CN115916331A

CN115916331A - Projection of defocused images on the peripheral retina to treat ametropia

Info

Publication number: CN115916331A
Application number: CN202180041303.6A
Authority: CN
Inventors: 辽·洼田; 纳宾·乔希; 阿尔卡迪·西莱诺; 史蒂文·阿里; 斯特凡·鲍尔; 让-诺尔·费尔; 莫里茨·海尔伯利; 帕特里齐亚·韦伯; 朱利安·索维特; 阿米塔瓦·古普塔
Original assignee: Acucela Inc
Current assignee: Acucela Inc
Priority date: 2020-06-08
Filing date: 2021-06-07
Publication date: 2023-04-04
Also published as: EP4161636A4; US20210382325A1; JP2023528301A; CA3174148A1; US20220155616A1; AU2021289593A1; US11480813B2; US20220413318A1; KR20230020951A; EP4161636A1; US11275259B2

Abstract

A device for treating refractive error of an eye comprising one or more optical elements configured to project a stimulus comprising an out-of-focus image onto a peripheral retina outside of the macula. While the stimulus may be configured in a variety of ways, in some embodiments the stimulus is arranged to reduce interference with central vision, such as macular vision. The stimulus canTo be an out-of-focus image, may include an amount of defocus in a range of about 3 diopters ("D") to about 6D. In some embodiments, the intensity of the stimulus is greater than the intensity of the background illumination by a suitable amount, such as at least 3 times the background intensity. In some embodiments, each of the plurality of stimuli includes a spatial frequency distribution having an amplitude profile with a spatial frequency of about 1 x 10 per degree ^‑1 One cycle to 2.5 × 10 ¹ Within a period.

Description

Projection of defocused images on the peripheral retina to treat ametropia

RELATED APPLICATIONS

This PCT application claims priority from the following provisional patent applications: provisional patent application 63/036,226 entitled "production OF DEFEC USED IMAGES ON THE PERIPHERAL RETINA TO TREAT REFRACTIVE ERROR" filed ON 8.2020, provisional patent application 62/706,153 entitled "production OF DEFEC USED IMAGES ON THE PERIPHERAL RETINA TO TREAT REFRACTIVE ERROR" filed ON 8.2020 and 3.2020, provisional patent application 62/706,456 entitled "production OF DEFEC USED IMAGES THE PERIPHERAL RETINATO TREAT REFRACTIVE ERROR" filed ON 8.2020 and 18.2020, the entire disclosures OF which are incorporated herein by reference.

The subject matter of the present application relates TO PCT/US2019/043692 entitled "electric CONTACT LENS TO simple MYOPIA progress" filed on 26.7.2019 (published as WO2020028177A1 on 6.2.2020), the entire disclosure of which is incorporated herein by reference.

Background

Existing methods of treating refractive errors, such as myopia, are less than ideal in at least some respects. Spectacle lenses, contact lenses and refractive surgery may be used to treat refractive errors of the eye. However, to correct for the refractive error, which affects one's ability to achieve and adequately participate in school activities, sports activities, and other activities, lenses must be worn. Although surgery can reduce refractive error, surgery is associated with risks such as infection and vision loss, at least in some cases. Furthermore, these methods do not address the potential variation in length of the eye associated with refractive errors (such as myopia).

Work in connection with the present disclosure suggests that retinas of many species, including humans, respond to defocused images and are repositioned by scleral remodeling to reduce blur caused by defocusing. The mechanism of growth signal generation is still under investigation, but one observable phenomenon is an increase in choroidal thickness. Defocused images cause changes in choroidal thickness that are related to the axial length of the eye. Changes in the axial length of the eye can modify refractive error by changing the position of the retina relative to the cornea. For example, an increase in axial length increases the myopia of the eye by increasing the distance between the cornea and the retina.

While defocusing of the image may play a role in changes in choroidal thickness and eye axial length, existing methods are less suitable for addressing refractive errors of the eye associated with axial length. Although drug treatments have been proposed to treat myopia associated with increased axial length, these treatments may not have the desired results, at least in some cases, have not been shown to be safe for treating refractive errors. Although light is proposed as a stimulus to alter eye growth, at least some existing devices may provide less than ideal results. In addition, the time of treatment may be longer than ideal and at least some of the existing methods may be more complex than ideal.

Accordingly, new methods that ameliorate at least some of the above-mentioned limitations of existing methods are needed to treat refractive errors of the eye.

SUMMARY

The presently disclosed methods, devices and apparatus provide improved treatment of refractive error with reduced treatment time. In some embodiments, the stimulus comprises one or more of a spatial frequency distribution or a ratio of stimulus intensity to background illumination intensity to promote an improved response. In some embodiments, the stimulus is presented at an appropriate time of day to boost the response.

A device for treating refractive error of an eye includes one or more optical elements configured to project a stimulus comprising an out-of-focus image onto a peripheral retina outside of the macula. Although the stimulus may be configured in a variety of ways, in some embodiments the stimulus is arranged to reduce interference with central vision, such as macular vision. The stimulus may be an out-of-focus image, may include an amount of defocus in a range of about 2 diopters ("D") to about 6D, and may range from about 3D to about 6D. In some embodiments, the intensity of the stimulus is greater than the intensity of the background illumination by a suitable amount, such as at least 3 times the background intensity. In some embodiments, each of the plurality of stimuli includes a spatial frequency distribution having an amplitude profile with 1 x 10 at each degree ^-1 Period to 1 × 10 ¹ A number of spatial frequencies within a range of one period. In some embodiments, each stimulus is sized and shaped to have an intensity profile distribution so as to be responsive to a stimulus of a predetermined magnitudeSpatial frequencies are provided to enhance the response to the stimulus. Each stimulus may include one or more local intensity peaks near the area of reduced illumination. In some embodiments, the area of reduced illumination is located between the plurality of peaks, although the area of reduced illumination may be bounded by annular peaks.

Is incorporated by reference

All patents, applications, and publications cited and identified herein are hereby incorporated by reference in their entirety, even if cited elsewhere in the application, are to be considered to be incorporated by reference in their entirety.

Brief Description of Drawings

A better understanding of the features, advantages, and principles of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments and the accompanying drawings of which:

fig. 1A illustrates a retinal stimulation device according to some embodiments;

FIG. 1B illustrates an eyeglass lens-based retinal stimulating device that includes a display and a housing that houses electronics for operating a near-eye display, in accordance with some embodiments;

fig. 1C illustrates an eyeglass lens-based retinal stimulation device as shown in fig. 1B in which the eye has moved and a different display element has been activated in response to eye movement, in accordance with some embodiments;

fig. 2A illustrates a soft contact lens according to some embodiments;

fig. 2B illustrates a soft contact lens having an embedded light source, optics, and electronics for projecting an image with defocus on the periphery of a user's retina, according to some embodiments;

FIG. 3 is a system diagram illustrating the function of the components of the contact lens as in FIG. 2;

FIG. 4A illustrates an optical configuration in which the optical path length is increased by folding the optical path with two mirrors, according to some embodiments;

FIG. 4B illustrates an optical configuration of projecting light into an eye as in FIG. 4A, in accordance with some embodiments;

FIG. 5A shows an optical configuration including a lens that focuses light onto the retina, according to some embodiments;

FIG. 5B illustrates an optical configuration for projecting light into an eye as in FIG. 5A, in accordance with some embodiments;

FIG. 6A illustrates a light pipe for increasing the optical path length according to some embodiments;

FIG. 6B illustrates an optical configuration for projecting light into an eye as in FIG. 6A, in accordance with some embodiments;

FIG. 7 illustrates a plurality of stimuli and images on a display as seen by a user, in accordance with some embodiments;

FIG. 8A illustrates stimuli on a screen that provide myopic defocus stimuli to a retina according to some embodiments;

FIG. 8B illustrates, in degrees, the respective sizes of myopic defocus stimuli on the retina, in accordance with some embodiments;

FIG. 9 illustrates a stimulus depicting a natural scene (such as a circular flower pattern), in accordance with some embodiments;

fig. 10 illustrates image contrast and histograms with red (R), blue (B) and green (G) values for the stimuli shown in fig. 8A-9, in accordance with some embodiments;

FIG. 11 illustrates an image suitable for modification and incorporation as a stimulus described herein, in accordance with some embodiments;

FIG. 12 shows an image similar to that of FIG. 11 that has been processed to provide improved stimulation, in accordance with some embodiments;

FIG. 13 illustrates an image of a spatial frequency distribution of the image of FIG. 11, in accordance with some embodiments;

FIG. 14 shows an image of the spatial frequency distribution of the image of FIG. 13 (which is used as a stimulus), in accordance with some embodiments;

fig. 15 illustrates a graph of image spatial frequency in cycles per degree and log of energy at each frequency for the stimulation images shown in fig. 8B and 9, in accordance with some embodiments;

fig. 16 shows a system for treating refractive error of an eye according to some embodiments;

fig. 17 illustrates a method of treating refractive error of an eye according to some embodiments;

figure 18A depicts a stimulus with myopic defocus of 6D ("6D stimulus") and another stimulus with myopic defocus of 3D ("3D stimulus"), according to some embodiments;

fig. 18B depicts stimulation with 25% coverage ("25% stimulation") and stimulation with 50% coverage ("50% stimulation"), according to some embodiments;

fig. 18C depicts a graph having a 0.1:1 brightness ratio and a stimulus with a 1:1 luminance ratio stimulus;

fig. 18D depicts black-and-white and red stimuli according to some embodiments;

fig. 19 depicts an optical system that projects a stimulus onto the retina according to some embodiments;

FIG. 20A illustrates a focus of a central entertainment area and a background pattern for a control eye (e.g., the left eye), according to some embodiments;

FIG. 20B illustrates stimulated myopic defocus, a central entertainment area, and a background pattern for the eye under test (e.g., the right eye), in accordance with some embodiments;

figure 21 shows clinical results similar to those of table 1, according to some embodiments;

fig. 22 shows aggregated data for 5-, 10-, and 20-fold luminance experiments, showing that the mean change in central axis length (in microns) for the test eye is significantly less (p < 0.025) than the mean change in central axis length for the control eye after a1 hour defocus period (session), in accordance with some embodiments; and

fig. 23 shows mean changes in axial length and choroidal thickness (mean ± SEM), in accordance with some embodiments: for all experimental aggregation, the axial length change of the test eye was significantly less than the axial length change of the control eye after a one hour defocus period.

Detailed Description

The following detailed description provides a better understanding of the features and advantages of the invention described in this disclosure in light of the embodiments disclosed herein. Although the detailed description includes many specific embodiments, these embodiments are provided by way of example only and should not be construed to limit the scope of the invention disclosed herein.

The presently disclosed methods and devices may be configured in a variety of ways to provide retinal stimulation as described herein. The presently disclosed methods and apparatus are well suited for combination with many existing devices, such as one or more of an ophthalmic device, a TV screen, a computer screen, a virtual reality ("VR") display, an augmented reality ("AR") display, a handheld device, a mobile computing device, a tablet computing device, a smartphone, a wearable device, a spectacle frame, a spectacle lens, a near-eye display, a head-mounted display, goggles, a contact lens, an implantable device, a corneal onlay, a corneal inlay, a corneal prosthesis, or an intraocular lens. Although specific reference is made to ophthalmic lenses and contact lenses, the presently disclosed methods and apparatus are well suited for use with any of the foregoing devices, and based on the teachings provided herein, one of ordinary skill in the art will readily understand how one or more of the presently disclosed components can be interchanged between devices.

Figure 1A shows a retinal stimulation device for one or more of reducing myopia progression or at least partially reversing myopia progression. The device comprises a lens 10 to support a plurality of light sources. A plurality of light sources may be coupled to one or more optical components to provide stimulation of the retina as described herein. In some embodiments, the lens 10 includes an eyeglass lens 74. In some embodiments, the lens 10 is shaped to correct spherical and cylindrical refractive errors of the user to provide corrected visual acuity (visual acuity) through the lens. The plurality of light sources may include one or more of the projection unit 12 or a display 74 (such as a near-eye display). A plurality of light sources are arranged around a central portion of the lens to provide light stimulation to an outer location of the retina, such as the peripheral retina as described herein. In some embodiments, the light source is located in an approximately annular region to provide stimulation to the peripheral retina. The light sources may be arranged in a generally annular pattern, e.g., in quadrants, so as to correspond to quadrants of the peripheral retina outside of the macula. Each of the plurality of light sources may be configured to project a pattern in front of the retina with an appropriate stimulation pattern as described herein. In some embodiments, light from the light source passes through the optical axis of the eye so as to stimulate the retina at a location on the opposite side of the retina from the light source.

In some embodiments, the projection unit 12 is configured to emit light rays to enter the pupil of the eye without substantial aliasing. In some embodiments, the pupil of the eye may be dilated by application of an appropriate amount of light or mydriatic agent, such that a larger area of the retinal surface is accessible to the stimulus projected by the projection unit 12.

In some embodiments, the plurality of light sources are configured to remain static while the user views the object. Alternatively, the light source may be configured to move in response to eye movements, e.g., with selective activation of pixels as described herein.

Although reference is made to a plurality of light sources supported on a lens, the light sources may be supported on any suitable optically transmissive substrate (such as a beam splitter or a substantially flat optical component), and the light sources may include light sources of a pixel display (such as an AR or VR display). In some embodiments, display 72 includes pixels 94, and pixels 94 are selectively activated to provide stimulation to the retina as described herein. Alternatively or in combination, the projection unit 12 may include a shaped structure to provide stimulation to the retina as described herein.

In some embodiments, for example, the pixels are configured to emit multiple colors, so that the projected light can be combined to produce any suitable color or hue, such as white light.

In some embodiments, the plurality of light sources are supported on a head-mounted support, such as an eyeglass frame 76 on eyeglasses 70.

Fig. 1B and 1C depict eyewear 70 for treating refractive errors of the eye (e.g., spherical refractive errors), although any suitable vision device as described herein may be suitably modified in accordance with embodiments disclosed herein. A plurality of light sources may be coupled to one or more optical components to provide stimulation of the retina as described herein. The glasses 70 may include one or more components of commercially available augmented reality glasses. The glasses 70 may include one or more displays 72 for retinal stimulation. The near-eye display 72 may be mounted to a lens 74. The lens 74 may be an eyeglass lens supported by an eyeglass frame 76. The lens 74 may be a corrective lens or a non-corrective lens. The lens 74 may be a flat lens, a spherical correction lens, an astigmatic correction lens, or a prismatic correction lens. In some embodiments, the near-eye display is positioned away from the optical zone to provide clear central vision. The optical axis may extend along a line of sight from an object of interest of the patient through the lens 74 to the fovea of the eye. In some embodiments, the glasses 70 include an eye tracker adapted to be incorporated in accordance with the present disclosure. As described herein, the near-eye display 72 may be programmed to selectively activate the pixels 94 to provide a peripheral stimulus to the retina. In some embodiments, a plastic substrate layer carrying microlenses is attached to the microdisplay to generate a desired level of defocus and stimulus at the retina. The selectively activatable pixels may include groups of pixels that may be selectively activated together, for example, a first group of pixels 94a, a second group of pixels 94B, a third group of pixels 94C, and a fourth group of pixels 94D. The pixel groups may be arranged to provide an appropriate eccentricity relative to the patient's line of sight in order to provide peripheral retinal stimulation as described herein.

In some embodiments, the near-eye display 72 includes a combination of a microdisplay and a micro-optical element. In some embodiments, the micro-optical elements are configured to collect, substantially collimate, and focus light emitted from the micro-display. In some embodiments, the micro-optical elements are configured to form an image in front of or behind the retina, as described herein. In some embodiments, the distance of the near-eye display from the entrance pupil of the eye is in the range from about 10mm to about 30mm, for example about 15mm. The microdisplays may be placed on a transparent substrate, such as on the front or back surface of the lens 74 of the glasses 70. When the microdisplay is placed on the front surface of the lens 94, then the focal point of the microdisplay may be affected by the cylindrical correction on the back surface of the lens 94.

In some embodiments, the focus of the pixels in the microdisplay may be varied based on their position on the lens 74 and the refractive correction provided by the lens in that region. In some embodiments, the focal point of a pixel may be fixed. In some embodiments, the focal point of the pixel may be varied based on the sensed position of the cornea to account for the refraction of the cornea and lens of the eye. In some embodiments, the pixels are defocused to produce a defocused spot of about 1mm in diameter on the retina.

The light emitted by the pixels 94 in the microdisplay of the near-eye display may be one or more of substantially collimated or focused light before being directed to the pupil of the eye. In some embodiments, the microlens array is aligned with pixels of the near-eye display so that light rays from the near-eye display can enter the pupil and form an image in front of or behind the retina. In some embodiments, the width of the near-eye display corresponds to the field of view of the patient. In some embodiments, the extent of the near-eye display may be substantially similar to the extent of the lens 74 of the glasses 70.

In some embodiments, the device provides unimpaired central vision such that the user's quality of life and vision quality is not adversely affected. In some embodiments, central vision includes a field of view of +/-5 degrees or more, preferably +/-7.5 degrees or more, for example +/-12.5 degrees, covering the macula, while foveal vision for fixation has a field of view of +/-1.0 degrees. In some embodiments, the defocused image is projected at the outer portion of the retina toward the periphery of the retina, for example, in a range of 15 degrees (full angle, or +/-7.5 degrees) to 40 degrees (full angle, or +/-20 degrees) off-center from the fovea, and may be in a range of 20 degrees to 40 degrees, for example in a range of 20 degrees to 30 degrees. In some embodiments, the microdisplay 72 does not obstruct the central visual field. In some embodiments, the pixels 94 do not obstruct the central visual field.

In some embodiments, the microdisplay and the optical element are configured to project light onto an outer region of the retina sufficiently far from the fovea such that the illumination remains substantially stationary even in the presence of eye movement. In some embodiments, the point of interest is monitored and the desired location of the pixel to be activated on the microdisplay is determined (e.g., by calculations using a processor) so that an image is projected at the desired location on the retina to allow for continuous stimulation at the same retinal location. In some embodiments, the point of interest on the glasses plane or microdisplay plane is calculated by monitoring the horizontal, vertical, and torsional displacement of the eye relative to the primary position.

The point of interest may be determined in a number of ways, for example using an eye position sensor, such as a magnetic sensor or an optical sensor. In some embodiments, search coils embedded in the eyeglass frame are used to track eye movements. The coils embedded in the eyeglass frame can be coupled to magnetic structures placed on the eye, such as one or more of coils on the contact lens, coils implanted in the eye, magnetic material on the contact lens, or magnetic material implanted in the eye. In some embodiments, the sensor comprises an optical sensor, such as a position sensitive detector or an array sensor, to optically measure the position of the eye. The optical sensor may be configured to measure the position of the eye in a variety of ways, for example, configured to measure the position of one or more of the corneal reflections from the light source, the pupil, the limbus, or the sclera. The eyeglass frame may support additional light sources to illuminate the eye, for example to generate corneal reflections. Data from the sensors may provide the location of the on-axis visible corneal light reflection ("CSCLR") and thus the orientation of the visual axis and the location of the fovea. By Srinivasan, s. In "Ocular axees and Angels: the point of interest, visual axis, optical axis, nodal point of the eyes and CSCLR are described in time for Goodering Generation "(J CATARACT REFRACT SURG-volume 42, month 3 2016). In some embodiments, a processor using an eye position sensor may be configured to adjust optical elements, such as pixels in a microdisplay, to reduce movement of the stimulated position of the retina in response to eye movement. In some embodiments, the target position of the peripheral image is calculated from the position of the fovea based on information from the eye position sensor, and the real-time ray-tracing calculations provide the position of the pixels in the microdisplay to be activated. The time to selectively switch to the plurality of second pixels in response to the eye movement may be less than 100 milliseconds, for example less than 20 milliseconds.

In some embodiments, the locations of pixels in the microdisplay to be activated to form an external image toward the periphery of the retina are referenced to the optical center of the spectacle optical sheet, as that optical center is a point of interest in primary gaze. In some embodiments, the position of the point of interest is calculated by considering eye movement relative to the position of the eye at the time of primary gaze, and the position of the pixel to be activated is calculated with reference to the new point of interest. For example, fig. 1B shows active pixels 94 when the patient looks straight up and straight ahead (i.e., a so-called primary gaze), while fig. 1C shows active pixels 94 when the patient looks up and to the left. In this case, the shape of the pixel array may be the same, but shifted up and to the left, or the shape of the array may change.

In some embodiments, the device is binocular and includes a microdisplay and an optical element for each eye of the user. The microdisplay may be optically coupled with one or more micro-optical components designed to substantially collimate the illumination generated by the pixels of the microdisplay before it enters the pupil and presents a convergence.

In some embodiments, the display 72 is mounted on the outside of the eyeglass lens and aligned with the eyeglass lens optical elements such that the near-eye display can provide a field of view of +/-40 degrees or more so that the microdisplay can continue to provide peripheral retinal stimulation for a normal range of eye movements, typically +/-15 degrees laterally, and +10 degrees to-20 degrees vertically, including downward gaze when reading or viewing nearby objects. In some embodiments, light from the microdisplay is transmitted through the eyeglass lens optical element and provides the user's refractive correction.

In some embodiments, the optical system is configured to form an image in front of the retina and includes one or more of a single microlens (lenslet), a plurality of microlenses (lenslet array), a compound lens (such as a Gabor lens), a microprism or a micro-mirror, or a combination thereof. In some embodiments, the light barrier and the micro-mirrors are arranged to ensure that the amount of light not captured by the micro-optical elements is significantly reduced, e.g. minimized, in order to reduce stray light and light escaping from the front side of the display.

In some embodiments, less than 10% (0.1) of the pixel fill factor is sparse enough to provide a clear view of the foveal and macular images. In some embodiments, the fill factor is in the range of 0.01 to 0.3, and may be in the range of 0.05 to 0.20. For example, a pixel array with a pixel size of 5 microns and a pixel pitch of 20 microns results in a fill factor of 0.06. Low fill factors can also reduce the complexity of the manufacturing process and reduce the cost of such micro-optical displays.

In some embodiments, the micro-optical element array is designed to be optically aligned with the display such that light from a single or multiple pixels 94 can be collected, collimated, and focused to be directed to the pupil of the user at the primary gaze. The density of these micro-optical elements can control the overall visibility of the near-eye display. In some embodiments, the micro-optical element has a low fill factor (preferably equal to or less than 0.1) such that the total light transmission through the near-eye display is acceptable to the user and allows the patient to view the object.

In some embodiments, the device comprises an array of switchable micro-optical elements that can be switched between a flat (no optical power) state and an active state by the electro-optical component, for example using liquid crystals or LC based materials that can be switched, for example, from one refractive index to another or from one polarisation to another. In some embodiments, the array of micro-optical elements does not scatter light or distort the real-world image when the array of micro-optical elements is not activated.

In some embodiments, the position of the pixels in the microdisplay that are to be activated to form the external image toward the periphery of the retina is referenced to the optical center of the spectacle optical sheet, since this optical center is the point of interest in dominant gaze. In some embodiments, the position of the point of interest is calculated by considering eye movements relative to the position of the eye at the time of primary gaze, and the position of the pixel to be activated is calculated with reference to the new point of interest.

In some embodiments, a plurality of pixels are activated to form a light source that is imaged by the micro-optical element. The optical design of the micro-optical elements and their separation from the microdisplay may be configured to provide the focal length of the image transfer system, image magnification of the image projected on the retina, and diffraction-induced blur, as measured by the Airy disc diameter (Airy disc diameter) of the optical transfer system.

Work in connection with the present disclosure suggests that the retina perceives changes in image blur caused by higher order aberrations present in the defocused image (in addition to spherical defocus), including Longitudinal Chromatic Aberration (LCA) which is sensitive to the sign of defocus, higher order spherical aberrations, astigmatism, etc. Based on the teachings provided herein, one of ordinary skill in the art may perform experiments to determine whether the retina is capable of distinguishing between myopic and hyperopic blur when the depth of focus of the device is greater than or nearly equal to the defocus magnitude. The apparatus as described herein may be suitably configured to provide a suitable amount of defocus, for example at a suitable location.

The device may be configured to provide appropriate image magnification, diffraction to limit image resolution, and depth of focus which is related to the magnitude of the applied myopic defocus, and the rate of change of image blur or image sharpness gradient as a function of defocus magnitude.

In some embodiments, the near-eye display is configured to provide a clear, substantially undistorted field of view of the foveal and macular images for comfortable vision. In some embodiments, for example, the field of view of the center image is at least +/-5 degrees, and may be larger (e.g., +/-12 degrees) to account for differences in inter-pupil distance (IPD) of different users, for example. The image quality and field of view of the real image may be provided using a substantially transparent near-eye display and may be provided by reducing the fill factor of the light emitting pixels in the microdisplay. In some embodiments, less than 10% (0.1) of the fill factor is sparse enough to provide a clear view of the foveal and macular images. In some embodiments, the fill factor is in the range of 0.01 to 0.3, and may be in the range of 0.05 to 0.20. For example, a pixel array with a pixel size of 5 microns and a pixel pitch of 20 microns would result in a fill factor of 0.06. Low fill factors can also reduce the complexity of the manufacturing process and reduce the cost of such micro-optical displays.

In some embodiments, the array of micro-optical elements is designed to be optically aligned with the display such that light from a single or multiple pixels can be collected, collimated, and focused to be directed to the pupil of the user at the primary gaze. The packing density of these micro-optical elements can control the overall visibility of the near-eye display. In some embodiments, the micro-optical element has a low fill factor (preferably equal to or less than 0.1) such that the total light transmission through the near-eye display is acceptable to the user.

Fig. 2A and 2B depict a contact lens 10, the contact lens 10 including a plurality of light sources configured to project a defocused image onto the retina, away from a central field including the macula, in order to stimulate changes in choroidal thickness. A plurality of light sources may be coupled to one or more optical components to provide stimulation of the retina as described herein. Although reference is made to a contact lens, lens 10 may comprise a lens of one or more of a projector, an ophthalmic device, a TV screen, a computer screen, an augmented reality display, a virtual reality display, a handheld device such as a smartphone, a wearable device such as eyeglasses, a near-eye display, a head-mounted display, goggles, a contact lens, a corneal onlay, a corneal inlay, a corneal prosthesis, or an intraocular lens.

The contact lens 10 comprises a base or carrier contact lens that includes embedded electronics and optical elements. The base soft contact lens 10 is made of a biocompatible material, such as a hydrogel or silicone hydrogel polymer, that is designed to be suitable for sustained wear. The contact lens includes a maximum total spanning distance, such as diameter 13. The biocompatible material may encapsulate the components of the soft contact lens 10. In some embodiments, contact lens 10 has a central optical zone 14, which central optical zone 14 is designed to cover the pupil of the user's eye under many lighting conditions. In some embodiments, the optical zone comprises a circular zone defined by a radius 15. In some embodiments, the plurality of projection units 12 are located a distance 17 from the center of the optical zone. Each of the plurality of projection units 12 includes a spanning distance 19. In some embodiments, the distance between the projection units is sized to place the projection units outside the optical zone to stimulate the peripheral region of the retina, although the projection units may also be placed inside the optical zone to stimulate the peripheral retina as described herein.

Optic zone 14 can be appropriately sized according to the pupil of the eye and the lighting conditions during treatment. In some embodiments, for example when the contact lens is configured for daytime use, the optical zone comprises a diameter of 6 mm. Optical zone 14 can have a diameter in the range of 6mm to 9mm, for example a diameter in the range of 7.0mm to 8.0 mm. The central optical zone 14 is designed to provide emmetropia correction or other suitable correction to the user, and may provide both spherical and astigmatic corrections. The central optical zone 14 is defined by an outer annular zone, such as a peripheral zone 16 having a width in the range of 2.5mm to 3.0 mm. The peripheral zone 16, sometimes referred to as the blending zone, is primarily designed to provide a good fit (fit) with the cornea, including good centering and minimal decentration. The outer annular region is surrounded by an outermost edge region 18 having a width in the range 0.5mm to 1.0 mm. Optical zone 14 is configured to provide refractive correction and may be spherical, curved, or multifocal in design, e.g., having 20/20 or better visual acuity. The outer annular zone at the periphery of optical zone 14 is configured to conform to corneal curvature and may include a rotational stabilization zone for translational and rotational stabilization while allowing contact lens 10 to move on the eye as the eye blinks. The edge region 18 may comprise a thickness in the range of 0.05mm to 0.15mm and may end in a wedge shape. The overall diameter 13 of the soft contact lens 10 may be in the range of 12.5mm to 15.0mm, for example in the range of 13.5mm to 14.8 mm.

The contact lens 10 includes a plurality of embedded projection units 12. Each of the plurality of projection units 12 includes a light source and one or more optical elements to focus light in front of the retina, as described herein. Each optical element may include one or more of a mirror, a plurality of mirrors, a lens, a plurality of lenses, a diffractive optical element, a fresnel lens, a light pipe, or a waveguide. The contact lens 10 may include a battery 20 and a sensor 22. The contact lens 10 may include a flexible Printed Circuit Board (PCB) 24, and the processor may be mounted on the flexible PCB 24. The processor may be mounted on the PCB 24 and coupled to the sensor 22 and the plurality of light sources 30. The soft contact lens 10 may also include wireless communication circuitry and one or more antennas 41 for electronic communication and inductive charging of the battery 20 of the contact lens 10. Although reference is made to a battery 20, the contact lens 10 may include any suitable energy storage device.

As described herein, the projection unit 12 may be configured to provide a defocused image to a peripheral portion of the retina, and may include a light source and projection optics. In some embodiments, one or more projection optics are configured with a light source to project a defocused image from the light source onto the peripheral retina away from the central field of view including the macula in order to stimulate changes in choroid thickness, such as increases or decreases in choroid thickness. The one or more projection units 12 may be configured to stimulate the retina without reducing the quality of central vision and corresponding images formed on one or more of the foveal or macular regions of the retina. In some embodiments, the one or more projection optical elements do not degrade the image forming characteristics of the vision correction optical elements prescribed to correct the user's refractive error. As described herein, this configuration may allow a user to have good visual acuity when receiving therapy from defocused images.

In some embodiments, light from the light source of projection unit 12 is substantially collimated and focused by one or more projection optics, as described herein. The function of the light source and projection optics is to substantially collimate the light emitted by the light source and direct the light to a focal point designed to be in front of or behind the retina to provide appropriate defocusing to stimulate changes in choroidal thickness. For example, for myopic defocus, the focused image may appear approximately 1.5mm to 2.5mm in front of the peripheral retina, and myopic by approximately 2.0D to 5.0D, such as 2.0D to 4.0D, or preferably 2.5D to 3.5D. For example, for hyperopic defocus, the focused image may appear about 1.5mm to 2.5mm behind the peripheral retina, such that hyperopia is approximately-2.0D to-5.0D, such as-2.0D to-4.0D, or preferably-2.5D to-3.5D.

The plurality of stimulation and clear zones may be arranged to allow movement of the eye relative to the projection optics and clear zones, which may be well suited for use in embodiments in which the eye moves relative to the projection optics, such as glasses, AR and VR applications. According to some embodiments, light from the projection unit may be directed at an oblique angle relative to the optical axis of the eye so as to enter the pupil while maintaining a clear central vision zone that is significantly larger than the pupil so as to provide a large field of view of the clear zone, e.g., a large viewing window. The size of the clear zone may be set in a variety of ways and may include a circular zone, an elliptical zone, a square zone, or a rectangular zone. In some embodiments, the viewing window may be 5.0mm by 4.0mm. In some embodiments, the clear region includes a window, which may be 15mm by 4.0mm. For example, when the eye changes gaze direction and the clear viewing zone defined by the viewport remains stationary, a larger clear viewing zone, such as a larger viewport, allows for a greater degree of eye movement without the stimulus being blocked by the pupil edge. In some embodiments, the oblique angle at which the stimulus is projected into the eye depends on the size of the viewing window.

According to some embodiments, the lens 10 or other suitable optical support structure comprises a projection unit comprising a projection optical element and a micro-display as a light source. The micro-display may comprise an OLED (organic light emitting diode) or micro LED array. The light emitted by these displays may be Lambertian light (Lambertian). In some embodiments, the microdisplay is optically coupled to a micro-optics array that substantially collimates and focuses light emitted from the microdisplay. The microdisplay may include one or more miniaturized pixels. In some embodiments, the microdisplay forms an extended pixel array characterized by a pixel size and a pixel pitch, where the pixel size and pixel pitch together correspond to a fill factor of the microdisplay. As described herein, for example, the size of each pixel may be in the range of about 2 microns to about 100 microns, and the pixel pitch may be in the range of 10 microns to 1.0 mm. The corresponding fill factor may be in the range of 0.1% to 10% or more. In some embodiments where real world viewing is desired, a smaller fill factor less blocks light from the real environment and provides a higher level of comfort and vision. Alternatively or in combination, larger fill factors may enhance the overall brightness of the stimulus and may be well suited for applications that do not rely on real world viewing and all peripheral vision. In some embodiments, the array of pixels is optically coupled to the array of micro-optical elements so as to substantially collimate and focus the light from the pixels.

According to some embodiments, the lens 10 or other suitable optical support structure comprises a projection unit comprising a projection optical element and a micro-display as a light source. The micro-display may comprise an OLED (organic light emitting diode) or micro LED array. The light emitted by these displays may be lambertian. In some embodiments, the microdisplay is optically coupled to a micro-optical array that substantially collimates and focuses light emitted from the microdisplay. The microdisplay may include one or more miniaturized pixels. In some embodiments, the microdisplay forms an extended pixel array characterized by a pixel size and a pixel pitch, where the pixel size and pixel pitch together correspond to a fill factor of the microdisplay. As described herein, for example, the size of each pixel may be in the range of about 2 microns to about 100 microns, and the pixel pitch may be in the range of 10 microns to 1.0 mm. The corresponding fill factor may be in the range of 0.1% to 10%. In some embodiments, the array of pixels is optically coupled to the array of micro-optical elements so as to substantially collimate and focus the light from the pixels.

The images produced by these displays are defocused and may be placed symmetrically in four quadrants of the field of view or eye (e.g., sub-nasal (nasal-interfereor), sub-nasal (nasal-superior), sub-temporal (temporal-interfereor), and temporal (temporal-superior)). The microdisplays may be located at a distance of 1.5mm to 4.0mm, preferably 2.5mm to 3.5mm, away from the optical center of the lens. The central optical element of the contact lens may be selected to normalize the user's refraction, and the diameter of the central optical element may be in the range of 3.0mm to 5.0 mm. In some embodiments, each microdisplay can be circular, rectangular, or arc-shaped in shape and have an area of 0.01mm ² To 8.0mm ² In the range of, for example, 0.04mm ² To 8.0mm ² In the range of, for example, 1mm ² To 8mm ² Or preferably in the range of 1.0mm ² To 4.0mm ² Within the range of (1).

For example, a microdisplay can be coupled to and supported by a body of corrective optical elements, such as a contact lens or spectacle lens, an augmented reality ("AR") headset, or a virtual reality ("VR") headset. In some embodiments, the micro-display is coupled to and supported by one or more of an intraocular lens, a corneal prosthesis, a corneal onlay, or a corneal inlay. For example, the optical configurations described herein with reference to contact lenses may be similarly used for one or more of intraocular lenses, corneal prostheses, corneal onlays, or corneal inlays.

In some embodiments, the microdisplay and the array of micro-optical elements are mounted in close proximity to each other on the same corrective optical element, separated by a fixed distance, so as to project a beam of light to the pupil of the eye in an orientation such that the beam of light forms a defocused image at a desired location on the retina, as described herein. In some embodiments, one or more projection optics are mounted on or in one or more corrective optics such that light rays from the projection optics refract through the corrective optics. The corrective optical element refracts light rays from the projection optical element to converge or diverge to facilitate clear vision so that the micro-optic array can provide a desired magnitude of add power, which can be positive or negative depending on the magnitude and sign of the desired defocus. The microdisplay may be, for example, monochromatic or polychromatic.

In some embodiments, the projected defocused image may be provided by a microdisplay comprising a screen comprising one or more of an LCD screen, a screen driven by OLEDs (organic light emitting diodes), a screen driven by TOLEDs, a screen driven by AMOLEDs, a screen driven by PMOLEDs, or a screen driven by QLEDs.

Fig. 3 shows a system diagram of the function of the components of a retinal stimulation device, such as the lens 10 in fig. 1A-2B. These components may be supported by the PCB 24. For example, a power source such as a battery 20 may be mounted on the PCB 24 and coupled to other components to provide the power source function 21. The sensor 22 may be configured to provide an activation function 23. The sensor 22 may be coupled to a processor mounted on the PCB 24 to provide a control function 25 of the lens 10. The control function 25 may include a light intensity setting 27 and a light switch 29. The processor may be configured to detect a signal from the sensor 22 that corresponds to an increase in intensity, a decrease in intensity, or an on/off signal from the sensor 22, e.g., a sequence of encoded signals from the sensor 22. The processor is coupled to the light projection unit 18, and the light projection unit 18 may include a light source 30 and an optical element 32 to provide a projection function 31. For example, the processor may be coupled to a plurality of light sources 30 (e.g., projection unit 12 or one or more displays 72) to control each light source 30 in response to user input to the sensor 22.

The retinal stimulation device may include Global Positioning System (GPS) circuitry for determining the location of the user, and an accelerometer for measuring body movement, such as head movement. The retinal stimulation device may include a processor coupled to one or more of the GPS or accelerometer to receive and store measurement data. In some embodiments, the processor uses the GPS and a local clock (a clock that maintains local time) to calculate the occurrence of a daily variation (digital variation) in the axial length of the wearer's eye. In some embodiments, the application of the stimulus may coincide with the occurrence of a maximum axial length under diurnal variation. The retinal stimulation device may include communication circuitry, such as wireless communication circuitry, e.g., bluetooth or WIFI, or wired communication circuitry, e.g., USB, to transmit data from the device to a remote server (such as a cloud-based data storage system). Such data transmission to a remote server may allow for remote monitoring of the user's treatment and compliance. In some embodiments, the processor includes a Graphics Processing Unit (GPU). The GPU may be used to efficiently and quickly process content from the web in order to utilize the content in forming a stimulus as described herein.

The methods and devices for retinal stimulation as described herein may be configured in a variety of ways and may include one or more attributes that encourage a user to receive treatment. For example, retinal stimulation as described herein may be combined with the display of a game to encourage a user to wear a therapeutic device. In some embodiments, the retinal stimulus may be combined with another stimulus (such as an emoticon) to encourage the user to wear the device for treatment. Components of the system may communicate with or receive information from the game or other stimulus to facilitate stimulation of the retina with the game or stimulus.

Referring to fig. 4A, optical arrangement 32 includes a plurality of mirrors configured to collect light emitted by the microdisplay and then direct the light beam to the pupil of eye 11 in order to form an eccentric retinal image, as shown in fig. 4B. The mirrors may substantially collimate the light beam or direct the light beam at an appropriate convergence (vergence) to the retina 33 in order to focus the light beam onto the retina 33.

Although the optical configurations shown in fig. 4A and 4B refer to lenses such as contact lenses, similar optical configurations may be used for lenses of one or more of a projector, an ophthalmic device, a TV screen, a computer screen, a handheld device such as a smartphone, a wearable device such as a spectacle lens, a near-eye display, a head-mounted display, a helmet-mounted display, an AR display, a VR display, a goggle, contact lenses, a corneal onlay, a corneal inlay, a corneal prosthesis, or an intraocular lens. Further, although reference is made to myopic defocus, the defocus may include, for example, hyperopic defocus, astigmatic defocus, or images focused on the retina, or other defocus used to correct refractive errors, as described herein.

The mirror assembly shown in fig. 4A may be configured to achieve a depth of focus of less than 1D, such that the applied 2.0D-4.0D defocus can be clearly perceived by peripheral retina 33 at a specified radial eccentricity (e.g., in the range of 5 degrees to 30 degrees, or in the range of 20 degrees to 30 degrees).

As shown in fig. 5A and 5B, another embodiment includes an optical element 32, the optical element 32 including a converging or collimating lens optically coupled to the light source 30. In this configuration, the lens 34, which may comprise a single lens, is used to substantially collimate the light output from the stimulus source and direct the light through a lens, such as the contact lens 10, to the cornea 37. Although reference is made to contact lenses, the lenses may include lenses for one or more of a projector, an ophthalmic device, a TV screen, a computer screen, a handheld device such as a smartphone, a wearable device such as a spectacle lens, a near-eye display, a head-mounted display, a VR display, and an AR display, goggles, a contact lens, a corneal onlay, a corneal inlay, a corneal prosthesis, or an intraocular lens.

The effectiveness of the collimating lens 34 depends on its refractive index, and its refractive index should be high enough to produce a significant refractive index difference between the lens material and the material of the contact lens 10 used as the substrate. In this example, it is assumed that the refractive index of the embedded lens 34 is 2.02 (e.g., the refractive index of lanthanum fluorosilicate glass LaSF 5), although other materials may be used.

Another embodiment includes a light pipe 36 to increase the optical path length, as shown in fig. 6A and 6B. The light pipe 36 may provide an increased optical path length to provide suitable image magnification (e.g., 0.5 to 8 times magnification, preferably 1 to 3 times magnification) and retinal image size.

Although reference is made to the light pipe 36 on the cornea 37, as would occur with contact lenses, the lenses combined with the light pipe 36 may include lenses of one or more of a projector, an ophthalmic device, a TV screen, a computer screen, a handheld device such as a smartphone, a wearable device such as a spectacle lens, a near-eye display, a head-mounted display, a VR display, an AR display, goggles, a contact lens, a corneal onlay, a corneal inlay, a corneal prosthesis, or an intraocular lens.

Many other optical configurations may be used, including the use of a microlens array with point sources, the use of diffractive optical elements so that thinner lenses are used, the use of a single point source and an optical processing unit to generate multiple retinal images.

Fig. 7 shows a plurality of stimuli 702 as seen by a user and an image 704 on a display 706. Stimulus 702 is located around display 706, where the display corresponds to a clear central vision region and the stimulus corresponds to peripheral vision of the user, such as vision outside the macula. Multiple stimuli may be imaged in front of the retina at myopic defocus to provide stimuli to increase choroidal thickness and reduce eye axial length growth.

The stimulation may be configured in a variety of ways as described herein. In some embodiments, the stimulus includes a light pattern 708, such as a black and white pattern, on a dark background 710. In some embodiments, the stimulus comprises a multi-colored pattern on a darker background, such as a white or almost white stimulus on a gray background or a substantially black background. In some embodiments, each stimulus comprises a dark inner region on a dark background and one or more light outer regions, e.g., a dark cross passing through a white circular region on a dark background. The stimuli may be selected based on their global contrast factor, their polarity (e.g., white or multi-colored on a black background, and conversely, black on a white or multi-colored background). The stimulus may be configured in a variety of ways and may include a plurality of repeated icons displayed on the display. The stimuli may be arranged in a circular or annular pattern of repeating icons. For example, the stimulus may include any suitable global contrast factor, such as a global contrast factor of at least 0.5, at least 0.7, or at least 0.8.

Fig. 8A shows stimulus 702 on screen 800 to provide a stimulus of myopic defocus to the retina, and fig. 8B shows the corresponding size in degrees of the myopic defocus stimulus on the retina. The size of the stimulus on the display is related to the distance between the user and the display, and the dimensions can be varied according to the viewing distance to provide the appropriate subtended angle (angular subtense) to the retina. One of ordinary skill in the art can readily perform calculations to determine the size of the stimulus on the display to provide an appropriate angular sizing of the defocused projected image.

As shown in fig. 8A and 8B, each stimulus includes a spanning distance 802, e.g., 18mm, corresponding to angular illumination (illumination) 812 on the retina, e.g., 3.3 degrees. The stimulus is arranged on the display to provide a clear central field of view 804 having a span distance 806, for example 70mm, providing an undisturbed central field of view 804, the central field of view 804 having a span distance 814 of 15 degrees. The plurality of stimuli includes a maximum spanning distance 815, e.g., 178mm, which corresponds to a subtended angle 816 of 35 degrees. The stimulus may be arranged to have any suitable object size in order to provide a suitable image size on the retina. Although specific dimensions are referenced, any suitable dimensions may be used, for example, by varying the distance to the eye and the corresponding angle of subtendation. In some embodiments, the stimulation is arranged to provide a clear central field of view, for example spanning 15mm, so as to provide an undisturbed central field of view of 15 degrees. In some embodiments, the plurality of stimuli includes a maximum spanning distance, e.g., 70mm, which corresponds to a subtended angle of 35 degrees.

Fig. 9 shows a stimulus 702, such as a ring-shaped flower pattern, depicting a natural scene 900. Although a flower pattern is shown, any image may be used. For example, the stimulus may be provided on the display alternately or in combination with the stimulus 702 shown in fig. 8A and 8B. The stimulus shown in fig. 9 may be sized and angled similar to the stimulus shown in fig. 8A and 8B. For example, the central field of view 814, shown as a dark circle, may include a spanning distance corresponding to, for example, about 15 degrees, and the maximum distance 806 across the annular region may be about 35 degrees. Work in connection with the present disclosure suggests that multi-colored natural scenes, such as flower patterns, may be more pleasing to the user. Work in connection with the present disclosure also indicates that, in some embodiments, a multi-colored flower scene may not be as effective as a stimulus as an annular array of white circles on a black background, with black crosses separating the circular icons, although other stimuli may be used.

Fig. 10 shows image contrast and histograms with red (R), blue (B) and green (G) values for the stimuli shown in fig. 8A to 9. For the circular patterns as shown in fig. 9A and 9B, the histogram shows about 3.5 × 10 with an intensity value of about 255 ⁵ Pixel count of individual stimulus pixels. Black pixels are excluded in the histogram to increase the clarity of the graphical representation (intensity = 0). For the flower pattern shown in FIG. 9, the blue intensity distribution shows an intensity peak at about 50, a red peak at about 110, and a green peak at about 120, with counts at these peaks being less than 0.5 × 10 ⁵ 。

In some embodiments, contrast is defined as the difference between the lowest intensity and the highest intensity of an image (segmentation). A Global Contrast Factor (GCF) may also be used to define the contrast of the stimulus image. GCF measures the richness of detail perceived by human observers. In some embodiments, the GCF of the stimulus is determined as described in Global constraint factor-a new approach to image constraint (by Matkovic, kresimir et al, 2005; computational aerodescription in Graphics, visualization and Imaging (2005); L.Neumann, M.Sbert, B.Gooch, W.Purgathofer (eds)).

The GCF values obtained were as follows:

and (3) flower: 6.46

Circle pattern (b/w): 9.94

Work related to the present disclosure suggests that white circles on a black background may be preferred over flowers in the field due to higher GCF.

Fig. 11 shows an image 1100 suitable for modification and incorporation as a stimulus as described herein. The image 1100 may comprise a processed image to provide a suitable spatial frequency distribution as described herein. The image may comprise a natural image or a computer generated image. The image may be masked to define, for example, a ring stimulus similar to fig. 9. Fig. 12 shows an image 1200 similar to that of fig. 11, the image 1200 having been processed to provide improved stimulation. This processed image can be digitally masked to form a ring stimulus as shown in fig. 9, with appropriate spatial frequency and contrast.

While the image may be processed in a variety of ways, in some embodiments, the image is processed with a digital spatial frequency filter and the contrast is adjusted to provide an image with an appropriate spatial frequency distribution to generate an improved response of the eye. At one step in the processing, the image is processed with a moving average filter having a length, for example, a filter having a length of 400 pixels. At another step, the RGB image is converted to a grayscale image. At another step, the RGB image is adjusted according to the moving average image. At a further step, the moving average filter is reapplied to the new image. In some embodiments, the moving average of the luminance is smoothed. For example, the initial image may have a 100% difference in brightness, while the adjusted image has a 25% difference in brightness.

Fig. 13 shows an image of the spatial frequency distribution of the image of fig. 11.

Fig. 14 shows an image of the spatial frequency distribution of the image of fig. 12, which image of fig. 12 can be used as the stimulus in fig. 9.

Fig. 15 shows a graph of image spatial frequency in cycles per degree and log of energy at each frequency for the stimulation images shown in fig. 8B and 9. In the graph shown in fig. 15, the mean radial profile of the spatial frequency spectrum is shown, where the log of the magnitude (in arbitrary units, "au") is related to the number density of features for a particular spatial frequency. For reference, the graph shows lines 1/f, 1/f ² And 1/f ^0.5 . Processed image including flower pattern having a circle shown in fig. 9 and fig. 7 to 7The white circle pattern with black crosses shown in fig. 8B has a similar frequency dependence. These graphs show that both the flower pattern and the circle pattern exhibit a slope dependence of approximately 1/f at an intermediate (e.g., mid-range) frequency of about 2 cycles to 10 cycles per degree. In some embodiments, the stimulus comprises a change in intensity (energy, au) for a frequency in a range of about 2 cycles to 10 cycles per degree, with a frequency dependence in a range of 1/f to 1/f ² In the range of frequency dependence.

The stimulus may be configured in a variety of ways with an appropriate spatial frequency distribution (e.g., with a profile of the spatial frequency distribution). In some embodiments, each of the plurality of stimuli includes a length, edge, and intensity profile distribution to generate a1 x 10 per degree when imaged into the eye in front of or behind the retina ^-1 One cycle to 2.5 × 10 ¹ Within the range of one period and optionally at 1 × 10 per degree ^-1 Period to 1 × 10 ¹ Spatial frequencies within a range of cycles. In some embodiments, the plurality of stimuli imaged in the eye comprises a spatial frequency distribution of about 1 x 10 for each degree ^-1 One cycle to about 5X 10 ⁰ A spatial frequency range of a period, the spatial frequency distribution providing a decrease in spatial frequency amplitude with an increase in spatial frequency. In some embodiments, the reduction in spatial frequency intensity is in the range of 1/(spatial frequency) to 1/(spatial frequency) for arbitrary units of spatial frequency amplitude ² Within the range of (1). In some embodiments, the spatial frequency ranges from about 3 × 10 per degree ^-1 From one period to about 1.0X 10 per degree ¹ One period, and optionally at about 3 x 10 per degree ^-1 From one period to about 2.0X 10 per degree ⁰ Within a period of one cycle, and further optionally at about 3 x 10 per degree ^-1 From one period to about 1.0X 10 per degree ⁰ Within a period.

Alternatively or in combination with the spatial frequency characteristic, the stimulus may be configured to have a suitable ratio of stimulus intensity to background intensity. In some embodiments, the brightness of the plurality of defocused stimulus images is at least 3 times as high as the brightness of the ambient lighting, optionally at least 5 times as high as the brightness of the background lighting, optionally in the range of 3 to 20 times as high as the brightness of the background lighting, further optionally in the range of 5 to 15 times as high as the brightness of the background lighting.

In some embodiments, the stimulus comprising spatial frequency and intensity characteristics is presented at a suitable ratio to one or more of background or ambient lighting. In some embodiments, each of the plurality of stimuli imaged in the eye is overlaid on a substantially uniform gray background. In some embodiments, each of the plurality of stimuli includes a multi-colored icon, such as a white icon, on a darker background to provide contrast such that the icon has an edge outline or total length of edges to generate spatial frequencies primarily 1 x 10 per degree ^-1 Period to 2.5 x 10 per degree ¹ Within the range of one period, and optionally at 1 × 10 per degree ^-1 From one period to 1 × 10 per degree ¹ Features within a range of cycles.

Fig. 16 shows a system 1600 for treating refractive error of an eye. The system 1600 includes a therapeutic device 1602, such as a user device operatively coupled to a server 1604 utilizing a secure two-way communication protocol. The server 1604 is configured to communicate with the treatment professional device 1608 using a secure two-way communication protocol 1606. In some embodiments, the server 1608 is coupled to the care device 1610 using a secure two-way communication protocol 1606. In some embodiments, the system 1600 includes a treatment database 1612, the treatment database 1612 storing treatment parameters and results from a plurality of treatments. The therapy database 1602 may be configured to communicate with the server 1604 using a secure two-way communication protocol 1606. In some embodiments, therapy system 1600 includes one or more clinical measurement devices 1614, the clinical measurement devices 1614 configured to communicate with a server using a secure two-way communication protocol 1606. Each of these devices is operatively coupled to the other device using a secure two-way communication protocol 1606. The secure communication may include any suitable secure communication protocol that transmits encrypted data, and the data may be stored in any suitable encrypted format. For example, the device shown in fig. 16 may be configured to conform to HIPAA and GDPR, as will be understood by one of ordinary skill in the art. The server 1604 may comprise any suitable server, such as a cloud-based server comprising a plurality of servers, which may be located in different geographic locations. Although the therapy database 1612 is shown separately, it may comprise a component of a server.

As described herein, the treatment device 1602 may be configured in a variety of ways and may include a user device including one or more of an ophthalmic device, a TV screen, a computer screen, a virtual reality ("VR") display, an augmented reality ("AR") display, a handheld device, a mobile computing device, a tablet computing device, a smartphone, a wearable device, a spectacle frame, a spectacle lens, a near-eye display, a head-mounted display, goggles, contact lenses, an implantable device, a corneal onlay, a corneal inlay, a corneal prosthesis, or an intraocular lens. For example, the therapeutic device 1602 may include an optical system with a beam splitter, as described herein. In some embodiments, for example, the therapeutic device 1602 includes a user device, such as a smartphone or tablet. The display 1620 of the user device may be configured to provide a plurality of stimuli 702, as described herein. In some embodiments, the user device 1602 includes a lenslet array 1622 placed above the plurality of stimuli 702 to provide an image 1624 of the stimuli 702 in front of or behind the retina. In some embodiments, each lenslet in the lenslet array is aligned with one of the plurality of stimuli. As described herein, a user device may be configured with a clear viewing area 804, e.g., a lenslet array that does not extend into the clear viewing area. Clear viewing area 804 may be configured to allow a user to view images, such as video, and to allow the user to use the device in a substantially normal manner, e.g., to use a web browser, play video games, send and receive text and email, etc. Lenslet array 1622 may be positioned a distance from the pixels to provide an appropriate amount of defocus as described herein. In some embodiments, treatment system 1600 includes one or more clinical measurement devices 1614.

The treatment professional device 1608 may be configured to cause the treatment professional to receive data, such as treatment data, from the user device 1602. The therapy data may include any suitable therapy data, such as a daily therapy duration, daily usage, screen time when the stimulation is activated. The treatment professional device 1608 may also be configured to send and receive data from the ophthalmic instrument, such as refractive data as described herein, in order to assess the efficacy of the treatment. The treatment professional device 1608 may be configured to send treatment instructions to the user device 1602. For example, the treatment instructions may include any suitable parameters as described herein, and may include the duration of the treatment and the treatment time. Work in relation to the present disclosure suggests that the circadian rhythm (circadian rhythms) may play a role in the efficacy of the treatment, and that the treatment instructions may include instructions for the user to perform the treatment at a certain time of day or within a certain time range (e.g., in the morning, e.g., at a certain time within the range of about 6 am to about 9 am of the local time of the patient's location).

For example, the clinical measurement device 1614 may include any suitable clinical measurement device, such as one or more of an autorefractor or OCT system. Alternatively or in combination, patient records such as the dominant refraction may be stored at the clinic site and transmitted to the server.

The care device 1610 may include any suitable device with a display, such as a smartphone or tablet. The care device 1610 may be configured to send and receive data related to the treatment of the user. The care device 1610 may be configured to enable a caregiver (such as a parent) to monitor therapy and facilitate compliance with a therapy protocol. For example, the server 1604 may be configured to send notifications to the care device 1610, such as notifications that the user is scheduled for treatment, and the caregiver may interact with the user to encourage the user to receive treatment.

The therapy database 1612 may be configured to store data related to therapy. For example, the data relating to the treatment may include treatment data and efficacy data. The efficacy data may include one or more of refractive data and axial length data. The refractive data may include refractive data, such as spherical, cylindrical, and axial data, of the user's eye at multiple points in time (e.g., longitudinal data). The axial length data may include data such as OCT data collected at multiple points in time. The therapy data 1612 may include data related to stimulation parameters as described herein, and may include, for example, daily therapy duration, stimulation intensity, stimulation type, and defocus data.

In some embodiments, the data is processed using algorithms such as artificial intelligence, machine learning, neural networks, or convolutional neural networks to determine improved treatment parameters such as duration of treatment, time of day of treatment, defocus, shape and intensity of stimulation, amount of defocus, spatial frequency of stimulation, ratio of stimulation to ambient light, background of stimulation, or any other parameter related to treatment. These parameters may be adjusted to provide improved therapy and may be suggested to a therapy professional on the therapy professional device to cause the therapy professional to push instructions to the user device.

While the treatment device 1602, such as a user device, may be configured in a variety of ways, in some embodiments, the device 1602 includes a sensor 1624, such as a photometric sensor or spectrophotometer, for detecting one or more of photometric (luminescence) or spectral data. The sensor 1624 may be configured to measure and detect ambient light exposure of a subject, such as a wearer or user. In some embodiments, the sensor is supported (e.g., mounted) on a therapeutic device as described herein, such as on eyeglasses, a wearable device, or a user device.

For example, the system of fig. 16 is well suited for clinical trials to perform clinical trials and generate efficacy data.

Fig. 17 shows a method 1700 of treating refractive error of an eye.

At step 1705, refractive data is received. The refractive data may include any suitable refractive data, such as one or more of a dominant refractive examination, retinoscopy (retinoscopy), cycloplegic refractive examination, or autorefraction. The refractive data may include one or more components of refraction at the time of measurement, such as one or more of spherical, cylindrical, or axial.

At step 1710, the axle length data is received. The axial length data may include axial length data from the eye being treated or the contralateral eye, and the axial length data may include OCT data, for example.

At step 1715, a treatment time is determined. The treatment time may include one or more of a series of treatment times, such as a morning time. For example, the time of treatment may be based on the patient's circadian rhythm.

At step 1720, treatment instructions are received from the healthcare provider. The treatment instructions may include any suitable parameters as described herein. For example, the treatment instructions may include one or more of a duration of the treatment, an intensity of the stimulation, a shape of the stimulation, a background of the stimulation, a chromaticity of the stimulation (chromanance), a ratio of the intensity of the stimulation to the central viewing region, a ratio of the intensity of the stimulation to ambient lighting, a shape profile of the stimulation, a defocus of the stimulation, or a spatial frequency profile of the stimulation.

At step 1725, the user is instructed to receive therapy. The user may be instructed in a number of ways, for example by having the user start treatment with a prompt which the user may accept when the user is ready to start treatment. The prompt may also include instructions for the user to begin treatment in an appropriate environment, such as an indoor environment. The prompt may provide the user with the option to delay the treatment for a period of time, such as five minutes, and prompt the user again at the appropriate time.

At step 1730, the caregiver is indicated that the user will receive treatment, e.g., it is time for the user to receive treatment. This may allow a caregiver, such as a parent, to encourage the user to receive treatment.

At step 1735, the user begins treatment. The user may initiate the therapy in a number of ways (e.g., via input to the user device 1602). For example, the input may include an input to a touch screen display. Alternatively or in combination, the user may respond to the prompt to receive therapy.

At step 1740, a stimulus is provided to the user. The stimulus may include any suitable stimulus, for example, stimulus 702 as described herein.

At step 1745, the user is allowed to view the central clear region 804 on the display. When a stimulus (e.g., multiple stimuli) is provided, the user may view the data on the central clear region.

At step 1750, the treatment ends. The user may be notified that the treatment has ended. The caregiver may also be notified.

At step 1755, the therapy data is sent to the server 1604. For example, the data may be sent to the healthcare provider 1608 or the therapy database 1612.

At step 1760, the steps are repeated as appropriate. For example, a subsequent treatment may be provided to the user and notified to the user and caregiver. Additional refractive data may be measured. Alternatively or in combination, additional OCT data may be measured.

Although fig. 17 illustrates a method of treating refractive error according to some embodiments, one of ordinary skill in the art will recognize many adaptations and variations. For example, the steps may be performed in any order, some steps may be omitted, and some steps may be repeated. Further, some steps may include sub-steps of other steps.

Any computing device, processor, or combination thereof may be configured to perform one or more of the steps of fig. 17.

Experimental study

Clinical studies were conducted on human subjects to evaluate efficacy on human subjects. The study relates to a clinical testing apparatus in which a subject is administered a stimulus and the efficacy and associated parameters of the various stimuli are assessed.

Clinical study

The following study parameters were evaluated in clinical studies.

1) Magnitude of myopic defocus. Myopic defocus values of 6D, 4.5D and 3D were evaluated. Fig. 18A depicts a stimulus 702, the stimulus 702 having an area 1802 myopic defocus of 6D ("6D stimulus") and another area 1804 myopic defocus in 3D ("3D stimulus").

2) The coverage of the retina. Coverage corresponds to a percentage of a ring having an inner diameter 1806 corresponding to 15 degrees (full angle) and an outer diameter 1808 corresponding to about 35 degrees (full angle). The percentage area listed below corresponds to the percentage coverage of this ring. The stimulus 702 tested includes segmented rings 1814 that account for 70%, 50%, and 25% of the entire ring. Fig. 18B depicts a stimulus 702, the stimulus 702 having an area 1810 with a coverage of 25% ("25% stimulus") and an area 1812 with a coverage of 50% ("50% stimulus").

3) Brightness over background image. Stimulated luminance cd/m compared to indoor lighting conditions with ratios of 1.0, 3.0, 5.0, 10.0 and 20.0 ² Evaluation was performed. Fig. 18C depicts a stimulus 702, the stimulus 702 having a luminance ratio of 0.1:1 and a luminance ratio of 1:1, region 1822.

3) And (4) chroma. Studies were carried out to determine the relationship between the effect of monochromatic light and that of white light, and the following chromaticity parameters were tested: white, green and red. Fig. 18D depicts the stimulation 702 with black and white stimulation regions 1830 and red stimulation regions 1832.

4) Stimulating a change in spatial frequency content. Spatial frequency content of the stimulus is assessed to determine how the stimulus pattern affects the efficiency of the stimulus. Various patterns were tested, including: a natural pattern as in fig. 9, a test circle including a disk of brighter intensity as in fig. 18A to 18D, and dots (cross dots) with crosses as in fig. 8 to 9B.

Fig. 19 depicts an optical system 1900 projecting a stimulus 702 onto the retina 33. In the study conducted, system 1900 comprises a desktop system. The system is configured to receive left and right eyes of a subject for testing purposes. The test eye 1902 is placed in front of a first beam splitter 1906 and the control eye 1904 is placed in front of a second beam splitter 1908. Test eye 1902 and control eye 1904 are allowed to similarly view a central display 1910 in front of a passive background 1912. Display 1910 may include a clear central vision area and display appropriate content, and may include a computer screen. In some embodiments, the central zone vision includes an entertainment area as seen by the patient through the clear central vision zone, the entertainment area having entertainment content displayed on the display. The active stimulation system includes a desktop mounted device having a head rest or chin rest. The system is configured to provide background images for both eyes at optical infinity and video for central (foveal) vision. The stimulus 702 is shown on a display 1920, which display 1920 is placed in front of a lens 1922 (e.g., an achromatic lens) to provide a superimposed stimulus image with myopic defocus to the test eye. The myopic stimulus is projected in front of the retina of the eye. The distance of the displayed stimulus from the lens 1922 and the optical power of the lens 1922 are configured to provide an appropriate amount of defocus. The stimulus 702 is superimposed with a first beam splitter 1906 with a central display 1910 and a passive background 1912. The second beam splitter 1908 is similar to the first beam splitter and the background light is blocked by a shutter 1924. The beam splitter includes a 50/50 reflectance to transmittance ratio for each eye, thereby transmitting 50% of the light and coupling 50% of the light to the stimulus. The stimulus is provided on a screen, such as display 1920, at an appropriate distance from the achromatic lens.

As described herein, parameters including the magnitude of defocus, the coverage of the stimulus on the retina (e.g., retinal image shell), dominance (e.g., contrast and brightness) relative to the background image, and chromaticity (e.g., wavelength distribution) are adjusted.

Background patterns were also considered in these experiments. The background pattern can include a uniform pattern 1930a or a patterned background 1930b, such as a grid pattern. The background pattern is projected onto the peripheral retina in hyperopic defocus. In some embodiments, this hyperopic defocus is provided in order to bring the focus of a distant object to optical infinity instead of hyper-focus (hyper-focal point). Work in connection with the present disclosure suggests that, according to some embodiments, the patterned background may compete with the stimulus of myopic defocus, and a uniform background pattern may be preferred. While the background may be presented in a variety of ways, the background is presented as a poster with an appropriate test pattern.

A camera 1926 is used to view one or more eyes. In the experiment performed, the right eye is the test eye 1902 and the control eye 1904 is the left eye. Although fig. 19 shows the left eye as the test eye and the right eye as the control eye, this can be easily changed by coupling the achromatic lens and display to the right eye and providing a shutter to the left eye. For example, the position of the display with the stimulus pattern and the achromatic lens may be placed on the right side, while the shutter is moved to the left.

Fig. 20A shows the focus of a clear central vision region 804 (e.g., entertainment region) and a background pattern 1930 for the control eye (e.g., left eye). The central region displayed to both eyes on the display is presented to the user without significant refractive error, for example at optical infinity. The background pattern 1930 is also presented to the user at infinity. A retinal image shell 2002 is also shown. Even if the central vision is corrected for objects at infinity (computer displays), the background pattern is projected in hyperopic defocus onto the peripheral retina.

Fig. 20B shows myopic defocus of stimulus 702, video displayed in central clear vision region 804, and background patterns for the eye being tested (e.g., the right eye). The optical configuration shows the stimulus as described herein imaged in front of the retina at myopic defocus.

These studies were conducted in a passive background comprising substantially uniform grey paper. The grey paper is illuminated by an adjustable lamp mounted on the ceiling (ceiling). The luminance level was measured at 9-11cd/m ² . The active display area, including central entertainment, is provided with a television ("TV"). The luminance level of TV is measured at 10 to 11cd/m ² 。

Although the ambient illumination of the room was measured at 500 lux to 700 lux, these values were controlled and reduced during experimental testing.

During the measurement, the axial length and choroidal thickness of the eye were measured at ambient light of about 5-6 lux. Axial length and choroidal thickness were measured using a commercially available biometer and optical coherence tomography ("OCT") system, respectively.

During the test, the background illumination was 9-10 lux and the TV screen was 9-10 lux.

The test was performed in the morning (typically 8 am to 12 am. The study was performed on the same subjects over a wash out period of 1 hour. In other words, the subject typically enters the office in the morning at 7-7. All axis length measurements are referenced to the axis length measurement at the beginning of the day.

In these studies, peripheral stimuli were provided as variables.

Table 1 experimental results for white stimulation on a black background.

These studies showed a decrease in retinal thickness as measured by OCT. The brightness of the peripheral stimulus may be interpreted as the ratio brightness of the defocused stimulus to the ambient lighting (e.g., a central display such as a television screen or a background such as grey paper). These studies showed that axial length decreased and choroidal thickness increased at ratios of at least 3-fold, with statistically significant changes at ratios of at least 10-fold. These data suggest that the ratio of stimulus to ambient light is in the range of 3 to at least 20, for example in the range of 5 to 15, such as 10.

Fig. 21 shows clinical results similar to those of table 1. As described herein, this data shows the effect of actively stimulating the peripheral retina with a projected image that is myopically defocused. Results were obtained with a1 hour stimulus with a projection image comprising a white target on black, as described herein. As described herein, the subject views a TV screen at 20 feet through a clear central area. The axial length (corneal vertex to retinal pigment epithelium "RPE") was measured without moving the subject. 192 data points were taken at each measurement. Changes in axial length due to diurnal fluctuations are compensated for by measuring changes in the test eye relative to the control eye in pairs. These results show the nominal change of the test eye (shown on the left) versus the control eye (shown on the right) under 5-fold stimulating illumination. However, when the stimulus to environment ratio is 10 times, the axial length of the test eye shown is much reduced compared to the axial length of the control eye. For 20 times stimulation illumination, this difference is about 15 microns, statistically significant, with a p value of 0.0016.

The above results are obtained with a white stimulus on a black background, with a black cross extending across the white stimulus, as shown with reference to fig. 8A and 8B. The stimulus comprises a spatial frequency distribution defined by a substantially linear relationship of amplitude to reciprocal spatial frequency (reciprocal spatial frequency) in a spatial frequency range of about 0.1 cycles to about 25 cycles per degree, for example about 0.3 cycles to about 10 cycles per degree, and optionally about 0.1 cycles to 5 cycles per degree.

Although the device used in these experiments comprised a monocular stimulation device, in some embodiments of the present disclosure, the device comprised a binocular stimulation device.

Additional clinical findings

The main objective of this study was to measure the extent of axial length reduction and central choroidal thickening after the defocus phase under controlled conditions using the proposed system.

12 subjects (9 males, 3 females) with normal vision, aged 21-32 years, participated in the study (7 Asians, 4 caucasians, 1 Spanish). The test subjects had sphere equivalent lenses (spherical equivalents) in the range of 0.00 to-3.50D, with an average of-0.70D. The subject experienced two periods of defocus under photopic room light conditions with one hour break between the two periods and no defocus. We use a non-wearable, augmented reality-based device to project digital defocus on the peripheral retina, as described herein. The projected annular peripheral defocus stimulus extends outward from approximately the 15 degree diameter of the visual field to the 35 degree diameter of the right eye, as described herein.

Referring again to fig. 8A and 8B, these figures show the range of stimulation in millimeters (fig. 8A) and degrees (fig. 8B).

The system described herein has easy programming control of important stimulation aspects for controlling eye growth, including the size of peripheral defocus stimuli, retinal location, brightness, chroma, duration of activation, and refractive amplitude.

Referring again to fig. 7, this image shows a view of a subject through a test eye through a device as described herein.

The left eye, as a control, does not receive any projected ambient defocus. The gray backdrop serves as a background for projected defocused stimuli of more than 15 degrees in diameter for both eyes. The content of the center hole is a color movie, which is displayed on an HD television located 4 meters away, which is used as a fixed area. We set the test conditions for the digital projection stimulus to be 5 times (5X), 10 times (10X) and 20 times (20X) the brightness of the gray poster background and the central 15 degree window (both are equal in brightness). For each subject, the test conditions for the luminance ratio were randomized. Axial length measurements of the posterior pole (posterior pole) or macula (Haag-Streit Lenstar APS 900) and optical coherence tomography (Heidelberg spectra SD-OCT) were obtained before and after each defocus period.

The 5-, 10-, and 20-fold brightness ratios in the gray poster background test conditions were subjected to 8, 9, and 7 trials, respectively, for a total of 24 trials.

Fig. 22 shows a graph 2200 of the aggregated data for 5-, 10-, and 20-fold brightness tests, which shows that the mean change in central axis length (in microns) of the test eye is significantly less than the mean change in central axis of the control eye (p < 0.025) after a1 hour defocus period. And similarly, the combined data of all trials revealed that the mean change in foveal choroidal thickness in the test eyes was significantly greater than the mean change in foveal choroidal thickness in the control eyes after the same defocus period (p < 0.025). Both p-values correspond to a two-tailed t-test comparison, where α =0.025 (Bonferroni correction).

Fig. 23 shows a graph 2300 (mean ± SEM) of the mean change in axial length and choroidal thickness: for all experimental aggregations, the axial length change of the test eye was significantly less than the axial length change of the control eye after a one hour defocus period. Similarly, the relative increase in foveal choroidal thickness in the test eyes was also significantly higher than in the control eyes after the defocus period (asterisk "@" refers to a p value less than or equal to 0.025, also referred to as "= p < 0.025).

For the control eye, exactly opposite behavior was observed in these two parameters. The axial length in the test eyes decreased on average by about 1 micron, while the axial length in the control eyes increased on average by about 7 microns. The foveal choroid thickness in the test eyes increased by an average of about 4 microns from baseline, while the foveal choroid thickness in the control eyes decreased by an average of about 2 microns. The average relative effect of the test eyes was a reduction in axial length of about 8 microns and an increase in central choroidal thickness of about 6 microns compared to the control eyes. Mean changes in central choroidal thickness measurements performed at 0.50mm (subfoveal), 1.00mm (parafovea), and 1.50mm (perifovea) of retinal eccentricity were significantly different in the test eyes versus the control eyes for all comparisons made before and after the defocus period (p < 0.025). The central choroid in the control eye was thinned in each region and thickened significantly after a projected peripheral defocus period of one hour, as shown in fig. 23.

Fig. 23 also shows the relative thickening of the choroid layer behind the retina (mean ± SEM): after one hour of projection defocus on 0.50mm (foveal), 1.00mm (parafoveal), and 1.50mm (perifoveal) of retinal eccentricity in the posterior pole, the choroid layer was significantly thickened (= p < 0.025).

When considering the luminance ratio of each test, the 20-fold condition was the only one condition (p = 0.02) showing the statistical significance (significant) of the mean axial length variation between the test eye and the control eye (independent t-test, two-tailed, uncorrected). Although the 20-fold brightness of the defocused stimulation condition performed more robustly than the 5-fold or 10-fold stimulation condition, there was a trend of increasing differences between the test and control eyes as the stimulation brightness was increased compared to the background.

Statistically, our results show a significant decrease in axial length and an increase in choroidal thickness in the test eye after a1 hour defocus period compared to the control eye. In addition, the central choroid layer thickened significantly after one hour of projection defocus. A significant advantage of such an augmented reality based system compared to a conventional defocused system or a multi-focal defocused system is that it allows for easy programmable control of important stimulation aspects. When testing several peripheral projection stimuli of different photometric intensities, we found an inverse correlation between increased luminosity and decreased axial length, and a positive correlation between increased luminosity and increased choroid thickness. The average axial length of the control eye after defocus for the 20-fold test condition varied more than the average change for the control eye for the other two luminance test conditions. This is likely due to the normal variability in the control eye, which occurs naturally, without defocus. It may also be a monocular coupling effect due to projection defocus, the binocular effect of which is still to be understood. This exploratory study successfully demonstrated the concept of physiological effects on ocular biometrics using an augmented reality-based peripheral defocused optical system.

Our results and the versatile nature of the proposed method show the promise of this concept of projected and programmable peripheral myopic defocus (promise) to help effectively understand the role of the periphery in regulating eye growth and find the fastest and most effective treatment strategy. In addition, it can be applied to augmented reality and virtual reality devices, office treatments, spectacles and contact lenses.

Referring again to fig. 1A-3, 16, and 19, the stimulating device may be configured to stimulate the eye through dilation of the pupil. Work in connection with the present disclosure suggests that an increase in pupil diameter, such as dilation of the pupil, may allow an increased amount of light to be provided to the peripheral portion of the retina. An increase in pupil diameter facilitates increasing the eccentricity of illumination away from the fovea, to illuminate areas of the retina more distant from the fovea, and to increase the amount of illumination to peripheral areas of the retina. Work in connection with the present disclosure suggests that the surface area of the stimulated region of the retina may be related to the efficacy of the response. Furthermore, by providing stimulation to the periretinal region while maintaining a substantially lower amount of illumination of the fovea and macula during stimulation, pupil constriction may be reduced.

While the stimulation device may be configured in a variety of ways, in some embodiments, the one or more optical elements are arranged to project a plurality of stimuli toward the peripheral portion of the retina when the pupil of the eye has dilated. The pupil may dilate in a number of ways, such as with a reduced amount of light to include a natural pupil, or with a mydriatic agent such as a cycloplegic agent to include a drug dilated pupil.

While one or more stimuli, e.g., a plurality of stimuli, may be arranged to illuminate the retina with the pupil dilated in a variety of ways, in some embodiments, the one or more stimuli are arranged to illuminate a peripheral portion of the retina at an angle of at least 35 degrees from the visual axis of the eye.

In some embodiments, the stimulation device includes a sensor for measuring pupil size and a processor configured with instructions to direct optical stimulation to the eye in response to the size of the pupil. This may allow for an increased amount of light to be delivered to the periretinal region, and in some cases, may more accurately deliver and estimate the amount of light delivered to the periretinal region. Although the size of the pupil may be measured in a variety of ways, in some embodiments, the measured size of the pupil includes the diameter of the pupil. In some embodiments, the processor is configured to adjust one or more of the intensity or duration of the optical stimulus in response to the size of the pupil. For example, a larger diameter pupil may receive stimuli in a shorter time or at a lesser intensity, while a smaller diameter pupil may receive stimuli in an increased amount of time or at an increased intensity. Although the sensor that measures pupil size may be configured in any suitable manner as will be known to those of ordinary skill in the art, in some embodiments the sensor comprises an array of sensors. For example, the sensor may comprise a sensor array of cameras. The camera may comprise any suitable device, such as a patient mobile device, e.g. a smartphone, or a measurement sensor built into a test and measurement device, as described herein.

In some embodiments, the plurality of stimuli is configured to allow the natural pupil to dilate when illuminated with the plurality of stimuli. Work in connection with the present disclosure suggests that illumination of the peripheral portion of the retina does not have as significant an effect on pupil diameter as illumination of the fovea or macula. In some embodiments, the plurality of stimuli is configured to constrict the pupil by no more than one millimeter (mm) when the stimuli are provided, as compared to the diameter of the pupil when the stimuli have not been provided.

In some embodiments, the pupil comprises a stimulus diameter when the eye is exposed to the plurality of stimuli, and the eye comprises a photopic diameter when the eye is exposed to photopic viewing conditions without the plurality of stimuli. In some embodiments, the photopic diameter is at least one millimeter less than the stimulation diameter. In some embodiments, the photopic viewing conditions include per square meter (m) ² ) A luminance of at least 3 candela (cd).

In some embodiments, the stimulus is configured to illuminate a peripheral portion of the retina having an eccentricity greater than 35 degrees, wherein when the stimulus is provided to the peripheral retina having an eccentricity greater than 35 degrees, the pupil of the eye is dilated by at least about 1 millimeter compared to photopic illumination.

In some embodiments, no more than 10% of the total amount of energy, and optionally no more than 5% of the total amount, and optionally no more than 1% of the total amount, of the plurality of stimuli is directed to the fovea of the eye to reduce the constriction of the pupil in response to the plurality of stimuli.

In some embodiments, the stimulus comprises a photopic stimulus directed to the periretinal region, and the illumination of one or more of the fovea or macula comprises one or more of mesopic or scotopic illumination, so as to reduce the size of the pupil. The device may be configured to provide the stimulus in a variety of ways. In some embodiments, the apparatus includes a display configured to provide one or more of mesopic or scotopic illumination, and the plurality of stimuli is configured to provide photopic illumination in any suitable manner, as described herein.

In some embodiments, a method of treating refractive error of an eye includes dilating a pupil of the eye and providing an optical stimulus to a peripheral portion of a retina to reduce refractive error of the eye. The stimulus may comprise any suitable stimulus as described herein, and may comprise a plurality of stimuli.

While the pupil may be dilated in a variety of ways, in some embodiments, the pupil is dilated with a mydriatic agent. While any suitable mydriatic agent may be used to pharmacologically increase the size of the pupil, in some embodiments, the mydriatic agent includes a cycloplegic agent.

In some embodiments, the cycloplegic agent is selected from the group consisting of atropine, cypionate, homatropine, scopolamine, and tropicamide. For example, a cycloplegic agent may include an appropriate percentage of atropine. In some embodiments, the weight percentage is in the range of 0.025% -0.2% and optionally in the range of 0.05% -0.1%.

In some embodiments, the size of the pupil is measured and the optical stimulus is directed to the eye in response to the size of the pupil, and one or more of the intensity or duration of the optical stimulus is adjusted in response to the size of the pupil. For example, in some embodiments, the size of the pupil is measured with a sensor, such as a sensor array, and the sensor array includes a sensor array of cameras.

In some embodiments, the pupil comprises a natural pupil of the eye that is dilated with an appropriate amount of illumination of the peripheral retina and light from other sources that passes through the natural pupil such that the natural pupil is able to contract and dilate in response to illumination of the eye.

In some embodiments, the natural pupil is dilated with mesopic background lighting or scotopic background lighting.

In some embodiments, the natural pupil constricts no more than one millimeter (mm) when the stimulus is provided, as compared to the natural pupil diameter when the stimulus is not provided.

In some embodiments, the natural pupil comprises a stimulus diameter when the eye is exposed to the stimulus, and wherein the natural pupil comprises a photopic diameter when the eye is exposed to photopic viewing conditions. In some embodiments, the photopic diameter is at least one millimeter less than the stimulation diameter.

In some embodiments, the stimulus is configured to illuminate the peripheral retina with an eccentricity greater than 35 degrees, wherein when the stimulus is provided to the peripheral retina with an eccentricity greater than 35 degrees, the pupil is dilated by at least about 1 millimeter compared to photopic illumination.

While the stimuli can be configured in a variety of ways to reduce pupil constriction, in some embodiments no more than 10% of the total amount of energy of the plurality of stimuli, and optionally no more than 5% of the total amount, and optionally no more than 1% of the total amount, is directed to the fovea of the eye to reduce constriction of the pupil in response to the plurality of stimuli.

In some embodiments, the stimulus comprises a photopic stimulus directed to the periretinal region, and wherein illumination of one or more of the fovea or macula comprises one or more of mesopic or scotopic illumination, so as to reduce the size of the pupil.

As described herein, the computing devices and systems described and/or illustrated herein broadly represent any type or form of computing device or system capable of executing computer-readable instructions, such as those contained in the modules described herein. In its most basic configuration, the computing devices may each include at least one memory device and at least one physical processor.

The term "memory" or "memory device" as used herein generally refers to any type or form of volatile or non-volatile storage device or medium capable of storing data and/or computer-readable instructions. In one example, a memory device may store, load, and/or maintain one or more modules described herein. Examples of memory devices include, but are not limited to, random Access Memory (RAM), read Only Memory (ROM), flash memory, a Hard Disk Drive (HDD), a Solid State Drive (SSD), an optical disk drive, a cache, variations or combinations of one or more of these, or any other suitable storage memory.

Furthermore, the terms "processor" or "physical processor" as used herein generally refer to any type or form of hardware-implemented processing unit capable of interpreting and/or executing computer-readable instructions. In one example, a physical processor may access and/or modify one or more modules stored in the memory device described above. Examples of physical processors include, but are not limited to, a microprocessor, a microcontroller, a Central Processing Unit (CPU), a Field Programmable Gate Array (FPGA) implementing a soft-core processor, an Application Specific Integrated Circuit (ASIC), portions of one or more thereof, variations or combinations of one or more thereof, or any other suitable physical processor. The processor may comprise a distributed processor system, such as running parallel processors or remote processors (e.g., servers), as well as combinations thereof.

Although illustrated as separate elements, method steps described and/or illustrated herein may represent portions of a single application. Further, in some embodiments, one or more of these steps may represent or correspond to one or more software applications or programs that, when executed by a computing device, may cause the computing device to perform one or more tasks, such as method steps.

Further, one or more devices described herein may convert data, physical devices, and/or representations of physical devices from one form to another. Additionally or alternatively, one or more modules described herein may transform a processor, volatile memory, non-volatile memory, and/or any other portion of a physical computing device from one form of computing device to another form of computing device by executing on the computing device, storing data on the computing device, and/or otherwise interacting with the computing device.

The term "computer-readable medium" as used herein generally refers to any form of device, carrier, or media capable of storing or carrying computer-readable instructions. Examples of computer readable media include, but are not limited to, transmission type media such as carrier waves, and non-transitory type media such as magnetic storage media (e.g., hard disk drives, tape drives, and floppy disks), optical storage media (e.g., compact Disks (CDs), digital Video Disks (DVDs), and BLU-RAY disks), electronic storage media (e.g., solid state drives and flash memory media), and other distribution systems.

One of ordinary skill in the art will recognize that any of the processes or methods disclosed herein can be modified in a variety of ways. The process parameters and sequence of steps described and/or illustrated herein are given by way of example only and may be varied as desired. For example, while the steps shown and/or described herein may be shown or discussed in a particular order, these steps need not necessarily be performed in the order shown or discussed.

Various exemplary methods described and/or illustrated herein may also omit one or more of the steps described or illustrated herein, or include additional steps in addition to those disclosed. Further, the steps of any method disclosed herein may be combined with any one or more steps of any other method disclosed herein.

A processor as described herein may be configured to perform one or more steps of any of the methods disclosed herein. Alternatively or in combination, the processor may be configured to combine one or more steps of one or more methods as disclosed herein.

Unless otherwise indicated, the terms "connected to" and "coupled to" (and derivatives thereof) as used in the specification and claims are to be construed to allow for direct and indirect (i.e., through other elements or components) connection. Furthermore, the terms "a" or "an" as used in the specification and claims should be interpreted to mean "at least one". Finally, for convenience in use, the terms "comprising" and "having" (and their derivatives) as used in the specification and claims are interchangeable with and shall have the same meaning as the term "comprising".

A processor as disclosed herein may be configured with instructions to perform any one or more steps of any method as disclosed herein.

It will be understood that, although the terms "first," "second," "third," etc. may be used herein to describe various layers, elements, components, regions or sections, these do not relate to any particular sequence or order of events. These terms are only used to distinguish one layer, element, component, region or section from another layer, element, component, region or section. A first layer, element, component, region or section described herein could be termed a second layer, element, component, region or section without departing from the teachings of the present disclosure.

As used herein, the term "or" is used inclusively to refer to both alternative and combination terms.

As used herein, characters such as numbers refer to similar elements.

The present disclosure includes the following numbered entries.

Item 1. A device for treating refractive error of an eye, the device comprising: a plurality of stimuli; and one or more optical elements for imaging the plurality of stimuli in front of or behind a peripheral portion of the retina to form a plurality of defocused images on the peripheral portion of the retina; wherein the plurality of stimuli and the one or more optical elements are arranged to reduce interference with central vision of the eye.

Item 2. The apparatus of item 1, wherein the plurality of images are defocused by an amount in a range of 3.0D to 6.0D, optionally myopic defocused, and optionally defocused by an amount in a range of 3.5D to 5.0D.

Item 3. The apparatus of item 1, wherein the brightness of the plurality of defocused images is at least 3 times higher than the background illumination brightness, optionally at least 5 times higher than the background illumination brightness, optionally in the range of 3 times to 20 times the background illumination brightness, further optionally in the range of 5 times to 15 times the background illumination brightness.

Item 4. The apparatus of item 1, wherein each of the plurality of defocused images comprises an intensity profile comprising one or more peaks distributed about an interior portion having a reduced intensity relative to the one or more peaks.

Item 5 the apparatus of item 4, wherein the one or more peaks comprise a plurality of peaks, and wherein the inner portion is located between the plurality of peaks.

Item 6 the apparatus of item 5, wherein the plurality of peaks includes four peaks, and the inner portion is located between the four peaks.

Item 7. The apparatus of item 6, wherein the inner portion comprises a cross extending between four peaks.

Item 8 the apparatus of item 4, wherein the one or more peaks comprise a circular peak, and wherein the inner portion is located within the circular peak.

Item 9 the apparatus of item 1, wherein each of the plurality of defocused images comprises a multi-colored icon on a darker background to provide contrast, and optionally wherein the multi-colored icon comprises a white icon and the darker background comprises a substantially black background.

Item 10. The apparatus of item 1, wherein each of the plurality of stimuli comprises a length, edge, and intensity profile distribution to generate a spatial frequency when imaged into the eye in front of or behind the retina at 1 x 10 per degree ^-1 One cycle to 2.5 × 10 ¹ Within the range of one period, and optionally at 1 × 10 per degree ^-1 Period to 1 × 10 ¹ Within a period.

Item 11 the apparatus of item 1, wherein the plurality of stimuli imaged in the eye comprises a spatial frequency distribution of about 1 x 10 per degree ^-1 One cycle to about 2.5X 10 ¹ Within the spatial frequency range of the period of the unit and optionally at 1 x 10 per degree ^-1 One cycle to about 5X 10 ⁰ Over a spatial frequency range of one period, a decrease in spatial frequency amplitude with an increase in spatial frequency is provided.

Item 12 the apparatus of item 11, wherein the spatial frequency intensity decreases from 1/(spatial frequency) for arbitrary units of spatial frequency amplitude ^0.5 To 1/(spatial frequency) ² And optionally, for arbitrary units of spatial frequency amplitude, the reduction in spatial frequency intensity is from 1/(spatial frequency) to 1/(spatial frequency) ² Within the range of (1).

Item 13 the apparatus of item 11, wherein the spatial frequency ranges from about 3 x 10 per degree ^-1 From one period to about 1.0X 10 per degree ¹ One period, and optionally at about 3 x 10 per degree ^-1 From one period to about 2.0X 10 per degree ⁰ Within a period, and further optionally, from about 3 x 10 per degree ^-1 From one period to about 1.0X 10 per degree ⁰ And (4) a period.

Item 14. The device of item 1, wherein the device is configured for monocular stimulation of a patient's eye.

Item 15. The device of item 1, wherein the device is configured for binocular stimulation of a patient.

Item 16. The apparatus of item 15, further comprising: a plurality of second stimuli for stimulating a contralateral eye of a patient; and one or more second optical elements for imaging a plurality of second stimuli in front of or behind a peripheral portion of a retina of the contralateral eye to form a plurality of second defocused images on the peripheral portion of the second retina; wherein the plurality of second stimuli and the one or more second optical elements are arranged to reduce interference with central vision of the contralateral eye.

Item 17 the apparatus of item 1, the plurality of stimuli and the one or more optical elements being arranged to provide a substantially undisturbed field of view in the range of 10 degrees to 30 degrees, optionally in the range of 10 degrees to 20 degrees, and optionally in the range of 12 degrees to 18 degrees, and optionally wherein each of the plurality of defocused images is projected onto the retina outside the field of view.

Item 18. The apparatus of item 1, wherein each of the plurality of stimuli imaged in the eye is superimposed on a substantially uniform gray background, each of the plurality of stimuli comprising a white icon such that the icon has a total edge length to generate a color that is predominantly 1 x 10 per degree ^-1 Period to 2.5 x 10 per degree ¹ Within the range of one period, and optionally at 1 × 10 per degree ^-1 From one period to 1 × 10 per degree ¹ The spatial frequency within a range of cycles.

Item 19. The apparatus of item 1, wherein each of the plurality of stimuli imaged in the eye comprises a multi-colored icon with an edge contour over a background that generates a1 x 10 color primarily at each degree ^-1 Period to 2.5 x 10 per degree ¹ In the range of 1 cycle, and optionally at 1 × 10 per degree ^-1 From one period to 1 × 10 per degree ¹ The spatial frequency over a range of cycles.

Item 20. The apparatus of item 1, wherein each of the plurality of stimuli comprises a global contrast factor greater than 0.7 and optionally greater than 8.0.

Item 21. The device of item 1, wherein the one or more optical elements comprise one or more of a hologram, a waveguide, a mirror, a lens, a spectacle lens, or a contact lens.

Item 22. The apparatus of item 1, further comprising a support to couple to a user to support one or more optical elements, the support comprising components of one or more of a head-mounted device, a spectacle lens, a spectacle frame, goggles, an AR display, a contact lens, or a VR display.

Item 23. The apparatus of item 1, further comprising a lens for correcting refractive error of the eye.

Item 24. The device of item 1, wherein the one or more optical elements are arranged to project the plurality of stimuli toward a peripheral portion of the retina when the pupil of the eye has been dilated with the mydriatic agent.

Item 25 the apparatus of item 24, wherein the plurality of stimuli are arranged to illuminate the peripheral portion of the retina at an angle of at least 35 degrees from the visual axis of the eye.

Item 26. The device of item 1, further comprising a sensor to measure a size of the pupil, and the device further comprising a processor configured with instructions to direct an optical stimulus to the eye in response to the size of the pupil, and optionally wherein the size of the pupil comprises a diameter of the pupil.

Item 27. The apparatus of item 26, wherein the processor is configured to adjust one or more of an intensity or a duration of the optical stimulus in response to a size of the pupil.

Item 28. The apparatus of item 26, wherein the sensor comprises a sensor array, and optionally wherein the sensor array comprises a sensor array of a camera.

Item 29 the device of item 26, wherein the plurality of stimuli are configured to allow the natural pupil to dilate when illuminated by the plurality of stimuli.

Item 30. The device of item 1, wherein the plurality of stimuli are configured to constrict the pupil by no more than one millimeter (mm) when the stimuli are presented as compared to the diameter of the pupil when the stimuli are not presented.

Item 31. The device of item 1, wherein the pupil comprises a stimulus diameter when the eye is exposed to the plurality of stimuli, and wherein the eye comprises a photopic diameter when the eye is exposed to photopic viewing conditions without the plurality of stimuli, and wherein the photopic diameter is at least one millimeter less than the stimulus diameter, and optionally wherein the photopic viewing conditions comprise per square meter (m) ² ) A luminance of at least 3 candela (cd).

Item 32. The apparatus of item 1, wherein the stimulus is configured to illuminate a peripheral portion of the retina having an eccentricity greater than 35 degrees, wherein when the stimulus is provided to the peripheral retina having an eccentricity greater than 35 degrees, the pupil of the eye dilates by at least about 1 millimeter compared to photopic illumination.

Item 33. The apparatus of item 1, wherein no more than 10% of the total amount of energy of the plurality of stimuli and optionally no more than 5% of the total amount, and optionally no more than 1% of the total amount, is directed to the fovea of the eye in order to reduce constriction of the pupil in response to the plurality of stimuli.

Item 34. A method of treating refractive error of an eye, the method comprising: providing a stimulus to a peripheral region of a retina of an eye, wherein the stimulus is provided in the morning.

Item 35. The method of item 34, wherein the stimulus is provided by the device of any of the preceding items.

Item 36. The method of item 34, wherein the stimulus is provided between 6 am and 10 am.

Item 37. The method of item 34, wherein the stimulus is provided between 6 am and 10 am.

Item 38 the method of item 34, wherein the stimulus is provided to the eye in the morning of a plurality of adjacent days, and wherein the total treatment time per day comprises no more than one hour.

Item 39. A tangible medium configured with instructions to be executed by a processor, the tangible medium configured to perform the method of any one of items 34 to 38.

Item 40. A patient database comprising: therapy data corresponding to a plurality of retinal stimulation therapies for a plurality of patients; and efficacy data for a plurality of patients, the efficacy data comprising refractive data for a plurality of treatments.

Item 41. A method of conducting a clinical trial, the method comprising: providing peripheral retinal stimulation to the test eye and not to the control eye on each of a plurality of days; measuring the axial length of the test and control eyes before and after treatment on each of a plurality of days; and comparing the axial length of the test eye to the axial length of the control eye to determine the efficacy of the peripheral retinal stimulus.

Item 42. A method of treating refractive error of an eye, the method comprising: dilating a pupil of the eye; and providing optical stimulation to a peripheral portion of the retina to reduce refractive error of the eye.

Item 43 the method of item 42, wherein the stimulus comprises a plurality of stimuli as described in any one of the preceding items.

Item 44. The method of item 42, wherein the pupil is dilated with a mydriatic agent.

Item 45 the method of item 44, wherein the mydriatic agent optionally comprises a cycloplegic agent, wherein the cycloplegic agent is selected from the group consisting of atropine, cypionate, homatropine, scopolamine, and tropicamide.

Item 46. The method of item 45, wherein the cycloplegic agent comprises atropine in a weight percentage in a range of 0.025% to 0.2%, and optionally in a range of 0.05% to 0.1%.

Item 47. The method of item 42, wherein a size of the pupil is measured and the optical stimulus is directed to the eye in response to the size of the pupil, and optionally wherein the size of the pupil comprises a diameter of the pupil.

Item 48. The method of item 47, wherein one or more of the intensity or duration of the optical stimulus is adjusted in response to the size of the pupil.

Item 49 the method of item 47, wherein the size of the pupil is measured with a sensor, and optionally wherein the sensor comprises a sensor array, and optionally wherein the sensor array comprises a sensor array of a camera.

Item 50. The method of item 42, wherein the pupil comprises a natural pupil of the eye, wherein the natural pupil is dilated with an appropriate amount of illumination of the peripheral retina and light from other sources that passes through the natural pupil, and optionally wherein the natural pupil is capable of contracting and dilating in response to illumination of the eye.

Item 51 the method of item 50, wherein the natural pupil is dilated with mesopic background lighting or scotopic background lighting, and optionally, wherein the mesopic background lighting comprises 0.01 candela per square meter(cd/m ² ) To 3cd/m ² An amount within the range of (1).

Item 52. The method of item 51, wherein the natural pupil constriction is no more than one millimeter (mm) when the stimulus is provided as compared to the diameter of the natural pupil when the stimulus is not provided.

Item 53. The method of item 51, wherein the natural pupil comprises a stimulus diameter when the eye is exposed to the stimulus, and wherein the natural pupil comprises a photopic diameter when the eye is exposed to photopic viewing conditions, and wherein the photopic diameter is at least one millimeter less than the stimulus diameter.

Item 54 the method of item 42, wherein the stimulus is configured to illuminate the peripheral retina with an eccentricity greater than 35 degrees, wherein when the stimulus is provided to the peripheral retina with an eccentricity greater than 35 degrees, the pupil dilates by at least about 1 millimeter compared to photopic illumination.

Item 55 the method of item 42, wherein no more than 10% of the total amount of energy, and optionally no more than 5% of the total amount, and optionally no more than 1% of the total amount of energy, of the plurality of stimuli is directed to the fovea of the eye in order to reduce constriction of the pupil in response to the plurality of stimuli.

Item 56 the method of item 42, wherein the stimulus comprises a photopic stimulus directed to a peripheral region of the retina, and wherein the illumination of one or more of the fovea or macula comprises one or more of mesopic or scotopic illumination, so as to reduce the size of the pupil.

Embodiments of the present disclosure have been shown and described as described herein, and are provided by way of example only. Those of ordinary skill in the art will recognize many adaptations, variations, modifications, and alternatives without departing from the scope of the present disclosure. Several alternatives and combinations of the embodiments disclosed herein may be used without departing from the present disclosure and the scope of the invention disclosed herein. Accordingly, the scope of the presently disclosed invention is to be defined only by the scope of the appended claims and equivalents thereof.

Claims

1. A device for treating refractive error of an eye, the device comprising:

a plurality of stimuli; and

one or more optical elements for imaging the plurality of stimuli in front of or behind a peripheral portion of a retina to form a plurality of defocused images on the peripheral portion of the retina;

wherein the plurality of stimuli and the one or more optical elements are arranged to reduce interference with central vision of the eye.

2. The apparatus of claim 1, wherein the plurality of images are defocused by an amount in a range of 3.0D to 6.0D, optionally myopic defocused, and optionally defocused by an amount in a range of 3.5D to 5.0D.

3. The apparatus of claim 1, wherein the brightness of the plurality of defocused images is at least 3 times higher than the background illumination brightness, optionally at least 5 times higher than the background illumination brightness, optionally in the range of 3 to 20 times the background illumination brightness, further optionally in the range of 5 to 15 times the background illumination brightness.

4. The apparatus of claim 1, wherein each of the plurality of defocused images includes an intensity profile including one or more peaks distributed about an interior portion having a reduced intensity relative to the one or more peaks.

5. The apparatus of claim 4, wherein the one or more peaks comprise a plurality of peaks, and wherein the inner portion is located between the plurality of peaks.

6. The apparatus of claim 5, wherein the plurality of peaks comprises four peaks, and the inner portion is located between the four peaks.

7. The apparatus of claim 6, wherein the inner portion comprises a cross extending between the four peaks.

8. The apparatus of claim 4, wherein the one or more peaks comprise an annular peak, and wherein the inner portion is located within the annular peak.

9. The apparatus of claim 1, wherein each of the plurality of defocused images comprises a multi-colored icon on a darker background to provide contrast, and optionally wherein the multi-colored icon comprises a white icon, the darker background comprising a substantially black background.

10. The apparatus of claim 1, wherein each of the plurality of stimuli comprises a length, edge, and intensity profile distribution to generate a spatial frequency when imaged into the eye in front of or behind the retina, the spatial frequency being 1 x 10 per degree ^-1 One cycle to 2.5 × 10 ¹ Within the range of one period and optionally at 1 × 10 per degree ^-1 Period to 1 × 10 ¹ Within a period.

11. The apparatus of claim 1, wherein the plurality of stimuli imaged in the eye comprises a spatial frequency distribution of about 1 x 10 per degree ^-1 One cycle to about 2.5X 10 ¹ Spatial frequency range of one period and optionally 1 × 10 per degree ^-1 One cycle to about 5X 10 ⁰ Within the spatial frequency range of a single period, a decrease in spatial frequency amplitude with an increase in spatial frequency is provided.

12. The apparatus of claim 11, wherein the reduction in spatial frequency intensity is from 1/(spatial frequency) for arbitrary units of spatial frequency amplitude ^0.5 To 1/(spatial frequency)Rate) ² And optionally, for arbitrary units of spatial frequency amplitude, the reduction in spatial frequency intensity is from 1/(spatial frequency) to 1/(spatial frequency) ² Within the range of (1).

13. The apparatus of claim 11, wherein the spatial frequency ranges from about 3 x 10 per degree ^-1 From one period to about 1.0X 10 per degree ¹ One period, and optionally at about 3 x 10 per degree ^-1 From one period to about 2.0X 10 per degree ⁰ Within a period, and further optionally, from about 3 x 10 per degree ^-1 From one period to about 1.0X 10 per degree ⁰ And (4) one period.

14. The apparatus of claim 1, wherein the apparatus is configured for monocular stimulation of a patient's eye.

15. The apparatus of claim 1, wherein the apparatus is configured for binocular stimulation of a patient.

16. The apparatus of claim 15, further comprising:

a plurality of second stimuli for stimulating a contralateral eye of a patient; and

one or more second optical elements for imaging the plurality of second stimuli in front of or behind a peripheral portion of the retina of the contralateral eye to form a plurality of second defocused images on a peripheral portion of a second retina;

wherein the plurality of second stimuli and the one or more second optical elements are arranged to reduce interference with central vision of the contralateral eye.

17. The apparatus of claim 1, the plurality of stimuli and the one or more optical elements arranged to provide a substantially undisturbed field of view in a range of 10 to 30 degrees, optionally in a range of 10 to 20 degrees, and optionally in a range of 12 to 18 degrees, and optionally wherein each of the plurality of defocused images is projected onto the retina outside the field of view.

18. The apparatus of claim 1, wherein each of the plurality of stimuli imaged in the eye is superimposed on a substantially uniform gray background, the each of the plurality of stimuli comprising a white icon such that the icon has a total edge length to generate a1 x 10 color predominantly at each degree ^-1 Period to 2.5 x 10 per degree ¹ Within the range of one period and optionally at 1 × 10 per degree ^-1 From one period to 1 × 10 per degree ¹ A characterization of spatial frequencies over a range of periods.

19. The apparatus of claim 1, wherein each of the plurality of stimuli imaged in the eye comprises a multi-colored icon with an edge contour over a background that generates a1 x 10 color primarily at each degree ^-1 Period to 2.5 x 10 per degree ¹ Within the range of one period and optionally at 1 × 10 per degree ^-1 From one period to 1 × 10 per degree ¹ A characterization of spatial frequencies over a range of periods.

20. The apparatus of claim 1, wherein each of the plurality of stimuli comprises a global contrast factor greater than 0.7 and optionally greater than 8.0.

21. The device of claim 1, wherein the one or more optical elements comprise one or more of a hologram, a waveguide, a mirror, a lens, a spectacle lens, or a contact lens.

22. The apparatus of claim 1, further comprising a support to couple to a user to support the one or more optical elements, the support comprising components of one or more of a head-mounted device, an eyeglass lens, an eyeglass frame, a visor, an AR display, a contact lens, or a VR display.

23. The apparatus of claim 1, further comprising a lens for correcting refractive error of the eye.

24. The device of claim 1, wherein the one or more optical elements are arranged to project the plurality of stimuli toward a peripheral portion of the retina when the pupil of the eye has been dilated with a mydriatic agent.

25. The apparatus of claim 24, wherein the plurality of stimuli are arranged to illuminate the peripheral portion of the retina at an angle of at least 35 degrees from the visual axis of the eye.

26. The device of claim 1, further comprising a sensor to measure a size of a pupil, and further comprising a processor configured with instructions to direct the optical stimulus to an eye in response to the size of the pupil, and optionally wherein the size of the pupil comprises a diameter of the pupil.

27. The apparatus of claim 26, wherein the processor is configured to adjust one or more of an intensity or duration of the optical stimulus in response to a size of the pupil.

28. The apparatus of claim 26, wherein the sensor comprises a sensor array, and optionally wherein the sensor array comprises a sensor array of a camera.

29. The device of claim 26, wherein the plurality of stimuli are configured to allow a natural pupil to dilate when illuminated by the plurality of stimuli.

30. The device of claim 1, wherein a plurality of stimuli are configured to constrict the pupil by no more than one millimeter (mm) when the stimuli are provided, as compared to the diameter of the pupil when the stimuli are not yet provided.

31. The device of claim 1, wherein the pupil comprises a stimulus diameter when the eye is exposed to the plurality of stimuli, and wherein the eye comprises a photopic diameter when the eye is exposed to photopic viewing conditions without the plurality of stimuli, and wherein the photopic diameter is at least one millimeter less than the stimulus diameter, and optionally wherein the photopic viewing conditions comprise per square meter (m) ² ) A luminance of at least 3 candelas (cd).

32. The apparatus of claim 1, wherein the stimulus is configured to illuminate a peripheral portion of the retina having an eccentricity greater than 35 degrees, wherein when the stimulus is provided to the peripheral retina having an eccentricity greater than 35 degrees, the pupil of the eye dilates by at least about 1 millimeter compared to photopic illumination.

33. The apparatus according to claim 1, wherein no more than 10% of the total amount of energy of the plurality of stimuli, and optionally no more than 5% of the total amount, and optionally no more than 1% of the total amount, is directed to the fovea of the eye in order to reduce constriction of the pupil in response to the plurality of stimuli.

34. A method of treating refractive error of an eye, the method comprising:

providing a stimulus to a peripheral region of a retina of an eye, wherein the stimulus is provided in the morning.

35. The method of claim 34, wherein the stimulus is provided by a device according to any of the preceding claims.

36. The method of claim 34, wherein the stimulus is provided between 6 am and 10 am.

37. The method of claim 34, wherein the stimulus is provided between 6 am and 10 am.

38. The method of claim 34, wherein the stimulus is provided to the eye in the morning of a plurality of adjacent days, and wherein the total treatment time per day comprises no more than one hour.

39. A tangible medium configured with instructions to be executed by a processor, the tangible medium configured to perform the method of any of claims 34-38.

40. A patient database comprising:

therapy data corresponding to a plurality of retinal stimulation therapies for a plurality of patients; and

efficacy data for a plurality of patients, the efficacy data comprising refractive data for the plurality of treatments.

41. A method of conducting a clinical trial, the method comprising:

providing peripheral retinal stimulation to the test eye and not to the control eye on each of a plurality of days;

measuring the axial length of the test eye and the control eye before and after treatment on each of a plurality of days; and

comparing the axial length of the test eye to the axial length of the control eye to determine the efficacy of the peripheral retinal stimulus.

42. A method of treating refractive error of an eye, the method comprising:

dilating the pupil of the eye; and

optical stimuli are provided to the peripheral portion of the retina to reduce the refractive error of the eye.

43. The method of claim 42, wherein the stimulus comprises the plurality of stimuli of any of the preceding claims.

44. The method of claim 42, wherein the pupil is dilated with a mydriatic agent.

45. The method of claim 44, wherein the mydriatic agent optionally comprises a cycloplegic agent, wherein the cycloplegic agent is selected from the group consisting of atropine, cypionate, homatropine, scopolamine, and tropicamide.

46. The method of claim 45, wherein the cycloplegic agent comprises atropine in a weight percentage in a range of 0.025% to 0.2%, and optionally in a range of 0.05% to 0.1%.

47. The method as recited in claim 42, wherein a size of the pupil is measured and the optical stimulus is directed to the eye in response to the size of the pupil, and optionally wherein the size of the pupil comprises a diameter of the pupil.

48. The method of claim 47, wherein one or more of the intensity or duration of the optical stimulus is adjusted in response to the size of the pupil.

49. The method of claim 47, wherein the size of the pupil is measured with a sensor, and optionally wherein the sensor comprises a sensor array, and optionally wherein the sensor array comprises a sensor array of a camera.

50. The method of claim 42, wherein the pupil comprises a natural pupil of the eye, wherein the natural pupil is dilated with an appropriate amount of illumination of the peripheral retina and light from other sources passing through the natural pupil, and optionally wherein the natural pupil is able to contract and dilate in response to illumination of the eye.

51. The method of claim 50, wherein the natural pupil is dilated with mesopic background lighting or scotopic background lighting, and optionally wherein the mesopic background lighting comprises at 0.01 candela per square meter (cd/m) ² ) To 3cd/m ² An amount within the range of (1).

52. The method of claim 51, wherein the natural pupil constriction is no more than one millimeter (mm) when the stimulus is provided as compared to the diameter of the natural pupil when the stimulus is not provided.

53. The method of claim 51, wherein the natural pupil comprises a stimulus diameter when the eye is exposed to the stimulus, and wherein the natural pupil comprises a photopic diameter when the eye is exposed to photopic viewing conditions, and wherein the photopic diameter is at least one millimeter less than the stimulus diameter.

54. The method of claim 42, wherein the stimulus is configured to illuminate the peripheral retina with an eccentricity greater than 35 degrees, wherein when the stimulus is provided to the peripheral retina with an eccentricity greater than 35 degrees, the pupil dilates by at least about 1 millimeter compared to photopic illumination.

55. A method as in claim 42, wherein no more than 10% of a total amount of energy of the plurality of stimuli, and optionally no more than 5% of the total amount, and optionally no more than 1% of the total amount, is directed to a fovea of the eye so as to reduce constriction of the pupil in response to the plurality of stimuli.

56. The method of claim 42, wherein the stimulus comprises a photopic stimulus directed to a peripheral region of the retina, and wherein the illumination of one or more of the fovea or macula comprises one or more of mesopic or scotopic illumination so as to reduce the size of the pupil.