Systems and methods for generating patient-specific corneal cross-linking treatment patterns

Abstract

An automated processing procedure receives input tomographic imaging data and generates an optimized (customized) treatment pattern for an individual patient without relying on physician analysis or judgment. For example, a method of treating a cornea includes receiving tomographic imaging data of the cornea. The method includes identifying a keratoconus defect in the cornea based on the tomographic imaging data. The method includes segmenting the keratoconus defect into a plurality of treatment zones based on predetermined geometric parameters, where the plurality of treatment zones indicate where a crosslinking agent should be applied and photoactivated on the cornea to treat the keratoconus defect.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 158,023 (filed March 8, 2021), the contents of which are incorporated by reference in their entirety herein.

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

[0003] Crosslinking treatments can be used to treat eyes suffering from diseases such as keratoconus. In particular, keratoconus is a degenerative eye disease in which structural changes within the cornea cause it to weaken and change into an abnormal conical shape. Crosslinking treatments can strengthen and stabilize the areas weakened by keratoconus, preventing the progression of the disease. Summary of the Invention

[0004] Means for solving the problem According to aspects of the present disclosure, an automated procedure receives input tomographic imaging data and generates a treatment pattern that is optimized (customized) for an individual patient without relying on physician analysis and judgment.

[0005] For example, a method of treating a cornea includes receiving tomographic imaging data related to the cornea. The method includes identifying a corneal keratoconus defect in the cornea based on the tomographic imaging data. The method includes segmenting the corneal keratoconus defect into treatment zones based on predetermined geometric parameters, the treatment zones indicating where a crosslinking agent should be applied and photoactivated on the cornea to treat the corneal keratoconus defect.

[0006] For example, a system for treating a cornea includes an illumination system configured to deliver radiation to activate a photosensitizer applied to the cornea. The system includes a controller configured to control the illumination system. The controller includes one or more processors and one or more computer-readable media, the one or more processors configured to execute instructions from the computer-readable media to cause the controller to: receive tomographic imaging data of the cornea; identify a corneal conus defect of the cornea based on the tomographic imaging data; and segment the corneal conus defect into treatment zones based on predetermined geometric parameters, where the treatment zones indicate where a crosslinking agent should be applied and photoactivated on the cornea to treat the corneal conus defect, and cause the illumination system to deliver radiation to photoactivate the crosslinking agent according to the treatment zones. [Brief description of the drawings]

[0007] [Figure 1] 1 illustrates an exemplary system for applying a crosslinking agent and photoactivating light to the cornea of ​​an eye to generate crosslinks in corneal collagen according to aspects of the present disclosure. [Diagram 2] 1 illustrates an exemplary automated procedure for generating an optimized treatment pattern for an eye with keratoconus. [Figure 3A] 1 shows an example topography map illustrating elevation float (for a reference shape of low order Zernike polynomials). [Figure 3B] 1 illustrates an example topography map showing tangent curvature. [Figure 3C] 1 shows an exemplary topographical map illustrating axial (sagittal) curvature. [Figure 4A] 1 illustrates an embodiment of evaluating an elliptical zone boundary for treating an eye with keratoconus. [Figure 4B] 1 illustrates an embodiment of evaluating an elliptical zone boundary for treating an eye with keratoconus. [Figure 5A]13 shows an example of segmentation (without post-processing) based on an elevation topography map (for a reference shape of low-order Zernike polynomials) as input. [Figure 5B] 13 shows an example of segmentation (without post-processing) based on an axial curvature topography map as input. [Figure 5C] 13 shows an example of segmentation (without post-processing) based on a tangent curvature topography map as input. [Figure 5D] 13 shows an example of segmentation (without post-processing) based on a pachymetry topography map as input. [Figure 6A] 6A-D show example partitions generated by act 230b with post-processing of act 230c, where the maximum eccentricity is limited to 0.606. They show example partitions (with post-processing specifying a maximum eccentricity) based on an elevation topography map (for a reference shape of low-order Zernike polynomials) as input. [Figure 6B] 13 shows an example of partitioning (with post-processing specifying maximum eccentricity) based on an axial curvature topography map as input. [Figure 6C] 13 shows an example of partitioning (with post-processing specifying maximum eccentricity) based on a tangent curvature topography map as input. [Figure 6D] 13 shows an example of segmentation (with post-processing specifying maximum eccentricity) based on a pachymetry topography map as input. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] While the disclosure is susceptible to various modifications and alternative forms, certain specific embodiments thereof have been shown by way of example in the drawings and will herein be described in detail. It is to be understood, however, that it is not intended to limit the disclosure to the particular forms disclosed herein, but on the contrary, it is intended to cover all modifications, equivalents, and alternatives falling within the spirit of the disclosure.

[0009] FIG. 1 illustrates an exemplary treatment system 100 for generating collagen cross-linking in a cornea 2 of an eye 1. The treatment system 100 includes an applicator 132 for applying a cross-linking agent 130 to the cornea 2. In an exemplary embodiment, the applicator 132 may be an eye dropper, syringe, or the like, that applies the photosensitizer agent 130 as drops to the cornea 2. Exemplary systems and methods for applying cross-linking agents are described in U.S. Patent Application Publication No. 2017 / 0296383, filed April 13, 2017, entitled "Systems and Methods for Delivering Drugs to an Eye," the contents of which are incorporated herein by reference in their entirety.

[0010] The cross-linking agent 130 may be provided in a formulation that allows for passage of the cross-linking agent 130 through the corneal epithelium 2a to the underlying region within 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).

[0011] The treatment system 100 includes an illumination system including a light source 110 and an optical element 112 for directing light to the cornea 2. In some embodiments, the light source 110 may include a light emitting diode (LED). In another embodiment, the light source 110 may include a laser. The light causes photoactivation of the crosslinking agent 130 to produce crosslinking activity in the cornea 2. For example, the crosslinking agent may include riboflavin, and the photoactivating light may include ultraviolet A (UVA) light (e.g., wavelengths of about 365 nm or 375 nm, or within the band of 315 nm to 400 nm). Alternatively, the photoactivating light may include another wavelength, such as a visible wavelength (e.g., about 452 nm), or any other wavelength selected to activate a photosensitizer. As described further below, corneal crosslinking improves corneal strength by creating chemical bonds in the corneal tissue according to a photochemical kinetic reaction mechanism.

[0012] Riboflavin and photoactivated light may be applied to stabilize and / or strengthen corneal tissue to address corneal ectasia disorders (e.g., keratoconus or post-LASIK ectasia). The application of riboflavin and photoactivated light may also allow for various degrees of refractive correction, which may include, for example, combinations of myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia, and complex corneal refractive surface correction due to other conditions of corneal ectasia disorders and corneal biomechanical changes / degeneration.

[0013] 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 elements 112. In one embodiment, the cornea 2 may be more broadly treated with the crosslinking agent 130 (e.g., using eye droppers, a syringe, etc.), and the photoactivating light from the light source 110 may be selectively directed to the areas of the cornea 2 to be treated according to a particular pattern.

[0014] The optical element 112 may include one or more mirrors, lenses, or other optical components to focus the photoactivating light emitted by the light source 110 toward 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 to select particular wavelengths of light to be directed toward the cornea 2 to photoactivate the crosslinking agent 130. Furthermore, 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., at a particular depth within the lower region 2b where crosslinking activity is desired).

[0015] According to some embodiments, the optical elements of one exemplary treatment system may be fiber optic elements. The use of fiber optic elements may eliminate the need for free space optics and opto-mechanical mounting in the treatment system. Advantageously, the use of fiber optics may reduce the size and footprint of the treatment system, reduce the complexity and cost of design and manufacturing, and increase reliability.

[0016] Additionally, the specific characteristics of the photoactivating light may be altered to achieve a desired degree of crosslinking in selected regions of the cornea 2. One or more controllers 120 may control the operation of the light source 110 and / or optics 112 to precisely apply the photoactivating light according to any combination of wavelength, bandwidth, intensity, power, location, depth of penetration, and / or treatment duration (duration of exposure cycles, duration of dark cycles, and ratio of duration of exposure cycles to dark cycles).

[0017] Parameters for photoactivation of the cross-linking agent 130 can be adjusted, for example, to reduce the time required to achieve the desired cross-linking. In one implementation, the time can be reduced from minutes to seconds. Some configurations use photoactivating light with a power of 5 mW / cm 2Although the crosslinking can be performed at an irradiance of 1000 nm, a more intense exposure to the photoactivating light (e.g., 5 mW / cm 2 ) can be used to reduce the time required to achieve the desired crosslinking. 2 The total dose of energy absorbed in the cornea 2 can be described 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 2A of the corneal surface can be, for example, 5 J / cm 2 , or 20 J / cm 2 or 30 J / cm 2 The recited effective doses may be provided by a single application of energy or by repeated applications of energy.

[0018] The optical element 112 of the present treatment system 100 may 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. With DMD technology, the photoactivating light from the light source 110 (e.g., an LED) is projected in a precise spatial pattern generated by tiny mirrors arranged in an array on a semiconductor chip. Each mirror represents one or more pixels in the projected light pattern. With DMD, topography-guided crosslinking can be performed. Control of the DMD by topography can use several different spatial and temporal irradiance and dose profiles. These spatial and temporal dose profiles can be created using continuous wave irradiation, but can also be adjusted through pulsed irradiation by pulsing the irradiation source under varying frequency and duty cycle characteristics. Alternatively, the DMD can be tuned to have different pixel frequencies and duty cycles for each pixel, giving the ultimate flexibility with continuous wave illumination. Alternatively, both pulsed illumination and a combination of tuned DMD frequencies and duty cycles may 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 patient-specific pre-treatment plans.

[0019] To control the aspect of the irradiation of the photoactivating light, the embodiment may also employ aspects of multi-photon excitation microscopy. Specifically, rather than irradiating the cornea 2 with a single photon of a particular wavelength, the present treatment system 100 may irradiate multiple photons of longer wavelengths (i.e., lower energy) that combine to initiate cross-linking. Advantageously, longer wavelengths are scattered less in the cornea 2 than shorter wavelengths, which allows longer wavelength light to penetrate the cornea 2 more efficiently than shorter wavelength light. The shadowing effect of incident irradiation deeper in the cornea is also reduced compared to conventional short wavelength irradiation, because the absorption of light by the photosensitizer is much less at longer wavelengths. This allows for enhanced control over depth-specific cross-linking. For example, in some embodiments, two photons may be used, where each photon carries approximately half the energy required to excite the molecules in the cross-linking agent 130 to generate the photochemical reaction described further below. When the crosslinker molecule absorbs both photons simultaneously, it absorbs enough energy to release reactive radicals in the corneal tissue. Embodiments may also utilize lower energy photons, such that the crosslinker molecule must absorb, for example, 3, 4, or 5 photons simultaneously to release reactive radicals. The probability of multiple photons being absorbed nearly simultaneously is low, and therefore a high flux of excitation photons may be required, which may be provided via a femtosecond laser.

[0020] A number of conditions and parameters affect the cross-linking of corneal collagen by the cross-linking agent 130. For example, the irradiance and dose of the photoactivating light affect the amount and rate of cross-linking.

[0021] When the cross-linking agent 130 is riboflavin in particular, the UVA light may be applied continuously (continuous wave (CW)) or as pulsed light, the choice of which affects the amount, rate and extent of cross-linking. When the UVA light is applied as pulsed light, the duration of the exposure cycle, the dark cycle, and the ratio of the exposure cycle to the dark cycle duration will affect the resulting corneal stiffening. Pulsed light exposure can be used to stiffen the corneal tissue more or less than can be achieved with continuous wave exposure applying the same irradiance or dose of energy. 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 and about 1 / 1000. The irradiance can be about 1 mW / cm2 with an average irradiance of about 1 mW / cm2. 2 to 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.

[0022] The present therapeutic system 100 may employ a DMD to generate pulsed light by electronically turning the light source 110 on and off and / or by using mechanical or optoelectronic (e.g., Pockels cell) shutters or mechanical choppers or rotating apertures. Due to the inherent modulation capabilities of the DMD's pixels and subsequent stiffening based on the modulated frequency, duty cycle, irradiance and dose delivered to the cornea, complex biomechanical stiffening patterns may be imparted to the cornea. A particular advantage of the DMD system and method is that it allows for topographic patterning of random asynchronous pulses to produce aperiodic, uniform appearing illumination, thereby eliminating the possibility of inducing photosensitive epileptic seizures or flicker vertigo to pulse frequencies between 2Hz and 84Hz.

[0023] Although the exemplary embodiment may use a stepped on / off pulsed light function, it is understood that other functions for applying light to the cornea may be used to achieve a similar effect. For example, light may be applied to the cornea according to a sinusoidal function, a sawtooth function, or another complex function or curve, or any combination of functions or curves. In fact, it will be understood that the function may be substantially stepped, even if there may be more gradual transitions between the on / off values. Furthermore, it will be understood that the irradiance need not decrease to a value of zero during the off cycle, but may exceed zero during the off cycle. The desired effect may be achieved by applying light to the cornea according to a curve that varies the irradiance between two or more values.

[0024] 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 may generate cross-linking activity within the cornea according to a circular and / or annular pattern defined by application of photoactivating light (e.g., via a DMD as described above). Additionally or alternatively, embodiments may generate cross-linking activity within the cornea according to a non-circular and / or non-annular pattern defined by application of photoactivating light (e.g., via a DMD).

[0025] Multiple patterns of photoactivating light can be applied (e.g., via a DMD) to the eye in separate treatment zones with different doses applied sequentially or sequentially. For example, one treatment zone can be "turned off" (i.e., application of the corresponding photoactivating light is stopped) while the other treatment zone can be "left on" (i.e., application of the corresponding photoactivating light continues). The treatment zones can be formed, for example, annularly, around a central point of the eye. Also, there can be discontinuous zones where the photoactivating light is not applied (e.g., a central treatment zone surrounded by an annulus of no light surrounded by an annular treatment zone of light, etc.). The widths of the annular zones can be of different dimensions (e.g., one annular zone has a width of 1 mm and another annular zone has a width of 2 mm). Applying photoactivating light to annular treatment zones around the eye, but not the central treatment zone, can result in the correction of hyperopia, for example, by increasing the curvature of the central region of the eye while strengthening the periphery. In some cases, the central and peripheral treatment zones can be elliptical in shape to address astigmatism, for example, by preferentially generating cross-linking activity in areas of the cornea to correct the astigmatism. Such elliptical 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 randomly asymmetric (i.e., have major and minor axes that are not perpendicular to each other and may be located with separate central points (centers of mass)).

[0026] The crosslinking treatment may be adjusted 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 may be achieved by applying a crosslinking agent and / or photoactivating light in one or more iterations, each with adjustable properties. In general, the developed treatment plan may include the number of applications of crosslinking agent, the amount and concentration of each application of crosslinking agent, the number and timing, duration, power, energy dosage, and dose and pattern of each application of photoactivating light. Additionally, the crosslinking treatment may be adapted based on feedback information regarding the biomechanical properties collected in real time during treatment or during interruptions in treatment.

[0027] The addition of oxygen also affects the amount of corneal crosslinking. In human tissue, the O2 content is extremely low compared to the atmosphere. However, the rate of crosslinking of the cornea is related to the O2 concentration 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 until the desired degree of crosslinking is achieved. Oxygen can be applied in many different ways during crosslinking treatment. One approach involves supersaturating riboflavin with O2. In this way, when riboflavin is applied to the eye, a higher concentration of O2 is applied directly to the cornea along with the riboflavin, influencing the reaction involving O2 when the riboflavin is exposed to photoactivating light. According to another approach, a steady state of O2 (at a selected concentration) can be maintained at the surface of the cornea to expose the cornea to a selected amount of O2 and allow O2 to enter the cornea. 1, for example, the treatment system 100 also includes an oxygen source 140 and an oxygen delivery device 142 that delivers oxygen, optionally at a selected concentration, to the cornea 2. Exemplary systems and methods for providing 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 Cross-Linking with Pulsed Light," filed October 31, 2012, the contents of which are incorporated herein by reference in their entireties. Additionally, an exemplary mask device for applying high concentrations of oxygen and photoactivating light in eye treatment 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 may be placed over the eye to provide a consistent and known oxygen concentration to the surface thereof.

[0028] Riboflavin undergoes photoactivation upon absorption of irradiating energy, particularly light. There are two photochemical kinetic pathways for the photoactivation of riboflavin: Type I and Type II. The reactions involved in both 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 Application Publication No. 2016 / 0310319, filed April 27, 2016, entitled "Systems and Methods for Cross-Linking Treatments of an Eye," the contents of which are incorporated herein by reference in their entirety.

[0029] As described above, the treatment system 100 includes optical elements 112 that direct light (e.g., UV light) from the light source 110 to photoactivate the crosslinking agent 130 (e.g., riboflavin) applied to the cornea 2, thereby creating crosslinking activity. 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.

[0030] Examples of treatment systems that treat different ocular conditions by providing different treatment patterns are described in U.S. Patent Application Publication No. 2020 / 0107953, entitled "Photoactivation Systems and Methods for Corneal Cross-Linking Treatment," filed October 9, 2019, the contents of which are incorporated herein by reference in their entirety.

[0031] To treat keratoconus patients, crosslinking treatment strengthens and stabilizes the cornea and prevents disease progression. Providing a crosslinking treatment that also restores quality of vision also represents a significant improvement for these patients. Restoring quality of vision includes reducing visual aberrations and regularizing the corneal surface. These can be achieved by customizing the treatment pattern (e.g., the pattern of UV light) to the specific morphology of the cornea of ​​each individual patient. According to aspects of the present disclosure, an automated procedure receives input tomographic imaging data and generates an optimized (customized) treatment pattern for each individual patient without relying on the physician's analysis and judgment. Advantageously, this procedure reduces the burden on the physician and also reduces subjectivity in determining the treatment pattern. In some cases, the one or more controllers 120 described above can implement the automated procedure, and aspects of the treatment system 100 (e.g., the light source 110 and the optical element 112) can deliver the optimized treatment pattern to the cornea 2 as part of the treatment plan.

[0032] 2, an exemplary automated procedure 200 for generating an optimized treatment pattern generally includes operation 210, in which patient-specific tomographic imaging data is received from a system such as, for example, a rotating Scheimpflug camera system (e.g., a PENTACAM® system) or an anterior segment OCT system. The procedure 200 also includes operation 220, which uses height, curvature, or thickness measurement data contained in the patient-specific tomographic imaging data to identify the location of the keratoconus defect or "cone." In particular, the patient-specific tomographic imaging data may provide a corneal topography map (either anterior or posterior) indicative of: · elevation float (relative to the best fitting ellipsoid); Elevation floats as shown in Figure 3A (for a reference shape of low order Zernike polynomials); · tangent curvature as shown in Figure 3B; · Axial (sagittal) curvature as shown in Figure 3C; Corneal thickness measurements. Spatial (averaging) filtering may optionally be applied to the corneal topography map to reduce noise.

[0033] Operation 220 may include operation 220a generating Zernike coefficients describing deviations of the corneal surface (anterior and / or posterior) from a reference shape. Additionally, operation 220 may include operation 220b performing a Corneal Location and Magnitude (CLMI) analysis that operates on the curvature data to generate estimates of the cone center and cone severity. Specifically, the following keratoconus indices may be assessed: · Axial Cone Location and Criticality Index (aCLMI) and Tangential Cone Location and Criticality Index (tCLMI); · A severity term based on both axial and tangential curvature maps; · Probability of the presence of keratoconus; · Vertical frame; Other indices based on the Zernike decomposition (astigmatism, spherical aberration, total higher order aberrations, etc.).

[0034] Inputs for the Zernike analysis in act 220a may include an elevation map (e.g., from a PENTACAM® system), an order of approximation, and a normalized diameter. The corresponding outputs may include Zernike coefficients and a map of elevation residuals relative to a Zernike reference shape. Act 220a may include a Zernike decomposition of the elevation map by a least-squares fit of the elevation map with a reference shape that includes a series of Zernike polynomials and the lower order terms of the series.

[0035] The inputs for the CLMI analysis in act 220b can include both axial and tangent curvature maps (e.g., from a PENTACAM® system), and the outputs can include the location of the cone center, the CLMI, and a cone severity term. Act 220b can include a CLMI algorithm, for example as follows: A 2mm circle is moved over the target area. The center of the cone is found at the position (x0, y0) of the circle where the mean curvature (either the axial or tangential curvature) inside the circle reaches its maximum value. The severity term is the maximum mean curvature above. CLMI is estimated from the mean inner and outer curvatures of a 2 mm circle C1 placed on a cone and a circle C2 placed symmetrically (with respect to the corneal apex). The same algorithm is used to find the center of the cone in the other maps (pachymetry and elevation residuals).

[0036] The process 200 further includes an operation 230 of partitioning the cone into separate treatment zones based on predetermined geometric parameters. The operation 230 may include an operation 230a of selecting base data for partitioning, which may be elevation, curvature, or pachymetry data. The operation 230 may also include an operation 230b of creating a predetermined number of zone boundaries based on the partition data. The operation 230 may further include an operation 230c of post-processing the boundaries to reduce the eccentricity of the treatment shape, to expand or shrink the treatment shape, and / or to modify the zone areas to ensure coverage by a minimum treatment area. Specifically, the exposed area around the cone is partitioned into several treatment zones using a topographical map and a set of various evaluation criteria. The innermost zone may be an elliptical area around the center of the cone, and the other zones may be bounded by ellipses from both the inside and the outside. The different zones may receive different doses of photoactivating light (e.g., UV light). For example, the dose of photoactivating light may decrease from the inner zone outward.

[0037] The inputs for operation 230 may include the topography map (altitude residuals, curvature, or pachymetry) selected in operation 230a (e.g., from a PENTACAM® system), the location of the cone center, the number of zones, processing settings (settings used for defining the zone boundaries), and post-processing settings (settings used to modify the zone boundaries after the processing steps are completed). The corresponding output includes a list of ellipse zone boundaries, including the following data for each zone: location of the ellipse center, the major and minor axes of the ellipse, and the inclination angle relative to the naso-temporal axis. During the definition of the zone boundaries in operation 230b: 1. Depending on the map used, the zone boundaries are fixed curvatures, elevation floats, or corneal thickness contours (segmentation variables (SV)). 2. SV values ​​at the innermost and outermost boundaries (SV1 and SV bkg ) can be assessed in different ways depending on the treatment setting. 3. SV value at other boundaries (SV b ) is SV bkg Divide the section from to SV1 equally It is evaluated by: 4. The above boundary value SV b The ellipse boundary given by is evaluated as described further herein.

[0038] Modifying the zone boundaries (post-processing) in operation 230c may include the following optional operations (in order); 1. Reducing eccentricity (Innermost and outermost zones only.) If the eccentricity of the innermost (outermost) boundary exceeds a given limit, the major (minor) axis is decreased (increased) until said limit is reached. 2. scaling All zones are expanded or contracted while keeping their centers fixed. 3. Expanding the zone area If the innermost zone area falls below a given limit, all zones are expanded until the limit is reached. 4. Swap outer zone The outer zone replaces the enlarged previous zone.

[0039] The division of the inner and outer zones may include: 1. Evaluation of the segmental variable at the cone center – SVm. 2. Evaluation of background values ​​of classification variables (values ​​at the outer zone boundaries above) - S bkg The options include: · Predetermined value (not used for thickness measurements and elevation float). -Average value over the region of interest. ·The average value over a circle of a given diameter centered at the vertex. 3. Evaluation of the section variable at the boundary of the innermost zone - SV1. This option includes: A given increase (thickness measurement) or decrease (other) of a category variable relative to SVm. (SVm-SV bkg ) a given fraction of 4. Evaluation of the division variables at the boundaries of the remaining zones - S b Section variable SV1-S bkg The remaining reduction is divided into equal parts. 5. Evaluation of the above elliptical zone boundaries (their locations and semi-axes).

[0040] With reference to FIGS. 4A-B, the evaluation of the elliptical zone boundary may include: 1. The boundary values ​​Sb of the classification variable are evaluated for each zone boundary as explained above. 2. A given number of meridians are constructed outward from the center of the cone. 3. For each meridian, a boundary point is found, which is the first point from the center where the division variable rises above (thickness measurements) or falls (others) Sb. 4. The boundary of the ellipse is evaluated as the ellipse that best fits the set of boundary points. 5. Optionally, after the ellipse is computed, the distance of all boundary points to the ellipse is evaluated along the meridians and outliers are identified and removed. 6. The ellipse is recalculated using the reduced set of points. 7. The size of the reduced point set may be limited from below.

[0041] 5A-D show examples of segments produced by act 230b without the post-processing of act 230c. FIG. 5A corresponds to processing an elevation topography map (for a reference shape in low-order Zernike polynomials) as input. FIG. 5B corresponds to processing an axial curvature topography map as input. FIG. 5C corresponds to processing a tangent curvature topography map as input. FIG. 5D corresponds to processing a thickness measurement topography map as input.

[0042] 6A-D show example partitions produced by operation 230b with post-processing in operation 230c, where the maximum eccentricity is limited to 0.606. FIG. 6A corresponds to processing an elevation topography map (for a reference shape of low order Zernike polynomials) as input. FIG. 6B corresponds to processing an axial curvature topography map as input. FIG. 6C corresponds to processing a tangent curvature topography map as input. FIG. 6D corresponds to processing a thickness measurement topography map as input.

[0043] Once an optimized treatment pattern based on the treatment zones is generated, it can be displayed to the operator for review or modification, for example, before implementation by the treatment system 100. An additional feature of the procedure 200 is that it can optionally allow some degree of adjustment by the user. For example, the operator can manually input an overall disease severity value (e.g., mild, moderate, or severe), which can instruct the procedure to adapt size, shape, or UV irradiation parameters (irradiance or dose) according to predefined rules. Alternatively, the user can manually input a cone center, which can override the automatically determined cone center calculated in the above approach. In response to this input, the treatment pattern can be re-centered according to the user-defined cone center.

[0044] In view of the above, systems and methods are provided to biomechanically strengthen locally weak areas of the corneal stroma, prevent further progression of keratoconus, and regularize the cornea to improve visual function in patients. The principles behind such systems and methods include: Keratoconus results from localized weakening of the stroma. · Crosslinking can be applied spatially to locally stiffen the cornea. Selective stiffening of keratoconus leads to greater flattening of the cone region and compensatory steepening elsewhere: thus normalizing the corneal shape. Topical corneal crosslinking patterns generate more topographic change than large diameter patterns because they do not prevent compensatory steepening outside the treatment center. Advantages of such systems and methods include an increased likelihood of improving the quality of vision in keratoconus patients, a reduced need for physician input to generate treatment patterns, and reduced subjectivity in the generation of treatment patterns.

[0045] The strategy behind virtual clinical trials of such systems and methods may include: Training a biomechanical finite element analysis (FEA) model with customized corneal crosslinking treatment results from clinics representing a variety of approaches; · Creating treatment pattern processing procedures capable of generating locally specific treatments; Parameterizing the treatment space and treatment protocols to generate different responses given the preoperative state of the eye; Designing a virtual clinical trial, where the response of each therapeutic treatment step forms a clinical trial cohort, and the biomechanical model is used to predict the therapeutic response; To compare the efficacy of clinical trial arms based on surrogates of visual function and keratoconus regularization.

[0046] The following parameters may be considered for a hypothetical clinical trial: 1. Centration: Change the treatment centration based on various corneal topographical features: ·Anterior curvature (maximum curvature) Thickness measurements (treatment point of maximum weakening) ·Elevation (rear or front); 2. Size: The size of the shape to make the treatment zone cone sized and expanded; 3. Tapering: The introduction of multiple geometries that reduce the radiation dose in zones surrounding the central treatment zone. Corresponding treatment protocols may be tailored to produce localized treatments of varying center, size, and tapering.

[0047] In an exemplary hypothetical clinical trial, a cohort of 20 keratoconic eyes was used with a total of 12 treatment groups: 3 centered using anterior tangent curvature maps, 3 centered using pachymetry maps, 3 centered using anterior elevation residuals (custom reference surface), and 3 centered using posterior elevation residuals (custom reference surface). Size and taper (relative size of central shape) were also varied.

[0048] The following performance indices based on wavefront analysis of the anterior corneal surface may be employed: vertical coma, total astigmatism, spherical aberration, and higher order aberrations (HOA). The mean predicted change (reduction) in each of these indices may be measured for each arm of the hypothetical clinical trial.

[0049] In the hypothetical clinical trial example, the following results were observed: The above approaches centered on posterior and anterior elevations showed the greatest reduction in vertical coma. This is perhaps to be expected, as these treatments are centered in the region of highest HOA terms, where vertical coma dominates in many / most eyes. The above approach of centering on tangent curvature showed a magnitude of change comparable to that of rear elevation centering. Larger treatment geometries showed slightly greater reductions in vertical coma. The above approaches based on thickness measurements, which are usually more centrally located, showed the smallest change in vertical coma. The above approach, centered on the lowest region of thickness measurements, showed the greatest reduction in spherical aberration. The above approach, which focuses on tangent curvature, showed a large variation in predictions with changes in spherical aberration. The above approach centered on elevation showed a slight increase in spherical aberration on average. · Generally, more extensive treatment in the center, centered around the thinnest pachymetry measurement, showed a reduction in total astigmatism. The above approach, centered on tangent curvature, showed a slight increase in astigmatism. The above approaches, focusing on posterior and anterior elevation, showed a large variability in the predicted change in total astigmatism and tended to increase astigmatism as much as decrease it.

[0050] The following performance indices based on topographical changes in the anterior corneal surface may also be used: Kmax (maximum keratometric curvature), Kmax-tan, SimK Steep, aCLMI, tCLMI, and tangential severity. The mean predicted change (reduction) in each of these indices may be measured for each arm of the hypothetical clinical trial.

[0051] In the hypothetical clinical trial example, the following results were observed: The above approach based on tangent curvature outperformed other centration options. Smaller treatment patterns centered around the maximum curvature showed the greatest predicted change. Results for tangential Kmax mirrored those for sagittal (axial) Kmax. The above approach based on tangent curvature outperformed other centration options. Small treatment patterns centered around the maximum curvature showed the greatest change. The approach based on pachymetry (more central) was predicted to produce larger changes in SimK. The tangent curvature-centered approach showed greater variability in the predicted changes. The elevation-centric approach showed that the predicted changes in SimK were minimal. Treatment focused on tangent curvature and thinnest thickness measurements showed the greatest change in aCLMI significance. Treatment focused on elevation residuals showed little mean change in aCLMI. Smaller treatment patterns showed slightly larger changes. Results for tCLMI were similar to those for aCLMI.

[0052] As mentioned above, according to some aspects of the present disclosure, some or all steps of the procedures described and illustrated above may be automated or guided under the control of a controller. In general, the controller may be implemented as a combination of hardware and software elements. The hardware aspects may include a combination of operatively coupled hardware components including a microprocessor, logic circuitry, communication / network ports, digital filters, memory, or logic circuitry. The controller may be adapted to perform operations specified by computer executable code, which may be stored on a computer readable medium.

[0053] As mentioned above, the controller may be a programmable processing device (e.g., an external conventional computer, or an on-board 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 by the embodiments of the present disclosure for any processing or evaluation may include one or more networked or non-networked general-purpose computer systems, microprocessors, field programmable gate arrays (FPGA), 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 appreciated 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. As will be appreciated by those skilled in the software arts, appropriate software may be readily prepared by a programmer of ordinary skill based on the teachings of the exemplary embodiments. Moreover, the devices and subsystems of the exemplary embodiments may be implemented by the preparation of application specific integrated circuits or by interconnecting a number of conventional component circuits in an appropriate network, as will be appreciated by those skilled in the art of electrical engineering. Thus, the exemplary embodiments are not limited to any specific combination of hardware circuitry and / or software.

[0054] Exemplary embodiments of the present disclosure may include software stored on any one or combination of computer readable media for controlling the devices and subsystems of the exemplary embodiments, for driving the devices and subsystems of the exemplary embodiments, for enabling the devices and subsystems of the exemplary embodiments to interact with a human user, etc. Such software may include, but is not limited to, device drivers, firmware, operating systems, development tools, application software, etc. Such computer readable media may further include computer program products of the embodiments of the present disclosure for performing all or a portion (if processing is distributed) of the processing performed in the implementation. Computer code devices 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, etc. Additionally, portions of the processing of the exemplary embodiments of the present disclosure may be distributed for better performance, reliability, cost, etc.

[0055] Common forms of computer readable media may include, for example, a floppy disk, a flexible disk, a hard disk, magnetic tape, other suitable magnetic media, CD-ROM, CDRW, DVD, other suitable optical media, punch cards, paper tape, optical mark sheets, other suitable physical media with a pattern of holes or other optically recognizable indicia, RAM, PROM, EPROM, FLASH-EPROM, other suitable memory chips or cartridges, a computer readable carrier wave, or other suitable medium.

[0056] 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 may be made thereto without departing from the spirit and scope of the present disclosure. Each of these embodiments and their obvious variations 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. A method for treating a cornea having a cone center, comprising: receiving tomographic imaging data of the cornea; identifying a keratoconus defect of the cornea based on the tomographic imaging data; and segmenting the keratoconus defect into treatment zones based on predetermined geometric parameters; the treatment zone indicates where on the cornea a crosslinking agent should be applied and photoactivated to treat the keratoconus defect; The method, wherein segmenting the keratoconus defect into the treatment zone includes generating an elliptical boundary for the treatment zone based on segmentation data, the elliptical boundary being created by evaluating a predetermined number of meridians drawn from a center of the cone.

2. applying the crosslinking agent to the cornea; and delivering radiation to photoactivate the crosslinking agent according to the treatment zone with an irradiation system; The method of claim 1 further comprising:

3. specifying respective doses of different photoactivating light to be delivered to said treatment zones; The method of claim 1 further comprising:

4. 4. The method of claim 3, wherein the respective doses of photoactivating light decrease from an innermost treatment zone outward.

5. The method of claim 1 , wherein the tomographic imaging data provides a topographical map indicative of at least one of elevation, curvature, or thickness measurements.

6. 2. The method of claim 1, wherein identifying a keratoconus defect of the cornea based on the tomographic imaging data comprises generating Zernike coefficients describing deviations of the anterior and / or posterior corneal surface from a reference shape.

7. 2. The method of claim 1, wherein identifying a corneal keratoconus defect based on the tomographic imaging data includes performing a Corneal Location and Severity Index (CLMI) analysis to generate an estimate of the location and severity of the corneal keratoconus defect.

8. The method of claim 1 , wherein segmenting the keratoconus defect into the treatment zones includes selecting elevation, curvature, or pachymetry data as a basis for segmentation.

9. 2. The method of claim 1, wherein partitioning the keratoconus defect into the treatment zones comprises manipulating a boundary of the treatment zone to one of: reducing an eccentricity of a treatment shape for the treatment zone, enlarging or shrinking a treatment shape for the treatment zone, or modifying a treatment zone area.

10. A system for treating a cornea having a cone center, comprising: an illumination system configured to deliver illumination to activate a photosensitizer applied to the cornea; and a controller configured to control the illumination system; The controller includes one or more processors and one or more computer readable media, the one or more processors controlling the controller: receiving tomographic imaging data relating to the cornea; identifying a keratoconus defect of the cornea based on the tomographic imaging data; segmenting the corneal defect into treatment zones based on predetermined geometric parameters, where the treatment zones indicate where on the cornea a crosslinking agent should be applied and photoactivated to treat the corneal defect, and the controller segments the corneal defect into the treatment zones by creating an elliptical boundary for the treatment zone based on segmentation data; and delivering radiation to said irradiation system to photoactivate said cross-linking agent according to said treatment zone; configured to execute instructions from the computer-readable medium to cause The boundary of the ellipse is created by evaluating a predetermined number of meridians made from the center of the cone.

11. The system of claim 10 , wherein the illumination is ultraviolet (UV) light.

12. 11. The system of claim 10, wherein the instructions from the computer readable medium further cause the controller to specify respective doses of different photoactivating light delivered to the treatment zone.

13. 13. The system of claim 12, wherein the respective doses of the photoactivating light decrease from an innermost treatment zone outward.

14. The system of claim 10 , wherein the tomographic imaging data provides a topographical map indicative of at least one of elevation, curvature, or thickness measurements.

15. 11. The system of claim 10, wherein the controller identifies keratoconus defects of the cornea by generating Zernike coefficients that describe deviations of the anterior and / or posterior corneal surfaces from a reference shape.

16. 11. The system of claim 10, wherein the controller identifies a corneal conus defect of the cornea by performing a Corneal Location and Severity Index (CLMI) analysis to generate an estimate of the location and severity of the corneal conus defect.

17. The system of claim 10 , wherein the controller segments the keratoconus defect into the treatment zones by selecting elevation, curvature, or pachymetry data as a basis for segmentation.

18. 11. The system of claim 10, wherein the controller partitions the keratoconus defect into the treatment zone by manipulating the boundaries of the treatment zone to at least one of: reduce an eccentricity of the treatment shape of the treatment zone, enlarge or reduce the treatment shape of the treatment zone, or modify the treatment zone area.

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