye l a, b to keep the eyelids from closing during the treatment. In such cases, the treatment device 200 may be configured to fit around or otherwise accommodate the use of the specula.

[0036] The treatment device 200 includes a right section 202a that is positioned over the right eye la and a left section 202b that is positioned over the left eye lb. Each section 202a, b is configured to provide cross-linking treatment for the cornea in the respective eye l a, b. The sections 202a, b may be physically divided by a wall 203 as shown in FIG. 2 to reduce any likelihood that treatment of one eye will affect treatment of the other eye. The wall 203, however, may be omitted in alternative embodiments.

[0037] Each section 202a, b includes a cross-linking applicator 132a, b, as described above. Each applicator 132a, b can apply a cross-linking agent, such as a riboflavin formulation, to the cornea of each eye l a, b, respectively. For instance, each delivery device 132a, b may include aspects of an eye dropper, syringe, or the like from which the cross-linking agent can be dripped onto the cornea. As shown in FIG. 2, the applicators 132a, b are integrated into the treatment device 200.

[0038] Each section 202a, b may also include an opening 204a, b that is positioned over each eye la, b, respectively. An illumination device 206 may be positioned relative to the treatment device 200 to deliver a dose of photoactivating light through one of the openings 204,a, b to the respective eye l a, b. If the cross-linking agent is riboflavin, the photoactivating light may be ultraviolet light. The illumination device 106 may include the light source 1 10 and the optical elements 1 12 as described above.

[0039] As shown in FIG. 2, the illumination device 206 is positioned over the opening 204b and can deliver the photoactivating light to the cornea of the left eye lb after the cross-linking agent has been applied to the cornea. In some cases, the illumination device 206 is separately supported, e.g., by a stand, over the opening 204 a, b. In other cases, the illumination device 206 may be fixedly coupled to the treatment device 200.

[0040] The dose, irradiance, partem, pulsing/continuous wave, and other treatment parameters for the photoactivating light may be controlled as described above. For instance, the controller 120 may be coupled to the light source 110 and/or the optical elements 112. Accordingly, the photoactivating light from the illumination device 206 generates cross-linking activity in the cornea.

[0041] As shown in FIG. 2, the applicators 132a, b are integrated into the treatment device 200 for delivering the cross-linking agent to the eyes l a, b. In alternative embodiments, however, a separate cross-linking applicator 132 may be introduced through the openings 204a, b to apply the cross-linking agent to the corneas of the eyes la, b.

[0042] Each section 202a, b may also allow a concentration of oxygen gas to be delivered from an oxygen source 140 to the eyes l a, b. As described above, the oxygen gas enhances or otherwise controls the cross-linking activity during photoactivation. As shown in FIG. 2, each section 202a, b may include a respective oxygen source 140a, b integrated into the treatment device 200. The oxygen from each oxygen source 140a,b can be released into the section 202a, b through an opening 208a, b, respectively. The treatment device 200 is configured so that the oxygen is introduced with minimal turbulence. The release can be controlled by removing a seal 210a, b that is placed over the opening 208a, b, respectively. For instances, the seal 210a, b may be a pull-off tab that can be manually removed by the practitioner. In alternative embodiments, rather than integrating the oxygen sources 140a, b into the treatment device 200, each section 202a, b may include a port that can be coupled to a controllable external oxygen source 140.

[0043] Where two illumination devices 206 are available, the treatment device 200 allows both eyes la, b to be treated with the photoactivating light simultaneously. As such, both eyes la, b can be treated with the same steps (cross-linking agent application, photoactivation) simultaneously.

[0044] Where only one illumination device 206 is available, however, the eyes la, b can be alternately treated with the photoactivating light. For instance, FIG. 2 shows a single illumination device 206 that treats one eye l a, b at a time. Advantageously, the treatment device 200 allows one eye to be treated with photo-activating light, while allowing the other eye to be treated with the cross-linking agent. As shown in FIG. 2, the right eye l a can be soaked with the cross-linking agent from the applicator 132a, while the left eye lb receives the photoactivating light after having already been soaked in the cross-linking agent from the applicator 132b. After the application of photoactivating light to the left eye lb is complete, the illumination device 106 may be shifted to the opening 104a to deliver photoactivating light to the right eye l a. By allowing both eyes la, b to receive some treatment step at the same time, the total treatment time can be reduced significantly even when only one illumination device 106 available. For instance, with the treatment device, the single illumination device 106 may be used to treat at least four pairs of eyes in one hour depending on treatment parameters.

[0045] FIG. 3 illustrates an example system 300 for cross-linking treatment. To direct photoactivating light to the cornea 2 treated with the cross-linking agent 130, the system 300 includes the light source 1 10 and the optical elements 1 12 as described above. The example system 300 also includes the one or more controllers 120, which can control aspects of the system 300, including the light source 1 10 and/or the optical elements 1 12.

[0046] As described above, the photoactivating light from the light source 110 can be selectively directed to sections of the treated cornea 2 according to a particular illumination pattern 10. For instance, the optical elements 1 12 may include a digital micro-mirror device (DMD) system to modulate the application of photoactivating light spatially and temporally. Using DMD technology, the photoactivating light from the light source 1 10 can be proj ected in a precise spatial pattern that is created by microscopically small mirrors laid out in a matrix on a semiconductor chip.

[0047] To effect higher rates of corneal healing after cross-linking treatment, the example system 300 can apply the photoactivating light according to an illumination partem 10 that promotes corneal healing after the treatment. In particular, the illumination pattern 10 exposes some sections of the corneal tissue 2bi to the photoactivating light, while leaving other sections 2b2 (e.g., microvolumes) unexposed to the photoactivating light. The unexposed sections 2b2 may be created, for instance, at the surface of the stroma, mid-stroma, and/or anterior stroma.

[0048] Keratocytes are specialized fibroblasts that reside in the stroma and play a major role in maintaining the health of corneal tissue, including maintaining clarity of corneal collagen, healing corneal wounds, and synthesizing corneal components. When a section of corneal tissue treated with a cross-linking agent (e.g., riboflavin) is exposed to photoactivating light (e.g., UVA light) and experiences the corresponding photochemical kinetic reactions, the keratocytes residing in that tissue may be destroyed. The destruction of keratocytes may slow the healing of the corneal tissue when responding to the cross-linking treatment.

[0049] Thus, by selectively leaving sections 2b2 of corneal tissue unexposed to the photoactivating light, the example system 300 helps to prevent the destruction of some keratocytes. The unexposed sections of corneal tissue 2b2 act as seeding reservoirs of live keratocytes which promote faster healing rates, but do not affect how the treatment area responds biomechanically to the cross-linking treatment. These healing rates may be two, three or four times faster depending on the spacing and number of the unexposed sections 2b2 of corneal tissue. For instance, treatment for refractive myopia may fully stabilize in one month instead of three months.

[0050] In the example system 300, the optical elements 112 can apply the photoactivating light according to an illumination pattem 10 that spans an area 10a corresponding to the treatment area for the cornea 2. The pattem 10 includes illumination areas lObi and micro- areas of non-illumination, or dark spots 10b2, distributed across the area 10a. The distribution of dark spots 10b2 is also known as dark dappling. For instance, the dark spots 10b2 may be approximately 50 μηι to approximately 250 μηι in diameter/width and may be spaced approximately every 0.5 mm to 5 mm across the area 10a. In general, the dark spots 10b2 may have any combination of sizes and shapes and may be distributed according to any uniform or non-uniform spacing.

[0051] In one embodiment, the light source 110 and the optical elements 112 may generate a collimated laser to provide the pattern 10 of photoactivating light with dark spots 10b2. Depending on the configuration of the optical elements 112 as well as the depth of focus and the collimation of the photoactivating light, different diameters and depths of darkness maybe achieved for the unexposed sections of corneal tissue 2b2.

[0052] The sections 2bi of the cornea 2 exposed to photoactivating light result from the illumination areas lObi defined by the pattern 10, and conversely, the sections 2b2 unexposed to the photoactivating light result from the dark spots 10b2 defined by the pattern 10. To illustrate aspects of the example system 300 more clearly, the pattem 10 is shown from a perspective view while the eye 1 is shown in cross-section. In some cases, the dark spots 10b2 may be organized in a grid as shown in FIG. 3. However, in other cases, the dark spots 10b2 may be organized according to other arrangements, which may be less structured, uniform, or symmetric. In general, the dark spots 10b2 may be arranged in any manner to achieve a more advantageous healing response.

[0053] The example system 300 also includes a tracking system 150 that dynamically monitors the eye 1 during the cross-linking treatment. The tracking system 150 may be coupled to the controller 120. The controller 120 can determine the location and orientation of the eye 1 according to information from the tracking system 150. By determining the location and orientation of the eye 1, the controller 120 can control the optical elements 112 to deliver the photoactivating light from the light source 110 to desired sections of the cornea 2. In particular, the tracking system 150 allows the example system 300 to ensure that the illumination pattern 10 aligns properly with the location and orientation of the cornea 2 to generate cross-linking activity in the desired sections. Advantageously, the tracking system 150 allows the example system 300 to account for changes in location and orientation of the eye 1 during the patterned delivery of the photoactivating light.

[0054] For instance, the tracking system 150 may include one or more cameras that capture images of the eye 1. The tracking system 150 may send the images to the controller 120, and the controller 120 can process the images to determine the location and orientation of the eye 1 relative to the optical elements 112. The images can be processed by identifying the pupil limbus and iris texture of the eye 1 at approximately 60 frames per second. Alternatively, the tracking system 150 can process the images on its own and determine the location and orientation information.

[0055] Alternatively or additionally, an applanator may be employed to engage the eye 1 to minimize unwanted movement and to allow more accurate delivery of the photoactivating light to desired sections of the cornea 2. The photoactivating light can be delivered through the applanator. Further aspects of an example applanator are described further below.

[0056] As described above, the optical elements 112 may include a DMD system to generate the pattern 10 of unexposed sections of corneal tissue 2b2. FIGS. 4A-C illustrate example irradiance maps and corresponding cross-linking distribution for a cornea, when an illumination pattern with a dark spot having diameters of 100 μιτι, 200 μιτι, and 300 μιτι, respectively, are proj ected onto the surface of the cornea. The corresponding models employ an optical ray tracing program by Zemax, LLC (Kirkland, WA). These ray trace models are blurred by an amount that is known from the tracking system 150 and algorithm of the DMD system. As described above, the tracking system 150 can track the eye 1 utilizing the pupil limbus and iris texture of the eye 1 at approximately 60 frames per second. Because there may be a slight lag between image capture and the response to a change in location and orientation of the eye 1, there may inherently be some blur of the projected photoactivating light due to minimal motion. Correspondingly, the dark spots 10b2 and the unexposed sections 2b2 may be blurred.

[0057] In the example system 300, irradiance maps that account for the motion blur can be generated. The irradiance maps can then be evaluated with the photochemical kinetic models described, for instance, in International Patent Application No. PCT/US 15/57628, filed October 27, 2015, the contents of which are incorporated entirely herein by reference. The evaluation predicts the cross-linking activity that occurs within the cornea, i.e., three- dimensional cross-linking distribution.

[0058] The crosslinking distributions shown in FIGS. 4A-C indicate the line of demarcation for each respective dark spot diameter. The line of demarcation as described in International Patent Application No. PCT/US15/57628 indicates the boundary of tissue that separates live cells from dead cells. As the diameter of the dark spot 10b2 is increased from 100 μηι to 300 μιτι, greater sections of untreated tissue (where no cross-linking occurs) are produced in columns extending to the corneal surface. The untreated tissue as shown in the cross-linking distribution does not correspond directly in shape to the section 2b2 that is left unexposed to the photoactivating light as shown in the irradiance map.

[0059] As shown in FIG. 4A, the 100 μηι dark spot provides minimal untreated tissue at the corneal surface. However, as the diameter of the dark spot increases as shown in FIGS. 4B-C, the dark spot provides larger and larger areas of untreated tissue. For instance, the 200 μιη dark spot provides a tapered column of untreated tissue with a diameter of approximately 75 μηι at the corneal surface and a larger diameter of approximately 300 μηι wide at a corneal depth of 300 μηι. The size of the dark spot may be significant as the keratocytes are approximately 10 μιτι to 15 μιτι in diameter and approximately 1 μιτι to 2 μιτι in thickness and are oriented to be generally planar relative to the lamella of the collagen fibers of the stroma. There may be approximately 800 cells/mm² at the surface of the stroma, 500 cells/mm² mid- stroma, and as few as 65 cells/mm² closer to the endothelium. The average number of cells throughout the stroma is approximately 25,000 cells/mm³. Therefore, the number of cells left alive with the 200 μιτι dark spot leaves approximately 5 to 6 live cells per lamellar layer with approximately 60 to 80 layers of cells through the treated region.

[0060] Cross-linking that exceeds the line of demarcation threshold causes an apoptotic response of the keratocytes in this region. The keratocytes release cytokines that trigger a healing response. The keratocytes adjacent to this area are activated to become fibroblasts or myofibroblasts. These transformed cells then migrate along the lamellar layers to the wound and deposit small amounts of collagen to heal the area. The number of transformed keratocytes starts to decline once the immediate damage is repaired and a slow remodeling phase takes place over weeks and months depending on the volume of the damage. Using in-vivo confocal microscopy comparing both the Dresden Protocol (conventional CXL) and Accelerated crosslinking protocol (AXL) utilizing a 9.0 mm beam, Mazzotta et al. reported that it took approximately 12 months for the tissue to heal and fully repopulate keratocyte populations and for sub-epithelial and stromal nerves to regenerate. (Mazzotta et al, In Vivo Confocal Microscopy after Corneal Collagen Crosslinking, Ocular Surface. October 2015, Vol. 13, No. 4, pp. 298-314.) This means that keratocytes that start at the edge of the circular treatment zone and migrate inward to effect healing must travel 4.5 mm into the center. Applying photoactivating light with 200 μιτι dark spots spaced at approximately 1 mm provides sections 2b2 of live keratocytes that can migrate in all directions and therefore only need to go approximately 0.5 mm. These keratocytes greatly enhance the healing response which may occur four to five times faster, e.g., within approximately one-and-a-half to three months.

[0061] Furthermore, the untreated sections are only 75 μιτι in diameter in contrast to the overall treatment area. Because the untreated sections are generally a small percentage of the treatment area, applying photoactivating light with dark spots I OD2 does not cause a significant change in biomechanical effect when compared to the application of photoactivating light without the dark spots 10b2. As such, the biomechanical effect of cross-linking treatments with dark spots 10b2 can be accurately predicted with the photochemical kinetic model described in International Patent Application No. PCT/US 15/57628. Controlling the irradiance distribution and/or other properties of the photoactivating light, different three-dimensional microvolumes for the unexposed sections 2b2 may be achieved to effect different healing attributes.

[0062] The size, depth and patterning of the dark spots 10b2 may be varied to optimize the best healing profile for a given cross-linking treatment. For instance, the illumination partem 10 for treating keratoconous may be different than the illumination pattern 10 for treating myopia.

[0063] To generate the illumination pattern 10 of photoactivating light with dark spots 10b2 in alternative embodiments, the example system 300 may include a structure with apertures that project the illumination pattern 10 from an optical object plane to the surface of the comea 2 (i.e., the image plane).

[0064] In further alternative embodiments, the example system 300 may include a mask that can be placed directly on or just above the eye. For instance, the mask may be an opaque material with holes or transparencies that transmit light in a defined pattern. The placement of the mask may depend on how the photoactivating light is delivered via the optical elements 112.

[0065] In some cases, the mask may be a mesh device 160 as shown in FIG. 5. The mesh device 160, for instance, may be formed from plastic (e.g., polypropylene) threads that define a pattern of pores through which photoactivating light can pass. Additional obscurations (not shown) may be coupled to and/or arranged on the mesh device 160 to provide the desired dark spots 10b2. Additionally, aspects of the mesh device 160 may be optically transparent to allow photoactivating light to pass through the mesh device 160 according to the desired illumination pattern 10. To illustrate aspects of the example system more clearly, the mesh device 10 is shown from a perspective view while the eye 1 is shown in cross-section. [0066] Advantageously, the mesh device 160 allows oxygen to be transmitted to the cornea 2 for the generation of cross-linking activity, as described above. The oxygen source 140 and an oxygen delivery device 142 may be employed with the mesh device 160 to deliver oxygen at a selected concentration to the cornea 2. In some embodiments, the oxygen delivery device 140 may include a chamber that is disposed above the mesh device 160 to supply a specific concentration of oxygen.

[0067] In addition to defining the illumination pattern 10 with dark spots 10b2, the mesh device 160 can be employed to applanate the cornea 2. (Indeed, alternative embodiments may employ the mesh device 160 primarily as an applanator.) When solid optical applanators are employed, only the oxygen already residing in the corneal tissue is available to generate cross- linking activity, because the solid optical applanators press against the corneal surface and cut off any additional oxygen supply to the tissue. When the mesh device 160 applanates the cornea 2, however, additional oxygen can be supplied to the corneal tissue during cross-linking treatment. If a mesh device 160 is sufficiently taut and has the right pore size(s) versus thread size, applanation of the cornea 2 can be achieved while allowing oxygen in the air or from another source to resupply the cornea with oxygen via diffusion. As such, a sufficient area of the cornea 2 receives oxygen and corresponding cross-linking activity produces the desired biomechanical effect. When the mesh device 160 is pressed against the surface of the eye 1, for instance, a chamber pressurized with oxygen may be positioned above the mesh device 160 to create a hyperbaric oxygen condition to achieve increased cross-linking efficiency.

[0068] As described above, to control aspects of the delivery of the photoactivating light, embodiments may also employ aspects of multiphoton (e.g., two photon) excitation microscopy. Delivery via multiphoton excitation may also be employed to create unexposed sections 2b2 of corneal tissue in the treatment area. Multiphoton excitation may be achieved via an XYZ scanning system that can also create the unexposed sections 2b2. The size and spacing of the unexposed sections 2b2 can be achieved precisely through the modulation of the XYZ scanning system and beam waist control. Additionally, to achieve a known amount of cross-linking activity, multiphoton excitation microscopy may be combined with the delivery of sufficient oxygen.

[0069] For multiphoton cross-linking, the distribution of cross-linking for a given pulse as a function of corneal depth is determined by (i) the concentration of oxygen as a function of corneal depth, (ii) the concentration of riboflavin as a function of corneal depth, and (iii) the shape of the Gaussian beam waist associated with the photoactivating light. As the multiphoton process occurs in a small amount of time, only what is resident at that time generates the cross- links for a specific three-dimensional cross-linking profile. The three-dimensional profile can be modulated by modifying the optical system to change the shape of the Gaussian beam waist. The distribution of generated multiphotons is forward scattering and determines the three- dimensional profile of photons. When the mesh device 160 above is employed as an applanator, the three-dimensional cross-linking profile can be modulated as one can also control the depth and distribution of oxygen. The distribution of oxygen can be controlled by varying the concentration of oxygen (hypobaric, normobaric or hyperbaric) over the tissue, where the amount of cross-linking activity increases with increasing oxygen concentration for a given pulse energy, beam waist shape, and riboflavin concentration.

[0070] By individually varying any one of pulse energy, beam waist shape, riboflavin concentration, and oxygen concentration, a desired three-dimensional cross-linking profile can be achieved for a single pulse. To effect refractive change, however, multiple pulses are generated and distributed in three-dimensional space, patterned to create an overall three- dimensional distribution. Because oxygen distribution is affected by the timing of the next pulse, the pattern of pulses is controlled to keep the oxygen concentration as constant as possible over the entire treatment time to ensure a predictable three-dimensional cross-linking profile. Therefore, in addition to supplying oxygen, the pulses are controlled so that they occur at a rate that allows the supplied oxygen to be sufficiently replenished by diffusion.

[0071] When an applanator blocks oxygen, the amount of oxygen is higher at the beginning of the procedure and diminishes over time as the oxygen is not being replaced and diffuses from higher concentration to lower concentration. If the partem of pulses fails to take this depletion of oxygen into account, the three-dimensional cross-linking profile may become asymmetric. In contrast, when the mesh device 160 is employed as an applanator, the concentration of oxygen can be replaced rapidly enough to create a homogenous three- dimensional cross-linking profile.

[0072] In general, aspects of the present disclosure involves systems and methods for delivering a pattern of photoactivating light that promotes healing after a cross-linking or other treatment. In some embodiments, the pattern of photoactivating light is applied via a mesh device. Such a mesh device may also be applied as an applanator (regardless of whether it is employed to define the illumination pattern). Advantageously, the mesh device allows controlled delivery of oxygen to the treated tissues to promote efficiency of cross-linking or other aspect of the treatment.

[0073] Although example embodiments above may employ the mesh device 160, other embodiments as shown with the example system 400 of FIG. 6 may employ any permeable structure 170 that can applanate the cornea 2 treated with a photosensitizer, e.g., riboflavin. Additionally, the permeable structure 170 can transmit photoactivating light from the light source 110/optical elements 1 12 and oxygen from the oxygen source 140/oxygen delivery device 142 to generate desired cross-linking activity in the cornea 2. The permeable structure 170, for instance, may be formed from a polymer that is sufficiently gas-permeable to allow controlled delivery of oxygen to promote efficiency of cross-linking or other aspect of the treatment. The permeable structure 170 may optionally transmit the photoactivating light according to a pattern as described above. In some cases, the permeable structure 170 may be a translucent polymer with a pattern of opaque areas to selectively block transmission of photoactivating light. In other cases, the permeable structure 170 may be an opaque material with holes or transparencies that transmit light in a defined pattern.

[0074] As described above, according to some aspects of the present disclosure, some or all of the steps of the above-described and illustrated procedures can be automated or guided under the control of a controller (e.g., the controller 120). Generally, the controllers may be implemented as a combination of hardware and software elements. The hardware aspects may include combinations of operatively coupled hardware components including microprocessors, logical circuitry, communication/networking ports, digital filters, memory, or logical circuitry. The controller may be adapted to perform operations specified by a computer-executable code, which may be stored on a computer readable medium.

[0075] As described above, the controller may be a programmable processing device, such as an external conventional computer or an on-board field programmable gate array (FPGA) or digital signal processor (DSP), that executes software, or stored instructions. In general, physical processors and/or machines employed by embodiments of the present disclosure for any processing or evaluation may include one or more networked or non-networked general purpose computer systems, microprocessors, field programmable gate arrays (FPGA's), digital signal processors (DSP's), micro-controllers, and the like, programmed according to the teachings of the example embodiments of the present disclosure, as is appreciated by those skilled in the computer and software arts. The physical processors and/or machines may be externally networked with the image capture device(s), or may be integrated to reside within the image capture device. Appropriate software can be readily prepared by programmers of ordinary skill based on the teachings of the example embodiments, as is appreciated by those skilled in the software art. In addition, the devices and subsystems of the example embodiments can be implemented by the preparation of application-specific integrated circuits or by interconnecting an appropriate network of conventional component circuits, as is appreciated by those skilled in the electrical art(s). Thus, the example embodiments are not limited to any specific combination of hardware circuitry and/or software.

[0076] Stored on any one or on a combination of computer readable media, the example embodiments of the present disclosure may include software for controlling the devices and subsystems of the example embodiments, for driving the devices and subsystems of the example embodiments, for enabling the devices and subsystems of the example embodiments to interact with a human user, and the like. Such software can include, but is not limited to, device drivers, firmware, operating systems, development tools, applications software, and the like. Such computer readable media further can include the computer program product of an embodiment of the present disclosure for performing all or a portion (if processing is distributed) of the processing performed in implementations. Computer code devices of the example embodiments of the present disclosure can include any suitable interpretable or executable code mechanism, including but not limited to scripts, interpretable programs, dynamic link libraries (DLLs), Java classes and applets, complete executable programs, and the like. Moreover, parts of the processing of the example embodiments of the present disclosure can be distributed for better performance, reliability, cost, and the like.

[0077] Common forms of computer-readable media may include, for example, a floppy disk, a flexible disk, hard disk, magnetic tape, any other suitable magnetic medium, a CD- ROM, CDRW, DVD, any other suitable optical medium, punch cards, paper tape, optical mark sheets, any other suitable physical medium with patterns of holes or other optically recognizable indicia, a RAM, a PROM, an EPROM, a FLASH-EPROM, any other suitable memory chip or cartridge, a carrier wave or any other suitable medium from which a computer can read.

[0078] While the present disclosure has been described with reference to one or more particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present disclosure. Each of these embodiments and obvious variations thereof is contemplated as falling within the spirit and scope of the present disclosure. It is also contemplated that additional embodiments according to aspects of the present disclosure may combine any number of features from any of the embodiments described herein.

Claims

WHAT IS CLAIMED IS :

1. A system for treating an eye, comprising:

a light source configured to emit photoactivating light;

one or more optical elements configured to direct the photoactivating light from the light source towards an eye treated with a photosensitizer; and

a permeable structure configured to be positioned on the eye, the permeable structure configured to transmit the photoactivating light from the one or more optical elements to the eye,

wherein the photoactivating light activates the photosensitizer to generate cross-linking activity in the eye.

2. The system of claim 1 , wherein the permeable structure is formed from a gas-permeable polymer.

3. The system of claim 1 , wherein the permeable structure is configured to applanate the eye.

4. The system of claim 1 , further comprising an oxygen delivery device coupled to an oxygen source, the permeable structure configured to transmit oxygen from the oxygen delivery device to the eye, the oxygen determining in part the cross-linking activity generated in the eye.

5. The system of claim 1 , further comprising a controller coupled to at least one of the light source or the one or more optical elements and configured control at least one of the light source or the one or more optical elements to direct the photoactivating light according to parameters relating to at least one of dose, illumination pattern, wavelength, bandwidth, intensity, power, location, depth of penetration, duration, or pulsing/continuous wave illumination.

6. The system of claim 5, further comprising an eye tracking system coupled to the controller, the eye tracking system configured to monitor the eye and to provide, to the controller, information relating to a location and an orientation of the eye, the controller controlling the at least one of the light source or the one or more optical elements to direct the photoactivating light to a desired area of the eye according to the information.

7. The system of claim 1, wherein the permeable structure is a mesh device including threads defining pores through which the photoactivating light is transmitted to the eye.

8. The system of claim 1, wherein the permeable structure transmits the photoactivating light according to an illumination pattern that spans an area corresponding to a treatment area for the eye, the illumination pattern including dark spots distributed across the area of the illumination partem.

9. The system of claim 8, wherein the dark spots are approximately 50 μηι to approximately 250 μηι in width or diameter.

10. The system of claim 8, wherein the dark spots are spaced from each other by approximately 0.5 mm to approximately 5 mm across the area of the illumination pattern.

11. A method for treating an eye, comprising:

applying a photosensitizer to an eye;

positioning a permeable structure on the eye;

directing, with one or more optical elements, photoactivating light from a light source towards the eye; and

transmitting, through the permeable structure, the photoactivating light from the one or more optical elements to the eye,

12. The method of claim 11, wherein the permeable structure is formed from a gas- permeable polymer.

13. The method of claim 11, further comprising applanating the eye with the permeable structure.

14. The method of claim 11, further comprising transmitting, through the permeable structure, oxygen from an oxygen delivery device to the eye, the oxygen determining in part the cross-linking activity generated in the eye.

15. The method of claim 11, further comprising controlling, with a controller, at least one of the light source or the one or more optical elements to deliver the photoactivating light according to parameters relating to at least one of dose, illumination pattern, wavelength, bandwidth, intensity, power, location, depth of penetration, duration, or pulsing/continuous illumination.

16. The method of claim 15, further comprising monitoring the eye with an eye tracking system coupled to the controller, and providing, from the eye tracking system, information relating to a location and an orientation of the eye, the controller controlling the at least one of the light source or the one or more optical elements to direct the photoactivating light to a desired area of the eye according to the information.

17. The method of claim 11 , wherein the permeable structure is a mesh device including threads defining pores through which the photoactivating light is transmitted to the eye.

18. The method of claim 11 , wherein the permeable structure transmits the photoactivating light according to an illumination pattem that spans an area corresponding to a treatment area for the eye, the illumination pattern including dark spots distributed across the area of the illumination pattem.

19. The method of claim 18, wherein the dark spots are approximately 50 μιτι to approximately 250 μιτι in width or diameter.

20. The method of claim 18, wherein the dark spots are spaced from each other by approximately 0.5 mm to approximately 5 mm across the area of the illumination pattem.

21. A method for treating an eye, comprising:

applying a concentration of photosensitizer to an eye;

applanating the eye with a permeable structure;

directing, with one or more optical elements, photoactivating light from a light source towards the eye according to a pattern of pulses and a Gaussian beam waist shape;

transmitting, through the permeable structure, a concentration of oxygen from an oxygen delivery device to the eye; and

wherein the photoactivating light activates the photosensitizer to generate three- dimensional cross-linking activity in the eye, the three-dimensional cross-linking activity being determined by the concentration of photosensitizer, the concentration of oxygen, and the pattern of pulses and the Gaussian beam waist shape of the photoactivating light.