Laser systems and methods for changing eye color

Abstract

Disclosed is a method of altering a patient's eye color by a color alteration procedure, the method may include determining a laser power to deliver to stromal pigment in an iris of the patient's eye by at least obtaining a set of laser criteria for delivery of an exposure dose that is less than 100 times a maximum allowable exposure dose that results in removal of at least a portion of the stromal pigment. A laser system may be configured to deliver laser light at a laser power that is less than the set of laser criteria, and the laser light may be delivered by the laser system.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to U.S. Patent Application No. 17 / 507,572, filed on 21 October 2021, which is a continuation application of U.S. Patent Application No. 17 / 238,070, filed on 22 April 2021, which claims priority to U.S. Provisional Patent Application No. 63 / 165,683, filed on 24 March 2021, entitled "Laser Systems And Methods For Alteration Of Eye Color," as incorporated herein by reference.

[0002] [Technical field] The present invention relates to delivering laser light at a specific power level and in a shape suitable for medical procedures relating to altering a patient's eye color. [Background technology]

[0003] The use of lasers in ophthalmic surgery has been increasing recently. However, while laser ophthalmic surgery is a known option for correcting one or more vision problems such as myopia, hyperopia, and astigmatism, there has been little interest in procedures other than those for correcting vision problems. For example, advances in laser ophthalmic surgery have focused on procedures in which the laser can reshape a patient's cornea, neglecting several other parts of the patient's eye and treatments for them. [Overview of the project]

[0004] In view of this, methods and systems for delivering laser light to a patient's iris are described herein. In particular, the methods and systems described herein are for performing eye color alteration procedures by this delivery of laser light. For example, altering a person's eye color can be done by delivering laser light to several parts of the eye (e.g., the iris) that are responsible for giving the eye its color.

[0005] To achieve this effect, the above methods and systems must overcome several technical hurdles. For example, in conventional laser ophthalmic surgery (e.g., aimed at correcting vision), the amount of laser power used is, to some extent, arbitrary and / or variable. When such systems are applied to the iris (e.g., for eye color alteration procedures), this can lead to inconsistent results and, in some cases, potential damage to the iris. A similar challenge exists in conventional approaches to ophthalmic surgery, as they use a uniform approach that treats the eye as a homogeneous structure. Such approaches overlook local differences in the eye that affect the outcome of eye color alteration procedures.

[0006] In light of these technical limitations, the methods and systems described herein deliver laser light with laser power based on a calculated minimum exposure (MRE) value in the iris of the eye to achieve effectiveness, and a maximum permissible exposure (MPE) value in the fundus of the eye to avoid undesirable damage. Diagnostic functions, including temperature monitoring during the procedure, precise distance measurement to ensure proper delivery of light to the target structure, and iris mapping to provide targeted power delivery to specific areas of the eye are also described.

[0007] These methods and systems offer numerous advantages over conventional methods for altering eye color, such as colored contact lenses, corneal dyeing and tattooing, and artificial iris implants. For example, with colored contact lenses, problems include the unnatural appearance when blue or green lenses are used to make brown eyes appear blue or green, the fact that the color change is only temporary, low tolerance in about 50% of patients, the risk of eye infection, corneal epithelial detachment, and other eye complications, as well as poor night vision because the central transparent portion does not expand with the pupil. Recent literature also suggests that the pigments used in colored contact lenses may be released into the body after prolonged use. Other available solutions include corneal pigmentation and colored iris implants. Problems with corneal pigmentation include the unnatural appearance and poor night vision, similar to colored contact lenses, plus the additional risks associated with invasive surgery. The problems with colored iris implants include all the issues associated with corneal pigmentation, plus low tolerance in approximately 50% of patients within 24 hours and over 90% within one year. Furthermore, colored iris implants are far more surgically invasive and often result in glaucoma and vision loss. Neither corneal pigmentation nor colored iris implants are approved for cosmetic purposes.

[0008] The above method and system overcome the shortcomings of conventional systems by delivering MPE-based laser power to perform safe and effective eye color alteration procedures. Such delivery has the advantage that the laser system settings are directed toward the result, rather than being set to arbitrary parameters that may or may not lead to proper delivery of laser power to the eye. A novel method of distance measurement is disclosed to ensure that the laser power is delivered accurately. Such a method may include micron-level resolution at the laser focal point of the eye to deliver the desired laser power precisely where needed. A method of applying laser treatment in stages is also disclosed to provide an optimized, purposeful treatment for the patient. By applying in stages, variability in the stroma pigment absorption coefficient and anterior iris topography (e.g., slope, folds, and fovea) can be eliminated. Applying in stages may also be beneficial from the assessment of elements of the patient's immune response, as this may have a direct impact on the above treatment and, therefore, on the laser system parameters used.

[0009] To facilitate the alteration of the patient's eye color, the system can determine the laser power to be delivered to the stroma pigment within the iris of the patient's eye, with an upper limit that is a fraction of the MPE. Once this determination is made, the laser system can be configured to deliver the required laser power. Furthermore, the system can optimize the laser spot size (i.e., 1 / x) at the location of the stroma pigment. 2 The spot diameter (as defined by) can be determined. This optimized spot size determination can then be used by the system to determine the laser power required for the above procedure.

[0010] In some embodiments, a method of changing a patient's eye color may include determining a laser power for delivery to stromal pigment within the iris of the eye. The determining step may be performed by the system obtaining a set of laser criteria for delivery of an exposure amount less than 100 times the MPE, which results in removal of at least a portion of the stromal pigment, thereby changing the eye color. The method may then include setting the laser system to deliver laser light at a power level less than the set of laser criteria, and delivering the laser light by the laser system.

[0011] In related embodiments, a method of changing a patient's eye color may include determining a spot size of laser light to be delivered to stromal pigment within the iris of the eye. The determining step may be performed by the system obtaining a set of laser criteria that can result in delivery of laser light having a spot size of at least 4 - 70 μm to the stromal pigment of the patient's iris. With these criteria, the laser power delivered by the laser light at the spot size is sufficient to result in removal of at least a portion of the stromal pigment. The method may then include setting the laser system to deliver the laser light at the spot size, and delivering the laser light by the laser system.

[0012] Another related aspect is a tangible, non - transient machine - readable medium that, when executed by a data processing apparatus, may store instructions that cause the data processing apparatus to perform operations comprising any of the above - described embodiments.

[0013] In yet another related aspect, a system may include one or more processors and a memory that stores instructions that, when executed by the one or more processors, cause the one or more processors to perform operations including any of the above - described embodiments.

[0014] Various other aspects, features, and advantages of the present invention will become apparent from the detailed description of the invention and the drawings attached hereto. It is to be understood that both the foregoing general description and the following detailed description are exemplary and not restrictive of the scope of the invention. As used in this specification and the appended claims, the singular forms of "a", "an", and "the" include the plural forms unless the context clearly dictates otherwise. Further, as used in this specification and the appended claims, the term "or" means "and / or" unless the context clearly indicates otherwise. Further, as used herein, "a portion" represents a part or the whole (i.e., the entirety) of a particular item (e.g., data) unless the context clearly indicates otherwise.

Brief Description of the Drawings

[0015] [Figure 1] Shows a simplified diagram of an eye and an iris. [Figure 2] Shows a simplified diagram of a laser system and a patient positioning system according to one or more embodiments. [Figure 3] Shows a simplified diagram of a laser system and an image sensor for use in mapping an iris according to one or more embodiments. [Figure 4] Shows the system of FIG. 3 that irradiates variable laser power to multiple regions of an iris according to one or more embodiments. [Figure 5] Shows an exemplary system for performing an eye color change treatment according to one or more embodiments. [Figure 6] Shows the process of determining the laser power of a laser system according to one or more embodiments. [Figure 7] Shows the process of determining the spot size of a laser system according to one or more embodiments.

Modes for Carrying Out the Invention

[0016] In the following description, for illustrative purposes, numerous specific details are provided to give a full understanding of the multiple embodiments of the present invention. However, it will be understood by those skilled in the art that the multiple embodiments of the present invention can be carried out without these specific details, or in equivalent arrangements. In other cases, well-known structures and apparatus are shown in block diagrams to avoid unnecessarily complicating the multiple embodiments of the present invention.

[0017] Introduction This disclosure describes improved methods and systems for facilitating medical procedures to alter a patient's eye color. Such medical procedures may involve delivering laser power to multiple parts of the eye to alter the pigment structure of the eye, thereby triggering a biological response that changes its color. Determining the appropriate laser power to use, based on the necessity of the procedure, patient safety, patient variability, and (in the case of multi-step procedures) variability between procedures, may be important for successful outcomes.

[0018] Before describing the color-changing procedures applicable to many embodiments of this disclosure, a brief overview of the anatomical structure of the eye is provided. As shown in Figure 1, the eye 100 consists of several anatomical structures, some of which are described below. The iris 110 is central to this disclosure and is responsible for the color of the eye. Several other parts of the eye include, for example, the cornea 120, lens 130, pupil 140, and retina 150. While care should be taken to avoid damaging any part of the eye, in laser safety practice, special care should be taken to avoid directing unnecessary laser light into the lens through the pupil, because this part of the eye naturally focuses light onto the retina. Such focusing of already strong laser light can result in damage to the retinal nerve.

[0019] The inset above the eye shows two examples of irises. The example on the left depicts the iris 110 of a person with brown eyes. The example on the right depicts the iris 110 of a person with blue or green eyes. Perceived color is due to the separation of light reaching the eye into its component wavelengths by stroma fibers (called the iris stroma 112) in the intermediate region of the iris. This separation is similar to the separation shown when light passes through a prism. In both cases, the iris has a posterior surface 114 containing a fairly thick (several cells deep) layer of pigmentation that absorbs visible light wavelengths longer than blue or green. However, in the example on the left of a person with brown eyes, there is an additional anterior surface containing a brown pigment, which is referred to herein as “stroma pigment” 116. The brown stroma pigment gives the eye its brown color. Eyes without stroma pigment reflect mostly blue or green light, as described above, and give the eye its blue or green color.

[0020] A brief summary of color-altering procedures, as referenced herein, is provided. Laser light can be delivered to the stroma pigment, resulting in an increase in its temperature. This process can be repeated several times, repeatedly increasing and decreasing the temperature of the stroma pigment. This increase and decrease in temperature causes multiple macrophages (part of the body's innate immune response) to be deployed to the stroma layer. These macrophages then remove a portion of the stroma pigment responsible for giving the eye its brown color. The procedure can be repeated to produce varying degrees of color change to make the eye appear deeper blue / green. The pattern of laser light delivery can be a scanning pattern (e.g., a spiral pattern surrounding the pupil, or a raster pattern avoiding the pupil) to treat the entire iris.

[0021] Figure 2 shows a simplified diagram of a laser system and a patient positioning system according to one or more embodiments. One embodiment of the overall system 200 may include a laser system 210 and a patient positioning system 280. The head of a patient 10 (having eyes 100) is shown supported by the patient positioning system in a location suitable for a color change procedure. The laser system may include a laser head 212 that supplies laser light 214. The laser head may include components for generating laser light at various wavelengths, for example, 1064 nm or 532 nm (Nd:YLF or Nd:YAG). Exemplary pulse widths are within 5 to 300 ns, repetition frequencies are 5 to 300 kHz, and M 2 It can be ≤ 1.2.

[0022] The laser head described above may include an energy source (also known as a pump or pump source), a gain medium, and two or more mirrors forming an optical resonator. Exemplary energy sources include electrical discharges, flash lamps, arc lamps, output from another laser, and chemical reactions. Exemplary gain mediums include liquids (e.g., dyes including chemical solvents and chemical dyes), gases (e.g., carbon dioxide, argon, krypton, and helium-neon), solids (e.g., crystals and glasses, e.g., yttrium aluminum garnet, lithium yttrium fluoride, sapphire, titanium sapphire, lithium strontium aluminum fluoride, neodymium glass, and erbium glass) which may be doped with impurities (e.g., chromium, neodymium, erbium, or titanium ions) and which may be excited by a flash lamp or output from another laser, and semiconductors (e.g., laser diodes) with a uniform or different dopant distribution.

[0023] Embodiments of a laser head may include optical frequency multipliers (e.g., frequency multipliers and sum frequency generators) in which the laser output frequency is increased by passing it through a nonlinear crystal or other material. The advantage of an optical frequency multiplier is that it increases the range of available frequencies / wavelengths from a particular gain medium. The nonlinear material may be inserted into the optical resonator for one-stage frequency multiplication, or the fundamental (i.e., unmultiplied) output beam may be passed through the nonlinear material after leaving the optical resonator for two-stage frequency multiplication. Exemplary nonlinear materials for frequency multiplication may include lithium niobate, lithium tantalate, potassium titanyl phosphate, or lithium triborate. Two-stage frequency triplication is typically performed in the first stage by frequency-doubling a portion of the fundamental output beam. The doubled portion of the fundamental beam and the remaining undoubled portion of the fundamental beam are then coupled in the second stage to a second nonlinear frequency triplicating material for sum frequency mixing. Exemplary nonlinear materials for frequency tripling may include potassium dihydrogen phosphate.

[0024] One combination of gain medium and optical frequency multiplier is Nd:YAG with a frequency multiplier. With an Nd:YAG gain medium, the intrinsic harmonic of the generated laser beam has a wavelength of 1,064 nm, which is then halved to 532 nm by the frequency multiplier. This wavelength can be utilized as follows: (a) it falls within the visible light spectrum (i.e., green), thereby passing through the clear cornea with little or no absorption; (b) it has a high absorption coefficient in the stroma pigment, thereby causing selective photothermal decomposition in the anterior stroma pigment of the iris; and (c) the wavelength is relatively short, thereby limiting the depth of penetration and avoiding unnecessary damage to the IPE (iris pigment epithelium). Any other combination of gain medium and optical frequency multiplier that satisfies these three criteria may also be realized in some embodiments.

[0025] The laser pulse width may be in the nanosecond range (i.e., between less than 1 nanosecond and 1 microsecond), and the pulse repetition frequency may be in the kilohertz range (i.e., between less than 1 kHz and 1 MHz). Some embodiments may have pulse widths between 5 ns and 300 ns, which may result in improved dye degeneration. Q-switching may be used as a preferred pulse oscillation method because it tends to be optimally suited to nanosecond pulse widths. Some embodiments include active Q-switching using a modulator device.

[0026] As used herein, “laser” means any device capable of generating a beam of light emission in the infrared, visible, or ultraviolet light spectrum. The term “laser” is not intended to be limited to (a) the characteristics of the light emission in terms of monochromaticity or coherence (e.g., exitance or directionality), (b) whether the emission is continuous or pulsed, (c) if pulsed, the specific pulse width (e.g., zeptosecond, attosecond, femtosecond, picosecond, nanosecond, millisecond, or microsecond), (d) repetition frequency, (e) laser power, (f) wavelength or frequency of the beam, (g) number of wavelengths or frequencies, i.e., single versus multiple frequency output (e.g., strong pulsed light), (h) number of beams, i.e., single versus multiple beams (e.g., splitting of a single beam or generation of multiple beams from multiple lasers), or (i) gain medium.

[0027] As used herein, "laser power" refers to W / cm². 2 or J / cm 2 It can mean either depending on the context, because they are associated with exposure time. MPE can be expressed in either of those units. For example, MPE may include the maximum level of laser radiation that can expose the fundus of the eye without causing adverse effects or biological changes.

[0028] Therefore, when this specification expresses laser power in terms of MPE, the exact value of the laser power depends, among other things, on the beam spot size, pulse duration, or wavelength, and whether the laser is pulsed or continuous. Thus, the determination of MPE provides a basis for those skilled in the art to determine the laser power in the various embodiments disclosed herein.

[0029] As used herein, when "reducing," "lowering," "less," etc., are referred to in the context of adjusting laser power, it is understood that this means the laser system may reduce the laser power from its current value to a lower (non-zero) value while still delivering laser light in some respect. These definitions also include redirecting the laser beam (for example, to a beam dump) so that the delivered laser power is reduced. These definitions also include turning off the laser system (i.e., reducing the laser power to zero). Finally, reducing laser power also includes repeatedly doing any of the above, thereby reducing the duty cycle of the laser beam, or intermittently doing any combination of the above.

[0030] The Garbo system 216 (also represented as an xy beam guidance system) may be included within the laser system and may include adjustable mirrors for providing means of delivering laser light to various positions on the XY plane (typically the plane of the iris, where the laser light is typically focused). Further realizations of the laser system may include, for example, a distance measuring device and / or optical tracking system, which may include a camera for determining the XY deviation of the center of the eye relative to the optical axis of the laser system.

[0031] In some embodiments, the xy beam guidance system may scan a beam spot around the iris surface. Scanning parameters may include the size, shape, and location of the target region, the lines and spot separation between each beam spot, and a predetermined scanning pattern. Computer imaging software may determine the size, shape, and location of the target region based on the iris image captured by the xy imaging system and transmitted to the computer for processing. Once processed, the size, shape, and location data may be transmitted to the scanning program to drive the xy beam guidance system. New iris images may be captured at predetermined intervals and transmitted to the computer for processing over time. Multiple captured images are compared, and if they show a change in iris position, the computer imaging software calculates the xy delta and transmits the shift coordinates to the scanning program, which in turn performs a shift in the scanning position. In some procedures, a topical cholinergic agonist, such as 2% pilocarpine hydrochloride eye drops (e.g., 2% isoptocarpine from Alcon, Geneva, Switzerland), may be administered intraocularly to the target eye before the procedure to constrict the pupil, flatten the iris surface, and mitigate changes in iris size and shape during the procedure. The separation of lines and spots between each beam spot may be predetermined before the procedure and programmed into the scanning program. In some cases, the separation of spots and lines positions each beam spot in contact with others across the entire target area. The scanning patterns may be raster (including slow-x / fast-y and slow-y / fast-x), helical (including limbus-to-pupil and pupil-to-limb), vector, and Lissajous scans.

[0032] In one embodiment, an xy beam guidance system may scan a beam spot around the iris surface by controlled deflection of a laser beam. Embodiments utilizing two-dimensional beam steering may drive a beam spot around the two-dimensional surface of the iris. The beam motion may be periodic (e.g., in barcode scanners and galvanoresonant scanners) or freely addressable (e.g., in servo-controlled galvanometer scanners). Exemplary two-dimensional beam steering may include rotating one mirror along two axes (e.g., one mirror scanning one dimension along a line and then shifting to scan one dimension along an adjacent one), as well as reflecting a laser beam off two closely spaced mirrors mounted on orthogonal axes.

[0033] Numerous methods exist for controlled beam deflection, both mechanical and non-mechanical. Exemplary non-mechanical methods may include stairable electroevanescent refractors or SEEORs, electro-optic beam modulation, and acousto-optic beam deflection. Exemplary mechanical methods may include nanopositioning using piezo-conversion stages, micro-electromechanical systems or MEMS-controllable microlens arrays, and controlled deflection devices. Mechanically controlled deflection devices may include motion controllers (e.g., motors, galvanometers, piezoelectric actuators, and supermagnetostrictive actuators), optical elements (e.g., mirrors, lenses, and prisms) attached to the motion controllers, and driver boards (also known as servos) or similar devices for managing the motion controllers. Optical elements can have various sizes, thicknesses, surface qualities, shapes, and multiple optical thin films, and their selection may depend on the beam diameter, wavelength, power, size and shape of the target area, and velocity requirements. Some embodiments may utilize optical elements that are planar or polygonal mirrors. Embodiments of the motion controller may include a rotor and stator (for managing torque efficiency), and a galvanometer including a position detector (PD) (for managing system performance). An exemplary PD may include one or more illumination diodes, a mask, and a photodetector. The driver board may be analog or digital. Scanning motion control may also include one or more rotary encoders and control electronics that supply a suitable current to the motion controller to achieve a desired angle or phase. The introduced scanning program disclosed herein may be configured to collect measured scanning and target area data.

[0034] The XY beam guided system can apply a laser spot to all or any portion of the anterior surface of the iris. The treated area of ​​the anterior surface of the iris is as follows (these are comprehensive and do not take into account residual tissue if there is line and / or spot separation): greater than 1 / 4, greater than 30%, greater than 1 / 3, greater than 1 / 2, greater than 3 / 4.

[0035] The system described above may include one or more types of distance measuring devices for measuring the Z distance from a reference point to a target (e.g., the iris surface). The Z distance as used herein is measured in a vertical direction perpendicular to the XY plane (e.g., the iris surface). The component referred to herein as the optical outlet 220 may be provided to allow the emission of laser light to reach the eye. The optical outlet 220 may include a window, a lens (e.g., a dichroic lens), a mirror, a shutter, or other optical component. In some embodiments, the system may include a platform control unit 230 which can be configured to make coarse adjustments (manually or by automated computer control) in the X, Y, or Z direction. The platform control unit 230 may also be configured to make fine adjustments similar to those described above, which are achieved by computer control. Some embodiments include a control computer and power supply, depicted by component 240 in Figure 1. Alternatively, the control computer or electronic circuitry, and some or all of the necessary power supplies, do not have to be contained within System 200 as depicted in Figure 1, but may be distributed elsewhere or networked to be operationally connected to the laser system. Examples of distance measuring devices include systems for triangulation, time-of-flight measurement, etc., and one specific example may be an optical coherence tomography system. Further descriptions of distance measuring and / or tracking devices are provided throughout this application, for example, in the description in Figure 4A.

[0036] The patient positioning system 280 is shown in a simplified diagram as including a patient support 282. Examples of patient supports may include a flatbed, recliner, couch, head or neck brace, etc. Control of the patient positioning system can be achieved, for example, by XY actuators 284 and / or Z actuator 286, which may be configured to move the patient in their respective directions for optimal alignment with the delivered laser beam.

[0037] Included in this disclosure are methods for improved delivery of laser light for performing the color-changing treatment described above. One method for delivering a consistent, clinically safe amount of laser light that is still effective for performing the color-changing treatment may include the system determining the laser standard in terms of this safe amount.

[0038] The laser settings used for the procedure as described in this disclosure may be determined by the system described above based on several parameters. One parameter may be the maximum permissible radiation exposure limit ("MPE") at the fundus of the eye. The MPE is a safety parameter to protect the retina from damage. A second parameter may be the minimum required radiation exposure ("MRE") at the iris of the eye. The MRE is an effectiveness parameter to ensure that the threshold radiation exposure value is achieved for stroma depigmentation.

[0039] The MPE can be obtained in accordance with international safety standards. Examples of such standards include (a) "American National Standard for Ophthalmics - Light Hazard Protection for Ophthalmic Instruments (ANSI Z80.36-2021)" issued by the American National Standards Institute (New York, NY, USA) in 2021, and (b) "Safety of Laser Products - Part 1: Equipment Classification and Requirements (IEC 60825-1)" issued by the International Electrotechnical Commission (Geneva, Switzerland) in 2014.

[0040] In some embodiments, the wavelength (λ) of the laser radiation can be 305 nm to 1350 nm (including both ends), and the single pulse width (t) of the laser radiation can be 100 fs to 5000 s (including both ends). To show an example that can change based on the update of the above-mentioned standards, within these ranges of λ and t, the MPE can be calculated as follows, that is, (a) When 100 fs < t ≤ 10 ps, (i) When λ = 700 nm, MPE = 8.0 mJ / cm 2 is. (ii) When λ ≠ 700 nm, MPE = 8.0 mJ / cm 2 ÷R(λ), where R(λ) is defined as the thermal injury weighting function for a given λ in Table 1. (b) When 10 ps < t < 3 μs, (i) When λ = 700 nm, MPE = 20.0 mJ / cm 2 is. (ii) When λ ≠ 700 nm, MPE = 20.0 mJ / cm 2 ÷R(λ). (c) When 3 μs ≤ t < 5000 s, the MPE is represented by the following formula (1):

Equation

[0041] MRE is the minimum radiation exposure value that can denature multiple pigment granules (multiple melanosomes) in melanocytes, which are mainly located along the front surface of the iris of the eye and secondarily located in the stromal fibers of the iris of the eye at a lower density. The denaturation of these pigment granules occurs at or around the temperature at which microbubbles first occur on the surface of the granules. These microbubbles usually occur at about 120°C. These microbubbles do not need to be maintained for a long period of time or repeated multiple times. A single exposure may be sufficient to induce the denaturation of the granules. When the critical amount of these granules denatures in a specific cell, the cell dies, sends a signal to macrophages present in and around the iris, digests the cell, and removes it through the vascular system of the iris.

[0042] Real-time detection of microbubbles on the melanosome surface can be achieved by the system optically or acoustically monitoring the anterior surface of the iris during treatment. One embodiment of the optical microbubble monitoring system may include a video microscope using a high-speed imaging device (e.g., a 4 Quik E ICCD nanosecond high-speed camera by Stanford Computer Optics, Inc. (Berkeley, California, USA)) with a standard 40x microscope objective lens through which high-speed flash photographs can be taken, a frame grabber (e.g., a Cyton-CXP4 by BitFlow, Inc. (Woburn, Massachusetts, USA)) and a 3-5 ns flash light source (e.g., a VSL-337ND-S pulsed nitrogen laser by Spectra-Physics, Inc. (Santa Clara, California, USA)). Another embodiment of the optical microbubble monitoring system uses confocal imaging to capture the increased light reflection from the generated bubble water interface into a photomultiplier tube (e.g., an H7827-001 optical sensor module by Hamamatsu, Inc. (Hamamatsu, Japan)). The system may then record output data using a transient recorder (e.g., TR40-16bit-3U by Licel GmbH, Berlin, Germany) and transfer the recorded data to a computer (e.g., TPC-2230 by NI, Austin, Texas, USA) for processing and analysis. Similarly, the system may include an electron microscope system configured to perform electron microscopy of the iris during a treatment session (e.g., in real time and in situ). For example, an electron microscope system (e.g., Quantax 70 by Bruker AXS Microanalysis GmbH, Berlin, Germany) may be configured to image and detect microbubbles as described above.

[0043] One embodiment of the acoustic microbubble monitoring system may include a hydrophone (e.g., an HFO-690 fiber optic hydrophone from Onda Corporation (Sunnyvale, California, USA)). In this case as well, the output data may be recorded using a transient recorder (e.g., a TR40-16bit-3U from Licel GmbH (Berlin, Germany)) and transferred to a computer (e.g., a TPC-2230 from NI Corporation (Austin, Texas, USA)) for processing and analysis.

[0044] The description of exemplary laser power that can be delivered is used to induce a biological effect that results in a desired change in eye color. Thus, in some realizations, the laser power may be sufficient to induce a simultaneous temperature change within the stroma pigment, which then causes macrophages in the iris to remove at least a portion of the stroma pigment. In this way, the system may monitor the iris temperature to determine the MRE (for example, by detecting the exposure level at which microbubbles begin to form). In some specific realizations, the laser power is at least 20 times the maximum allowable exposure so that reducing the laser power to less than 20 times the maximum allowable exposure does not cause a mitigation of the denaturation of the stroma pigment and the resulting mitigation of the eye color change. To facilitate the delivery of laser power to induce a sufficient temperature change in the stroma pigment, some methods may include the step of determining the temperature of at least a portion of the iris, including the stroma pigment, using a temperature sensor. In some embodiments, the temperature sensor may be of a non-invasive type to the iris. Examples of temperature sensors may include more direct temperature sensors, such as passive infrared detectors that image the eye, or more indirect temperature sensors that utilize acoustic monitoring to detect acoustic signals (sound or pressure waves) indicating microbubble formation (e.g., expected to occur at approximately 120°C, thus approximating temperatures above that threshold). Heat transfer from within the iris may manifest as localized heating on the surface of the eye. Computer modeling of predicted or known thermal patterns can be associated with measured thermal patterns to derive thermal patterns in the activated stroma pigment. For example, in embodiments utilizing an infrared imaging system, the received infrared radiation can be converted to localized iris temperature by the imaging system, or a connected computer receiving data from it. Such conversion may be performed using blackbody approximation or other similar methods.

[0045] One factor complicating MRE identification is that it can differ between one melanosome and the next based on the absorption coefficient between the wavelength of radiant energy and the color value and / or concentration of the melanosome. If the MRE for a particular melanosome is too low, microbubbles will not form, the melanosome will not be denatured, and it will not be digested and removed. Conversely, if the MRE for a particular melanosome is too high, too much heat will be generated within the melanocyte, leading to ablation of multiple melanocytes, causing them to rupture and release melanosomes into the anterior chamber of the eye, potentially causing inflammation in adjacent tissues and associated adverse conditions. The MRE for a particular melanosome, therefore, must be appropriate for each melanosome.

[0046] For example, a laser system may generate a wavelength of 532 nm to treat an iris containing melanosomes with three color values / densities: tan, medium brown, and dark brown. The MRE required to denature dark brown melanosomes will be lower than the MRE required to denature tan and medium brown melanosomes (because the absorption coefficient between the wavelength and the dark brown color value / density is higher). The MRE required to denature medium brown melanosomes will be higher than the MRE required to denature dark brown melanosomes (because the absorption coefficient between the wavelength and the medium brown color value / density is lower), and the MRE required to denature medium brown melanosomes will be lower than the MRE required to treat tan melanosomes (because the absorption coefficient between the wavelength and the medium brown color value / density is higher). Furthermore, the MRE required to denature tan melanosomes is higher than the MRE required to denature medium and dark brown melanosomes (because the absorption coefficient between the wavelength and the tan color value / density is lower). Therefore, the denature of these iris stroma melanosomes will require three different MREs.

[0047] Real-time detection of microbubbles on the melanosome surface indicates each MRE in the above examples. In one embodiment, the initial radiation exposure value is too low to induce microbubbles, but is gradually increased until microbubbles are first detected. This will be referred to as "MRE I". The entire iris may then be treated with MRE I. This treatment denatures several dark brown melanosomes, and these melanocytes are digested and removed over the next 3-4 weeks. After 4 weeks, the treatment protocol may be repeated. Since most or all of the several dark brown melanosomes are removed, the first microbubbles are detected at a higher radiation exposure value. This will be referred to as "MRE II". The entire iris may then be treated with MRE II. This treatment denatures several medium brown melanosomes, and these melanocytes are digested and removed over the next 3-4 weeks. After 4 weeks, the treatment protocol may be repeated. Because most or all of several medium-brown melanosomes are removed, the first microbubbles are detected at higher radiation exposure values. We will refer to this as "MRE III". The entire iris may then be treated with MRE III. This treatment denatures several tan melanosomes, and these melanocytes are digested and removed over the next 3-4 weeks. If several stroma melanocytes remain on the anterior surface of the iris, the treatment may be performed using MRE III.

[0048] If melanocytes remain within the iris stroma, they absorb backscattered blue or green light, making the gray of the stroma fibers more visible and producing an iris color perceived as gray-blue or gray-green. Many patients are satisfied with this perceived color because the gray increases the color value of the eye, making it appear brighter. For patients who prefer a more saturated blue or green, the procedure can be repeated at an MRE III value, but with the laser beam waist moved from the anterior iris to the inner stroma. This procedure denatures the melanocytes remaining within the iris stroma, eliminating or reducing the absorption of backscattered blue or green light.

[0049] Highly sensitive methods and apparatus should be used for real-time microbubble detection. If the detection sensitivity is insufficient and microbubbles are not detected when they first appear, the radiant energy will be too high, causing melanocyte ablation and inflammation of the anterior chamber tissue. The radiation doses for two laser iris procedures, “argon laser trabeculoplasty” (“ALT”) and “selective laser trabeculoplasty” (“SLT”), are established by increasing the radiant energy until “multiple champagne bubbles” become visible on the trabecular meshwork (“TM”), and then slightly decreasing it. These champagne bubbles are considerably larger than multiple microbubbles, and they occur at higher radiation exposure values. Since ALT and SLT procedures are limited to scattered clusters of melanocytes originating from the iris pigment epithelium and remaining in the TM, the delivery of excessive radiation exposure values ​​and the ablation of these clusters are unlikely to release enough melanosomes to cause serious inflammation or damage to the eye. However, excessive radiation exposure and stromal melanocyte ablation can cause serious inflammation and, theoretically, long-term damage.

[0050] In one implementation, the following exemplary MRE ranges are given for each melanosome color value / density, where λ = 532 nm, t = 11.475 ns, pulse repetition frequency (prr) = 135 kHz, and the incident angle of the beam (θ) relative to the iris surface. i ) = 0°.

[0051] [Table 1]

[0052] The above MRE range is inherent to the aforementioned laser emission parameters, but it can vary with changes in these parameters. However, the method for determining MPE takes into account several related parameters. Therefore, multiple MRE ranges inevitably take into account these parameters, if they are expressed as multiples of MPE.

[0053] When λ = 532 nm and t = 11.475 ns, using the weighting coefficient R(λ) = 2.10 shown in Appendix 1, the MPE is 9.52 mJ / cm². 2 (That is, 20 mJ / cm²) 2 ( / 2.10). The MPE of the parameters used in the exemplary embodiment is therefore about 9.52 mJ / cm². 2 Therefore, MRE can be expressed by the following MPE multiples.

[0054] [Table 2]

[0055] As indicated by the MPE multiples above, MRE is considerably higher than MPE. The iris is far less sensitive to excessive radiation exposure, and the effects of excessive radiation exposure to the iris are not as severe in any case. Furthermore, the melanocytes in the fundus (known as the "retinal pigment epithelium," or "RPE") are generally darker and denser than those in the anterior iris, and therefore the absorption coefficient in the fundus is higher. In addition, the lens focuses the beam into the fundus, thereby increasing its energy density there. However, MRE must be achieved without exceeding MPE if the beam mistakenly passes through the pupil (or any other opening in the iris) into the fundus.

[0056] In most cases, pulses emitted through the pupil and focused on the fundus of the eye represent a "pulse train." A pulse train occurs when two or more consecutive pulses completely or partially overlap the target plane. This is because, during the above procedure, θ i This is especially true in preferred embodiments where the beam remains at or around 0°. Even if the beam moves during the procedure (as assumed), the lens focuses the pulse onto a single spot on the fundus.

[0057] Regardless of the specific iris scanning pattern, the beam path is likely to circulate between the pupil and the iris. The iris cycle is likely to have a duration sufficient to separate the pupil cycle into independent pulse trains. Under these circumstances, the maximum number of pulses in the pulse train (hereinafter represented by N) will be the pre-treatment pupil diameter (in mm) divided by the spot separation (in mm). If the practitioner follows the following preferred embodiment, administering 2% pilocarpine three times before treatment, the pupil diameter should be ≤1.0 mm. (1 / e 2 If the spot diameter is, for example, 0.05 mm and the spot separation is 0.05 mm (i.e., multiple spots are in contact), then N = 1 / 0.05 = 20 pulses. Unless otherwise specified, 1 / e 2 However, it is used to define the beam waist.

[0058] If a pulse is a component of a pulse train, the MPE calculated above is the attenuation coefficient C, which is calculated as follows. P It may also be multiplied by . (a) If t ≥ 3 μs, C P This is expressed by the following equation (2).

number

number

[0059] Therefore, a method based on the above may include a system for determining the laser power to deliver to the stroma dye simultaneously with or sequentially with tracking, by obtaining at least a set of laser references for delivering an exposure dose less than 100 times the maximum allowable exposure dose, resulting in the removal of at least a portion of the stroma dye. The removal of the stroma dye is preferably achieved by initiating macrophage digestion of the stroma dye. However, in some realizations, removal may be achieved by ablation of the stroma dye. Ablation is typically achieved with a higher laser power than that used to initiate macrophage digestion.

[0060] Laser criteria may include arbitrary settings of the laser system, such as energy per pulse, spot size, pulse duration, pulse width, repetition frequency, beam profile, beam angle, beam position, etc. Therefore, it is conceivable that there may be multiple sets of laser criteria that satisfy the exposure limits described above. The above multiples are just examples, but it is further conceivable that exposures may be, for example, less than 50 times the MPE, less than 75 times the MPE, etc.

[0061] In some realizations, the above difference may be due to the beam divergence angle (i.e., an out-of-focus beam results in a lower power density in the fundus). Various realizations may involve generating a Gaussian beam that can diverge at least partially behind the iris and converge in front of the iris. Thus, the focal plane (i.e., the location of the beam waist) may be anywhere within this range, including but optionally further in front of the iris, although it may be within the iris itself. Where this disclosure refers to focusing laser power in the stroma pigment, it means that the laser power can be focused at a specific location which may include the anterior or posterior surface of the iris, or in the iris or a specific cell layer within the stroma pigment layer therein.

[0062] The beam divergence, as well as the size and location of the beam waist, determine the spot size on the target. For example, if the beam waist is at the target, the spot size is the beam waist. However, if the beam waist is in front of or behind the target, the spot size will be larger based on the beam's convergence or divergence. Since the spot size does not have a sharp edge, the measurement must be defined by a specific measurement convention. An example convention is FWHM, 1 / e, 1 / e 2 Includes D4σ, 10 / 90 or 20 / 80 knife edge, and D86. Unless otherwise specified herein, the spot size is 1 / e 2The term represents a spot width as defined by convention. Several methods may include the step of determining the spot size of a laser beam to be delivered to the stroma pigment of the iris of a patient's eye. This determination may include the step of obtaining a set of laser references that result in the delivery of a laser beam to the stroma pigment having a spot size of 4 to 70 microns (inclusive). From the available sets of laser references, a particular laser reference may be selected to control the laser system to produce a laser having a desired spot size. The laser system may be configured to deliver laser beams with the above spot sizes, and then deliver laser beams with the above spot sizes. In some embodiments, the system may determine that the spot sizes can be 4 to 50, 10 to 60, 20 to 30, 25 to 30, 20 to 60, or 30 to 60 microns. Such multiple spot sizes can be created using at least one positive lens. To deliver an effective fluence on the iris surface but to comply with MPE in the fundus, the formation of such a high divergence angle results in a short depth of focus ("DOF"), as defined herein, in which 90% to 100% of the peak fluence is realized. The DOF depends not only on the spot size and associated divergence angle but also on the wavelength of the beam. Generally, all other things being equal, longer wavelengths result in longer DOFs. Thus, this disclosure assumes that the spot size, combined with the laser power, can be selected to produce a simultaneous temperature change (and / or possible acoustic effect) within the iris, thereby being sufficient to initiate macrophage digestion of stroma pigment while remaining safe for the patient. In some realizations, the spot size of the laser system may be set (and nearly constant) with the laser power adjusted as described herein (to perform the procedure but ensure that the exposure in the fundus is still below MPE).

[0063] The above is described as one feasible example of determining beam waist / spot size, but this should not be considered limiting, as the details of the calculation may vary depending on the individual treatment plan.

[0064] To achieve MRE without exceeding MPE, a relatively high beam divergence angle may be used. As a result, the radius of the beam at its focal plane (w0) may be relatively small compared to the radius of the beam waist at the retinal plane (w(z)).

[0065] Equation (4) is w(z) 2 w0 2 Represents the ratio (S) to:

number

[0066] Using the laser parameters from an exemplary embodiment, R(λ) = 2.10. Equation (4) then expresses the following S range.

[0067] [Table 3]

[0068] To avoid the need to change w0 for each patient / procedure, in a preferred embodiment, w0 is set to the expected highest MRE so that w0 satisfies the MPE for all MREs. In the example above, the expected highest MRE is 0.850 mJ / cm². 2 Therefore, S becomes 89.25, which is necessary to ensure that the best MRE does not exceed MPE, w(z) 2 However, w0 2 This means it must be 89.25 times that amount.

[0069] To find w0 from S, we can use the following equation (5):

number

[0070] Using 20 mm as the average z from the iris surface to the fundus surface, and 1.336 as the n for the aqueous humor and vitreous fluid of the eye, we obtain w0 = 0.0164 mm from equation (5).

[0071] The following equation (6) can be used to find w(z):

number

[0072] According to equation (6), w(z) = 0.15519155 mm.

[0073] It is recalled that w0 and w(z) are the radii of the beam, at its waist, and at the fundus. Therefore, the (1 / e) of the beam, at its waist. 2 The diameter (d0) as is 0.0328 mm, and the beam, at the fundus (1 / e 2 The diameter (d(z)) is 0.31038 mm.

[0074] The depth of field (DOF) of a beam is the total distance (+ / -z) from the beam waist. The distance z is given by equation (7) below:

number

[0075] DOF can be defined as the portion of the beam axis where the beam fluence is at least 90% of the fluence at the beam waist, i.e., S = 1 / 0.9. Using this and other laser parameters from the disclosed example, equation (7) yields z = 0.707312185 mm and DOF = 1.41462437 mm.

[0076] This relatively short DOF requires fairly high-resolution distance measurement to locate the initial focal plane and position the beam waist at a desired position relative to the initial focal plane, and fairly high-resolution autofocus to maintain the desired position of the beam waist relative to the focal plane. These high-resolution systems are described herein. In one implementation, the beam waist may be located within the stroma pigment layer or slightly anterior to the anterior surface of the iris.

[0077] Figure 3 shows a simplified diagram of a laser system 210 and an image sensor 310 for use in iris mapping according to one or more embodiments. Determining the appropriate laser power may depend on the variability in the absorption of the delivered laser power due to heterogeneity within the stroma pigment layer regions 330, 332, and 334. Such variability may result from, for example, variations in the density of the stroma pigment, variations in the size of the stroma pigment cells, the type and composition of the stroma pigment, etc. Therefore, regions of the iris where the stroma pigment has a higher absorption coefficient will reach a higher temperature (or reach the target temperature more quickly) for a given laser power. If these differences are not taken into consideration, they may result in uneven color changes or, in some cases, damage to the eye. To address this problem, some realizations of the disclosed method may include the step of imaging the iris with an image sensor operably connected to a computer 312 prior to the above procedure in order to generate an image of the iris. Examples of image sensors may include a CCD, CMOS, or camera used with the illumination light source 320, wherein the wavelength range of the sensor includes the wavelength of the illumination light source. Exemplary wavelengths include near and mid-infrared, visible light, or specific wavelengths of the treatment laser beam. Embodiments may also include a software program that can create a digital color model from the captured image and map stroma pigment coefficients to the treatment wavelength based on the above model, or otherwise analyze it. Exemplary digital color models include RGB (red-green-blue), HSI (hue-saturation-intensity), HSL (hue-saturation-luminance), HSV (hue-saturation-lightness), CMY (cyan-magenta-yellow), and YIQ (luminance-in-phase chrominance-orthogonal chrominance).

[0078] To facilitate integration of the image sensor with existing laser systems, the image sensor may incorporate a dichroic optical system 314 (e.g., a dichroic lens, mirror, or prism) to guide the incident light reflected from the iris towards the reflective or refracting side of the optical system, allowing the emitted laser light to pass through the optical system to the iris surface for treatment, while guiding it to the image sensor. Such an embodiment has the advantage that the light can be focused on the same optical axis as the laser system. This has the advantage of both simplifying and increasing the accuracy of generating a mapping to the shape of the laser system, because it avoids the need to consider an off-axis image sensor.

[0079] Based on the above image, an iris mapping may be generated by the system, and the iris mapping may include multiple regions in the stroma pigment of the iris corresponding to different absorption coefficients of the treatment wavelength. As shown in Figure 3, regions 330, 332, and 334 are drawn to show different absorption coefficients. The mapping may be, for example, 2D (or 3D) data of pixels or multiple voxels of the imaged iris, where each pixel or voxel has a corresponding calculated absorption coefficient. The mapping does not have to be stored at the pixel / voxel level, but may be in terms of larger regions (e.g., combining pixels / voxels that may have similar absorption coefficients (e.g., using a watershed algorithm)). In other embodiments, regions may be identified at the subpixel / voxel level by 2D (or 3D) interpolation of adjacent pixels / voxels, providing a continuous function of absorption across pixels / voxels.

[0080] As described above, the process of generating a mapping may include calculating the absorption coefficients at different wavelengths of laser light in various regions of the iris. This disclosure envisions numerous embodiments for calculating absorption coefficients. For example, an image sensor (or data obtained thereby) may determine the absorption coefficient by measuring the absorptivity or reflectivity at a given wavelength in an image of the iris. The fluence required to increase the temperature within a target stroma pigment and thereby initiate the biological reaction necessary to remove the target pigment is a direct function of the absorption of laser light energy within the pigment. Thus, by determining the absorption coefficient of the stroma pigment in a specific region for a given wavelength, the system can accurately determine and deliver the laser power required for pigment removal.

[0081] The above system may include various devices for determining absorption coefficients, such as those used in scanning electron microscope ("SEM") images using hyperspectral imaging ("HSI"); color modeling (e.g., RGB, HSI, HSL, HSV, CMY, and YIQ) with filters appropriate to the laser wavelength.

[0082] Various types of light, such as infrared or visible light, can be used by the system to map the pigment concentrations. In some realizations, the chroma channel of the iris image can provide a very good estimate of the stroma pigment concentration. In other embodiments, the system may use the blue or green channel of the image. In yet another embodiment, the system may use monochromatic infrared light for approximating the stroma pigment.

[0083] Specifically, in some embodiments, the reflectance of an image is based on the reciprocal of the saturation within the image. The system can determine reflectance, saturation, etc., on a pixel-by-pixel basis or over a wider area of ​​the image. For example, based on an analysis of the intensity of light received by an image sensor, the system can divide the iris into multiple regions of similar intensity (e.g., within 1%, within 5%, within 10%, etc.). The system can then determine the average reflectance and / or saturation of these regions in order to determine the absorption coefficient for all points of light delivery within those regions.

[0084] To help obtain more accurate measurements in determining the absorption coefficient, several optional features are disclosed. Firstly, the illumination source may have the same (or nearly the same, e.g., within 5% or 10%) wavelength as the wavelength delivered by the laser system. For example, if the planned procedure introduces a 1064 nm laser, the illumination source may supply infrared light covering that wavelength. Similarly, if the laser wavelength is 532 nm (green), the illumination source may supply green light. Furthermore, in certain realizations, this imaging may further include filtering the reflected light received from the stroma dye at the image sensor through a bandpass filter configured to allow the laser light and / or wavelengths corresponding to the illumination source to pass through. In other realizations, the system may include a similar bandpass filter in the illumination source, for example, if such a light source is broader bandwidth than required.

[0085] The laser system may include a power modulator 318 for varying the laser power based on a determined mapping. Exemplary optical power modulators may include acousto-optic modulators, electro-optic intensity modulators, field absorption modulators, semiconductor optical modulators, and liquid crystal modulators. An exemplary acousto-optic modulator may include a transducer that generates sound waves to partially diffract the laser beam. A structural embodiment of an exemplary electro-optic intensity modulator may include a Pockels cell between two polarizers. The Pockels cell modulates the phase of the beam, and the two polarizers convert the phase modulation to intensity modulation. The Pockels cell may have a single crystal or two or more crystals to reduce its power requirements. The two polarizers may be replaced by an interferometer, as in the case of a Mach-Zehnder modulator. A structural embodiment of an exemplary field absorption modulator may include one or more semiconductor devices operating in the Franz-Keldisch effect. Such modulators may act on light in a waveguide and may be coupled to an optical fiber or placed on a chip with other components such as a laser diode to form a telecommunications transmitter. Exemplary semiconductor optical amplifiers used as intensity modulators may include semiconductor optical amplifiers with or without drive current. In the absence of drive current, the amplifier produces some attenuation as negative gain. When a pump current is supplied, the attenuation is realized as positive gain. An exemplary crystal modulator obtains intensity modulation by applying a voltage to a liquid crystal material to modulate the polarization of light and then adding a polarizer.

[0086] Figure 4 shows the system of Figure 3 for delivering variable laser power to multiple regions of the iris, according to one or more embodiments. With the mapping derived as described herein, the power modulator can control the delivery of laser power considering multiple regions with different absorption coefficients. As the laser beam scans the target region of the iris, when it reaches a region with a different absorption coefficient, the system can control the power modulator to adjust the laser power accordingly. For example, the system may set the laser power based on the mapping such that regions with higher absorption coefficients receive lower laser power than regions with lower absorption coefficients. This is illustrated by exemplary laser beams 420, 422, and 424 corresponding to regions 330, 332, and 334. The system can modulate the delivered laser power by such beams using the power modulator described above.

[0087] The system may be configured to shut off the beam when little or no stroma dye is present. Beam shutoff can be achieved in several ways, including deactivating the laser, deflecting the beam into a beam dump using an optical system such as a prism or mirror, or reducing the radiant power to an asymptomatic level using an energy modulator as disclosed elsewhere in this application. Deactivating the laser may not be used in some cases due to time delays and other potential problems during reactivation.

[0088] In one embodiment, the anterior iris region is selected or deselected for automatic blocking by illuminating the anterior iris, capturing an image of the anterior surface of the iris using a CCD or other camera, transmitting the image to a computer via image analysis software program (e.g., Celleste Image Analysis Software by Thermo Fisher Scientific Inc., Waltham, Massachusetts, USA), identifying the pigmented area, generating a lookup table with the coordinate range of the pigmented area, and working in conjunction with beam guidance software and energy interference or modulation software to block the treatment beam anywhere outside the pigmented area.

[0089] In an alternative embodiment, the anterior iris region may be selected or deselected for blocking manually or automatically by the system illuminating the anterior iris, capturing still or moving images with a CCD or other camera, displaying the images on a user interface touchscreen, prompting the practitioner to outline the area to be blocked or illuminated, and prompting the practitioner to select (e.g., via icons on a GUI displayed on the same screen) whether the outlined area is to be treated or blocked. The display computer and software may display the outline drawn by the practitioner on the display, generate a lookup table with the coordinate range of the outline, and, in conjunction with beam guidance software and energy interference or modulation software, block the treatment beam anywhere inside or outside (as selected) the outlined area.

[0090] One of the advantages of these selective beam blocking embodiments is that, without them, further stromatous pigment would be removed from within the iris stroma by retreatment of the anterior surface of the iris after the pigment has been removed, which increases the possibility of increasing saturation, as described herein, and which may be contrary to the patient's preference.

[0091] Some embodiments of the disclosed method may involve utilizing a rangefinder as part of an optical tracking system to provide a precise distance to a target location within the eye. For example, the rangefinder may determine the distance between the iris and a reference component of the optical tracking system. Examples of reference components may include the last optical component in the laser system (e.g., the window or lens closest to the patient), a mirror or Garbo, or any other component or location in the laser system at a known location to provide a reference point for distance measurement.

[0092] Based on the determined distance, the system may control the focus of the laser beam so that it remains substantially in focus between the anterior and posterior surfaces of the iris, in the stroma pigment targeted for removal, or in one of the disclosed possible focal planes. Examples of distance measuring devices may include, for example, triangulation lasers, time-of-flight detectors, phase-shift detectors, ultrasonic detectors, frequency modulation detectors, interferometers, cameras, or optical sensors.

[0093] Triangulation can utilize lasers for distance measurement. A structural embodiment of an exemplary triangulation method may include three elements: an imaging device, an illumination source, and a further imaging device or further illumination source. The (multiple) illumination sources may include image projectors that project a light image onto the iris, sclera, or other field of the patient. The exemplary light image includes circles and lines. In one embodiment, a laser beam may illuminate a location on the surface of a target (e.g., the iris, sclera, or a specific other location on the patient's face). Diffusion or specular reflection from the illuminated location can be monitored by a position-sensitive detector, which may be positioned at a predetermined distance from the laser source such that the laser source, the target location, and the detector form a triangle. Assuming the beam incidence angle to the target is 0°, and the position-sensitive detector determines the incidence angle of the detector to the target, and the distance between the laser source and the detector is known, the distance from the laser source to the target can be determined by appropriate trigonometric functions.

[0094] Time-of-flight or pulse measurement can measure the time of flight of a radiant pulse from a measuring device to a target and back. Exemplary forms of radiation include light (e.g., near-infrared lasers) and ultrasound. Exemplary time-of-flight devices include a radiation source, a radiation sensor, and a timer. Time of flight can be measured based on a timed pulse or the phase shift of an amplitude-modulated wave. In the case of a timed pulse, since the velocity of radiation is already known, the timer measures the turnaround time of each pulse to determine the distance, where distance = (velocity of radiation × time of flight) / 2.

[0095] Phase-shifting methods can utilize intensity-modulated laser beams. The phase shift of the intensity modulation may be related to the time of flight. Compared to interferometry, its accuracy is lower, but it allows for clearer measurements over larger distances and is more suitable for targets with diffuse reflectance. For small distances, ultrasonic time-of-flight methods may be used, and the apparatus may include a aiming laser not for distance measurement itself, but to establish the direction of the ultrasonic sensor.

[0096] Frequency modulation methods may include, for example, a frequency-modulated laser beam with a repetitive linear frequency ramp. The distance to be measured can be converted into a frequency offset that can be measured via the beat tones of the transmitted and received beams.

[0097] Interferometers can be realized for distance measurements with much better accuracy than the wavelength of light used.

[0098] Various distance measurement systems can provide highly accurate measurements, for example, determining distance with a resolution of at least 10-20 μm. Such systems may include, for example, time-domain optical coherence tomography systems or spectral-domain optical coherence tomography systems.

[0099] Using the disclosed distance measurement, several methods may utilize the same structure to include automatically adjusting the focus of the laser system in response to changes in the determined distance and corresponding shifts in the beam's focal point. A computer system communicating with the laser system may automatically adjust the focus of the laser system and measure the distance to the stroma pigment of the iris at periodic intervals (e.g., at approximately 1 kHz, 10 kHz, 100 kHz, etc.).

[0100] Exemplary methods for focusing a lens include, manually or electronically, (a) moving the position of one or more focal lenses (e.g., lenses mounted on a motor stage to move along a beam access), (b) moving the position of one or more focal mirrors (e.g., by adding a third mirror to a Garbo beam steering system), (c) changing the shape of one or more focal lenses or mirrors, (d) deflecting or refracting a beam using an acoustic-optical or electro-optical device, or (e) moving the focal position of a beam using an electrostatic or electromagnetic lens or mirror.

[0101] Movement of the patient's head and eyes along the z-axis can interfere with accurate distance measurement and autofocus. By positioning the patient so that the head is supported and the neck muscles are relaxed, changes in head position along the z-axis can be minimized.

[0102] Topographic variations on the anterior surface of the iris can also hinder accurate distance measurement and autofocus. These variations are primarily caused by three factors: iris tilt, iris folds, and foveal. Iris tilt is a naturally occurring phenomenon. As a result, the iris surface is rarely perpendicular to the beam axis. The iris surface is tilted with respect to both its horizontal and vertical axes, and can be tilted by up to 5°, resulting in a z-axis variation of up to 700 μm from one edge of the iris to the other (assuming a horizontal iris diameter of approximately 11 mm). Iris tilt systems can be used to significantly reduce or eliminate this variation in the iris surface.

[0103] Iris folds are also a naturally occurring phenomenon. As the iris dilates, it folds like a drape concentrically with respect to the pupil and away from it. These folds can result in significant z-axis variations in iris topography. To significantly reduce or eliminate iris folds, several methods may involve the introduction of a topical miotic solution, such as pilocarpine eye drops. In one embodiment, the patient may be given a drop of 2% pilocarpine eye drops 15, 10, and 5 minutes prior to the procedure to achieve high miosis, given their tolerance to the potential dilating effect of irradiating the iris anterior to the dilator muscle with laser light during the procedure. Each patient may also be given 500 mg of acetaminophen (oral) 30 minutes prior to the procedure as a preventative measure against headache due to ciliary tension.

[0104] Iris foves are another common phenomenon. They arise from spaces between the iris stroma fibers. In brown eyes, these foves are usually filled with pigment and can therefore be ignored for the purposes of the initial treatment session. Even after the stroma pigment has been largely removed from the outside of the fovea, some stroma pigment may remain in the deeper parts of the iris fovea. In light eyes, pigment spots occur naturally, so this remaining pigment in the fovea should not look unnatural and should be hardly noticeable.

[0105] If multiple residual pigmented spots are bothering the patient, the system may remove or reduce the remaining foveal pigment by slightly moving the beam waist posteriorly towards the stroma and rescanning the iris using this moved waist position. This moved waist setting may be an option displayed on the touchscreen interface for the operator to select. The distance of the beam waist movement can be equal to approximately 80% of the beam DOF to ensure high fluence delivery in the pigmented fovea. If foveal pigment persists 3-4 weeks after this posterior waist movement procedure, the waist movement procedure may be repeated, each time by moving the beam waist posteriorly by another 80% of the DOF until the foveal pigment is sufficiently removed.

[0106] The color-altering treatments described herein may be divided into multiple treatment stages to remove different amounts or types of stroma pigment at different times. As previously stated, stroma pigments may have changing physical properties that affect their response to delivered laser power. Certain stroma pigments may require higher laser power to raise their temperature so that they can be removed by macrophage digestion. Thus, there may be certain stroma pigments that need to be removed after an initial treatment at lower power, and for that purpose require higher laser power. In this way, some methods of treatment may include a step of determining multiple stages of laser power delivery to the iris as part of the color-altering treatment, such that subsequent stages result in the removal of less pigment but are delivered at higher laser power. Thus, a given treatment session may include setting the laser system to the required laser power, further based on the current stage of delivery, and delivery of laser power based on the above setting. A single treatment session may include any number of delivery stages, but typically only one delivery stage is included in a single treatment session, since the removal of denatured stroma pigment may take several days or weeks.

[0107] In some embodiments, the system may deliver laser power in multiple steps to allow for finer control of pigment degeneration. This can be a safety feature of the system to ensure that the lowest power is applied to cells with the highest absorption coefficient to avoid ablation, the highest power is applied to cells with the lowest absorption coefficient to achieve efficacy, and intermediate power is applied to cells with an intermediate absorption coefficient to avoid ablation and achieve efficacy.

[0108] For example, in one exemplary embodiment based on the aforementioned multiples of the MPE, as shown below, any number of subranges can be set and laser power can be delivered within those subranges. In the table below, “full range” is reproduced above. For each of several eye colors, five examples of subranges are shown, but the system can deliver laser power to any number of subranges (e.g., 2, 3, 7, 10, etc.). Another optional feature reflected in the following example is that multiple subranges are selected so as to overlap with adjacent subranges. In the following example, the overlap is 20%, but this may vary in other embodiments (e.g., 5%, 10%, 30%, etc.).

[0109] [Table 4]

[0110] Therefore, in one embodiment, the system may be configured to perform multi-stage delivery, which involves at least three stages. In this example (for dark brown eyes), of the three stages, the first stage may deliver approximately 26 times the MPE to the stroma pigment, the second stage may deliver approximately 30 times the MPE to the stroma pigment, and the third stage may deliver approximately 34 times the MPE to the stroma pigment.

[0111] Some methods of this disclosure may further include a step of determining an appropriate amount of laser power to deliver based on the patient's immune response. Since macrophage digestion is a method of removing stroma pigment, and macrophage activation is an immune response, the removal of stroma pigment is proportional to the patient's immune response. Therefore, some methods may include a step of pre-screening the patient to determine the efficiency or aggressiveness of their macrophage response to laser destruction of stroma melanocytes, thereby further informing of MPE and MRE. Macrophage response data may be entered into a system computer to calculate adjustments for baseline fluence settings.

[0112] The system can tailor the time intervals between multiple treatment phases to a particular individual based on their immune response. This may involve comparing the level of immune response to the range of immune response associated with the time interval between two phases. For example, the two phases may be spaced 3-4 weeks apart based on a normal immune response (e.g., 5 on a 1-10 scale, where 10 is the best immune response). Treatment procedures may have intervals of 2-3 weeks for patients with an immune response rated 8-10, and 5-6 weeks for patients with an immune response rated 1-3. The above method may then include a step of reducing the time intervals based on comparisons showing, for example, that the level of immune response is higher than the above range. The system may make similar adjustments to the above intervals based on knowledge of the patient's inflammatory response. Examples of possible inflammatory response tests may include skin tests in which the patient is exposed to substances expected to cause an allergic reaction. Data representing the level of inflammatory response would quantify the results of the skin test and may be used as described above. Similarly, in some embodiments, quantification of the immune response may be used to reduce or increase the laser power in any given treatment session, and / or to reduce or increase the time between multiple procedures. For example, if the immune response indicates that dye removal occurs 50% faster than a given baseline (e.g., for a normal immune response), the time between sessions may be reduced by 50%.

[0113] Furthermore, inflammation is also an immune response to free melanin in the anterior chamber of the eye. Therefore, pre-screening of patients to determine the aggressiveness of their immune response to free melanin may be used by the system for adjusting or determining MPE and MRE, and inflammatory response data may be used by the system for calculating adjustments for baseline fluence settings. For macrophage responses to thermal destruction of stroma pigments, the system may be used to test responsiveness by examining the prevalence of cleaved caspase-1 p20 (a marker of inflammasome activation), as well as the pro-inflammatory cytokines IL-1β and IL-6, at baseline, possibly in response to some perturbation. The system may examine, or use, the prevalence of CD4+ T cells, angiogenin (AG), and pro-inflammatory cytokines (e.g., IL-1α, IL-Iβ, TNF-α, MMP-9, IL-2, IL-17), both at baseline and optionally in response to treatment, in order to determine the immune response to free melanin in the anterior chamber (AC).

[0114] Figure 5 shows an exemplary system for performing an eye color alteration procedure according to one or more embodiments. For example, system 500 may represent components used to perform an eye color alteration procedure. For example, system 500 may power a local device for performing an eye color alteration procedure, where necessary decisions (e.g., the pattern to follow, the laser power to deliver, patient identification, etc.) are determined remotely and / or in the cloud. As shown in Figure 5, system 500 may include user terminals 522 and 524. Although shown as a personal computer, it should be noted that in Figure 5, it may be any computer device, including, but not limited to, laptop computers, tablet computers, handheld computers, "smart," wireless, wearable, and / or mobile devices (e.g., servers). Figure 5 also includes multiple cloud components 510. The multiple cloud components 510 may alternatively be any of the computing devices described above, and may include any type of mobile terminal, fixed terminal, or other device. For example, multiple cloud components 510 may be implemented as a cloud computing system and may feature one or more component devices. It should also be noted that system 500 is not limited to three devices. Users may, for example, use one or more other devices to interact with one or more servers or other components of system 500. Although one or more operations are described herein as being performed by a particular component of system 500, it should be noted that in some embodiments such operations may be performed by other components of system 500. For example, although one or more operations are described herein as being performed by a component of user terminal 522, such operations may in some embodiments be performed by components of multiple cloud components 510.In some embodiments, the various computers and systems described herein may include one or more computing devices programmed to perform the functions described. Additionally or alternatively, multiple users may interact with system 500 and / or one or more components of system 500. For example, in one embodiment, a first user and a second user (e.g., a technician and a physician) may interact with system 500 using two different components.

[0115] With respect to user terminals 522, 524, and the components of the cloud component 510, each of these devices may receive content and data via input / output (hereinafter, "I / O") paths. Each of these devices may also include a processor and / or control circuit for sending and receiving commands, requests, and other suitable data using the I / O paths. The control circuit may comprise any suitable processing circuit. Each of these devices may also include a user input interface and / or user output interface (e.g., a display) for use in receiving and displaying data. For example, as shown in Figure 5, both user terminals 522 and 524 include a display on which data (e.g., information regarding eye color change treatments) is displayed.

[0116] Furthermore, since user terminals 522 and 524 are shown as touchscreen smartphones, their displays also function as user input interfaces. It should be noted that in some embodiments, the device may not have a user input interface or a display, and instead may receive and display content using another device (for example, a dedicated display device such as a computer screen, and / or a dedicated input device such as a remote control, mouse, voice input, etc.). Furthermore, the device within system 500 may run an application (or another preferred program). The application may cause the processor and / or control circuit to perform operations relating to eye color changing procedures.

[0117] Each of these multiple devices may also include multiple electronic storage devices. The above multiple electronic storage devices may include multiple non-temporary storage media for electronically storing information. The above multiple storage media of the above multiple electronic storage devices may include (i) system storage devices provided integrally with the server or client device (e.g., stromatously and indistinctly), or (ii) removable storage devices that are removablely connected to the server or client device via, for example, a port (e.g., a USB port, a FireWire port, etc.) or a drive (e.g., a disk drive, etc.). The electronic storage devices may include one or more optically readable storage media (e.g., optical discs, etc.), magnetically readable storage media (e.g., magnetic tape, magnetic hard drives, floppy drives, etc.), charge-based storage media (e.g., EEPROM, RAM, etc.), solid-state storage media (e.g., flash drives, etc.), and / or other electronically readable storage media. The electronic storage devices may include one or more virtual storage resources (e.g., cloud storage, virtual private networks, and / or other virtual storage resources). The electronic storage device may store information determined by software algorithms, processors, information obtained from servers, information obtained from client devices, or other information that enables the performance of functions as described herein.

[0118] Figure 5 also includes communication paths 528, 530, and 532. Communication paths 528, 530, and 532 may include the Internet, cellular networks, mobile voice or data networks (e.g., 5G or LTE networks), cable networks, public switched telephone networks, or other types of networks, or combinations of multiple communication networks. Communication paths 528, 530, and 532 may include one or more communication paths, such as satellite paths, fiber optic paths, cable paths, paths supporting Internet communications (e.g., IPTV), free-space connections (e.g., for broadcast or other radio signals), or any other suitable wired or wireless communication paths, or combinations of multiple such paths, individually or together. Multiple computing devices may include further communication paths connecting multiple hardware, software, and / or firmware components that work together. For example, computing devices may be realized by a cloud of computing platforms that work together as computing devices.

[0119] The cloud component 510 may be a database configured to store user data for the user. For example, the database may contain user data that the system has collected about the user through preceding operations and / or procedures. Additionally or alternatively, the system may function as a clearinghouse for multiple sources of information about the user. The cloud component 510 may also include a control circuit configured to perform various actions necessary to perform an eye color change procedure.

[0120] The cloud component 510 includes a machine learning model 502. The machine learning model 502 may receive multiple inputs 504 and supply multiple outputs 506. The inputs may include multiple datasets, such as a training dataset and a test dataset. Each of the above datasets (e.g., input 504) may include a subset of data relating to user data, eye color change procedures, patient progress, and / or outcomes. In some embodiments, the outputs 506 may be fed back to the machine learning model 502 as input for training the machine learning model 502 (e.g., alone, or with user indications of accuracy for multiple outputs 506, labels associated with multiple inputs, or other reference feedback information). In another embodiment, the machine learning model 502 may update its configuration (e.g., weights, biases, or other parameters) based on evaluations of its predictions (e.g., outputs 506) and reference feedback information (e.g., accuracy indications, procedure outcomes, reference labels, and / or other information). In another embodiment, if the machine learning model 502 is a neural network, the coupling weights may be adjusted to match the difference between the neural network's predictions and the reference feedback. In a further use case, one or more neurons (or nodes) in a neural network may require their respective errors to be sent backward through the neural network to facilitate an update process (e.g., error backpropagation). Updates to the connection weights may, for example, reflect the magnitude of the error propagated backward after the forward pass was completed. In this way, a machine learning model 502, for example, can be trained to produce better predictions (e.g., predictions about the appropriate patterns to follow, laser power, level of eye color change, number of procedures, length of procedures, etc.).

[0121] In some embodiments, the machine learning model 502 may include an artificial neural network. In such embodiments, the machine learning model 502 may include an input layer and one or more hidden layers. Each neural unit of the machine learning model 502 may be coupled with many other neural units of the machine learning model 502. Such multiple couplings may be coercive or suppressive in their influence on the activation state of the coupled neural units. In some embodiments, each individual neural unit may have a sum function that combines all the values ​​of its inputs together. In some embodiments, each coupling (or the neural unit itself) may have a threshold function over which a signal must pass before it propagates to other neural units. The machine learning model 502 is self-learning and may be trained rather than explicitly programmed, and may perform significantly better in certain areas of problem-solving than conventional computer programs. During training, the output layer of the machine learning model 502 may correspond to the classification of the machine learning model 502, and inputs known to correspond to its separation may be input to the input layer of the machine learning model 502 during training. During testing, inputs with no known classification may be fed into the input layer, and determined classifications may be output.

[0122] In some embodiments, the machine learning model 502 may include multiple layers (for example, signal paths traversing from a front layer to a back layer). In some embodiments, a backpropagation technique may be utilized by the machine learning model 502, where a forward stimulus may be used to reset weights on the “forward” neural units. In some embodiments, the stimuli and inhibitors of the machine learning model 502 may flow more freely, with couplings that are more chaotic and interact in complex ways. During testing, the output layer of the machine learning model 502 may indicate whether a given input corresponds to a classification of the machine learning model 502 (e.g., a requested eye color change, a pattern to follow, a laser power to be delivered, etc.).

[0123] Figure 6 shows the process for determining the laser power of the laser system. For example, process 600 may represent the steps taken when performing an eye color alteration procedure using one or more devices as shown in Figures 1-5. For example, process 600 may represent the decision made by system 500 to power the laser system (as described in Figures 2-4, for example).

[0124] In step 610, process 600 may track the eye (for example, via one or more components of Figures 1-5). For example, the system may track the patient's eye during the color-changing procedure by an optical tracking system (for example, via a control circuit). In some embodiments, the system may generate multiple images of the iris by imaging the iris with an image sensor before the procedure. Based on the images, the system may generate a mapping of the iris, which has multiple regions corresponding to the changing absorption coefficients of the therapeutic wavelength of the stroma pigment of the iris. Based on the mapping, the system may configure the laser system to deliver laser light at a first laser power to a predetermined location on the patient's eye, which is sufficient to result in the removal of at least a portion of the stroma pigment of the iris.

[0125] In some embodiments, the optical tracking system includes a distance measuring instrument, and process 600 may include the distance measuring instrument determining the distance between the iris and a reference component of the optical tracking system. The system may determine the distance with a resolution of at least 10 microns. The distance measuring instrument may be a time-domain optical coherence tomography system or a spectral-domain optical coherence tomography system. The reference component may be the last lens in the optical tracking system. In some embodiments, the system may autofocus the laser system in response to the distance. Autofocusing may include the steps of measuring the distance to the stroma pigment of the iris at periodic intervals and controlling the system to remain in a state where the laser system is approximately in focus between the front and back surfaces of the iris based on the distance. In some embodiments, the distance measuring instrument may include one or more of a triangulation laser, a time-of-flight detector, a phase-shift detector, an ultrasonic detector, a frequency modulation detector, an interferometer, a camera, or an optical sensor.

[0126] In step 620, process 600 may determine the laser power to be delivered (for example, via one or more components in Figures 1-5). For example, the system may determine the laser power to be delivered to the stroma pigment in the iris by obtaining a set of laser references (via a control circuit). The laser references identify the delivery of an exposure less than 100 times the maximum permissible exposure, which may result in the removal of at least a portion of the stroma pigment without damaging the iris or fundus. The system may obtain the above laser power from a database storing user-specific information and determine the optimal laser power (for example, via a machine learning model 502 (Figure 5) and / or other information regarding the eye color alteration procedure).

[0127] In some embodiments, the laser power may be at least 20 times the MPE such that reducing the laser power to less than 20 times the MPE does not cause loosening of the stroma pigment and consequently result in a change of eye color.

[0128] In some embodiments, removal may occur by initiating macrophage digestion of the stroma pigment and ablation of the stroma pigment, and the system may monitor for the initiation of macrophage digestion of the stroma pigment and ablation of the stroma pigment. In some embodiments, the laser power may be sufficient to induce a simultaneous temperature change within the iris, causing the patient's macrophages to remove at least a portion of the stroma pigment.

[0129] In step 630, process 600 may configure the laser system to deliver laser light (for example, via one or more components of Figures 1-5). For example, the system may configure the laser system to deliver laser light at a laser power less than the laser power specified by a set of laser references (for example, via a control circuit). The system may configure the laser power based on data retrieved from a database in step 620. Additionally or alternatively, the system may determine a pattern or route to follow during the procedure. For example, the system may decide to deliver laser light across the entire iris in a predetermined scanning pattern (for example, a spiral pattern surrounding the pupil that limits sharp angles and abrupt changes in direction, which could increase the length of the procedure, increase the potential for irritation / injury to the eye, and / or risk uneven application).

[0130] In step 640, process 600 may deliver laser light (for example, via one or more components of Figures 1-5). For example, the system may deliver laser light by a laser system (for example, system 200 (Figure 2)) (for example, via a control circuit). For example, the system may deliver laser light to the anterior boundary layer of the iris or the deep stroma (for example, iris stroma 112 (Figure 1)). In some embodiments, process 600 may be repeated several times to repeatedly raise and lower the temperature of the stroma pigment. This rise and fall of temperature causes stroma melanocytes to deploy multiple macrophages (part of the body's innate immune response) into the stroma layer. These multiple macrophages then digest and remove via the iris vascular system a portion of the stroma pigment that is responsible for giving the eye its brown color. The system may repeat process 600 to make color changes of varying degrees to make the eye appear deeper blue / green. In some embodiments, the system may monitor the temperature of at least a portion of the stroma dye using a temperature sensor and control the laser system to deliver laser power so that the delivery does not raise the temperature of the stroma dye above 125°C as monitored by the temperature sensor. In some embodiments, a target temperature of 120°C may be set by the system. Thus, in some embodiments, the temperature sensor may be configured to monitor the delivery of laser power that raises the temperature to 115-125°C.

[0131] In some implementations, process 600 may include the system determining, as part of the color-changing procedure, multiple stages of laser power delivery to the iris, such that subsequent stages result in less pigment removal but are delivered at higher laser power. The system may set the laser system to laser power based on the current stage of delivery and then deliver the laser power based on the above setting. There may be three stages, and in some embodiments, the first of the three stages delivers approximately 26 times the MPE to the stroma pigment, the second of the three stages delivers approximately 30 times the MPE to the stroma pigment, and the third of the three stages delivers approximately 34 times the MPE to the stroma pigment. The system may determine the patient's immune response level based on access by a control computer communicating with the laser system to the patient's medical records, which contain data representing the immune response level. The system may compare the immune response level with the range of the immune response associated with the time interval between two stages and reduce the time interval based on the comparison indicating that the immune response level is higher than the range. The data may represent the level of immune response and quantifies the results of pro-inflammatory cytokine tests performed on patients.

[0132] Figure 7 shows the process of determining the spot size of the laser system. For example, process 700 may represent the steps taken by one or more devices as shown in Figures 1-5 when performing an eye color alteration procedure (e.g., via one or more components in Figures 1-5). For example, process 700 may represent the decision made by system 500 to power the laser system (e.g., as described in Figures 2-4). In some embodiments, removal may occur by initiating macrophage digestion of the stroma pigment and / or ablation of the stroma pigment, and the system may monitor for the initiation of macrophage digestion of the stroma pigment and ablation of the stroma pigment. In some embodiments, the laser power may be sufficient to cause a simultaneous temperature change in the iris and cause the patient's macrophages to remove at least a portion of the stroma pigment. In some embodiments, the system may generate multiple images of the iris by imaging the iris with an image sensor before the procedure. Based on the images, the system may generate a mapping of the iris, which has regions of the iris corresponding to the changing absorption coefficient of the treatment wavelength of the stroma pigment. Based on the mapping, the system may be configured to deliver laser light at a first laser power to one location on the patient's eye, the first laser power being sufficient to result in the removal of at least a portion of the stroma pigment of the iris.

[0133] In step 710, process 700 may track the eye (for example, via one or more components of Figures 1-5). For example, the system may track the eye during a color change procedure using an optical tracking system (for example, via a control circuit). In some embodiments, the optical tracking system includes a distance measuring instrument, and process 600 may include the distance measuring instrument determining the distance between the iris and a reference component of the optical tracking system. The system may determine the distance with a resolution of at least 10 microns. The distance measuring instrument may be a time-domain optical coherence tomography system or a spectral-domain optical coherence tomography system. The reference component may be the last lens in the optical tracking system. In some embodiments, the system may autofocus the laser system in response to the distance. Autofocusing may include measuring the distance to the stroma pigment of the iris at periodic intervals and controlling the system to remain in a state where the laser system is approximately in focus between the front and back surfaces of the iris based on the distance. In some embodiments, the distance measuring device may include one or more of a triangulation laser, a time-of-flight detector, a phase-shift detector, an ultrasonic detector, a frequency modulation detector, an interferometer, a camera, or an optical sensor.

[0134] In step 720, process 700 determines the spot size (for example, via one or more components of Figures 1-5). For example, the system may determine the spot size of the laser light delivered to the stroma pigment (via a control circuit). This embodiment may include a step of obtaining a set of laser references that result in the delivery of laser light to the iris having a spot size of 10-40 microns. In some embodiments, the spot size may be 25-30 μm.

[0135] In step 730, process 700 configures the laser system (for example, via one or more components shown in Figures 1-5). For example, the system may be configured (for example, via a control circuit) to deliver laser light with the spot size described above.

[0136] In some implementations, the system may use a temperature sensor to determine the temperature of at least a portion of the iris containing stroma pigment, and the temperature sensor may be non-invasive to the iris. The laser system is configured to deliver laser light at any laser power so as not to exceed 140°C during the color change procedure.

[0137] In step 740, process 700 may deliver laser light (for example, via one or more components shown in Figures 1-5). For example, the system may deliver laser light (for example, via a control circuit) by a laser system (for example, system 200 (Figure 2)).

[0138] In some implementations, process 700 may include the system determining, as part of the color-changing procedure, multiple stages of laser power delivery to the iris, such that subsequent stages result in less pigment removal but are delivered at higher laser power. The system may set the laser system to laser power based on the current stage of delivery and deliver the laser power based on the above setting. There may be three stages, and in some embodiments, the first stage of the three stages delivers 26 times the MPE to the stroma pigment, the second stage of the three stages delivers 30 times the MPE to the stroma pigment, and the third stage of the three stages delivers 34 times the MPE to the stroma pigment. The system may determine the patient's immune response level based on accessing the patient's medical records, which contain data representing the immune response level, via a control computer communicating with the laser system. The system may compare the immune response level with the range of the immune response associated with the time interval between two stages and reduce the time interval based on the comparison indicating that the immune response level is higher than the range. The data may represent the level of immune response and quantifies the results of pro-inflammatory cytokine tests performed on patients.

[0139] The embodiments described herein are presented for illustrative purposes only, not for limiting purposes. Furthermore, it should be noted that features and limitations described in any one embodiment may apply to any other embodiment herein, and that a flowchart or example relating to one embodiment may be combined with any other embodiment in a preferred manner, performed in a different order, or performed in parallel. Furthermore, the systems and methods described herein may be performed in real time. It should be further noted that the systems and / or methods described herein may apply to or be used in accordance with other systems and / or methods.

[0140] This method will be better understood by referring to the following embodiments listed below.

[0141] Embodiment 1: A method for changing a patient's eye color by a color-changing procedure, the method comprising: tracking the patient's eye during the color-changing procedure using an optical tracking system; determining a laser power to be delivered to the stroma pigment in the iris of the patient's eye by obtaining at least a set of laser references for delivering an exposure less than 100 times the maximum permissible exposure that results in the removal of at least a portion of the stroma pigment; configuring a laser system to deliver laser light with a laser power less than the set of laser references; and delivering the laser light using the laser system. Methods that include...

[0142] Embodiment 2: The method according to any of the preceding embodiments, wherein the removal is caused by the initiation of macrophage digestion of the stroma pigment.

[0143] Embodiment 3: The method according to any of the preceding embodiments, wherein the removal is achieved by ablation of the stroma dye.

[0144] Embodiment 4: The method according to any of the prior embodiments, wherein the laser power is less than 75 times the maximum allowable exposure amount.

[0145] Embodiment 5: The method according to any of the prior embodiments, wherein the laser power is less than 50 times the maximum allowable exposure amount.

[0146] Embodiment 6: The method according to any of the preceding embodiments, wherein the laser power is sufficient to cause a simultaneous temperature change within the iris, thereby causing the patient's macrophages to remove at least a portion of the stroma pigment.

[0147] Embodiment 7: The method according to any of the prior embodiments, wherein the laser power is at least 20 times the maximum allowable exposure so that a reduction in the laser power to less than 20 times the maximum allowable exposure does not cause denaturation of the stroma pigment, resulting in macrophage removal and a change in eye color.

[0148] Embodiment 8: A method according to any of the prior embodiments, further comprising the steps of monitoring the temperature of at least a portion of the stroma dye using a temperature sensor, and controlling the laser system to deliver the laser power such that, when monitored by the temperature sensor, the delivery of the laser power raises the temperature to 115-125°C (including both ends).

[0149] Embodiment 9: The method according to any of the preceding embodiments, wherein the monitoring step includes a step of performing real-time imaging of the iris to detect microbubbles.

[0150] Embodiment 10: The method according to any of the preceding embodiments, wherein the monitoring step includes the step of performing real-time acoustic monitoring of the iris to detect microbubbles.

[0151] Embodiment 11: The method according to any of the preceding embodiments, further comprising the steps of: imaging the iris with an image sensor to generate a plurality of images of the iris before the procedure; analyzing the images with image processing software; generating a mapping of the iris based on the image analysis, wherein the mapping includes a plurality of regions corresponding to varying absorption coefficients of therapeutic wavelengths of the stroma pigment of the iris; and configuring the laser system to deliver laser light at a first laser power to a predetermined location in the eye of the patient based on the mapping, wherein the first laser power is sufficient to result in the removal of at least a portion of the stroma pigment of the iris.

[0152] Embodiment 12: The method according to any of the prior embodiments, further comprising the step of tracking the patient's eye during the color change procedure using an optical tracking system.

[0153] Embodiment 13: The method according to any of the preceding embodiments, wherein the tracking step includes the steps of capturing an image of the iris by the optical tracking system, comparing the image with a previous image of the iris to determine whether or not a change in the iris position exists, and calculating a delta of the change in position from the image and the previous image, and the delivery of the laser light is shifted based on the delta.

[0154] Embodiment 14: The method according to any of the preceding embodiments, wherein the optical tracking system includes a distance measuring device, and the method further includes the step of using the distance measuring device to determine the distance between the iris and a reference component of the optical tracking system.

[0155] Embodiment 15: The method according to any of the prior embodiments, wherein the above distance is determined with a resolution of at least 10 microns.

[0156] Embodiment 16: The method according to any of the prior embodiments, wherein the distance measuring instrument is a time-domain optical coherence tomography system or a spectral-domain optical coherence tomography system.

[0157] Embodiment 17: The method according to any of the preceding embodiments, wherein the reference component is the last lens of the optical tracking system.

[0158] Embodiment 18: The method of any of the prior embodiments, further comprising the step of performing automatic focus adjustment of the laser system according to the distance.

[0159] Embodiment 19: The method according to any of the preceding embodiments, wherein the step of performing the autofocus adjustment includes measuring the distance to the stroma pigment of the iris at periodic intervals, and controlling the laser system based on the distance to remain substantially in focus between the front and back surfaces of the iris.

[0160] Embodiment 20: The method according to any of the prior embodiments, wherein the distance measuring device comprises one or more of a triangulation laser, a time-of-flight detector, a phase-shift detector, an ultrasonic detector, a frequency modulation detector, an interferometer, a camera, or an optical sensor.

[0161] Embodiment 21: The method of any of the preceding embodiments, further comprising the steps of: determining a number of stages of delivering laser power to the iris as part of the color-changing treatment such that subsequent stages result in less pigment removal but are delivered with higher laser power; setting the laser system to the laser power based on the current stage of delivery; and delivering the laser power based on the setting step.

[0162] Embodiment 22: The method according to any of the prior embodiments, wherein the plurality of steps described above includes at least three steps.

[0163] Embodiment 23: The method according to any of the prior embodiments, wherein of at least three steps, the first step delivers approximately 25.4 to 26.6 times the MPE to the stroma pigment, of the above at least three steps, the second step delivers approximately 29.4 to 30.6 times the MPE to the stroma pigment, and of the three steps, the third step delivers approximately 33.4 to 34.6 times the MPE to the stroma pigment.

[0164] Embodiment 24: The method of any of the preceding embodiments, further comprising the steps of: determining the level of an immune response of a patient based on accessing the patient's medical record, which includes data representing the level of immune response, by a control computer communicating with the laser system; comparing the level of immune response to a range of immune responses associated with a time interval between two of the steps; and reducing the time interval based on a comparison indicating that the level of immune response is higher than the range.

[0165] Embodiment 25: The method according to any of the prior embodiments, wherein data representing the level of immune response are obtained by quantifying the results of a pro-inflammatory cytokine test performed on a patient.

[0166] Embodiment 26: A method for changing a patient's eye color by a color-changing procedure, the method comprising: tracking the patient's eye during the color-changing procedure using an optical tracking system; determining the spot size of the laser light to be delivered to the stroma pigment of the patient's eye by obtaining at least a set of laser references that result in the delivery of laser light having a spot size of 4 to 70 microns (including both ends) to the stroma pigment of the patient's iris; configuring a laser system to deliver the laser light with the spot size; and delivering the laser light using the laser system.

[0167] Embodiment 27: The method according to any of the preceding embodiments, wherein the spot size is 10 to 40 microns (including both ends).

[0168] Embodiment 28: The method according to any of the preceding embodiments, wherein the spot size is 25 to 30 microns (including both ends).

[0169] Embodiment 29: The method according to any of the preceding embodiments, wherein the laser power combined with the spot size described above is sufficient to cause a simultaneous temperature change within the iris, thereby initiating macrophage digestion of the stroma pigment.

[0170] Embodiment 30: The method according to any of the preceding embodiments, further comprising the steps of: determining the temperature of at least a portion of the iris, which includes stroma pigment, using a temperature sensor, wherein the temperature sensor determines the temperature of at least a portion of the iris in a non-invasive manner to the iris; and setting up a laser system to deliver laser light with a laser power such that the temperature does not exceed 140 degrees during the color-changing procedure.

[0171] Embodiment 31: The method of any of the preceding embodiments, further comprising the steps of: imaging the iris with an image sensor to generate a plurality of images of the iris before the procedure; generating a mapping of the iris based on the images, wherein the mapping includes a plurality of regions corresponding to varying absorption coefficients of therapeutic wavelengths of the stroma pigment of the iris; and configuring the laser system to deliver laser light at a first laser power to a predetermined location in the eye of the patient based on the mapping, wherein the first laser power is sufficient to result in the removal of at least a portion of the stroma pigment of the iris.

[0172] Embodiment 32: The method according to any of the prior embodiments, further comprising the step of tracking the patient's eye during the color-changing procedure using an optical tracking system.

[0173] Embodiment 33: The method according to any of the preceding embodiments, wherein the optical tracking system includes a distance measuring device, and the method further includes the step of using the distance measuring device to determine the distance between the iris of the eye and a reference component of the optical tracking system.

[0174] Embodiment 34: The method according to any of the preceding embodiments, wherein the reference component is the last lens of the optical tracking system.

[0175] Embodiment 35: The method according to any of the prior embodiments, further comprising the step of performing automatic focus adjustment of the laser system according to the distance.

[0176] Embodiment 36: The method according to any of the preceding embodiments, wherein the step of performing the autofocus adjustment includes measuring the distance of the iris to the stroma pigment at periodic intervals, and controlling the laser system based on the distance to remain substantially in focus on the stroma pigment.

[0177] Embodiment 37: The method according to any of the preceding embodiments, wherein the distance measuring device comprises one or more of a triangulation laser, a time-of-flight detector, a phase-shift detector, an ultrasonic detector, a frequency modulation detector, an interferometer, a camera, or an optical sensor.

[0178] Embodiment 38: The method of any of the preceding embodiments, further comprising the steps of: determining a number of stages of delivering laser power to the iris as part of the color-changing treatment such that subsequent stages result in less pigment removal but are delivered with higher laser power; setting the laser system to the laser power based on the current stage of delivery; and delivering the laser power based on the setting step.

[0179] Embodiment 39: The method according to any of the prior embodiments, wherein the plurality of steps described above includes at least three steps.

[0180] Embodiment 40: The method according to any of the prior embodiments, wherein of at least three steps, the first step delivers 25.4 to 26.6 times the MPE to the stroma pigment, of the above at least three steps, the second step delivers 29.4 to 30.6 times the MPE to the stroma pigment, and of the three steps, the third step delivers 33.4 to 34.6 times the MPE to the stroma pigment.

[0181] Embodiment 41: The method of any of the preceding embodiments, further comprising the steps of: determining the level of an immune response of a patient based on accessing the patient's medical record, which includes data representing the level of immune response, by a control computer communicating with the laser system; comparing the level of immune response to a range of immune responses associated with a time interval between two of the steps; and reducing the time interval based on a comparison indicating that the patient's immune response is higher than the range.

[0182] Embodiment 42: The method according to any of the prior embodiments, wherein data representing the level of immune response are obtained by quantifying the results of a pro-inflammatory cytokine test performed on a patient.

[0183] Embodiment 43: A tangible, non-temporary, machine-readable medium that stores instructions, when executed by a data processing device, causing the data processing device to perform an operation including one of the methods of Embodiments 1 to 42.

[0184] Embodiment 44: A system comprising one or more processors and a memory that stores instructions, when executed by the processors, causing the processors to perform operations including any of the methods of Embodiments 1 to 42.

[0185] [Table 5] TIFF0007872798000013.tif206147 TIFF0007872798000014.tif46147

Claims

1. A device for altering a patient's eye color, comprising: a laser system configured to deliver laser light to the stroma pigment in the iris of the patient's eye; a control system configured to control the delivery of the laser light by the laser system; and a microbubble monitoring system configured to image or acoustically monitor the front surface of the iris to detect microbubbles during the delivery of the laser light to the iris, wherein the control system is configured to determine the minimum radiation exposure applied to the iris by the laser system based on real-time detection of microbubbles.

2. The aforementioned microbubble monitoring system An optical monitoring system that uses a video microscope and confocal imaging to capture increased light reflection from the bubble / water interface into a photomultiplier tube, an electron microscope system, and a hydrophone. The apparatus according to claim 1, comprising at least one of the following.

3. The apparatus according to claim 1 or 2, further comprising a transient recorder configured to record output data of the microbubble monitoring system, and a computer configured to analyze the output data.

4. The apparatus according to any one of claims 1 to 3, wherein the control system is configured to control the delivery of the laser light such that the delivery raises the temperature of the stroma dye to 115 to 125°C.

5. The aforementioned device further, To generate multiple images of the iris, an image sensor is used to capture images of the iris before the delivery of the laser light. Image processing software that analyzes an image and generates an iris mapping based on the image analysis, wherein the mapping includes multiple regions corresponding to the changing absorption coefficients of the therapeutic wavelength of the stroma pigment of the iris. Equipped with, The apparatus according to any one of claims 1 to 4, wherein the control system is configured to control the laser system based on the mapping of the iris so as to deliver laser light at a predetermined laser power to a predetermined location in the patient's eye, the predetermined laser power being sufficient to remove at least a portion of the stroma pigment of the iris.

6. The apparatus according to any one of claims 1 to 5, further comprising an optical tracking system for tracking the patient's eye during the delivery of the laser light.

7. The optical tracking system, The image of the iris is captured, To determine whether or not there is a change in the iris position, the aforementioned image is compared with a previous image of the iris. From the aforementioned image and the previous image, calculate the delta of change in position. It is configured in such a way, The apparatus according to claim 6, wherein the control system is configured to shift the delivery of the laser light based on the calculated delta.

8. The apparatus according to claim 6 or 7, wherein the optical tracking system includes a distance measuring device, and is configured to use the distance measuring device to determine the distance between the iris and a reference component of the optical tracking system.

9. The aforementioned distance measuring device is It is either a time-domain optical coherence tomography system or a spectral-domain optical coherence tomography system, or It is equipped with one or more of the following: a triangulation laser, a time-of-flight detector, a phase-shift detector, an ultrasonic detector, a frequency modulation detector, an interferometer, a camera, or an optical sensor. The apparatus according to claim 8.

10. The apparatus according to claim 8 or 9, wherein the control system is configured to automatically adjust the focus of the laser system according to the distance.

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