Photoactivation system and method for corneal cross-linking treatment

Abstract

To provide a system for treating an eye that includes a laser light source providing photoactivating light.SOLUTION: A system includes a scanning system to receive photoactivating light as a laser beam and to move the laser beam over a cornea treated with a cross-linking agent. The system includes a controller that provides control signal(s) to programmatically control a laser light source and the scanning system. The control signal(s) cause the laser beam to visit region(s) of the cornea more than once according to a scan pattern and expose the region(s) to the photoactivating light. The photoactivating light causes the cross-linking agent in the exposed region(s) to react with oxygen to generate cross-linking activity in the exposed region(s). The scan pattern causes a predetermined period of time to pass between visits by the laser beam to the exposed region(s), the predetermined period of time allowing oxygen in the exposed region(s) to replenish.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 883,197, filed August 6, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to systems and methods for ocular treatment, and more particularly, to systems and methods for photoactivating crosslinking agents. [Background technology]

[0003] 2. Description of Related Art Cross-linking treatments can be used to treat eyes affected by diseases such as keratoconus. In particular, keratoconus is a degenerative disease of the eye in which structural changes within the cornea weaken it and cause it to deform into an abnormal conical shape. Cross-linking treatments can strengthen and stabilize the areas weakened by keratoconus, preventing undesirable shape changes.

[0004] Crosslinking therapy can also be used after surgical procedures such as LASIK (Laser-Assisted in site Keratomileusis) surgery. For example, LASIK surgery can thin and weaken the cornea, which can lead to a complication known as post-LASIK ectasia. Post-LASIK ectasia causes progressive steepening (bulging) of the cornea. Therefore, crosslinking therapy can strengthen and stabilize the structure of the cornea after LASIK surgery and prevent post-LASIK ectasia.

[0005] Crosslinking treatments can also be used to induce refractive changes in the cornea to correct disorders such as myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia. Summary of the Invention

[0006] Each embodiment includes a system and method for photoactivating a crosslinking agent in a corneal crosslinking treatment. The use of a laser light source to achieve a scanning light pattern can provide advantages for photoactivating a crosslinking agent. In particular, the scanning parameters of the laser can be optimized to enhance the effectiveness of an individual treatment. For example, crosslinking activity can be enhanced by controlling the treatment time, total dose, intensity / irradiance of the laser beam, pulsing of the laser beam, size of the spot defined by the laser beam (laser spot size), speed or duration of application of the laser spot, and / or frequency of repetition of parts of the scanning pattern. Such parameters can be optimized according to the speed of the photochemical reactions involved in the crosslinking activity as described above. These reactions determine the consumption and replenishment of oxygen during crosslinking activity, the supply and photolysis of crosslinking agent molecules, and the depth of action.

[0007] An example of a system for treating an eye according to an embodiment includes a laser light source configured to provide photoactivating light. The system includes a scanning system configured to receive the photoactivating light as a laser beam and move the laser beam over a cornea treated with a crosslinking agent. The system includes a controller configured to provide control signals to programmatically control the laser light source and the scanning system. The one or more control signals cause the laser beam to visit one or more areas of the cornea multiple times according to a scanning pattern to expose the one or more areas to the photoactivating light. The photoactivating light causes the crosslinking agent in the one or more exposed areas to react with oxygen, thereby generating crosslinking activity in the one or more exposed areas. The scanning pattern allows a predetermined time to elapse between each visit of the laser beam to the one or more exposed areas, which allows oxygen to be replenished in the one or more exposed areas to generate a desired amount of crosslinking activity with sufficient oxygen between each visit of the one or more exposed areas.

[0008] A method of treating an eye according to another exemplary embodiment includes generating photoactivating light using a laser light source. The method includes directing the photoactivating light as a laser beam to a scanning system. The method includes operating the scanning system to move the laser beam over the cornea and visit one or more areas of the cornea multiple times according to a scanning pattern to expose the one or more areas to the photoactivating light. The photoactivating light reacts the crosslinking agent in the one or more exposed areas with oxygen to generate crosslinking activity in the one or more exposed areas. The method includes optimizing the scanning pattern to allow a predetermined time to elapse between each visit of the laser beam to the one or more exposed areas, the predetermined time allowing oxygen to be replenished in the one or more exposed areas and allowing sufficient oxygen to generate a desired amount of crosslinking activity between each visit of the one or more exposed areas. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 illustrates an exemplary system for administering a crosslinking agent and photoactivating light to the cornea of ​​an eye to generate crosslinks of corneal collagen, according to aspects of the present disclosure. [Figure 2A] FIG. 13 illustrates an example of a circular treatment pattern that can be generated using an XY scanning mirror pair. [Figure 2B] FIG. 13 illustrates an example of an annular treatment pattern that can be generated using an XY scanning mirror pair. [Diagram 3] FIG. 1 illustrates an example of a treatment system that provides a laser-based approach to projecting a pattern of photoactivating light onto the cornea using an XY scanning system, according to an embodiment of the present disclosure. [Figure 4]FIG. 4A is a diagram illustrating an example of a treatment zone according to an embodiment of the present disclosure, where the laser beam has a spot size with a diameter large enough to apply photoactivating light in a spiral to 100% of an area defined by a substantially circular boundary; FIG. 4B is a diagram illustrating another exemplary treatment zone according to an embodiment of the present disclosure, where the laser beam has a spot size with a diameter that is 50% of the diameter shown in FIG. 4A; and FIG. 4C is a diagram illustrating yet another exemplary treatment zone according to an embodiment of the present disclosure, where the laser beam has a spot size with a diameter that is 25% of the diameter shown in FIG. 4A. [Diagram 5] FIG. 1 illustrates a flow chart of an exemplary process for optimizing laser scanning parameters for a cross-linking process, according to an aspect of the present disclosure. [Figure 6] FIG. 1 illustrates an exemplary repeat cycle for laser scanning in crosslinking treatment, according to aspects of the present disclosure. [Figure 7] FIG. 13 illustrates oxygen concentration and fluorescence intensity for a cross-linking agent at a location during an exemplary cross-linking treatment using laser scanning, according to aspects of the present disclosure. [Figure 8A] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes where the epithelial layer is left on the eye (epi-on), according to an embodiment of the present disclosure. [Figure 8B] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes where the epithelial layer is left on the eye (epi-on), according to an embodiment of the present disclosure. [Figure 8C] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes where the epithelial layer is left on the eye (epi-on), according to an embodiment of the present disclosure. [Figure 8D] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes where the epithelial layer is left on the eye (epi-on), according to an embodiment of the present disclosure. [Figure 8E] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes where the epithelial layer is left on the eye (epi-on), according to an embodiment of the present disclosure. [Figure 9A]FIG. 13 illustrates the curvature changes resulting from treatment of five eyes in which the epithelial layer is completely removed (epi-off), according to an embodiment of the present disclosure. [Figure 9B] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes in which the epithelial layer is completely removed (epi-off), according to an embodiment of the present disclosure. [Figure 9C] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes in which the epithelial layer is completely removed (epi-off), according to an embodiment of the present disclosure. [Figure 9D] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes in which the epithelial layer is completely removed (epi-off), according to an embodiment of the present disclosure. [Figure 9E] FIG. 13 illustrates the curvature changes resulting from treatment of five eyes in which the epithelial layer is completely removed (epi-off), according to an embodiment of the present disclosure. [Figure 10] 1A-1C illustrate aspects of an exemplary scanning pattern defined by discrete dots applied according to a grid within a boundary defining a treatment zone, in accordance with aspects of the present disclosure. [Figure 11] 11A-11C illustrate different example combinations of parameter values ​​for laser scanning to dispense discrete dots according to a grid within a boundary defining a treatment zone, in accordance with aspects of the present disclosure. [Figure 12A] 13A-13C show example scanner position graph time series for implementation of the treatment parameter combinations shown in row B of FIG. 11 using different respective values ​​for maximum travel distance (MTD), in accordance with an embodiment of the present disclosure. [Figure 12B] FIG. 13 illustrates an example of a scanner position graph time series for an implementation of the treatment parameter combinations shown in row B of FIG. 11 using different respective values ​​for maximum travel distance (MTD), in accordance with an embodiment of the present disclosure. [Figure 12C] FIG. 13 illustrates an example of a scanner position graph time series for an implementation of the treatment parameter combinations shown in row B of FIG. 11 using different respective values ​​for maximum travel distance (MTD), in accordance with an embodiment of the present disclosure. [Figure 13]FIG. 13 illustrates the delay between eye position and application of photoactivating light due to the finite response time of the eye discrete-time detection and treatment system, according to aspects of the present disclosure. [Figure 14] FIG. 1 illustrates an example approach for accounting for position errors in a modified grid-based point-and-shoot approach, in accordance with aspects of the present disclosure. [Figure 15] FIG. 1 illustrates an example of a raster scan pattern according to aspects of the present disclosure. [Figure 16] FIG. 2 illustrates an exemplary zigzag scan pattern, according to aspects of the present disclosure. [Figure 17] FIG. 1 illustrates an exemplary treatment system providing a laser-based approach for projecting a pattern of photoactivating light onto the cornea using a diffractive multi-beam splitter in accordance with aspects of the present disclosure. [Figure 18] FIG. 1 illustrates an exemplary treatment system providing a laser-based approach for projecting a pattern of photoactivating light onto the cornea using a diffractive beam shaper in accordance with aspects of the present disclosure. [Figure 19A] FIG. 13 illustrates an exemplary annular treatment pattern having an outer diameter of approximately 4 mm, generated by pulsing the laser beam with a 50% duty cycle and a fixed pulse frequency on a helical trace, according to an embodiment of the present disclosure. [Figure 19B] FIG. 13 shows an exemplary annular treatment pattern having an outer diameter of approximately 8 mm, generated by pulsing the laser beam with a 50% duty cycle and a fixed pulse frequency on a helical trace, according to an embodiment of the present disclosure. [Figure 20A] FIG. 13 illustrates an exemplary annular treatment pattern having an outer diameter of approximately 4 mm, generated by pulsing the laser beam with a 50% duty cycle and variable pulse frequency on a helical trace, according to an embodiment of the present disclosure. [Figure 20B]FIG. 13 illustrates an exemplary annular treatment pattern having an outer diameter of approximately 8 mm, generated by pulsing the laser beam with a 50% duty cycle and variable pulse frequency on a helical trace, according to an embodiment of the present disclosure. [Figure 20C] FIG. 1 illustrates an exemplary annular treatment pattern having an outer diameter of about 9 mm generated by a laser beam with variable pulse frequency, according to an embodiment of the present disclosure. [Figure 21] FIG. 13 illustrates example waveforms for driving galvanometers, as well as laser modulation waveforms during a portion of a treatment using laser scanning, according to aspects of the present disclosure. [Figure 22A] FIG. 13 illustrates an example waveform for driving a galvanometer during full treatment, in accordance with aspects of the present disclosure. [Figure 22B] FIG. 22B illustrates a laser modulation waveform for the treatment of FIG. 22A according to an embodiment of the present disclosure. [Diagram 23] FIG. 1 illustrates an example laser modulation waveform divided into multiple radial zones, in accordance with aspects of the present disclosure. [Figure 24A] FIG. 13 illustrates an exemplary annular treatment pattern with an outer diameter of approximately 4 mm generated with a pulsed laser beam scanned with a variable laser modulation frequency implementing a laser modulation waveform divided into multiple radial zones based on modulation frequency limits, in accordance with an embodiment of the present disclosure. [Figure 24B] FIG. 24B illustrates an exemplary laser modulation waveform divided into multiple radial zones based on modulation frequency limits for the treatment of FIG. 24A in accordance with an embodiment of the present disclosure. [Figure 25A] FIG. 13 illustrates an exemplary annular treatment pattern with an outer diameter of approximately 9 mm generated with a pulsed laser beam scanned with a variable laser modulation frequency implementing a laser modulation waveform divided into multiple radial zones based on modulation frequency limits, in accordance with an embodiment of the present disclosure. [Figure 25B] FIG. 25B illustrates an exemplary laser modulation waveform divided into multiple radial zones based on modulation frequency limits for the treatment of FIG. 25A in accordance with an embodiment of the present disclosure. [Figure 26A] FIG. 26 illustrates an exemplary annular treatment pattern 2600a with an outer diameter of approximately 9 mm generated with a pulsed laser beam scanned with a variable laser modulation frequency implementing a laser modulation waveform having one radial zone based on modulation frequency limits, in accordance with an embodiment of the present disclosure. [Figure 26B] FIG. 25B illustrates an exemplary laser modulation waveform having one radial zone based on the modulation frequency limits for the treatment of FIG. 25A, according to an embodiment of the present disclosure. [Figure 27] 4A-4C illustrate aspects of spot profiles generated by a pulsed laser beam moving along a scan in accordance with an aspect of the present invention. [Figure 28-1] FIG. 28A illustrates a Gaussian laser spot with a laser modulation frequency of 25 kHz, and FIG. 28B illustrates a Gaussian laser spot with a laser modulation frequency of 50 kHz, according to an embodiment of the present invention. [Figure 28-2] FIG. 28C illustrates a Gaussian laser spot with a laser modulation frequency of 75 kHz, and FIG. 28D illustrates a Gaussian laser spot with a laser modulation frequency of 100 kHz, according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] While the disclosure is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail, It should be understood, however, that the disclosure is not intended to be limited 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 disclosure.

[0011] FIG. 1 illustrates one exemplary treatment system 100 for creating collagen cross-linking in a cornea 2 of an eye 1. The treatment system 100 includes an applicator 132 that applies a cross-linking agent 130 to the cornea 2. In this exemplary embodiment, the applicator 132 may be an eye dropper, syringe, or the like that applies the photosensitizer agent 130 as droplets to the cornea 2. Exemplary systems and methods for applying the cross-linking agent are described in U.S. Patent Application Publication No. 2017 / 0296383, filed April 13, 2017, tabled under "Systems and Methods for Delivering Drugs to an Eye," the contents of which are incorporated herein by reference in their entirety.

[0012] 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 to reach the underlying area of ​​the corneal stroma 2b (also known as an "epi-on" procedure). 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 (also known as an "epi-off" procedure).

[0013] The treatment system 100 includes an illumination system having a light source 110 and an optical element 112 for directing light to the cornea 2. In some embodiments, the light source 110 can include a light emitting diode (LED). In other embodiments, the light source 110 can provide a laser. The light causes photoactivation of the crosslinking agent 130 to generate crosslinking activity in the cornea 2. For example, the crosslinking agent can include riboflavin and the photoactivating light can include ultraviolet A (UVA) light (e.g., about 365 nm or 375 nm, or a wavelength that falls within the band of 315 nm to 400 nm). Alternatively, the photoactivating light can include another wavelength, such as a visible wavelength (e.g., about 452 nm), or any other wavelength selected to activate the photosensitizer. As described further below, corneal crosslinking improves corneal strength by creating chemical bonds in the corneal tissue according to a system of photochemical reactions.

[0014] Riboflavin and photoactivated light can be administered to stabilize and / or strengthen corneal tissue to address corneal ectatic disorders such as keratoconus or post-LASIK ectasia. Administration of riboflavin and photoactivated light can also enable various degrees of refractive correction, including, for example, combinations of myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia, and complex corneal refractive surface correction due to corneal ectatic disorders and other conditions such as corneal biomechanical changes / degeneration.

[0015] The treatment system 100 includes one or more controllers 120 that control aspects of the treatment system 100, including the light source 110 and / or the optical element 112. In one embodiment, the cornea 2 can be broadly treated with a crosslinking agent 130 (e.g., using eye droppers, a syringe, etc.), and photoactivating light from the light source 110 can be selectively directed according to a particular pattern to the areas of the cornea 2 to be treated.

[0016] The optical element 112 may include one or more mirrors, lenses, or other optical components to direct and focus the photoactivating light emitted by the light source 110 in a particular pattern on the cornea 2. The optical element 112 may further include filters to partially block wavelengths of light emitted by the light source 110 and select particular wavelengths of light to be directed to the cornea 2 to photoactivate the crosslinking agent 130. Additionally, the optical element 112 may include one or more beam splitters to split the beam of light emitted by the light source 110 and may include one or more optical sinks to absorb the light emitted by the light source 110. The optical element 112 may also accurately and precisely focus the photoactivating light to a particular focal plane within the cornea 2 (e.g., a particular depth within the lower region 2b where crosslinking activity is desired).

[0017] According to some aspects, the optical elements of the exemplary treatment system can use fiber optic elements. The use of fiber optic elements can eliminate the need for free space optics and opto-mechanical mounts in the treatment system. Advantageously, the use of optical fibers can reduce the size and footprint of the treatment system, reduce design and manufacturing complexity and cost, and increase reliability.

[0018] Additionally, the specific characteristics of the photoactivating light can be altered to achieve a desired degree of crosslinking in selected areas of the cornea 2. One or more controllers 120 can be used to control the operation of the light source 110 and / or optical elements 112 to precisely dispense the photoactivating light according to any combination of wavelength, bandwidth, intensity, power, position, depth of penetration, and / or treatment time (duration of exposure cycles, duration of dark cycles, and ratio of duration of exposure cycles to dark cycles).

[0019] Parameters for light activation 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 one implementation, the time can be reduced from minutes to seconds. Some configurations use light with powers of up to 5 mW / cm. 2 Although the photoactivating light can be irradiated at an irradiance of 1000 nm to 1500 nm, a larger irradiance of the photoactivating light, e.g., 5 mW / cm2, can be used. 2 to reduce the time required to achieve the desired crosslinking. The total dose of energy absorbed by the cornea 2 can be expressed as an effective dose, which is the amount of energy absorbed through an area of ​​the corneal epithelium 2a. For example, the effective dose for an area of ​​the corneal surface 2A can be, for example, 5 J / cm 2 , or 20 J / cm 2 , or 30 J / cm 2 The effective doses listed can be from a single administration of energy or from repeated administrations of energy.

[0020] The optical element 112 of the present treatment system 100 can include a MicroElectroMechanical System (MEMS) device, such as a Digital Micro-mirror Device (DMD), to spatially and temporally modulate the irradiation of the photoactivating light. Using DMD technology, the photoactivating light from the light source 110, such as an LED, is projected in a precise spatial pattern generated by microscopically tiny mirrors arranged in an array on a semiconductor chip. Each mirror represents one or more pixels in the projected light pattern. The DMD can be used to perform topography-induced crosslinking. Control of the DMD according to the topography can use several different spatial and temporal irradiance and dose profiles. As further described below, these spatial and temporal dose profiles can be created using continuous wave (CW) irradiation, but can also be modulated via pulsed irradiation by pulsing the irradiation source with varying frequency and duty cycle. Alternatively, the DMD can be tuned to different frequencies and duty cycles for each pixel to give ultimate flexibility using continuous wave illumination. Alternatively, both pulsed illumination and a combination of tuned DMD frequencies and duty cycles can be combined. This allows for a specific amount of spatially determined corneal crosslinking. This spatially determined crosslinking can be combined with dosimetry, interferometry, optical coherence tomography (OCT), corneal topography, etc. for pre-treatment planning and / or real-time monitoring and adjustment of corneal crosslinking during treatment. Additionally, pre-clinical patient information can be combined with finite element biomechanical computer modeling to create a patient-specific pre-treatment plan.

[0021] To control aspects of the projection of the photoactivating light, embodiments may also use aspects of multi-photon excitation microscopy. In particular, rather than irradiating the cornea 2 with a single photon of a particular wavelength, the treatment system 100 may irradiate multiple photons of longer wavelengths, i.e., lower energy, that combine to initiate crosslinking. Advantageously, longer wavelengths are scattered less within the cornea 2 than shorter wavelengths, allowing longer wavelengths of light to penetrate the cornea 2 more efficiently than shorter wavelengths. The shielding effect of incident radiation at greater depths within the cornea is also reduced compared to conventional shorter wavelength radiation, since light is absorbed less by the photosensitizer at longer wavelengths. This allows for increased control over depth-specific crosslinking. For example, in some embodiments, two photons may be used, with each photon carrying approximately half the energy required to excite molecules in the crosslinking agent 130 to generate the photochemical reaction kinetics described further below. When the crosslinking agent molecules simultaneously absorb both photons, they absorb enough energy to release reactive radicals in the corneal tissue. Embodiments may also utilize low energy photons, such that a crosslinker molecule must absorb, for example, three, four, or five photons simultaneously to release a reactive radical. The probability of near simultaneous absorption of multiple photons is low, and therefore a high flux of excitation photons is required, which can be provided through a femtosecond laser.

[0022] A number of conditions and parameters affect the crosslinking of the corneal collagen with the crosslinking agent 130. For example, the irradiance and dose of the photoactivating light affect the amount and rate of crosslinking. The UVA light can be applied as a continuous light (CW: continuous wave) or pulsed light, the choice of which affects the amount, rate, and extent of crosslinking. When the UVA light is applied as a pulsed light, the duration of the exposure cycle, the duration of the dark cycle, and the ratio of the duration of the exposure cycle to the dark cycle affect the resulting corneal stiffening. The same amount of energy applied using pulsed light irradiation, or the same amount of continuous wave irradiation, can result in more or less stiffening of the corneal tissue than can be achieved. Light pulses of appropriate length and frequency can be used to achieve more optimal chemical amplification. For pulsed light treatment, the on / off duty cycle can be between about 1000 / 1 to about 1 / 1000. The irradiance can be adjusted to an average irradiance of about 1 mW / cm. 2 ~About 1000mW / cm 2 and the pulse rate can be between about 0.01 Hz and about 1000 Hz, or between about 1000 Hz and about 100,000 Hz.

[0023] The present therapeutic system 100 can generate pulsed light by using a DMD, electronically turning the light source 110 on and off, and / or using a mechanical or optoelectronic (e.g., Pockels cell) shutter or mechanical chopper or rotating aperture. Due to the inherent modulation capability of the DMD's pixels and the subsequent stiffness imparted based on the modulated frequency, duty cycle, irradiance, and dose delivered to the cornea, complex biomechanical stiffness patterns can be imparted to the cornea. A particular advantage of the DMD system and method is that it allows randomized asynchronous pulsed topographic patterning to generate aperiodic and uniform appearing illumination, thereby eliminating the possibility of inducing photosensitive epileptic seizures or flicker dizziness to pulse frequencies between 2 Hz and 84 Hz.

[0024] While the present exemplary embodiment may use a stepped on / off pulsed light function, it is understood that other functions for irradiating the cornea with light may be used to achieve a similar effect. For example, light may be irradiated to the cornea according to a sinusoidal function, a sawtooth function, or other complex functions or curves, or any combination of those functions or curves. In fact, it is understood that the function may be substantially stepped, where there may be a more gradual (stepped) transition between the on / off values. Furthermore, it is understood that the irradiance need not decrease to a value of 0 during the off cycle, but may exceed 0 during the off cycle. The desired effect may be achieved by irradiating the cornea with light according to a curve that varies the irradiance between two or more values.

[0025] Examples of systems and methods for applying photoactivating light are described, for example, in U.S. Patent Application Publication No. 2011 / 0237999, entitled "Systems and Methods for Applying and Monitoring Eye Therapy," filed March 18, 2011, U.S. Patent Application Publication No. 2012 / 0215155, entitled "Systems and Methods for Applying and Monitoring Eye Therapy," filed April 3, 2012, and U.S. Patent Application Publication No. 2013 / 0245536, entitled "Systems and Methods for Corneal Cross-Linking with Pulsed Light," filed March 15, 2013, the contents of which are incorporated herein by reference in their entireties. Embodiments can generate cross-linking activity in the cornea according to circular and / or annular patterns defined by application of photoactivating light (e.g., via a DMD as described above). Additionally or alternatively, embodiments can generate cross-linking activity in the cornea according to non-circular and / or non-annular patterns defined by application of photoactivating light (e.g., via a DMD).

[0026] Multiple patterns of photoactivating light can be delivered to the eye (e.g., via a DMD) in separate treatment zones, delivered sequentially or sequentially at different doses. For example, one treatment zone can be "turned off" (i.e., the corresponding photoactivating light is stopped from being delivered) while another treatment zone can be "left on" (i.e., the corresponding photoactivating light continues to be delivered). The treatment zones can be formed, for example, in an annular shape around a central point of the eye. There can also be discontinuous zones where the photoactivating light is not applied (e.g., a central treatment zone surrounded by a ring of no light surrounded by an annular light treatment zone). The width of the annular zones can be of different dimensions, for example, one annular zone may have a width of 1 mm and another zone may have a width of 2 mm. Delivering photoactivating light to an annular treatment zone in the periphery of the eye without a central treatment zone can provide hyperopia correction, for example, by increasing the curvature of the central region of the eye while the periphery is strengthened. In some cases, for example to address astigmatism, the central and peripheral treatment zones can be elliptical in shape by preferentially generating cross-linking activity in areas of the cornea to correct the astigmatism. Such elliptical shaped annular treatment zones are preferentially oriented with the axis of the annular treatment zone aligned according to the orientation of the astigmatism. Elliptical shaped treatment zones can also be irregularly asymmetric (i.e., the major and minor axes are not perpendicular and can be located at separate central points (centroids)).

[0027] The crosslinking treatment can be tailored according to one or more biomechanical properties of the eye, such as corneal topography (i.e., shape), corneal strength (i.e., stiffness), and / or corneal thickness. Optical correction and / or strengthening of the cornea can be achieved by administering the crosslinking agent and / or photoactivating light in one or more repeated applications, with adjustable properties for each repetition. In general, the treatment plan developed can include multiple applications of the crosslinking agent, the dosage and concentration of the crosslinking agent for each application, the number of applications of the photoactivating light, and the timing, duration, power, energy dosage, and pattern of the photoactivating light for each application. Additionally, the crosslinking treatment can be adapted based on feedback information regarding the biomechanical properties collected in real time during treatment or during interruptions in treatment.

[0028] Riboflavin undergoes photoactivation upon absorption of irradiated energy, particularly light. There are two photochemical kinetic pathways for the photoactivation of riboflavin: Type I and Type II. The reactions involved in both the Type I and Type II mechanisms, as well as other aspects of the photochemical kinetic reactions that generate cross-linking activity, are described in U.S. Patent No. 10,350,111, entitled "Systems and Methods for Cross-Linking Treatments of an Eye," filed April 27, 2016, the contents of which are incorporated herein by reference in their entirety.

[0029] The corneal crosslinking reaction is rate-limited by the oxygen concentration in the corneal tissue. Thus, the addition of oxygen also affects the amount of crosslinking in the cornea. In human tissue, the O2 content is very low compared to the atmosphere. However, the crosslinking rate in the cornea is related to the concentration of O2 at the time of irradiation with photoactivating light. Therefore, it may be advantageous to actively increase or decrease the concentration of O2 during irradiation to control the crosslinking rate so that a desired amount of crosslinking is achieved. Oxygen can be administered in many different ways during crosslinking treatment. One approach involves supersaturating riboflavin with O2. When riboflavin is administered to the eye, a higher concentration of O2 is administered directly to the cornea along with the riboflavin, which affects the reaction involving O2 when exposed to photoactivating light. According to another approach, a steady state of O2 (at a selected concentration) is maintained at the surface of the cornea, and the cornea is exposed to a selected amount of O2, allowing O2 to enter the cornea. 1, the treatment system 100 also includes an oxygen source 140 and an oxygen delivery device 142 that optionally delivers a selected concentration of oxygen to the cornea 2. Exemplary systems and methods for administering oxygen during crosslinking treatment are described, for example, in U.S. Patent No. 8,574,277, entitled "Eye Therapy," filed October 21, 2010, and U.S. Patent Application Publication No. 2013 / 0060187, entitled "Systems and Methods for Corneal Crossing-Linking with Pulsed Light," filed October 31, 2012, the contents of which are incorporated herein by reference in their entireties. Additionally, one example of a mask device for delivering concentrations of oxygen and photoactivating light in treating an eye is described in U.S. Patent Application Publication No. 2017 / 0156926, entitled "Systems and Methods for Treating an Eye with a Mask Device," filed December 3, 2016, the contents of which are incorporated herein by reference in their entirety.For example, a mask can be placed over the eye to generate a constant, known concentration of oxygen on the surface of the eye.

[0030] As described above, the treatment system 100 includes an optical element 112 that directs light (e.g., UV light) from a light source 110 to a cornea 2 that has been administered a cross-linking agent 130e (e.g., riboflavin) to cause cross-linking activity and photoactivation. In particular, the photoactivating light can be selectively directed to regions of the cornea 2 according to specific spatial treatment patterns. In some embodiments, the treatment system can provide adjustable treatment patterns such that different ocular conditions can be treated with the same treatment system.

[0031] One example of a treatment system that treats different eye diseases by providing different treatment patterns is described in U.S. Patent Application Publication No. 2020 / 0107953, entitled "Photoactivation Systems and Methods for Corneal Cross-Linking Treatments," filed October 9, 2019, the contents of which are incorporated herein by reference in their entirety.

[0032] [Scanning treatment system] The optical elements of the exemplary treatment system include an XY scanning mirror pair (e.g., instead of a DMD) that can scan a UV light beam to form a UV light pattern with a small, high-quality spot. (The corneal depth is measured along the z-axis, and the photoactivating light pattern can be projected onto the lateral xy plane.) For example, Figure 2A shows an exemplary circular treatment pattern 200a that can be generated using an XY scanning mirror pair. Figure 2B shows an exemplary annular treatment pattern 200b that can be generated using an XY scanning mirror pair.

[0033] FIG. 3 illustrates an exemplary scanning treatment system 300. The treatment system 300 includes a UV (e.g., UVA) laser source 310 and a galvanometer mirror system (or biaxial MEMS mirror) 312 that functions as an XY scanning system. The laser source 310 can be a Xenon Fluoride (XeF) excimer laser, a femtosecond pulsed laser, or a laser diode. The laser source 310 can be implemented with an optical amplitude modulator (either internal or external to the laser source 310). The treatment system 300 includes a controller 320 that can control aspects of the treatment system 300. In particular, the controller 320 can trigger the laser source 310 to emit a laser beam in pulses as described above.

[0034] The laser beam from the laser source 310 produces a small, high-quality spot on the galvanometer mirror system 312. The galvanometer mirror system 312 includes an X mirror 312a capable of scanning the UV light beam in an x-direction and a Y mirror 312b capable of scanning the UV light beam in a y-direction. The controller 320 can control the galvanometer mirror system 312 to scan the laser beam in the X-direction and the Y-direction according to a predefined scan pattern 10. The scan pattern 10 can displace the X mirror 312a and the Y mirror 312b to scan the laser beam in the X-direction and the Y-direction, respectively. In particular, the controller 320 can send an X position signal to the X mirror 312a to control the tilt angle of the X mirror 312a to direct the laser beam to a desired position along the X-axis. In this regard, the controller 320 can send a Y position signal to the Y mirror 312b to control the tilt angle of the Y mirror 312b to direct the laser beam to a desired position along the y-axis. The treatment system 300 also includes a lens 314 (e.g., a telecentric, f-theta, or other scanning lens) that delivers the scanned laser beam to the cornea 2. Additionally or alternatively, a lens can be placed between the laser 310 and the X-mirror 312a. The light from the laser source 310 can be delivered via free space or can be coupled to an optical fiber for delivery in the vicinity of the galvanometer mirror system 312 or the lens 314. Optical fiber delivery has the added advantage of allowing the laser source 310 to be located away from other system elements, simplifying the system design. The speed of the first and / or second mirrors of the galvanometer mirror system 312 can be adjusted during a portion of the scan to increase or decrease the dwell time over the portion of the scan pattern, thereby adjusting the corresponding dose of UV light delivered to the portion of the scan pattern.

[0035] The treatment system 300 also includes an eye tracking system. In particular, the treatment system 300 includes an eye position and orientation detection system 316 (e.g., a camera that captures images of the eye 1). The controller 320 can receive and process information (e.g., images) from the eye position detection system 316 to determine the position of the cornea 2 relative to the treatment system 300. To compensate for changes in the position of the cornea 2, the controller 320 can control the galvanometer mirror system 312 to adjust the scanned laser beam to apply the scan pattern 10 to a desired area of ​​the cornea 2. In this manner, the detection system 316 and the controller 320 combine to provide an eye tracking system.

[0036] In general, the scanning treatment system can apply photoactivating light according to a pattern to obtain a predetermined treatment zone (e.g., circular, annular, or other shape) on the corneal surface. The scanning pattern can be defined by a continuous line. As shown in the exemplary patterns 200a, 200b in Figures 2A-2B, the continuous line can be formed by scanning a laser in a connected piecewise path.

[0037] Alternatively, a continuous line may be formed by scanning the laser without interruption. For example, as shown in Figures 4A-C, a continuous line can be formed by scanning the laser in a spiral 404 without interruption.

[0038] Additionally or alternatively, the aspect of the scan pattern may be defined by a number of unconnected straight or curved lines. For example, the scan pattern may include a line defined by a series of dashes (-).

[0039] Additionally or alternatively, aspects of the scan pattern may be defined by a plurality of discrete dots. For example, the scan pattern may include a line defined by a series of discrete dots. In some embodiments, a series of discrete dots may be applied in conjunction with an optical element, such as a diffractive element, as described further below, to simultaneously form multiple laser spots that are discretely scanned to define a treatment zone.

[0040] Various types of photoactivating light patterns for crosslinking treatment are described herein. The selection of the pattern can depend on different optimization criteria, including but not limited to uniformity of the dose of photoactivating light across the treatment zone, maximum crosslinking efficiency desired, and maximum correction (e.g., refractive correction) to the eye. Furthermore, the selection of the pattern may be constrained by considerations including but not limited to compliance with eye safety standards, a predetermined treatment time, a predetermined light dose, scanning speed limitations imposed by the optics and other components of the treatment system, and the power specifications of the laser.

[0041] [Laser scanning optimization] Using a laser light source to obtain a scanned light pattern can provide advantages for corneal crosslinking treatment over approaches using LED light sources. In particular, the scanning parameters of the laser can be optimized to enhance the effectiveness of the individual treatments. For example, the treatment time, the total dose, the intensity / irradiance of the laser beam, the pulses of the laser beam, the size of the spot defined by the laser beam (laser spot size), the speed or duration of the irradiation of the laser spot, and / or the frequency of repetition of parts of the scanning pattern can be controlled to enhance the crosslinking activity. Such parameters can be optimized according to the photochemical reaction rates involved in the crosslinking activity as described above. These reactions determine the consumption and replenishment of oxygen during the crosslinking activity, the supply and photolysis of the crosslinker molecules, and the depth of action / effect.

[0042] For example, the laser spot size can be optimized to achieve the desired treatment. Figures 4A-4C also illustrate how different treatment zones can be achieved by varying the laser spot size. Specifically, Figure 4A illustrates an exemplary treatment zone 400a in which the beam from a laser source, e.g., UV laser source 210 or UV light source 310, forms a spot size with a diameter 402a large enough to irradiate the photoactivating light in a spiral 404 for 100% of the area 408 defined by a substantially circular boundary 406. Meanwhile, Figure 4B illustrates an exemplary treatment zone 400b in which the beam from the laser source has a spot size with a diameter 402b that is 50% of the diameter shown in Figure 4A. In this case, as the beam in Figure 4B travels along the same spiral 404, the photoactivating light is irradiated in less of the area 408 defined by the substantially circular boundary 406. As shown in FIG. 4B, the diameter 402b is too small to allow the laser beam to cover all of the space between adjacent portions of the spiral 404. FIG. 4C shows yet another exemplary treatment zone 400c in which the beam from the laser source has a spot size with a diameter 402c that is 25% of the diameter 402a shown in FIG. 4A. In this case, as the beam of FIG. 4C moves over the same spiral 404, the photoactivating light is irradiated over even less of the area 408 defined by the substantially circular boundary 406. Thus, by varying the laser spot size, the area of ​​the cornea that receives the photoactivating light and experiences crosslinking activity (treatment zone) can be determined. Optimizing the size of the laser spot in relation to the pitch of the spiral pattern has the effect of increasing oxygen diffusion from the untreated spot to the treated spot, which is advantageous for maintaining aerobic conditions in the treated spot, and therefore increasing crosslinking efficiency.

[0043] Additionally or alternatively, the repetition frequency of the portions of the scan pattern can be optimized to achieve the desired treatment. For example, the laser beam can pass through a portion of a given scan pattern multiple times. Furthermore, the laser beam can scan these portions in different sequences. For example, the scan pattern can include portions A, B, and C. In a first pass, the laser beam can move over portion A, then portion B, and then portion C. In a second pass, the laser beam can move over portion C, then portion B, and then portion A. The aspect of the scan pattern can also be modified when the laser beam moves over a portion of a given scan multiple times. For example, during the passage of the subsequent pass by the laser beam, the scan pattern or a portion thereof can be rotated and / or shifted laterally with respect to the first pass. Optimizing the repetition frequency of the scan pattern has the effect of preventing oxygen depletion in the treated spot, which is advantageous for maintaining aerobic conditions in the treated spot and therefore for increasing crosslinking efficiency.

[0044] Additionally or alternatively, the characteristics of the laser beam projected onto the XY scanning system can be optimized to achieve the desired treatment. For example, the laser beam can be projected according to specific pulse parameters as described above. In some cases, a pulsed laser beam can be projected onto the XY scanning system while the XY scanning system is moving continuously across selected portions of the scan pattern, thereby generating a pattern of dashes across those portions.

[0045] The intensity and / or duration of the laser beam delivered to the XY scanning system at different portions of the scan pattern can be optimized to provide a desired dose of photoactivating light to a desired area of ​​the treatment zone. For example, the intensity of the laser beam can be modulated for selected portions of the scan pattern to deliver different irradiances to different locations on the cornea. The laser beam can also be delivered at a specific duration and irradiance for selected portions of the scan pattern.

[0046] When a continuous scanning pattern such as a spiral pattern is applied, the pitch between the spiral lines can be further optimized. When a discontinuous scanning pattern such as a random, semi-random, or matrix-based pattern is applied, the dwell time on each spot, the distance between spots, and the transit time between spots can be further optimized.

[0047] FIG. 5 shows a flow chart of an exemplary process 500 for optimizing laser scanning parameters for crosslinking treatment. For the optimization process 500, an initial treatment time 502a, a dose of photoactivating light 502b, a pitch of the scanning pattern 502c, and an initial repetition rate 502d are specified. In operation 504, the optimization process 500 calculates a laser power based on the initial treatment time 502a, the initial dose 502b, and the pitch 502c. In operation 506, the optimization process 506 determines whether the calculated laser power significantly affects the photostability of the crosslinking agent. If the photostability is affected, the optimization process 500 returns to operation 504 to recalculate the laser power until it determines in operation 506 that the photostability is not affected. In operation 510, the optimization process 500 selects a laser power that does not affect the photostability. In operation 512, the optimization process 500 recalculates the treatment time based on the selected laser power. In operation 514, the optimization process 500 calculates a duty cycle based on the initial repetition rate 502d and the selected laser power. In operation 516, the optimization process 500 compares the oxygen depletion and oxygen supplementation to the calculated loading rate. If the oxygen depletion is less than the oxygen supplementation, the optimization process 500 increases the repetition rate in operation 518 and returns to operation 514 where it recalculates the duty cycle based on the increased repetition rate. After the optimization process 500 determines that the oxygen depletion is not less than the oxygen supplementation, it selects a duty cycle in operation 520. In operation 522, the optimization process 500 calculates the irradiance for the photoactivating light based on the selected duty cycle. The optimization process can be conceptually completed once or at separate times, e.g., in a laboratory, to generate a preset list of optimized parameter combinations. Alternatively, the optimization process may be performed on-demand by the software in response to user input to generate specific parameter combinations prior to treatment.

[0048] Certain scanning parameters can be correlated. For example, if the total dose is kept constant, increasing the laser power decreases the treatment time and vice versa. Experimental data show that longer treatment times and higher repetition rates usually significantly increase corneal flattening, while changes in laser power do not significantly affect flattening. (Note, however, that very high laser powers may negatively affect flattening by decomposing drug molecules into by-products that generate less efficient cross-linking, in addition to safety concerns.)

[0049] Experimental results showed that increasing the repetition rate, i.e., the number of visits by the laser beam to the same location, can significantly enhance the crosslinking activity. To achieve better planarization, the repetition rate or equivalently the number of visits can be increased until the time for oxygen replenishment falls within the off-duty period of each location. This allows enough time for oxygen to be replenished at each location between two consecutive visits. FIG. 6 shows an exemplary repetition cycle 600 for crosslinking treatment. During each visit, one location receives a certain amount of laser irradiation for photoactivation, followed by an off-cycle during which the laser beam is delivered to the other location. The total irradiance per iteration per location depends on the scanning speed and the laser power. The number of laser visits per location is maximized when the off-duty period can sufficiently replenish oxygen. The on-duty period is preferably shorter than the time required for complete oxygen depletion.

[0050] FIG. 7 shows oxygen concentration and fluorescence intensity indicating the presence of crosslinking agent at certain locations during an exemplary treatment. Laser scanning was optimized based on ex-vivo experiments in pig eyes. In particular, the dose was 15 J / cm. 2, the treatment time is 18 min, and the laser power is 1.75 mW. The circular treatment zone has a diameter of 4 mm, and the scanning pattern completely covers the treatment zone (full pitch). Oxygen is measured under the 200 mm flap. Fluorescence intensity is measured by averaging wavelengths from 520 to 540 nm. Figure 7 shows that a repetition frequency of 8 Hz provides a good balance between oxygen depletion and replenishment in each repetition cycle, such that the oxygen level at a depth of 200 mm is still slightly higher than 0. The drug is consumed during the treatment, and the rate of drug destruction by the laser beam is negligible and negligible.

[0051] Similarly, Figures 8A-8E show the change in curvature resulting from treatment of five eyes where the epithelial layer was left on the eye (epi-on), while Figures 9A-9E show the change in curvature resulting from treatment of five eyes where the epithelial layer was completely removed (epi-off). Experimental results showed that laser scanning with the above parameters and a repetition rate of 8 Hz provided greater planarization than treatment with UV LEDs.

[0052] As mentioned above, the rate of corneal crosslinking activity is limited by the oxygen concentration in the corneal tissue. Thus, in the present embodiment, parameters for the laser scanning can be optimized to implement a scanning pattern that affects the depletion / replenishment of oxygen for crosslinking activity. In one embodiment, a pulsed laser beam is scanned over the corneal tissue with a 50% duty cycle and a fixed pulse frequency. As the laser beam scans the pattern, it leaves unexposed areas of corneal tissue before and after each exposed area along the scan. The exposed areas receive photoactivating light from the laser beam, and the resulting crosslinking activity depletes oxygen in the exposed areas. Advantageously, the adjacent unexposed areas enhance the diffusion of oxygen back into the exposed area after the laser beam leaves the exposed area. The pattern scanned by the laser beam can be dithered back and forth to ensure that crosslinking activity occurs throughout the desired treatment area. In some cases, the pulses may be selected based on the scanning speed to expose an area of ​​corneal tissue approximately equal to the diameter of the laser beam at one time.

[0053] FIG. 19A shows an example of an annular treatment pattern 1900a with an outer diameter of about 4 mm. FIG. 19B shows an example of an annular treatment pattern 1900b with an outer diameter of about 8 mm. Treatment patterns 1900a,b are generated by pulsing the laser beam at a 50% duty cycle and fixed pulse frequency over a spiral scan (spiralling inward toward the center). The cross-hatched spots indicate exposed areas where the laser beam is "on" and the non-cross-hatched spots indicate adjacent unexposed areas where the laser beam is "off". The size of the exposed areas is determined by the pulse frequency and the scan speed.

[0054] To generate patterns 1900a,b, the equations for the scanning parameters are given as follows: · input: o D min - Inner diameter of the circular treatment pattern o D max - Outer diameter of the annular treatment pattern o P r - Radial pitch of upd - Update frequency (update frequency) o θ0 - initial spiral angle (changing θ0 will rotate the spiral) · Formula: Spiral Update Time:

number

number

number

number

number

number

number

number

number

[0055] In another embodiment, the pulsed laser beam may be scanned over the corneal tissue with a 50% duty cycle and a variable pulse frequency, such that the laser beam leaves unexposed areas in the corneal tissue on all four sides of each exposed area in a resulting pattern. The resulting pattern resembles a checkerboard. Advantageously, compared to a laser beam with a fixed pulse frequency as described above, the unexposed areas of adjacent corneal tissue on all four sides of the exposed area promote greater diffusion of oxygen back into the exposed area after the laser beam leaves the exposed area. The pulse frequency may be varied between predetermined predetermined minimum and maximum values, resulting in corresponding minimum and maximum exposed areas.

[0056] FIG. 20A shows an example of an annular treatment pattern 2000a with an outer diameter of approximately 4 mm. FIG. 20B shows an example of an annular treatment pattern 2000b with an outer diameter of approximately 8 mm. Treatment patterns 2000a,bc are generated by pulsing the laser beam with a 50% duty cycle and providing a variable pulse frequency over a helical pattern (spiralling inward toward the center). The shaded areas in FIGS. 20A-B indicate exposed areas where the laser beam is "on" and the unshaded areas indicate adjacent unexposed areas where the laser beam is "off."

[0057] To generate the patterns 2000a,b, the equations for the scanning parameters are given as follows: · input: o DC - Duty Cycle o N sct - Number of sectors exceeding 2π radian angle · Formula: o Angle Pitch:

number

number

number

number

number

number

number

number

number

number

number

[0058] Implementation of a laser beam with variable pulse frequency can use a laser modulation signal where the laser on / off times are set to match a predetermined number of meridians (longitude lines) in the treatment pattern.

[0059] The size of the exposed area is determined by the pulse frequency and the scanning speed, but the pulse frequency can be varied in relation to the radial position of the laser beam. In particular, the modulation signal can have a variable frequency that increases towards the center of the spiral. The instantaneous laser modulation frequency is given by equation (25) and the linear velocity is given by equation (3). The radial pitch of the laser modulation is not constant.

[0060] When implementing a variable pulse frequency laser beam, the exposed area becomes smaller and smaller as the laser beam approaches the center of the treatment pattern. FIG. 20C shows an example of an annular treatment pattern 2000c with an outer diameter of about 9 mm produced by a variable pulse frequency laser beam. The cross-hatched areas in FIG. 20C indicate exposed areas where the laser light is "on," and the areas without cross-hatched areas indicate unexposed areas where the laser light is "off." As shown in FIG. 20C in particular, a layered set of meridians (longitude lines) can be used to keep the exposed area within a pre-determined size range.

[0061] The laser modulation signal is synchronized with the galvanometer drive signal. The laser modulation signal is reset and alternates at every restart of the spiral. Figure 21 shows an example of an exemplary waveform 2100a (Galvo-x, Galvo-y) for driving the galvanometer and a laser modulation waveform 2100b during a portion of the crosslinking treatment. As shown in Figure 21, the laser modulation frequency changes with time and increases as the laser beam spirals inward toward the center of the pattern. Meanwhile, the instantaneous laser duty cycle remains a constant 50%.

[0062] FIG. 22A shows an example of an exemplary waveform 2200a (Galvo-x, Galvo-y) for driving the galvanometer during a complete crosslinking treatment. Correspondingly, FIG. 22B shows a laser modulation waveform 2200b during a complete treatment. The laser modulation frequency increases rapidly near the end of the scan when the laser beam is near the center of the treatment pattern. This can result in the exposed tissue area being too small near the center and can increase the complexity of the electronics required to drive the laser.

[0063] To overcome the potential problem of undesirably high laser modulation frequency near the center of the treatment pattern, the checkerboard angular pattern can be divided into multiple radial (radial) zones based on the instantaneous laser modulation frequency. FIG. 23 shows an example of a laser modulation waveform 2300 implementing such an approach. In the outermost zone, the sector angle has a pre-determined, predetermined value, and the laser modulation frequency increases as the laser moves inward. As soon as the modulation frequency reaches a pre-determined, predetermined limit, the sector angle is doubled and the modulation frequency is halved at the start of the second zone. Subsequent zones are introduced in a similar manner. The number of zones is automatically determined to keep the modulation frequency below the pre-determined limit. (Hence, this approach is referred to herein as the "auto-zone" approach.) The number of sectors in the first zone is a power of two and is halved when switching to the next zone.

[0064] Table 1 shows exemplary output data for annular patterns generated by (i) a pulsed laser beam scanned with a fixed laser modulation frequency, (ii) a pulsed laser beam scanned with a variable laser modulation frequency without implementing the auto-zone approach, and (iii) a pulsed laser beam scanned with a variable laser modulation frequency using the auto-zone approach. [Table 1]

[0065] Common input parameters for the patterns in Table 1 include: Pattern inner diameter: 100mm Pattern outer diameter: 9mm Spot diameter: 100mm Radial pitch: 100mm Update frequency: 16Hz Duty cycle: 50%

[0066] In the case of a pulsed laser beam scanned with a fixed laser modulation frequency, the inputs further include a tangential pitch equal to 100 mm. In the case of a pulsed laser beam scanned with a variable laser modulation frequency not implementing an autozone approach, the inputs further include a number of sectors equal to 25. In the case of a pulsed laser beam scanned with a variable laser modulation frequency implementing an autozone approach, the inputs further include an initial number of sectors equal to 128 and a modulation frequency limit equal to 100 kHz.

[0067] Figure 24A shows an example of an exemplary annular treatment pattern 2400a with an outer diameter of approximately 4 mm generated with a pulsed laser beam scanned at a variable laser modulation frequency implementing an auto-zonal approach laser modulation waveform divided into multiple radial zones based on modulation frequency limitations. Figure 24(b) shows an example of a laser modulation waveform 2400b corresponding to treatment pattern 2400a.

[0068] The input parameters for pattern 2400a include: Pattern inner diameter: 85mm Pattern outer diameter: 4mm Radial pitch: 85mm Update frequency: 16Hz · Maximum number of meridians: 64 Maximum modulation frequency: 22kHz

[0069] The output data of pattern 2400a includes: Number of zones: 6 Length of the spiral: 147.8m Scanning speed: 2.3644m / s Minimum modulation length: 52.4mm Maximum modulation length: 107.2mm Minimum laser modulation frequency: 11.014kHz Maximum laser modulation frequency: 22.139kHz

[0070] Figure 25A shows an example of an exemplary annular treatment pattern 2500a with an outer diameter of approximately 9 mm generated with a pulsed laser beam scanned with a variable laser modulation frequency implementing an auto-zone technique. Figure 25B shows an example of a laser modulation waveform 2500b corresponding to treatment pattern 2500a.

[0071] The input parameters for pattern 2500a include: Pattern inner diameter: 85mm Pattern outer diameter: 9mm Radial pitch: 85mm Update frequency: 16Hz Maximum number of meridians: 128 Maximum modulation frequency: 75kHz

[0072] The output data of pattern 2500a includes the following: Number of zones: 7 Spiral length: 748.37mm Scanning speed: 11.9739m / s Minimum modulation length: 74.37mm Maximum modulation length: 159.60mm Minimum laser modulation frequency: 37.507kHz Maximum laser modulation frequency: 76.225kHz

[0073] Figure 26A shows an example annular treatment pattern 2600a with an outer diameter of approximately 9 mm generated with a pulsed laser beam scanned with a variable laser modulation frequency implementing an auto-zonal technique. Figure 26(b) shows an example of a laser modulation waveform 2600b corresponding to treatment pattern 2600a.

[0074] The input parameters for pattern 2600a include: Pattern inner diameter: 5mm Pattern outer diameter: 9mm Radial pitch: 85mm Update frequency: 16Hz Maximum number of meridians: 128 Maximum modulation frequency: 75kHz

[0075] The output data of pattern 2600a includes the following: Number of zones: 1 Spiral length: 517.4mm Scanning speed: 8.279m / s Minimum modulation length: 61.34mm Maximum modulation length: 110.45mm Minimum laser modulation frequency: 37.47kHz Maximum laser modulation frequency: 67.47kHz The autozone approach is used, but the pattern includes only one zone.

[0076] Figure 27 illustrates an embodiment of a spot profile 2700 generated by a pulsed laser beam traveling along a scan s. As shown in Figure 27, the laser beam has a laser spot diameter Dspand and produces a scan length Lsc, which is the product of the scan speed Vsc and the pulse width tp.

[0077] The following parameters can be used to generate, for example, a pattern with an outer diameter of 9 mm: · Scanning speed Vsc:10.2m / s Laser spot diameter Dsp: 100mm Radial pitch: 100mm Duty cycle: 50% Spot Profiles: Flat Top and Gaussian Laser power: 8mW

[0078] The modulation frequency can be optimized. For Gaussian laser beams, the modulation frequency is preferably less than 50 kHz to maintain sufficient contrast in dose between treated and untreated spots in a single scan. For example, at 50 kHz, the contrast ((max-min) / average) is approximately 50%. This estimate depends on the spot profile (inner and outer diameter) and the galvanometer speed. Figures 28A-D show the contrast as a function of modulation frequency. Figure 28A shows a Gaussian laser spot with a laser modulation frequency of 25 kHz. Figure 28B shows a Gaussian laser spot with a laser modulation frequency of 50 kHz. Figure 28C shows a Gaussian laser spot with a laser modulation frequency of 75 kHz. Figure 28D shows a Gaussian laser spot with a modulation frequency of 100 kHz.

[0079] Table 2A provides input parameters for generating various annular treatment patterns A-F by pulsed laser scanning implementing an auto-zonal approach. Correspondingly, Table 2B provides output data for the various treatment patterns A-F. The requirement imposed on patterns A-F is a minimum modulation length of 85 mm. [Table 2A] [Table 2B]

[0080] [Point-and-shoot laser scanning approach] As discussed above, aspects of the scan pattern can be defined by a plurality of discrete dots, and the treatment pattern can be defined by scanning the discrete dots in a randomized or semi-randomized manner based on continuous x,y variables.

[0081] According to some embodiments, a point-and-shoot technique can be used to apply a series of discrete dots to define a desired treatment zone. As shown in FIG. 10, a scan pattern 1000 may be defined by scanning discrete dots 1002 according to a grid 1006 inside a boundary 1004 (e.g., a circular boundary) that defines the treatment zone. In particular, the grid 1006 includes an arrangement of hexagonal cells 1007, within which the dots 1002 are sampled (shot) by the laser beam. The hexagonal cells 1007 may be arranged to uniformly space the dots 1002 within the boundary 1004, i.e., to maximize the uniformity of the photoactivating light across the treatment zone. The size (e.g., diameter) of the laser beam spot and the pitch of the grid 1006 can be matched to maximize this uniformity.

[0082] After the grid of the scan pattern is defined, the order of irradiating the cells of the grid with the laser beam spots can be optimized. The order of the shots, the duration of the shots, the intensity of the shots, and the number of repeated shots to each cell can affect the efficiency of the crosslinking activity and the desired amount of shape change of the cornea. According to one approach, each cell is sampled at least once in a random order. According to another approach, the treatment system tracks the total dose irradiated to each cell based on the accumulation of shots received. In other words, the treatment system maintains a dose map as the treatment progresses and determines where to irradiate the next shot according to this dose map. During the treatment, the treatment system can irradiate the next shot to the cell with the smallest total dose (which may be the cell that received the smallest number of shots). If multiple cells have the smallest total dose, the treatment system can also select for the next shot the cell located at the greatest distance from the cell receiving the previous shot. Selecting cells based on the greatest distance between successive shots can provide more efficient and uniform crosslinking activity across the scan pattern. In particular, a larger distance between shots improves the local supply of oxygen for crosslinking at the next cell. Furthermore, the influence of activity in a previous cell (crosstalk) is less likely to affect activity in a subsequent cell that is more distant from the previous cell.

[0083] A possible drawback of selecting cells to maximize the distance between successive shots is that the time between the delivery of successive shots increases due to the time to travel across the distance (transit time). Therefore, to address this possible drawback, the treatment system can limit the distance between successive shots, for example, the distance is maximized but does not exceed a predetermined maximum travel distance (MTD). Thus, the treatment system can select the cell with the minimum total dose within the MTD. If all cells receive the same dose or the same number of shots, the treatment system can randomly select the next cell.

[0084] In general, point-and-shoot technology can be optimized according to various parameters to achieve the desired treatment, including but not limited to: (i) size of the laser beam spot, (ii) pitch of the grid, (iii) number of shots per cell (also called visits) across the scan pattern, (iv) total treatment time, (v) irradiance of the laser beam, (vi) time between application of successive dots; and / or (vi) the order in which the spots are applied. For example, FIG. 11 shows a 2 11 shows different combinations of parameter values ​​for treatment using a hexagonal grid within a circular boundary of about 4 mm in diameter (corresponding to the treatment zone), with about 1000 s of UVA light, a treatment time of about 1000 s, a time taken to pass between successive spots of about 0.2 ms, and a Gaussian spot profile. The parameters in FIG. 11 are the size of the laser beam spot measured as diameter Dsp (μm) full width at half maximum (FWHM), the pitch of the grid (μm), the number of visits (where a visit corresponds to a single pass of the scan pattern in which all cells receive a shot), the number of spots in the entire scan pattern, the number of shots, the time of each visit, the time of each shot (in ms) (time of imaging), the peak irradiance (W / cm 2 ), power of the laser beam (mW), peak dose per shot (J / cm 2 ), and non-uniformity (%).

[0085] 12A-12C show graphs for the implementation of the treatment parameters shown in column B of FIG. 11 using a galvanometer mirror system (e.g., galvanometer mirror system 312 shown in FIG. 3). Each graph shows the drive voltage applied to induce the tilt angle of the X mirror as a function of time as the treatment progresses. In particular, the mirror tilt angle is represented by the X voltage that controls the X mirror as described above. The mirror tilt angle remains fixed when a shot is delivered to a cell (during the imaging time) and changes when the galvanometer mirror system is adjusted to deliver a shot to the next cell (during the transfer time). No photoactivating light is delivered to the galvanometer mirror system during the transfer time. In practice, a transient time is required to allow the mirror to stop moving when the galvanometer mirror system is adjusted to deliver a shot to the next cell. According to one approach, the laser beam is modulated and the galvanometer mirror system is synchronized such that no photoactivating light is irradiated onto the galvanometer mirror system during this transient time. FIG. 12A shows the tilt angle (X voltage) during the first 10 shots of a treatment where the travel distance is unconstrained, i.e., MTD=∞. FIG. 12B shows the tilt angle (X voltage) during the first 10 shots of a treatment where the travel distance is unconstrained, i.e., MTD=∞. sp (100μm) or less traveled distance, i.e. MTD=10D sp FIG. 12C shows the tilt angle (X voltage) during the first 10 shots of treatment, which is limited to a diameter D sp (100μm) or less than 5 times the travel distance, i.e. MTD=5D sp 12A-12C show that by limiting the travel distance to a few times the laser spot size, the travel distance between successive spots is short, i.e., the change in tilt angle between spots is small.

[0086] [Eye movement correction] As mentioned above, the treatment system 300 shown in FIG. 3 includes an eye tracking system to account for the movement of the eye 1 during treatment. According to some approaches, the position of the eye can be monitored during treatment by tracking images captured by an imaging system. In response, the treatment system dynamically adjusts the application of the photoactivating light so that the pattern is applied to the desired area of ​​the cornea.

[0087] However, as shown in the timeline 1300 of FIG. 13, due to the individual time detection of the eye and the finite response time of the treatment system, a delay occurs between the detection of the eye position and the application of the photoactivating light. For example, FIG. 13 shows that an imaging system captures an image i of an eye. The image i is processed to calculate the eye position in image i as X(i). The position X(i) is then processed to calculate the position of the desired treatment zone, and the photoactivating light H(i) is sent to the desired treatment zone. The time required to process the image i introduces a system delay of δ1. Furthermore, the time required to process the position X(i) and trigger the application of the photoactivating light introduces another system delay of δ2. Thus, the total time Δ between the capture of the image i and the actual application of the photoactivating light is at least the sum of the system delays δ1 and δ2. Therefore, if there is further eye movement during the delay time Δ, inaccuracies in the application of the photoactivating light may occur.

[0088] In particular, rapid eye movements can cause positional errors due to this delay in delivery of the photoactivating light. In the point-and-shoot approach described above, positional errors can be large if the size of the laser spot is comparable to the amount of eye movement during the delay time. Figures 14(A)-(D) show a grid 1406 defined by an arrangement of hexagonal cells 1407 for a grid-based point-and-shoot approach. As shown in Figure 14(A), the treatment system intends to deliver a shot to cell 1407a at time (i-Δ). The imaging system captures a series of frames from which the position of the eye and the relative position of the shot can be determined. In particular, Figures 14(B) and 14(C) show successive frames at times i and (i+1), respectively. The frames show that the eye has moved and the shot has been received by other unintended cells (positional error). Since the grid 1406 is fixed relative to the eye, the position of the shot has moved relative to the grid 1406. As shown in Figure 14(B), a shot is received over a portion of cells 1407a-d at time i, while Figure 14(C) shows a shot being received over a portion of cells 1407a, d, and e at time (i+1).

[0089] A motion model (e.g., a linear model, a Kalman filter, or an FIR filter, etc.) is used to model the eye's motion between successive frames and determine which cells receive photoactivating light between successive frames. The dose map can then be updated to indicate that each such cell received a dose of photoactivating light proportional to the area covered by the photoactivating light in the frame. Thus, as shown in FIG. 14(D), the dose map indicates that a dose of photoactivating light was received by cells 1407a-e based on information in frames at times i and (i+1). Furthermore, the dose map indicates the relative dose of photoactivating light received by cells 1407a-e, as indicated by the relative cross-hatching of cells 1407a-e in FIG. 14(D). For example, based on the total area of ​​each cell 1407a-e covered by the photoactivating light in both frames, cell 1407a will have received the maximum dose, while cells 1407c, d will have received a larger dose than cells 1407b, e. The updated dose map can then be used to determine the location of the next shot as described above. Figure 14 therefore shows a modification of the grid-based point-and-shoot approach that uses a dose map to account for the effects of positional errors.

[0090] 14 illustrates a modification of the grid-based point-and-shoot approach, other approaches for scanning photoactivating light across the cornea can include similar mechanisms in which the dose map is dynamically updated to account for measured errors in the delivery of photoactivating light, and the scan path is dynamically adjusted to spatially optimize the dose delivered during treatment. Additionally, in alternative embodiments, fluorescent signals resulting from the delivery of photoactivating light can be detected to determine the location of such delivery and account for eye movement as described above.

[0091] [Lissajous curve scan] 3, a Lissajous curve scan pattern can be created using a galvanometer mirror system 312. Such a scan pattern can be converted into independent mirror drive waveforms that cause the X mirror 312a and the Y mirror 312b to scan the laser beam in the X and Y directions, respectively. For example, each of the mirrors 312a,b

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[0092] By using very dense Lissajous scanning paths, a proper crosslinking effect can be achieved. The process of crosslinking in the area of ​​corneal tissue requires a local supply of oxygen and a crosslinking agent, e.g., riboflavin. Thus, if successive scanning paths are too close to each other, crosslinking efficiency may decrease. To minimize the decrease in crosslinking efficiency, the scanning of n total paths can be interlaced by scanning n total scanning paths in a sequence defined by an interval m. For example, if a scanning pattern includes n=20 total scanning paths (e.g., circular paths) and an interval m=5 is selected, the scanning sequence can start with scanning path 1 and proceed to the scanning path every 5 intervals after scanning path 1, i.e., scanning paths 6, 11, 16. The sequence can then move to scanning path 2 and proceed to the scanning path every 5 intervals after scanning path 2, i.e., scanning paths 7, 12, 17, etc. The total sequence order is scan path 1, 6, 11, 16, 2, 7, 12, 17, 3, 8, 13, 18, 4, 9, 14, 19, 5, 10, 15, 20. Alternatively, the sequence can start with scan path 20 and proceed in the opposite direction of the scan path every 5 intervals, i.e. the total sequence order can proceed as follows: scan path 20, 15, 10, 5, 19, 14, 9, 4, 18, 13, 8, 3, 17, 12, 7, 2, 16, 11, 6, 1.

[0093] The scanning of each path can start at any part of the path. For example, if a circular path is scanned according to the previous sequence, the scanning of paths 20, 15, 10, 5 can start at 45° on the circle; the scanning of paths 19, 14, 9, 4 can start at 40° on the circle; the scanning of paths 18, 13, 8, 3 can start at 35° on the circle; and so on. Since the scanning pattern for the entire treatment can include many scanning paths, a uniform distribution of the starting angles can be achieved by using many starting angles.

[0094] [Existence of dead zones] For effective crosslinking, very high linear scanning speeds can be used in some cases. For example, if the linear scanning speed is 3.14 mm / ms, a scanning circle with a diameter of 0.1 mm is completed in 0.1 ms, and the functional frequency w of the galvanometer is 10 kHz. This functional frequency is very difficult to achieve with most commercially available galvanometer mirror systems. In fact, it is a common practice to apply one or more notch filters on the galvanometer servo board to avoid problems with resonances in that range. Thus, due to the performance limitations of conventional galvanometers, there is a dead zone in the scan. Moreover, this dead zone can cause problems for achieving the peak power of the photoactivating light for crosslinking treatment.

[0095] However, for each scan path, the laser beam may move into the dead zone and remain in the dead zone for a short period of time as it scans the portion closest to the dead zone. For example, if a crosslinking treatment lasts a total of 1000 seconds and there are 10 interlaced paths (e.g., circular scan paths) scanned 10 times for each scan pattern with a repetition rate of 10 Hz, there will be 100,000 opportunities to move into the dead zone. If the size of the dead zone is 1 percent of the total scan area, the total dwell time is 10 seconds, with 100 ms for each move into the dead zone.

[0096] Although a deterministic equation can be used to generate a uniform dead zone presence location, the dead zone presence can also be achieved randomly. For example, if we use two uniformly distributed numbers r1 and r2 between 0 and 1, and the dead zone radius is R, then the random dead zone occupancy positions are:

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[0097] [Laser output control and synchronization] The laser output is synchronized with the laser beam position during crosslinking treatment. Furthermore, the laser modulation signal is used to maintain precise control over the temporal and spatial characteristics of the scanning pattern by synchronizing it with the position sensor.

[0098] Such synchronization may be necessary, for example, because a scan pattern having Lissajous scan paths may not correspond exactly to a desired treatment area. For example, a scan pattern may be defined by a circular boundary and a circular scan path, but the zone for crosslinking treatment may not be a corresponding circle. Thus, it may be necessary to turn on the laser power when the laser beam is within the treatment zone and turn off the laser power when the laser beam is outside the treatment zone. Such synchronization may also be necessary because a non-uniform laser power is required for parts of the treatment zone.

[0099] The modulated CW laser output can be manipulated via a trigger signal from an acousto-optic or electro-optic modulator, directly via a diode current, etc. A time delay, also known as rise time and fall time, generally occurs when the laser is turned on or off. High quality synchronization takes this time delay into account through calibration.

[0100] The trigger signal for modulation of the laser output can be provided via an open-loop or closed-loop control system. A closed-loop control system uses a feedback signal for position. An open-loop control system includes careful pre-calibration of a time delay for the trigger signal.

[0101] TTL (Transistor-Transistor Logic) typically has fast rise and fall times and can be used for digital modulation. Other differential signaling formats such as PECL (Positive Emitter Coupled Logic), LV-PECL (Low-Voltage Positive Emitter Coupled Logic), and LVDS (Low-Voltage Differential Signaling) can also modulate high frequencies with minimal noise.

[0102] [[Probabilistic Models, Estimation, and Control for Eye Tracking]] [Kalman filter] An algorithm based on the Kalman filter can be used to remove errors from eye tracking measurements. The Kalman filter is a set of mathematical equations that implements a predictive-corrective estimator for stochastic systems. It is optimal in the sense that it minimizes the estimation error when several estimation conditions are met. Using the Kalman filter, the accuracy of eye tracking can be significantly improved in contrast to approaches that use direct measurements of eye position. Such eye trackers can effectively estimate eye movements with regular position-velocity-acceleration components and occasional random components. To realize such eye trackers in a two-dimensional space, two independent filters were used, i.e., one filter for each spatial dimension.

[0103] [State space model of the Kalman filter] The Kalman filter is a linear stochastic differential equation

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[0104] [Discrete Kalman Filter Algorithm] The equations of the Kalman filter are divided into two groups: time update equations and measurement update equations. Initial estimate

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[0105] The time update equations cause the current state and error covariance estimates to be projected forward to obtain a priori estimates for the next time step. Projecting the state forward:

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[0106] [Raster scan using polygon scan] FIG. 15 shows an example of a raster scan pattern 1500. In raster scanning, the laser beam can start from the top row and sweep horizontally from left to right at a constant speed, then quickly return to the left and sweep the next row. Meanwhile, the vertical position of the laser beam moves steadily downwards. The movement can be continuous or intermittent. Once the scan path is completed, the laser beam can start from the top row or from a position between the first and second rows to perform an interlaced scan. In raster scanning, the laser modulation is synchronized with the crosslinking treatment area, as described above.

[0107] Polygonal scans can usually be performed quickly because they do not have dead zones like Lassajou curve scans. The vertical movement of a raster scan is very slow and can be realized with simpler, slower scans, for example MEMS-based scans.

[0108] [Zigzag scanning using a resonant scanner] FIG. 16 shows an example of a zigzag scan pattern 1600. Similar to raster scanning, zigzag scanning as shown in FIG. 16 includes a faster horizontal scan and a slower vertical scan. Zigzag scanning can sweep horizontally in both directions. Vertical motion can be continuous or intermittent. Zigzag scanning can be implemented with a resonant scanner. In zigzag scanning, the laser modulation is synchronized with the cross-linking treatment area as described above.

[0109] [Alternative laser treatment system] As discussed above, the use of a laser light source to deliver a photoactivating light pattern can provide advantages for corneal crosslinking treatment over approaches using LED light sources. LED light sources may provide a beam of light with lower optical quality, including lower coherence, lower collimation, and / or larger diameter. With such a lower quality beam, the selection of patterns available for delivery of the photoactivating light may be more limited and may require more complex, expansive aspheric optics for pattern formation.

[0110] In addition to the laser-based approach using an XY scanner as described above, Figures 17 and 18 show examples of other treatment systems that provide other laser-based approaches for projecting a pattern of photoactivating light onto the cornea. In particular, Figure 17 shows an exemplary treatment system 1700 employing a diffractive multi-beam splitter, and Figure 18 shows an exemplary treatment system 1800 employing a diffractive beam shaper. These treatment systems are more efficient with respect to the use of a single mode laser.

[0111] The treatment system 1700 shown in FIG. 17 includes a UV (e.g., UVA) laser light source 1710, a beam expander 1711, a two-dimensional beam splitter 1712, a laser beam deflector 1713, and a focusing lens 1714. The laser light source 1710 can be implemented with an optical amplitude modulator (either internal or external to the laser light source 1710). The laser beam from the laser light source 1710 is directed to the beam expander 1711, and the resulting expanded beam is directed to a two-dimensional beam splitter 1712 (e.g., a diffractive beam splitter) to generate multiple laser beam spots. The laser light deflector 1713 receives and directs the laser beam spots to a focusing lens 1714, which projects a pattern of laser beam spots onto the cornea 2. The spot pattern is generated from the laser light spots on the surface of the cornea 2, with the pattern size determined by the distance from the cornea 2 to the focusing lens 1714. Cross-linking activity is generated simultaneously at all spots using continuous and / or pulsed laser light.

[0112] The treatment system 1700 includes a controller 1720 that can control aspects of the treatment system 1700. Additionally, the treatment system 1700 includes an imaging system 1716 (e.g., a camera) that captures images of the eye 1. The controller 1720 can receive and process images from the imaging system 1716 to determine the position of the cornea 2 relative to the treatment system 1700. To compensate for changes in the position of the cornea 2, the controller 1720 can control the laser beam deflector 1713 to adjust the scanned laser beam to apply a spot pattern to a desired area of ​​the cornea 2. In this manner, the imaging system 1716 and the controller 1720 combine to provide an eye tracking system.

[0113] On the other hand, the treatment system 1800 shown in FIG. 18 includes a UV (e.g., UVA) laser source 1810, a beam expander 1811, a focusing lens 1812, a diffractive beam shaper 1813, and a laser beam deflector 1814. The laser source 1810 can be implemented using an optical amplitude modulator (either internal or external to the laser source 1810). The laser beam from the laser source 1810 is directed to the beam expander 1811, and the resulting expanded beam is directed to the focusing lens 1812 and the diffractive beam shaper 1813 (e.g., a flat-top generator, a ring generator, or a custom shape generator). The laser beam deflector 1814 receives and directs the laser beam from the diffractive beam shaper 1813 to the cornea 2. This generates a laser beam spot of a desired size and shape on the surface of the cornea 2. Further embodiments can optionally use additional lenses and beam shaping devices.

[0114] Similar to the treatment system 1700, the treatment system 1800 includes a controller 1820 that can control aspects of the treatment system 1800. Additionally, the treatment system 1800 includes an imaging system 1816 (e.g., a camera) that captures images of the eye 1. The controller 1820 can receive and process images from the imaging system 1816 to determine the position of the cornea 2 relative to the treatment system 1800. To compensate for changes in the position of the cornea 2, the controller 1820 can control the laser beam deflector 1814 to adjust the scanned laser beam to apply a spot pattern to a desired area of ​​the cornea 2. In this manner, the imaging system 1816 and the controller 1820 combine to provide an eye tracking system.

[0115] In general, crosslinking treatment systems using laser light sources can provide more sophisticated and sharper photoactivation light patterns. As described above, embodiments can use XY scanners, diffractive multi-beam splitters, and diffractive beam shapers to achieve the desired patterns.

[0116] Also, as mentioned above, the photoactivation light pattern from the laser-based treatment system can be optimized to achieve clinical efficacy and desired treatment objectives (e.g., refractive correction) based on the specific ocular parameters for each individual subject. The optimized laser-based treatment system can precisely control the shape and local intensity of the treatment zone for a patient-specific treatment pattern. Advantageously, the optimized laser-based treatment system can enhance crosslinking by efficiently using a crosslinking agent based on photochemical kinetics and ambient oxygen. In fact, such a treatment system can eliminate the need to have hyperoxic conditions during treatment, i.e., no external gas source, treatment mask, etc. is required to provide supplemental concentrated oxygen.

[0117] As mentioned above, according to some aspects of the present disclosure, some or all steps of the procedure described and illustrated above can be automated or guided under the control of a controller. In general, the controller can be implemented as a combination of hardware and software elements. The hardware aspects can include a combination of operatively coupled hardware components including a microprocessor, logic circuitry, communication / network ports, digital filters, memory, or logic circuitry. The controller can be adapted to perform operations specified by computer executable code that can be stored on a computer readable medium.

[0118] As mentioned above, the controller may be an external conventional computer or an on-board programmable processing device such as a field programmable gate array (FPGA), application specific integrated circuit (ASIC), or digital signal processor (DSP) that executes software or stored instructions. In general, the physical processor and / or machine used for any processing or evaluation by the embodiments of the present disclosure may include one or more networked or non-networked general-purpose computer systems, microprocessors, field programmable gate arrays (FPGA), application specific integrated circuits (ASIC), digital signal processors (DSP), microcontrollers, etc., programmed according to the teachings of the exemplary embodiments of the present disclosure, as will be understood by those skilled in the computer and software arts. The physical processor and / or machine may be externally networked with the image capture device, or may be integrated to reside within the image capture device. Appropriate software may be readily prepared by those skilled in the art based on the teachings of the embodiments, as will be understood by those skilled in the art, and further, the devices and subsystems of the embodiments may be implemented by preparing application specific integrated circuits or by interconnecting conventional component circuits in an appropriate network, as will be understood by those skilled in the electrical arts. Thus, example embodiments are not limited to any specific combination of hardware circuitry and / or software.

[0119] The embodiments of the present disclosure may be stored on any one or combination of computer readable media, and the exemplary embodiments of the present disclosure may include software for controlling the devices and subsystems of the exemplary embodiments, software for driving the devices and subsystems of the exemplary embodiments, software for enabling the devices and subsystems of the exemplary embodiments to interact with a human user, and the like. Such software may include, but is not limited to, device drivers, firmware, operating systems, development tools, application software, and the like. Such computer readable media may further include a computer program product of an embodiment of the present disclosure for performing all or a portion (if the processing is distributed) of the processing performed in the implementation. The computer code device of the exemplary embodiments of the present disclosure may 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. Additionally, some of the processing of the exemplary embodiments of the present disclosure may be distributed for better performance, reliability, cost, and the like.

[0120] Common forms of computer readable media include, for example, a floppy disk, a flexible disk, a hard disk, magnetic tape, any other suitable magnetic medium, a CD-ROM, a CDRW, a DVD, any other suitable optical medium, punch cards, paper tape, optical mark sheets, any other suitable physical medium having a pattern of holes or other optically recognizable indicia, RAM, PROM, EPROM, FLASH-EPROM, any other suitable memory chip or cartridge, a carrier wave from which a computer can read, or any other suitable medium.

[0121] Although the present disclosure has been described with reference to one or more specific embodiments, those skilled in the art will recognize that many modifications can be made thereto without departing from the spirit and scope of the present disclosure. Each of these embodiments and obvious variations therefrom are considered to be 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 of any of the embodiments described herein.

Claims

1. 1. A system for treating an eye, comprising: a laser light source configured to provide photoactivating light; a scanning system configured to receive the photoactivating light as a laser beam and move the laser beam over the cornea treated with the crosslinking agent; and a controller configured to provide control signals programmatically controlling the laser light source and the scanning system, one or more of the control signals causing the laser beam to visit one or more areas of the cornea multiple times in a scan pattern to expose the one or more areas to the photoactivating light; the activating light generates crosslinking activity in the one or more exposed regions by reacting the crosslinking agent in the one or more exposed regions with oxygen; The system, wherein the scanning pattern allows a predetermined time to elapse between each visit of the laser beam to the one or more exposed regions, the predetermined time allowing oxygen to be replenished within the one or more exposed regions and allowing sufficient oxygen to generate a desired amount of crosslinking activity between each visit of the one or more exposed regions.

2. The system of claim 1 , wherein the light source is operable to adjust a power output for the laser beam, and the scan pattern is optimized according to the power output for the laser beam.

3. The system of claim 1 , wherein the scanning system is operable to adjust a speed of the laser beam as it moves over the cornea, and the scan pattern is optimized according to the speed of the laser beam.

4. 10. The system of claim 1, further comprising one or more optical elements configured to receive the photoactivating light and adjust a spot size for the laser beam, wherein the scanning pattern is optimized according to the spot size for the laser beam.

5. 2. The system of claim 1, wherein the scanning system includes a galvanometer pair including a first mirror configured to move the laser beam along a first axis and a second mirror configured to move the laser beam along a second axis.

6. 2. The system of claim 1, wherein the scanning pattern causes the laser beam to visit the one or more exposed regions while maintaining one or more adjacent regions not exposed to the actinic light, each of the adjacent unexposed regions determining the rate at which oxygen in the one or more exposed regions is replenished.

7. 2. The system of claim 1, wherein the scanning pattern is defined by pulsing the laser beam according to a duty cycle, and as the scanning system scans the laser beam over the cornea, the pulsing causes the laser beam to visit the one or more exposed areas when the laser beam is on during the duty cycle while causing adjacent areas not to be exposed to the photoactivating light when the laser beam is off during the duty cycle, and the adjacent unexposed areas determine the rate at which oxygen in the one or more exposed areas is replenished.

8. 8. The system of claim 7, wherein the scanning pattern uses a variable pulse frequency and leaves areas on four sides of each exposed area remaining unexposed.

9. The system of claim 7 , wherein the pulsing of the laser beam has a frequency that varies depending on the position of the laser beam in the scan pattern.

10. The system of claim 1 , wherein the one or more exposure areas correspond to a plurality of discrete dots that define the scan pattern.

11. 1. A method of treating an eye, comprising: generating photoactivating light using a laser light source; directing the photoactivating light as a laser beam to a scanning system; operating the scanning system to move the laser beam over the cornea, visiting one or more areas of the cornea multiple times according to a scanning pattern and exposing the one or more areas to the photoactivating light, the photoactivating light reacting the crosslinking agent in the one or more exposed areas with oxygen to generate crosslinking activity in the one or more exposed areas; and optimizing the scanning pattern to allow a predetermined time to elapse between each visit of the laser beam to the one or more exposed regions, the predetermined time allowing oxygen to be replenished within the one or more exposed regions and allowing a desired amount of cross-linking activity to occur between each visit to the one or more exposed regions; A method of treating the eye, comprising:

12. The method of claim 11 , wherein optimizing the scan pattern comprises adjusting a power for the laser beam.

13. The method of claim 11 , wherein optimizing the scan pattern comprises adjusting a speed of the laser beam.

14. The method of claim 11 , wherein optimizing the scan pattern comprises adjusting a spot size for the laser beam.

15. 12. The method of claim 11 , wherein the scanning system includes a galvanometer pair including a first mirror configured to move the laser beam along a first axis and a second mirror configured to move the laser beam along a second axis.

16. 12. The method of claim 11 , wherein optimizing the scan pattern comprises defining a scan pattern such that the laser beam visits the one or more exposed regions while maintaining one or more adjacent regions not exposed to the actinic light, each of the adjacent unexposed regions determining the rate at which oxygen in the one or more exposed regions is replenished.

17. 12. The method of claim 11, wherein optimizing the scan pattern includes defining a scan pattern by pulsing the laser beam according to a duty cycle, such that as the scanning system scans the laser beam over the cornea, the pulsing causes the laser beam to visit the one or more exposed areas when the laser beam is on during the duty cycle while causing adjacent areas not to be exposed to the photoactivating light when the laser beam is off during the duty cycle, and the adjacent unexposed areas determine the rate at which oxygen in the one or more exposed areas is replenished.

18. 20. The method of claim 17, wherein the scanning pattern uses a variable pulse frequency and leaves areas on four sides of each exposed area remaining unexposed.

19. 20. The method of claim 17, wherein the pulsing of the laser beam has a frequency that varies depending on the position of the laser beam in the scan pattern.

20. The method of claim 11 , wherein the one or more exposure areas correspond to a plurality of discrete dots that define the scan pattern.

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