Patent Description:
Cross-linking treatments are generally known in the art, e.g. from documents <CIT>; <CIT>; <CIT> and <CIT>. Such 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.

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.

Cross-linking treatments may also be employed to induce refractive changes in the cornea to correct disorders such as myopia, hyperopia, myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia, etc..

To treat keratoconus or to achieve refractive correction, for instance, an effective cross-linking procedure applies photoactivating light as precisely as possible to specified areas of a cornea treated with a cross-linking agent. Application of the photoactivating light outside the specified areas might generate undesired structural changes in the cornea and negatively affect treatment results. Precise application of the photoactivating light, however, may be difficult to achieve due to eye movement that may occur during the procedure. Such eye movement, for instance, might include translation along a plane (transverse to corneal depth), changes in gaze angle, and/or bulk head motion. Because a cross-linking procedure might require exposing the cornea to the photoactivating light for at least a minute, e.g., one to twenty minutes, some eye movement is very likely to occur during the procedure. To address the occurrence of eye movement, systems and methods can employ an active eye tracking system to determine any changes in the position of the cornea and, in response, an illumination system can be adjusted to apply photoactivating light precisely to specified areas of the cornea.

According to an example embodiment, a system for applying a cross-linking treatment to a cornea of an eye includes a light source configured to emit a photoactivating light and an oxygen delivery device coupled to an oxygen source, the oxygen delivery device configured to deliver oxygen at a selected concentration to the cornea.

The system includes a spatial light modulator configured to receive the photoactivating light from the light source and provide a pixelated illumination with the photoactivating light. The spatial light modulator defines a maximum area for the pixelated illumination.

The system includes a controller configured to cause the spatial light modulator to project a first pixelated illumination onto the cornea to generate cross-linking activity in a treatment area by photoactivating a cross-linking agent applied to the treatment area, wherein the system is further configured to detect a change in eye gaze angle and/or head position, and in response to the change in eye gaze angle and/or head position, the controller is configured to control the spatial light modulator to generate a second pixelated illumination which is a geometric transformation of the first pixelated illumination to compensate for a geometric distortion caused by the change in eye gaze angle and/ or head position, and to project the second pixelated illumination to the treatment area to continue photoactivating the cross-linking agent applied to the treatment area.

In the example embodiment above, using a smaller pixelated illumination can provide a greater range of positional adjustments for the spatial light modulator. Smaller pixelated illumination patterns, however, are composed of fewer pixels. Decreasing the size of pixelated illumination might degrade the minimum resolvable spatial feature that can be projected onto the eye and can produce "pixelation" artifacts. To address such effects, a system for applying a cross-linking treatment to a cornea of an eye includes a light source configured to emit a photoactivating light. The system includes a spatial light modulator configured to receive the photoactivating light from the light source and provide a pixelated illumination with the photoactivating light. The system includes a controller configured to cause the spatial light modulator to project a first pixelated illumination and a second pixelated illumination onto a cornea to generate cross-linking activity in a desired treatment area by photoactivating a cross-linking agent applied to the desired treatment area. The desired treatment area includes at least one portion that is not illuminated by the first pixelated illumination. The second pixelated illumination includes one or more pixels that illuminate the at least one portion of the desired treatment area that is not illuminated by the first pixelated illumination. The spatial light modulator projects the first pixelated illumination and the second pixelated illumination to the cornea according to different temporal parameters. For instance, the first pixelated illumination includes all complete pixels that can be projected within the desired treatment area, and the one or more pixels of the second pixelated illumination include remaining pixels that, in combination with the pixels of the first pixelated illumination, illuminate the entire desired treatment area.

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, and alternatives falling within the scope of the present disclosure.

<FIG> illustrates an example treatment system <NUM> for generating cross-linking of collagen in a cornea <NUM> of an eye <NUM>. The treatment system <NUM> includes an applicator <NUM> for applying a cross-linking agent <NUM> to the cornea <NUM>. In example embodiments, the applicator <NUM> may be an eye dropper, syringe, or the like that applies the photosensitizer <NUM> as drops to the cornea <NUM>. Example systems and methods for applying the cross-linking agent is described in <CIT> and titled "Systems and Methods for Delivering Drugs to an Eye,".

The cross-linking agent <NUM> may be provided in a formulation that allows the cross-linking agent <NUM> 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 <NUM> to be applied more directly to the underlying tissue.

The treatment system <NUM> includes an illumination system with a light source <NUM> and optical elements <NUM> for directing light to the cornea <NUM>. The light causes photoactivation of the cross-linking agent <NUM> to generate cross-linking activity in the cornea <NUM>. For example, the cross-linking agent may include riboflavin and the photoactivating light may include ultraviolet A (UVA) (e.g., approximately <NUM>) light. Alternatively, the photoactivating light may include another wavelength, such as a visible wavelength (e.g., approximately <NUM>). As described further below, corneal cross-linking improves corneal strength by creating chemical bonds within the corneal tissue according to a system of photochemical kinetic reactions. For instance, riboflavin and the photoactivating light may be applied to stabilize and/or strengthen corneal tissue to address diseases such as keratoconus or post-LASIK ectasia.

The treatment system <NUM> includes one or more controllers <NUM> that control aspects of the system <NUM>, including the light source <NUM> and/or the optical elements <NUM>. In an implementation, the cornea <NUM> can be more broadly treated with the cross-linking agent <NUM> (e.g., with an eye dropper, syringe, etc.), and the photoactivating light from the light source <NUM> can be selectively directed to regions of the treated cornea <NUM> according to a particular pattern.

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

Moreover, specific regimes of the photoactivating light can be modulated to achieve a desired degree of cross-linking in the selected regions of the cornea <NUM>. The one or more controllers <NUM> may be used to control the operation of the light source <NUM> and/or the optical elements <NUM> 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).

The parameters for photoactivation of the cross-linking agent <NUM> 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 <NUM> mW/cm<NUM>, larger irradiance of the photoactivating light, e.g., multiples of <NUM> mW/cm<NUM>, can be applied to reduce the time required to achieve the desired cross-linking. The total dose of energy absorbed in the cornea <NUM> 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 region of the corneal surface 2A can be, for example, <NUM> J/cm<NUM>, or as high as <NUM> J/cm<NUM> or <NUM> J/cm<NUM>. The effective dose described can be delivered from a single application of energy, or from repeated applications of energy.

The optical elements <NUM> of the treatment system <NUM> may include a microelectromechanical system (MEMS) device, e.g., 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 <NUM> is projected in a precise spatial pattern that is created by microscopically small mirrors laid out in an array 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. 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 real-time monitoring and modulation of corneal cross-linking during treatment. Aspects of a dosimetry system are described in further detail below. Additionally, pre-clinical patient information may be combined with finite element biomechanical computer modeling to create patient specific pre-treatment plans.

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 <NUM>, the treatment system <NUM> 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 <NUM> to a lesser degree than shorter wavelengths, which allows longer wavelengths of light to penetrate the cornea <NUM> more efficiently than light of shorter wavelengths. 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 photosensitizer 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 <NUM> 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.

A large number of conditions and parameters affect the cross-linking of corneal collagen with the cross-linking agent <NUM>. For example, the irradiance and the dose of photoactivating light affect the amount and the rate of cross-linking.

When the cross-linking agent <NUM> is riboflavin in particular, the UVA light may be applied continuously (CW) or as pulsed light, and this selection has an effect on the amount, the rate, and the extent of cross-linking. 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 <NUM>/<NUM> to approximately <NUM>/<NUM>; the irradiance may be between approximately <NUM> mW/cm<NUM> to approximately <NUM> mW/cm<NUM> average irradiance, and the pulse rate may be between approximately <NUM> to approximately <NUM> or between approximately <NUM> to approximately <NUM>,<NUM>.

The treatment system <NUM> may generate pulsed light by employing a DMD, electronically turning the light source <NUM> 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 instance, 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 <NUM> and <NUM>.

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.

Examples of systems and methods for delivering photoactivating light are described, for example, in <CIT> and titled "Systems and Methods for Applying and Monitoring Eye Therapy," <CIT> and titled "Systems and Methods for Applying and Monitoring Eye Therapy," and <CIT> and titled "Systems and Methods for Corneal Cross-Linking with Pulsed Light,".

The addition of oxygen also affects the amount of corneal stiffening. In human tissue, O<NUM> content is very low compared to the atmosphere. The rate of cross-linking in the cornea, however, is related to the concentration of O<NUM> when it is irradiated with photoactivating light. Therefore, it may be advantageous to increase or decrease the concentration of O<NUM> 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 O<NUM>. Thus, when the riboflavin is applied to the eye, a higher concentration of O<NUM> is delivered directly into the cornea with the riboflavin and affects the reactions involving O<NUM> when the riboflavin is exposed to the photoactivating light. According to another approach, a steady state of O<NUM> (at a selected concentration) may be maintained at the surface of the cornea to expose the cornea to a selected amount of O<NUM> and cause O<NUM> to enter the cornea. As shown in <FIG>, for instance, the treatment system <NUM> also includes an oxygen source <NUM> and an oxygen delivery device <NUM> that delivers oxygen at a selected concentration to the cornea <NUM>. Example systems and methods for applying oxygen during cross-linking treatments are described, for example, in <CIT> and titled "Eye Therapy," <CIT> and titled "Systems and Methods for Corneal Cross-Linking with Pulsed Light,".

Additionally, an example mask device for delivering concentrations of oxygen as well as photoactivating light in eye treatments is described in <CIT> and titled "Systems and Methods for Treating an Eye with a Mask Device,".

For instance, a mask may be placed over the eye(s) to produce a consistent and known oxygen concentration above the surface.

When riboflavin absorbs radiant energy, especially light, it undergoes photoactivation. There are two photochemical kinetic pathways for riboflavin photoactivation, Type I and Type II. The reactions involved in both the Type I and Type II mechanisms and other aspects of the photochemical kinetic reactions generating cross-linking activity are described in <CIT> and titled "Systems and Methods for Cross-Linking Treatments of an Eye,".

To treat keratoconus or to achieve refractive correction for instance, an effective cross-linking procedure applies photoactivating light as precisely as possible to specified areas of a cornea treated with a cross-linking agent. Application of the photoactivating light outside the specified areas might generate undesired structural changes in the cornea and negatively affect treatment results. Precise application of the photoactivating light, however, may be difficult to achieve due to eye movement that may occur during the procedure. Such eye movement, for instance, might include translation along the x-y plane as shown in <FIG>, changes in gaze angle, and/or bulk head motion. (In <FIG>, the depth of the cornea <NUM> is measured along a z-axis and patterns of photoactivating light may be projected on transverse x-y planes. ) Because a cross-linking procedure might require exposing the cornea to the photoactivating light for at least one minute, e.g., one to twenty minutes, some eye movement is very likely to occur during the procedure.

To address the occurrence of eye movement, embodiments can employ an active eye tracking system to determine any changes in the position of the cornea and, in response, the illumination system can be adjusted to apply photoactivating light precisely to specified areas of the cornea. <FIG> illustrates an example treatment system <NUM> with an active eye tracking system. The treatment system <NUM> includes an illumination system for directing photoactivating light to the cornea <NUM> of the eye <NUM>. The illumination system includes the light source <NUM> and the optical elements <NUM> as described above. The light source <NUM>, for instance, may include one or more LED's that emit UV light to photoactivate riboflavin that has been applied to the cornea <NUM>. The optical elements <NUM>, including a DMD <NUM>, project the photoactivating light in a precise spatial pattern onto the cornea <NUM> along an x-y plane. Additionally, the treatment system <NUM> includes one or more controllers <NUM> to control aspects of the treatment system <NUM>.

For the active eye tracking system, the treatment system <NUM> includes a camera (image capture device) <NUM> that dynamically captures images of the eye <NUM> during a procedure. The one or more controllers <NUM> can process the images to detect a position of a fiducial point, such as the pupil, for the eye <NUM> relative to the treatment system <NUM>. Using the position of the fiducial point as a reference, the one or more controllers <NUM> can determine the location of the specified areas of the cornea <NUM>. Thus, the one or more controllers <NUM> can adjust the treatment system <NUM> to deliver the photoactivating light to the location of the specified areas. In some cases, the camera <NUM> and the software (e.g., computer-readable instructions stored on a non-transitory medium) for processing the images and adjusting the treatment system <NUM> may collectively be known as a vision system.

Referring to <FIG>, the entire mirror array of the DMD <NUM> defines a maximum area <NUM> for delivering photoactivating light. The maximum area <NUM> includes boundaries 202a-d. Any part of the array of the DMD <NUM> can be activated to deliver photoactivating light from any portion of the maximum area <NUM>. For instance, as shown in <FIG>, a part of the array of the DMD <NUM> can be activated to produce an illumination pattern <NUM> that is substantially circular and centered at a position (xc, yc) with a diameter D<NUM>. The diameter D<NUM> of the illumination pattern <NUM> may be slightly smaller than the distance along the y-axis between the opposing boundaries 202a, b and the distance along the x-axis between the opposing boundaries 202c, d. As such, there may be space between the illumination pattern <NUM> and the boundaries 202a-d. This space allows the center of the illumination pattern <NUM> to be translated a small distance within the area <NUM> while maintaining the same shape with the diameter D<NUM>. For instance, another part of the array of the DMD <NUM> can be activated to produce the illumination pattern <NUM> centered at a different position (xc+δx1, yc+δy1), where δx1 represents possible translation along the x-axis and δy1 represents possible translation along the y-axis. The translation of the illumination pattern <NUM> within the area <NUM> changes the position of corresponding photoactivating light as delivered to the cornea <NUM>. Thus, in response to eye movement detected via the camera <NUM>, the one or more controllers <NUM> can control the DMD <NUM> to adjust the delivery of the photoactivating light so that it reaches specified areas of the cornea <NUM> to achieve desired results.

The adjustments that the one or more controllers <NUM> can make with the DMD <NUM>, however, are limited by the small amount of space between the illumination pattern <NUM> and the boundaries 202a-d. With the DMD <NUM> alone, the one or more controllers <NUM> might be unable to make sufficiently large adjustments to the position of the illumination pattern <NUM> within the area <NUM> to respond to larger eye movements. In other words, the illumination pattern <NUM> might reach one of the boundaries 202a-d before the illumination pattern <NUM> can be moved a desired distance. To make larger adjustments that cannot be made with the DMD <NUM>, the treatment system <NUM> includes an electromechanical X-Y motion system <NUM> coupled to one or more of the optical elements <NUM>. The one or more controllers <NUM> can control the X-Y motion system <NUM> to move one or more of the optical elements <NUM> into better mechanical alignment with the cornea <NUM> in response to larger eye movement. For instance, the X-Y motion system <NUM> may include electromechanical stages that can be operated to move one or more of the optical elements <NUM> and the corresponding photoactivating light along the x-axis and/or the y-axis. Thus, the treatment system <NUM> employs the DMD <NUM> for smaller adjustments and the X-Y motion system <NUM> for larger adjustments in response to varying amounts of eye movement.

<FIG> illustrates an example treatment system <NUM> with an alternative active eye tracking system. In contrast to the treatment system <NUM> shown in <FIG>, the treatment system <NUM> does not employ the X-Y motion system <NUM>. Rather, the treatment system <NUM> uses a DMD <NUM> to make substantially all desired adjustments digitally. Similar to the DMD <NUM> above, the entire mirror array in the DMD <NUM> defines the same maximum area <NUM> for delivering photoactivating light as shown in <FIG>. The maximum area <NUM> includes the same boundaries 202a-d. Any part of the array of the DMD <NUM> can be activated to deliver light from any portion of this maximum area <NUM>. To eliminate the need for the X-Y motion system <NUM> employed for the illumination pattern <NUM> shown in <FIG>, the DMD <NUM> delivers an illumination pattern <NUM> that is significantly smaller than the illumination pattern <NUM>.

A comparison of <FIG> demonstrates the difference between the respective illumination patterns <NUM>, <NUM> within the same maximum area <NUM>. The smaller area illumination pattern <NUM> is generated by activating even less of the DMD array. The illumination pattern <NUM> is substantially circular and centered at a position (xc, yc) but has a diameter D<NUM> that is smaller than the diameter D<NUM> of the illumination pattern <NUM>. As such, there is more space between the illumination pattern <NUM> and the boundaries 202a-d than between the illumination pattern <NUM> and the boundaries 202a-d. This greater space allows the center of the illumination pattern <NUM> to be translated within the area <NUM> along the x-axis and/or y-axis to a greater degree than the center of the illumination pattern <NUM>. In other words, another part of the array of the DMD <NUM> can be activated to produce the illumination pattern <NUM> centered at a different position (xc+δx2, yc+δy2) where δx2 is greater than δx1, δy2 is greater than δy1, and δx1 and δy1 represent possible translation along respective axes with the treatment system <NUM>.

The translation of the illumination pattern <NUM> within the area <NUM> changes the position of corresponding photoactivating light as applied to the cornea <NUM>. Greater possible translation of the illumination pattern <NUM> with the DMD <NUM> allows greater range of adjustments for the delivery of the photoactivating light along the x-axis and/or y-axis. Thus, in response to eye movement detected via the camera <NUM>, the one or more controllers <NUM> can employ the DMD <NUM> to make substantially all desired adjustments so that the photoactivating light reaches specified areas of the cornea <NUM> to achieve desired results.

The treatment system <NUM> relies on the electromechanical X-Y motion system <NUM>, which might employ slower motors. In contrast, the DMD <NUM> can respond digitally to instructions at rates of approximately <NUM>, so the treatment system <NUM> can make positional adjustments to the delivery of photoactivating light more quickly.

By using the DMD <NUM>, the treatment system <NUM> can also make other positional corrections that are not possible with the X-Y motion system <NUM>. For instance, the treatment system <NUM> can respond more effectively to rotational changes in the position of the eye by applying a corresponding rotational transformation to the illumination pattern applied to the eye via the DMD <NUM>. <FIG> illustrates an initial illumination pattern 404a generated by activating a portion of the array of the DMD <NUM>. The illumination pattern 404a has an initial rotational state. When the treatment system <NUM> detects a rotational change in the position of the eye via the camera <NUM>, another portion of the array of the DMD <NUM> can be activated to generate an illumination pattern 404b shown in <FIG>. The illumination pattern 404b provides a geometric transformation of the initial illumination pattern 404a, with a different rotational state that responds to the rotational change in the position of the eye.

Additionally, the treatment system <NUM> can respond more effectively to geometric distortions caused by changes in eye gaze angle and/or head position. For instance, <FIG> illustrates an initial illumination pattern 504a generated by activating a portion of the array of the DMD <NUM>. As shown, the illumination pattern 504a is substantially circular. Preferably, the photoactivating light from the treatment system <NUM> is projected as predicted onto a desired plane (e.g., x-y plane) in the cornea <NUM> with a corresponding substantially circular shape. A change in eye gaze angle and/or head position, however, may change the angle of the desired plane in the cornea <NUM> and geometrically distort the projection of the photoactivating light into a shape that is different from the initial illumination pattern 504a. For instance, the change in eye gaze angle and/or head position may cause the illumination pattern 504a to be elongated, so that an elliptical shape is be projected onto the desired plane. When the treatment system <NUM> detects a change in eye gaze angle and/or head position via the camera <NUM>, another portion of the array of the DMD <NUM> can be activated to generate an illumination pattern 504b as shown in <FIG>. The illumination pattern 504b provides a geometric transformation of the initial illumination pattern 504a, with a different shape that can compensate for the geometric distortion caused by the change in eye gaze angle and/or head position. When the illumination pattern 504b is projected onto the desired plane of the cornea, the projection has precisely the desired shape. In particular, in the example of <FIG>, the projection has a substantially circular shape. In other applications, however, the projection may have other desired shapes (e.g., elliptical, etc.).

Using smaller illumination patterns provide a greater range of positional adjustments for the DMD <NUM>. As described above, a DMD provides an illumination pattern that is pixelated according to the array of mirrors. Because illumination patterns from the DMD are composed of a discrete number of pixels, smaller illumination patterns are composed of fewer pixels. As such, decreasing the size of an illumination pattern degrades the minimum resolvable spatial feature that can be projected onto the eye and can produce "pixelation" artifacts. As shown in <FIG>, the DMD <NUM> provides a maximum illumination area <NUM> defined by a plurality pixels 602a. The treatment system <NUM> can activate a subset of these pixels to produce a smaller illumination pattern that allows a greater range of positional adjustments. For instance, FIG. 602a illustrates the boundary (outline) of a desired illumination pattern <NUM>. Due to the size of the desired illumination pattern <NUM>, however, only pixels 604a fit substantially within the desired illumination pattern <NUM>. If only the pixels 604a are activated, portions of the desired illumination pattern <NUM> remain unfilled. If pixels 604b are activated to fill the remaining portions of the desired illumination pattern <NUM>, however, the resulting illumination pattern does not have the desired shape. In either case, the resulting illumination pattern does not have smoothed edges that correspond to the desired illumination pattern <NUM>. In general, the example of <FIG> demonstrates, for a given DMD array size, a tradeoff between the range of possible adjustments for active eye tracking with a DMD and resolution for achieving a desired illumination pattern.

<FIG> illustrates an approach for resolving the pixilation artifact illustrated by <FIG> and producing an illumination pattern with smoother edges that correspond to the desired illumination pattern <NUM>. In particular, the one or more controllers <NUM> can operate the DMD <NUM> to dither the pixels 604b at a rapid rate during the procedure. For instance, the pixels 604b can be alternately activated every second update cycle for the DMD <NUM>. The total dose of photoactivating light delivered by the pixels 604b when dithered during a procedure is less than activating the pixels 604b for the entire duration of the procedure. As such, dithering can be applied to provide a smoother illumination pattern that more closely approximates the desired illumination pattern <NUM> and the corresponding dose of photoactivating light.

<FIG> illustrates another approach for smoothing out the pixilation artifact illustrated by <FIG>. In particular, dithering can be applied by alternately shifting a base shape defined by the pixels 604a shown in <FIG> by +/- <NUM> pixel along the x-axis or the y-axis at interleaved time points. For instance, at one update cycle, the DMD <NUM> is operated to translate the base shape by one pixel in the positive-y direction (from the position shown in <FIG>) to include boundaries defined partially by the pixels 608a. At the next update cycle, the DMD <NUM> is operated to translate the base shape by one pixel in the positive-x direction (from the position shown in <FIG>) to include boundaries defined partially by the pixels 608b. At the next update cycle, the DMD <NUM> is operated to translate the base shape by one pixel in the negative-y direction (from the position shown in <FIG>) to include boundaries defined partially by the pixels 608c. At the next update cycle, the DMD <NUM> is operated to translate the base shape by one pixel in the negative-x direction (from the position shown in <FIG>) to include boundaries defined partially by the pixels 608d. These series of steps are repeated to provide a smoother illumination pattern that more closely approximates the desired illumination pattern <NUM> and the corresponding dose of photoactivating light.

The maximum acceptable pixel size for a DMD and optimal parameters for the embodiments above can be determined by biomechanical modeling of the response of the cornea to a cross-linking procedure.

<FIG> illustrate the use of increasing pixel size for delivering a substantially circular UV illumination pattern <NUM> with a diameter of approximately <NUM>. The illumination pattern <NUM> may be employed, for instance, to generate a corresponding area of cross-linking activity in the cornea to treat myopia. In <FIG>, the illumination pattern <NUM> is defined by pixels 708a, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 708b, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 708c, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 708d, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 708e, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 708f, which are <NUM> x <NUM> in size. The effects of eye motion on the illumination pattern <NUM> are modeled in <FIG> with a <NUM> blurring function along the edge of the illumination pattern <NUM>.

Correspondingly, <FIG> illustrate modeled changes (from pre-treatment to post-treatment) in tangential curvature of the anterior cornea following cross-linking treatments using increasing pixel size for delivering the UV illumination pattern <NUM> as shown in <FIG>, respectively. <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 708a (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 708b (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 708c (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 708d (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 708e (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 708f (<NUM> x <NUM>). TABLE <NUM> illustrates the change in keratometry (D) over the central <NUM> area for various pixel sizes.

<FIG> illustrate a modeled difference between the results of two cross-linking treatments using a larger pixel and a smaller pixel, respectively, for delivering a substantially circular UV illumination pattern. In particular, the larger pixel is <NUM> x <NUM> in size, and the smaller pixel is <NUM> x <NUM> in size. <FIG> illustrates the resulting elevation (µm) of the anterior cornea after using the larger pixel minus the resulting elevation (µm) in the anterior cornea after using the smaller pixel. <FIG> illustrates the resulting tangential curvature (D) of the anterior cornea after using the larger pixel minus the tangential curvature (D) of the anterior cornea after using the smaller pixel.

As the results of 8A-F and TABLE <NUM> demonstrate, however, the changes in tangential curvature and keratometry are effectively similar for treatments using pixel sizes of up to <NUM> x <NUM>, or even <NUM> x <NUM>, for substantially circular illumination patterns. The similar results of the larger pixel sizes (e.g., compared to smaller <NUM> x <NUM> pixels) allow effective implementation of the eye tracking approach of the example system <NUM> described above.

<FIG> illustrate the use of increasing pixel size for delivering a substantially annular UV illumination pattern <NUM>. The illumination pattern <NUM> has an inner diameter of approximately <NUM> and an outer diameter of approximately <NUM>. The illumination pattern <NUM> may be employed, for instance, to generate a corresponding area of cross-linking activity in the cornea to treat hyperopia or presbyopia. In <FIG>, the illumination pattern <NUM> is defined by pixels 1008a, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 1008b, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 1008c, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 1008d, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 1008e, which are <NUM> x <NUM> in size. In <FIG>, the illumination pattern <NUM> is defined by pixels 1008f, which are <NUM> x <NUM> in size. The effects of eye motion on the illumination pattern <NUM> are modeled in <FIG> with a <NUM> blurring function along the edge of the illumination pattern <NUM>.

Correspondingly, <FIG> illustrate modeled changes (from pre-treatment to post-treatment) in tangential curvature of the anterior cornea following cross-linking treatments using increasing pixel size for delivering the UV illumination pattern <NUM> as shown in <FIG>, respectively. <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 1008a (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 1008b (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 1008c (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 1008d (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 1008e (<NUM> x <NUM>). <FIG> illustrates the results when the illumination pattern <NUM> is defined by the pixels 1008f (<NUM> x <NUM>). TABLE <NUM> illustrates the change in keratometry (D) over the central <NUM> area for various pixel sizes.

<FIG> illustrate a modeled difference between the results of two cross-linking treatments using a larger pixel and a smaller pixel, respectively, for delivering a substantially annular UV illumination pattern. In particular, the larger pixel is <NUM> x <NUM> in size, and the smaller pixel is <NUM> x <NUM> in size. <FIG> illustrates the resulting elevation (µm) of the anterior cornea after using the larger pixel minus the resulting elevation (µm) in the anterior cornea after using the smaller pixel. <FIG> illustrates the resulting tangential curvature (D) of the anterior cornea after using the larger pixel minus the tangential curvature (D) of the anterior cornea after using the smaller pixel.

As the results of 11A-F and TABLE <NUM> demonstrate, however, the changes in tangential curvature and keratometry are effectively similar for treatments using pixel sizes of up to <NUM> x <NUM>, or even <NUM> x <NUM>, for substantially annular illumination patterns. Again, the similar results of the larger pixel sizes (e.g., compared to smaller <NUM> x <NUM> pixels) allow effective implementation of the eye tracking approach of the example system <NUM> described above.

Although the embodiments above may involve the use of a DMD device, other embodiments may employ any type of programmable spatial light modulator to achieve similar results. For instance, embodiments may employ a liquid crystal microdisplay, which is transmissive or reflective. Spatial light modulators that impart a polarization change can be used in conjunction with a fixed polarizer to achieve similar results. Transmissive implementations may also have additional advantages with respect to overall system size.

In view of the foregoing, embodiments employ a purely digital means for eye tracking that can be used with an illumination system to perform corneal cross-linking. In particular, the embodiments do not require electromechanical motion systems (e.g., for adjustments along an x-y plane) to keep the beam photoactivating light aligned with desired area of the subject's eye. Advantageously, this allows the cost and complexity of treatment systems to be significantly reduced. Additionally, among other advantages, the system allows for increased response time relative to other systems, adjustments to rotational movement of the eye, and compensation for geometric distortions caused by change in eye gaze angle and/or head movement.

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 <NUM>). 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.

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 image capture device(s) (e.g., the camera <NUM>), 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.

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.

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.

Claim 1:
A system for applying a cross-linking treatment to a cornea of an eye, comprising:
a light source (<NUM>) configured to emit a photoactivating light;
an oxygen delivery device (<NUM>) coupled to an oxygen source (<NUM>), the oxygen delivery device configured to deliver oxygen at a selected concentration to the cornea;
a spatial light modulator configured to receive the photoactivating light from the light source and provide a pixelated illumination with the photoactivating light; and
a controller (<NUM>) configured to cause the spatial light modulator to project a first pixelated illumination onto the cornea to generate cross-linking activity in a treatment area by photoactivating a cross-linking agent applied to the treatment area,
wherein the system is further configured to detect a change in eye gaze angle and/or head position, and in response to the change in eye gaze angle and/or head position, the controller is configured to control the spatial light modulator to generate a second pixelated illumination which is a geometric transformation of the first pixelated illumination to compensate for a geometric distortion caused by the change in eye gaze angle and/or head position, and to project the second pixelated illumination to the treatment area to continue photoactivating the cross-linking agent applied to the treatment area.