Laser Therapy for the Treatment and Prevention of Eye Diseases

Abstract

Providing laser therapy for the treatment and prevention of eye diseases. [Solution] An extraocular automated laser treatment system for treating an eye in a subject includes a non-contact laser source configured to generate a laser beam having at least one wavelength and treat the eye by directing the laser beam from a location spaced from the eye, wherein the at least one wavelength is a near-infrared wavelength in the range of approximately 0.5 to 2.2 μm; a laser scanner optically coupled to the non-contact laser source to receive the laser beam from the non-contact laser source and scan the laser beam across the eye; and a processor and memory, the memory including stored computer-readable instructions that, in response to execution by the processor, cause the laser treatment system to direct the laser beam to a plurality of transscleral treatment locations to be irradiated in a predetermined treatment pattern on the external surface of the eye.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is related to U.S. Provisional Application No. 62 / 755,298, filed November 2, 2018, and U.S. Provisional Application No. 62 / 888,153, filed August 16, 2019, each of which is incorporated by reference in its entirety.

[0002] (Field) Transscleral extraocular IOP lowering and transpupillary neuroprotective laser therapy is disclosed for the clinical management of patients with ocular hypertension and / or glaucoma and for the treatment and / or prevention of related disorders. [Background technology]

[0003] (background) Glaucoma is an optic neuropathy characterized by increased intraocular pressure (IOP), which damages retinal ganglion cells and nerve fibers in the optic disc. Aqueous humor is produced from the ciliary body processes, travels through the pupil, then into the anterior chamber, from where it travels through the trabecular meshwork, Schlemm's canal, and the uveoscleral outflow pathway. Increased IOP results from an imbalance between the production of aqueous humor and its resistance to outflow through the normal outflow pathway. Glaucoma can lead to chronic progressive deterioration of the optic nerve, resulting in embryogenesis and atrophy of the optic disc. Nerve damage, if not treated in a timely manner, causes progressive visual loss of the peripheral field, followed by loss of central vision and irreversible blindness. The goal of current glaucoma treatment is to stop or slow disease progression by reducing IOP, the only known modifiable risk factor. The most common treatment for glaucoma is the lifelong use of IOP-lowering medications, such as eye drops containing prostaglandin analogs, beta-adrenergic receptor antagonists, alpha2-adrenergic agonists, and miotic agents. Although these medications have improved the treatment of glaucoma, they have local and systemic side effects. Patient adherence to medication protocols is also unpredictable, and lifelong use of medications can be costly. Poor compliance with medication use is the leading cause of blindness in glaucoma patients.

[0004] Glaucoma surgical procedures such as trabeculotomy and canal shunts with anti-fibrosis avoid some of these problems. Laser-based therapies such as laser trabeculoplasty (LT) and laser cyclophotocoagulation have also been performed to lower IOP, the former by increasing aqueous humor (AH) outflow and the latter by decreasing its production. Argon laser trabeculoplasty (ALT) uses a gonioscopy lens applied to the eye to deflect a laser beam through the cornea into the angle of the anterior chamber of the eye to directly irradiate the trabecular meshwork. ALT was the first type of LT introduced in the 1970s and has since been practiced using a variety of lasers, wavelengths, and treatment techniques. Some of these techniques are diode laser trabeculoplasty (DLT), selective laser trabeculoplasty (SLT), micropulse laser trabeculoplasty (MLT), and titanium-sapphire laser trabeculoplasty (TLT).

[0005] However, LT is an intraocular procedure that is usually performed transcorneally using a slit lamp delivery system and a corneal contact gonioscopy lens to visualize the anterior chamber angle of the eye and precisely direct a laser beam therein, below Schwalbe's line (SL), and into the pigmented trabecular meshwork, where the laser energy is absorbed and converted to heat. Laser wavelengths in the 488-810 nm range have been used for these procedures, interacting specifically with the darkly pigmented cells in the TM. Transcorneal LT procedures are difficult, and contact between the gonioscopy lens and the eye can induce iatrogenic corneal lesions, such as punctate keratopathy and infections.

[0006] LT has also been demonstrated using a 532 nm SLT frequency-doubled Q-switched 3-ns Nd:YAG laser beam (Geffen et al., J. Glaucoma 26:201-207, 2017) or an 810 nm MDLT micropulsed laser beam (Aquino MC and Chew PK, External Micropulse Diode Laser Trabeculoplasty(EMDLT) for Primary Open Angle Glaucoma:apilotstudy.P4-097 It has also been performed extraocularly using a transscleral approach with a corneal graft (see European Glaucoma Society 2018 Annual Congress, Firenze, Italy, and U.S. Pat. No. 8,945,103). The SLT or EMDLT laser beam is applied extraocularly over the perilimbal area through the corneoscleral junction, affecting traditional outflow tract structures (collecting canal, Schlemm's canal, paraschlemm's canal, corneoscleral, and uveal TM). Transscleral procedures have generally not used infrared wavelengths known to be absorbed by water in superficial scleral cells, as superficial absorption would prevent the laser energy from reaching targeted deeper structures such as the trabecular meshwork. U.S. Pat. No. 6,319,274 uses longer wavelength laser energy directed transsclerally from a probe that indents the surface of the eye and facilitates laser energy penetration through the thickness of the sclera (750-950 μm) to reach the trabecular meshwork.

[0007] Manual guidance of a physical probe relative to the eye inflames the ocular surface and produces variable operator-dependent outcomes. Scleral indentation can also induce intraocular pressure spikes and cause glaucomatous damage to the eye. Laser energy in the probe-conjunctival interface can cause contact burns, and a probe touching the eye is a potential infectious disease vector. Despite these issues, scleral indentation probes are generally considered necessary to maximize laser energy penetration deep into the sclera. Scleral indentation moves the laser energy source closer to the deep scleral target, surface water from the underlying scleral cells, and reduces both absorption and scattering of light energy by water molecules in the superficial sclera. However, manual movement of the laser probe relative to the eye limits the speed of laser movement because fast movements abrade or otherwise traumatize the eye being treated. Furthermore, with manual movement, the speed and positioning of the laser probe cannot be precisely controlled by the surgeon in a consistent manner, resulting in practically non-reproducible and grossly variable laser energy deposition with each treatment.

[0008] Reduction and control of IOP has been and remains the primary goal in the management of glaucomatous patients. Unfortunately, even when IOP is successfully controlled, nearly 60% of glaucoma patients suffer progressive visual field loss due to a continued neurodegenerative process involving loss of retinal ganglion cells and thinning of papillary nerve fiber axons.

[0009] Optical coherence tomography angiography (OCTA) has facilitated the detection of areas of retinal capillary hypoperfusion in patients with chronic progressive neurotrophic neurodegenerative retinopathies, including age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), and in patients with POAG. Glaucoma is associated with reduced blood perfusion in the retina, and the presence of capillary hypoperfusion correlates with later measures of nerve fiber thinning and visual field defect progression. Concerns that IOP-lowering treatments alone may not be sufficient to prevent visual loss progression have led to increased interest in neuroprotective treatments to improve neurotrophic balance and thus optic nerve and retinal health and function. For example, US9,962,291 discloses the use of subliminal photocoagulation of the retina in a grid or rotating line pattern. However, there remains a need for improved systems and methods for treating glaucoma by reducing / controlling IOP and by administering effective neuroprotective therapy to slow, halt, and potentially reverse the neurodegenerative progression. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Patent No. 6,319,274 Summary of the Invention [Means for solving the problem]

[0011] (summary) The laser beam irradiating the ocular structure is rapidly moved in a periodic cycle, such as a circular motion, to heat the targeted ocular tissue. The temperature of the targeted tissue increases during irradiation and then decreases for the remaining interval of the cycle until the tissue is again irradiated in the next cycle. The rapidly moving laser beam can be directed to different locations on or within the eye, for example, by using contact lenses of different refractive index. The wavelength of the laser can also be selected to improve laser energy delivery to the targeted ocular structure. The laser beam can be directed transscleral and / or transpupillary, and the wavelength of the laser beam can be different for different targeted ocular structures. The transpupillary beam can be continuously scanned at a selected scanning speed while delivering continuous wave and / or pulsed laser energy to a treatment location pattern. An embodiment can irradiate the laser beam in the absence of specific glaucoma indicators to provide preventative treatment for various ocular diseases.

[0012] In some embodiments, transscleral IOP-lowering laser treatment is performed without contacting the eye with a laser probe. The laser beam does not directly irradiate the deep sclera and subscleral target structures, such as the trabecular meshwork or ciliary processes, but instead indirectly thermally stimulates them with heat generated by absorption of laser energy in more superficial layers of the eye. The laser beam is projected across the eye and moved rapidly to induce heat waves that propagate from the superficial structures to the targeted subscleral or intraocular structures. The rapid laser movement repeatedly irradiates the same treatment location on the sclera at spaced apart time intervals during sequential cycles of treatment. For example, the laser may move in a cycle through 360° and repeatedly return to a previous treatment location in a subsequent cycle to irradiate that same treatment location during the subsequent cycle. In some embodiments, the laser irradiates the scleral surface continuously or at spaced apart locations around a 360° path, inducing heat waves in tissues below the surface of the sclera throughout the entire path of irradiation. The thermal wave propagates 360° in three dimensions by conduction through the subscleral tissue without direct laser irradiation to reach the targeted subscleral structures (such as the trabecular meshwork, ciliary body, and / or other targets of aqueous humor production and outflow).

[0013] A patient interface that is docked to the eye may hold the laser emission source at a distance from the eye. The laser wavelength may be in a range that targets selected tissue, e.g., penetrates the scleral surface and interacts with cellular moisture of the superficial sclera. In some embodiments, the wavelength may be a near-infrared wavelength of 0.8-2.2 μm or 1-2.2 μm, such as 1.0-1.7 μm, e.g., a wavelength of about 0.80-0.85 μm or a wavelength of about 1.4-1.6 μm. In some disclosed embodiments, the wavelength is 1.47 μm. The laser energy directly reaches and is not absorbed by deeper scleral structures (e.g., structures deeper than 700 μm), heating the superficial sclera at the treatment site over a short period of time (e.g., to a depth of 100-700 μm, such as 100-200 μm, 100-550 μm, or 100-500 μm). These deeper structures that are not directly irradiated and / or heated include the trabecular meshwork, the uveoscleral outflow network, the collecting ducts and / or ostium, and / or the ciliary body.

[0014] The superficial scleral heating is followed by a period of thermal relaxation during which heat is transmitted deeper into the sclera toward the trabecular meshwork and / or ciliary body. The repeated heating and thermal relaxation cycles are intended to achieve protective thermal preconditioning, hyperthermia, and therapeutic biostimulation of intended targets such as the trabecular meshwork, uveoscleral outflow network, and / or ciliary body. In disclosed embodiments, the repeated heating cycles are specifically targeted to the same location on the scleral surface by an imaging system that repeatedly targets the same treatment location throughout multiple cycles of heating, thermal relaxation, and thermal wave propagation to deeper target tissues. The treatment location can be 0-4 mm (e.g., 1-4 mm) posterior to the corneal limbal junction.

[0015] A method of precisely delivering pre-programmed patterns of laser energy while cooling the surface of the eye is described, as is a method of lowering IOP, for example, by performing any of the steps performed by the present system.

[0016] In accordance with one aspect of the disclosed technology, an extraocular automated laser treatment system for treating an eye in a subject includes a non-contact laser source configured to generate a laser beam having at least one wavelength and treat the eye by directing the laser beam from a location spaced from the eye, the at least one wavelength being a near infrared wavelength in a range of about 0.5 to 2.2 μm; a laser scanner optically coupled to the non-contact laser source for receiving the laser beam from the non-contact laser source and scanning the laser beam relative to the eye; and a processor, and in response to execution by the processor: The laser treatment system comprises: a processor and memory including stored computer readable instructions for directing a laser beam to a plurality of transscleral treatment locations to be irradiated in a predetermined treatment pattern on an external surface of the eye, the transscleral treatment locations being 0-4 mm posterior to the limbal junction, the laser beam being repeatedly directed to identical irradiated transscleral treatment locations on the surface of the eye, the transscleral treatment locations being irradiated at time intervals sufficient to induce protective thermal preconditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of ocular tissue.

[0017] In some examples, the memory includes stored computer readable instructions that cause the laser treatment system to direct a laser beam to a plurality of transpupillary treatment locations to induce a sublethal thermal rise and induce therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including various one or combinations of: (a) a predetermined curvilinear treatment pattern on the target ocular tissue of the eye comprising a plurality of concentric annuli on the macula around but not on the foveal avascular zone; (b) an area that (i) surrounds the macula but is not on the foveal avascular zone; (ii) surrounds the optic disc but is not on the optic disc or adjacent peripapillary crescent; (c) an area that surrounds the optic disc but is not on the optic disc or adjacent peripapillary crescent; or (d) an area that is adjacent the foveal avascular zone but is not on the area of ​​the papillomacular bundle.

[0018] In some examples, the stored computer readable instructions cause the laser treatment system to direct a laser beam to multiple transscleral and / or transpupillary treatment locations, and the subject has clinically normal intraocular pressure and / or is free of glaucoma symptoms or diagnosis.

[0019] In selected embodiments, the stored computer readable instructions direct the laser treatment system to direct a laser beam to a plurality of transscleral treatment locations at time intervals sufficient to induce protective thermal preconditioning and biostimulation of the targeted structures and elicit a biomechanical and biochemical response to reduce intraocular pressure in the subject's eye. In some embodiments, the processor is configured with instructions to repeatedly deliver the laser beam to a plurality of irradiated transscleral treatment locations at time intervals that target an increase in temperature of the outer 200-500 μm scleral layer to a temperature of about 45-57° C. Examples can include laser parameters configured to provide an irradiance of the laser beam, a scanning speed at which the laser beam moves around in a predetermined treatment pattern, and an increase in temperature of the outer 200 μm scleral layer to a temperature of about 43-57° C., optionally about 43-45° C.

[0020] In some examples, a processor is configured with instructions to receive an input corresponding to a location of a target limbal junction or limbus, and the processor is configured to determine a plurality of transscleral treatment locations in response to the input, the plurality of transscleral treatment locations being offset radially outward from an input location corresponding to the limbal junction or limbus to contour a treatment pattern to a target ocular anatomy. In some examples, the transscleral treatment locations are within a 360° annular pattern posterior to the limbal junction, and the processor is configured to direct the laser beam to a set of pre-identified transscleral treatment locations on a surface of the eye during a first treatment cycle and to direct the laser beam to the same pre-identified transscleral treatment locations during subsequent treatment cycles to achieve a precise cyclical thermal elevation of scleral tissue underlying the pre-identified transscleral treatment locations during a time interval involving thermal relaxation of the irradiated tissue between treatment cycles. In some embodiments, the processor is configured to set the rate of each treatment cycle to achieve thermal relaxation by spaced irradiation of the transscleral treatment locations at sufficient time intervals to produce a time-temperature history with targeted exposure and relaxation times. In some embodiments, the time intervals between irradiation of the same transscleral treatment location produce a duty time ratio that corresponds to a ratio between active exposure on time / (active exposure+relaxation off time) in the range of 2-50%. Exemplary time intervals between irradiation of the same transscleral treatment location can be about 10-300 ms, optionally about 100-200 ms. In some embodiments, the predetermined treatment pattern is located about 1.5 mm posterior to the limbal junction. In certain embodiments, the predetermined treatment pattern comprises a plurality of annular treatment patterns, the plurality of annular treatment patterns being spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the limbal junction, the annular treatment patterns comprising one or more of a circular, oval, elliptical, ovoid, non-circular, non-elliptical, or asymmetric pattern, or a pattern corresponding to the shape of Schlemm's canal or limbus. In further embodiments, the 360° pattern is interrupted 10-30° nasally and 10-30° temporally. In some embodiments, the plurality of annular treatment patterns targets perilimbal outflow structures, ciliary processes, and pars plana.

[0021] Some embodiments further include a heat sink placed in contact with the eye over the transscleral treatment location to transfer heat away from the surface of the eye. In some embodiments, the heat sink comprises a curved contact lens placed on the surface of the eye. In some embodiments, the contact lens comprises a cooled contact lens that substantially conforms to the surface of the eye. In some embodiments, the laser beam has a near infrared wavelength including wavelengths of 0.8-2.2 μm, optionally 1-2.2 μm, 1.0-1.7 μm, 0.80-0.85 μm, 1.4-1.6 μm, and / or 1.47 μm. In some embodiments, the laser beam has a near infrared wavelength of about 1.4-1.5 μm, optionally 1.47 μm. In some embodiments, the protective thermal preconditioning and therapeutic biostimulation are controlled by one or more of the laser power, irradiance, scan speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle. In some embodiments, the processor is configured to direct the laser beam to the transscleral treatment location within a spot having a diameter of 500-1,000 μm, optionally about 600 μm. Some embodiments further include an optical imaging system for detecting the limbus and / or limbal junction of the subject. In some embodiments, the processor is configured to identify the predetermined transscleral treatment location at a location determined by the shape of the limbus and / or limbal junction of the subject's eye.

[0022] Some embodiments further include a patient interface for docking the non-contact laser source at a distance from the eye, the patient interface comprising a spacer that maintains the eye in a substantially fixed location for imaging and treatment, the spacer maintaining the non-contact laser source at a distance from and without contact with the surface of the eye. In some embodiments, the patient interface further comprises a speculum for placement between the subject's eyelids to expose the eye to the laser beam. In further embodiments, the patient interface further comprises a fixation ring for a contact lens, the fixation ring comprising a resilient sealing surface, the system configured to maintain a negative pressure between the contact lens and the fixation ring to secure the patient interface to the surface of the eye and substantially immobilize the subject's eye. In some embodiments, the negative pressure is adjustable. In further embodiments, the system is configured to cool the spacer and / or the fixation ring and / or the contact lens. In some embodiments, the spacer and / or the fixation ring comprise an internal fluid flow channel, the system configured to introduce a cooled fluid through the fluid flow channel to cool the spacer and / or the fixation ring and / or the contact lens. Some embodiments further include a positioning arm for positioning the patient interface at a location relative to the surface of the subject's eye.

[0023] In some embodiments, each annulus on the macula of the curvilinear treatment pattern comprises a plurality of uniformly spaced, overlapping laser pulse spots delivered in succession along a perfect circle to produce an irradiated annular treatment zone within each annulus, the laser pulse spots being delivered at a common scan speed for all macular annuli. In some embodiments, the plurality of concentric annuli comprise radially successive irradiated annular treatment zones on the macula. In some embodiments, each concentric annulus has a width of 400 μm to 600 μm. In various embodiments, the laser source is configured to produce a laser beam with pulses at a pulse repetition period in the range of 1 to 3 ms, a pulse repetition rate of 1,000 to 333 pulses / sec, and a pulse duration in the range of 20 to 500 μs. In some embodiments, the laser source is configured to produce a laser beam with pulses at a pulse repetition period in the range of 1.5 to 2.5 ms, a pulse repetition rate of 666 to 400 pulses / sec, and a pulse duration in the range of 50 to 150 μs. In selected embodiments, the laser source is configured to produce a laser beam with pulses at a pulse repetition period in the range of 1.8-2.2 ms, a pulse repetition rate of 556-455 pulses / sec, and a pulse duration in the range of 80-120 μs. In some embodiments, the annulus comprises 3-5 consecutive concentric annuli on the macula, each annulus having a substantially equal width, and the plurality of transscleral treatment locations comprises three concentric annuli on the sclera around the limbus at radii R1, R2, and R3 corresponding to locations covering the primary aqueous outflow tract, the ciliary body process, and the pars plana, respectively. In some embodiments, the annulus comprises five consecutive annuli on the sclera, each annulus having a width of about 500 microns, and the plurality of transscleral treatment locations comprises three concentric annuli on the sclera at distances of about 1.5, 2.5, and 3.5 mm from the corneoscleral junction. In some embodiments, the sublethal thermal increase corresponds to an increase in the temperature of the target tissue within the annulus on the macula to a temperature of 47°C or less, and the laser beam increases the temperature of the target tissue within the transscleral treatment site to 57°C or less.

[0024] In some embodiments, the laser source comprises a first diode laser source operable to produce a pulsed laser beam at 810 nm for directing to the transpupillary treatment location, a second diode laser source operable to produce a continuous wave laser beam at 1,475 nm for directing to the transscleral treatment location, and at least one beam splitter mounted to receive the beam at 810 nm and the beam at 1,475 nm and direct them along a common optical path for receipt by the laser scanner. Some embodiments further include a detector optically coupled to the target ocular tissue, the stored computer readable instructions causing the laser scanner to selectively direct the laser beam to the target ocular location based on a change in position of the target ocular tissue detected using the detector.

[0025] According to another aspect of the disclosed technology, an extraocular automated method for treating an eye in a subject includes directing laser energy having a near-infrared wavelength of about 0.5-2.2 μm from a location spaced from the eye to a plurality of transscleral treatment locations for irradiation in a predetermined treatment pattern on an external surface of the eye, the transscleral treatment locations being 0-4 mm posterior to the limbal junction, the laser energy being repeatedly directed to the same irradiated transscleral treatment locations on the surface of the eye, the transscleral treatment locations being irradiated at time intervals sufficient to induce protective thermal preconditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of ocular tissue.

[0026] Some embodiments further include directing laser energy having a near-infrared wavelength of about 0.5 to 2.2 μm from a location spaced from the eye to a plurality of transpupillary treatment locations to induce a sublethal thermal rise and induce therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including various one or combinations of: (a) a predetermined curvilinear treatment pattern on the target ocular tissue of the eye comprising a plurality of concentric annuli on the macula around, but not on, the foveal avascular zone; (b) an area that (i) surrounds the macula but is not on the foveal avascular zone; (ii) surrounds the optic disc but is not on the optic disc or adjacent peripapillary crescent; (c) an area that surrounds the optic disc but is not on the optic disc or adjacent peripapillary crescent; or (d) an area that is adjacent the foveal avascular zone but is not on the area of ​​the papillomacular bundle.

[0027] In some examples, the step of directing laser energy to the multiple transscleral and / or transpupillary treatment locations is performed based on the subject having clinically normal intraocular pressure and / or not having any glaucoma symptoms or diagnosis.

[0028] In some embodiments, directing laser energy to a plurality of transscleral treatment locations at a time interval sufficient to induce protective thermal preconditioning and biostimulation of targeted structures and elicit biomechanical and biochemical responses is configured to reduce intraocular pressure in the eye. In some embodiments, repetitively delivering energy to a plurality of irradiated transscleral treatment locations includes delivering energy at a time interval that targets an increase in temperature of the outer 200-500 μm scleral layer to a temperature of about 45-57° C. In some embodiments, directing laser energy includes a selected irradiance and scan speed that increases the temperature of the outer 200 μm scleral layer to a temperature of about 43-57° C., optionally about 43-45° C.

[0029] In some embodiments, the transscleral treatment locations are offset radially outward at a substantially uniform distance from the limbal junction or limbus to contour the treatment pattern to the target ocular anatomy. In some embodiments, the transscleral treatment locations are in a 360° annular pattern posterior to the limbal junction, and laser energy is directed to a set of pre-identified transscleral treatment locations on the surface of the eye during a first treatment cycle, and during subsequent treatment cycles, laser energy is directed to the same pre-identified transscleral treatment locations to achieve precise cyclical thermal elevation of the scleral tissue underlying the pre-identified transscleral treatment locations at time intervals involving thermal relaxation of the irradiated tissue between treatment cycles. In some embodiments, each treatment cycle is performed for a duration that achieves thermal relaxation by spaced irradiation of the transscleral treatment locations at sufficient time intervals that the exposure and relaxation times produce a targeted time-temperature history. In some embodiments, the same transscleral treatment location is irradiated at time intervals producing a duty time rate corresponding to a ratio between active exposure on time / (active exposure+relaxation off time) in the range of 2-50%. In some embodiments, the same transscleral treatment location is irradiated at time intervals of about 10-300 ms, optionally about 100-200 ms. In some embodiments, the predetermined treatment pattern to which the laser energy is directed is located about 1.5 mm posterior to the limbal junction. In some embodiments, the predetermined treatment pattern to which the laser energy is directed comprises a plurality of annular treatment patterns, the plurality of annular treatment patterns being spaced apart about 1.5 mm, 2.5 mm, and 3.5 mm posterior to the limbal junction, the plurality of annular treatment patterns comprising one or more of a circular, oval, elliptical, ovoid, non-circular, non-elliptical, or asymmetric pattern, or a pattern corresponding to the shape of the limbal junction or the limbus. In some embodiments, the laser energy is directed in a 360° predetermined treatment pattern interrupted by 10-30° nasally and 10-30° temporally. In some embodiments, the laser energy is directed to transscleral treatment locations on multiple annular treatment patterns targeting perilibal outflow structures, ciliary processes, and pars plana.

[0030] Some embodiments further include placing a heat sink in contact with the eye over the transscleral treatment location to transfer heat away from the surface of the eye. In some embodiments, placing the heat sink in contact with the eye includes placing a curved contact lens on the surface of the eye. In some embodiments, placing the contact lens on the eye includes placing a cooled contact lens that substantially conforms to the surface of the eye. In some embodiments, the contact lens is cooled in situ on the surface of the eye. In various embodiments, the laser energy has a near infrared wavelength, including wavelengths of 0.8-2.2 μm, optionally about 1-2.2 μm, 1.0-1.7 μm, 0.80-0.85 μm, 1.4-1.6 μm, and / or 1.47 μm. In some embodiments, the laser energy has a near infrared wavelength of about 1.4-1.5 μm, optionally about 1.47 μm. In some embodiments, the protective thermal preconditioning and therapeutic biostimulation are controlled by one or more of the laser power, irradiance, scan speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle. In some embodiments, the laser energy is directed to the treatment location in a spot having a diameter of 500-1,000 μm, optionally about 600 μm. Some embodiments further include detecting the subject's limbus and / or limbal junction with an optical imaging system. In some embodiments, the predetermined transscleral treatment location is determined by the shape of the limbus and / or limbal junction of the subject's eye.

[0031] Some embodiments further include spacing the non-contact laser away from the eye with a patient interface, the patient interface comprising a spacer that maintains the eye in a substantially fixed location for imaging and treatment, the spacer maintaining the non-contact laser energy source configured to produce laser energy away from and out of contact with the surface of the eye. In some embodiments, the patient interface further comprises a speculum for placement between the eyelids of the subject to expose the eye to the laser energy, the speculum being placed between the eyelids to expose the sclera of the subject. In some embodiments, the patient interface further comprises a fixation ring for the contact lens, the fixation ring comprising a resilient sealing surface, the fixation ring being placed against the subject's eye, and a suction force being applied between the contact lens and the eye to generate a negative pressure to secure the fixation ring to the eye and substantially immobilize the subject's eye. In some embodiments, the negative pressure is adjustable. In some embodiments, the spacer and / or the fixation ring and / or the contact lens are cooled while the method is being performed. In some embodiments, the spacer and / or fixation ring are cooled by directing a cooling fluid through internal fluid flow channels in the spacer and / or fixation ring and / or contact lens. Some embodiments further include positioning the patient interface within the treatment location relative to the subject's ocular surface with the positioning arm.

[0032] In some embodiments, the laser energy is directed in a curvilinear pattern to form successive concentric annular treatment zones at different radii from the foveal avascular zone. In some embodiments, the laser energy is directed in a curvilinear pattern onto the macula through all macular annuli at a common scan speed such that for each macular annulus, multiple evenly spaced, overlapping laser pulse spots are delivered in a continuous circular fashion to produce an irradiated annular treatment zone within each annulus. In various embodiments, the laser energy is directed annularly, delivering a total laser energy in the range of 50 mJ to 12 J within a 20 cm 2 ~30cm 2In some embodiments, the laser energy is directed to 3-5 consecutive concentric annuli on the macula, each having a substantially equal width, and the plurality of transscleral treatment locations comprises three concentric annuli on the sclera around the limbus at radii R1, R2, and R3, corresponding to locations covering the primary aqueous outflow tract, the ciliary body process, and the pars plana, respectively. In some embodiments, the laser energy is directed to 5 consecutive annuli on the sclera, each having a width of about 500 microns, and the plurality of transscleral treatment locations comprises three concentric annuli on the sclera at distances of about 1.5, 2.5, and 3.5 mm from the corneoscleral junction. In some embodiments, the sublethal thermal increase corresponds to an increase in the temperature of the target tissue within the annulus on the macula to a temperature of 47°C or less, and the laser beam increases the temperature of the target tissue within the transscleral treatment site to 57°C or less.

[0033] In some embodiments, the laser energy directed to the transpupillary treatment location comprises a pulsed laser beam at 810 nm, and the laser energy directed to the transscleral treatment location comprises a continuous wave laser beam at 1,475 nm, and the laser energy is directed along a common optical path from at least one beam splitter. Some embodiments further include detecting a location of the target ocular tissue, and the directing of the laser energy is performed using a laser scanner based on the detected location. Some embodiments further include detecting a location of the foveal avascular zone and / or optic disc of the subject. In some embodiments, the laser energy is directed in a curvilinear pattern at a constant circumferential scan speed of 1.5 mm / s to 2 mm / s producing a pulse-to-pulse overlap of 99% or greater. In some embodiments, the laser energy is directed transpupillarily at a pulse repetition period of 2 ms and a pulse duration of 100 μs. In an exemplary embodiment, the curvilinear pattern is configured to target retinal pigment epithelial (RPE) cells.

[0034] According to a further aspect of the disclosed technology, a patient interface assembly for docking a laser therapy device to an eye to be treated with the laser therapy device includes a lens holder configured to hold a contact lens heat sink against the eye, the lens holder including an internal cooling channel in communication with the fluid flow inlet and outlet ports, and a spacer dockable with the lens holder to hold the laser output at a spaced distance from the contact lens heat sink. Some embodiments further include a resilient seal ring on the lens holder that extends around the contact lens and creates a seal chamber between the contact lens and the eye, and holds the lens holder against the eye when a suction force is applied to the seal chamber and the seal chamber is in communication with the suction input port. In some embodiments, the contact lens comprises a contact lens with a central opening that allows air to pass into the seal chamber while still maintaining a negative pressure in the seal chamber. Some embodiments further include a speculum, the speculum having jaws that hold opposing eyelid blades in a spaced apart relationship, the blades configured to fit around and hold the lens holder. Some embodiments further include a laser triangulation system for Z-focus camera viewing of the contact lens. Some embodiments further include an XYZ positioner for positioning the patient interface relative to the subject's eye using a sealing ring of the lens holder, and the spacer is docked to the lens holder.

[0035] According to a further aspect of the disclosed technology, a patient interface for docking a laser treatment device to an eye to be treated with the laser treatment device includes a spacer, such as a frusto-conical spacer, tapering from an enlarged first side to a smaller second side, and a laser emitting source carried by the cone and spaced from the smaller second side, a lens holder collar tapering from a larger first side for mating with the second side of the spacer to a smaller second side circumscribed by a resilient patient fixation ring and forming a seal against the eye to be treated, the collar including internal cooling fluid passages, inlet ports, and outlet ports for circulating a cooling fluid through the collar, a heat sink contact lens held within the collar above the fixation ring and forming an intake chamber between the contact lens and the eye when the collar is docked against the subject's eye, and an intake port in communication with the intake chamber. According to a further aspect of the disclosed technology, a method of docking a laser treatment device to an eye to be treated with the laser treatment device includes inserting a speculum blade into the eye to separate the eyelids and expose the sclera, holding a lens holder between the speculum blades and optionally aspirating air from a seal chamber, activating an XYZ positioner to dock a spacer to the lens holder, and directing coolant through an internal cooling channel of the lens holder by directing coolant through a fluid inlet port and out of a fluid outlet port. Some embodiments further include viewing the contact lens and the eye with optical viewing software. Some embodiments further include viewing a retina of the eye with optical viewing software. Some embodiments further include performing a laser treatment of the sclera and / or retina through a patient interface with a laser held in a spaced relationship to the sclera.

[0036] The foregoing description describes various aspects of the systems, devices, and methods disclosed in further detail throughout this specification. The description is provided for the convenience of the reader and is not a limitation on the scope of any claims. The foregoing and other objects, features, and advantages of the disclosed technology will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures. The present invention provides, for example, the following: (Item 1) 1. An automated extraocular laser treatment system for treating an eye in a subject, comprising: a non-contact laser source configured to generate a laser beam having at least one wavelength and to treat the eye by directing the laser beam from a location spaced from the eye, the at least one wavelength being a near infrared wavelength in a range of about 0.5 to 2.2 μm; a laser scanner optically coupled to the non-contact laser source to receive the laser beam from the non-contact laser source and scan the laser beam over the eye; a processor and a memory, the memory including stored computer readable instructions that, in response to execution by the processor, cause the laser treatment system to direct the laser beam to a plurality of transscleral treatment locations to be delivered in a predetermined treatment pattern on an external surface of the eye, the transscleral treatment locations being 0-4 mm posterior to the limbal junction, the laser beam being repeatedly directed to identical delivered transscleral treatment locations on the surface of the eye, the transscleral treatment locations being delivered at time intervals sufficient to induce protective thermal preconditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of tissue of the eye; A system comprising: (Item 2) 2. The system of claim 1, wherein the memory includes stored computer readable instructions that cause the laser treatment system to direct the laser beam to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including a predetermined curvilinear treatment pattern on the target ocular tissue of the eye comprising a plurality of concentric annuli on the macula surrounding but not on the foveal avascular zone. (Item 3) The system of any one of items 1 to 2, wherein the memory includes stored computer readable instructions that cause the laser treatment system to direct the laser beam to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including an area that (i) surrounds the macula but is not over the foveal avascular zone, and (ii) surrounds the optic disc but is not over the optic disc or adjacent peripapillary crescent. (Item 4) The system of any one of items 1-3, wherein the memory includes stored computer readable instructions that cause the laser treatment system to direct the laser beam to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including an area surrounding the optic disc but not on the optic disc or an adjacent peripapillary crescent. (Item 5) The system of any one of items 1-4, wherein the memory includes stored computer readable instructions that cause the laser treatment system to direct the laser beam to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including areas adjacent to the foveal avascular zone but not over an area of ​​the papillomacular bundle. (Item 6) The system of any one of items 1-5, wherein the stored computer readable instructions cause the laser treatment system to direct the laser beam to the multiple transscleral and / or transpupillary treatment locations, and the subject has clinically normal intraocular pressure and / or is free of glaucoma symptoms or diagnosis. (Item 7) The system of any one of items 1-6, wherein the stored computer readable instructions cause the laser treatment system to direct the laser beam to the multiple transscleral treatment locations at intervals of time sufficient to induce protective thermal preconditioning and biostimulation of the targeted structures and elicit a biomechanical and biochemical response to lower intraocular pressure. (Item 8) 8. The system of any one of items 1-7, wherein the processor is configured with instructions to repetitively deliver the laser beam to the multiple irradiated transscleral treatment locations in a time interval that targets an increase in temperature of the outer 200-500 μm scleral layer to a temperature of approximately 45-57° C. (Item 9) 9. The system of any one of claims 1-8, wherein the laser parameters are configured to provide an irradiance of the laser beam and a scanning speed at which the laser beam moves about in the predetermined treatment pattern that increases the temperature of the outer 200 μm scleral layer to a temperature of about 43-57°C, optionally about 43-45°C. (Item 10) 10. The system of any one of items 1-9, wherein the processor is configured with instructions to receive an input corresponding to a location of the limbal junction or limbus of the subject, and the processor is configured to determine, in response to the input, a plurality of transscleral treatment locations, the plurality of transscleral treatment locations being offset radially outward from the input location corresponding to the limbal junction or limbus to contour the treatment pattern to the anatomical structure of the subject's eye. (Item 11) 11. The system of any one of items 1-10, wherein the transscleral treatment locations are within a 360° annular pattern posterior to the limbal junction, and the processor is configured to direct the laser beam to a set of pre-identified transscleral treatment locations on the surface of the eye during a first treatment cycle and to direct the laser beam to the same pre-identified transscleral treatment locations during subsequent treatment cycles to achieve precise cyclical thermal elevation of the scleral tissue underlying the pre-identified transscleral treatment locations during time intervals involving thermal relaxation of the irradiated tissue between treatment cycles. (Item 12) Item 12. The system of item 11, wherein the processor is configured to set a rate for each treatment cycle to achieve the thermal relaxation by spaced irradiation of the transcleral treatment site at sufficient time intervals to produce a targeted time-temperature history with exposure and relaxation times. (Item 13) 13. The system of any one of items 1-12, wherein the time interval between irradiations of the same transscleral treatment location produces a duty time ratio corresponding to a ratio between active exposure on time / (active exposure + relaxation off time) in the range of 2-50%. (Item 14) Item 14. The system of item 13, wherein the time interval between irradiation of the same transscleral treatment location is about 10-300 ms, optionally about 100-200 ms. (Item 15) 15. The system of any one of claims 1-14, wherein the predetermined treatment pattern is located approximately 1.5 mm posterior to the limbal junction. (Item 16) 16. The system of any one of claims 1-15, wherein the predetermined treatment pattern comprises a plurality of annular treatment patterns spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the limbal junction, and the annular treatment patterns comprise one or more of a circular, oval, elliptical, ovoid, non-circular, non-elliptical, or asymmetric pattern, or a pattern corresponding to a shape of Schlemm's canal or the limbus. (Item 17) 17. The system of any one of claims 11-16, wherein the 360° pattern is interrupted by 10-30° nasally and 10-30° temporally. (Item 18) The plurality of annular treatment patterns include: (a) Perilibal outflow structure and (b) Ciliary process; (c) Pars plana and 18. The system according to item 16 or 17, which targets (Item 19) 19. The system of any one of items 1-18, further comprising a heat sink positioned in contact with the eye across the transcleral treatment location to transfer heat away from the surface of the eye. (Item 20) 20. The system of claim 19, wherein the heat sink comprises a curved contact lens placed on the surface of the eye. (Item 21) 21. The system of claim 20, wherein the contact lens comprises a cooled contact lens that substantially conforms to the surface of the eye. (Item 22) 22. The system of any one of items 1-21, wherein the laser beam has a near infrared wavelength including wavelengths of 0.8 to 2.2 μm, optionally 1 to 2.2 μm, 1.0 to 1.7 μm, 0.80 to 0.85 μm, 1.4 to 1.6 μm, and / or 1.47 μm. (Item 23) 23. The system of claim 22, wherein the laser beam has a near infrared wavelength of about 1.4 to 1.5 μm, optionally 1.47 μm. (Item 24) 24. The system of any one of items 1-23, wherein the protective thermal preconditioning and therapeutic biostimulation are controlled by one or more of the power, irradiance, scan speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle of the laser. (Item 25) 25. The system of any one of claims 1-24, wherein the processor is configured to direct the laser beam to the transscleral treatment location within a spot having a diameter of 500 to 1,000 μm, optionally about 600 μm. (Item 26) 26. The system of any one of items 1-25, further comprising an optical imaging system for detecting the limbus and / or limbal junction of the subject. (Item 27) 27. The system of claim 26, wherein the processor is configured to identify the predetermined transscleral treatment location at a location determined by the shape of the anterior limbus and / or limbal junction of the subject's eye. (Item 28) 28. The system of any one of items 1-27, further comprising a patient interface for docking the non-contact laser source at a distance from the eye, the patient interface comprising a spacer that maintains the eye in a substantially fixed location for imaging and treatment, the spacer maintaining the non-contact laser source at a distance from and out of contact with the surface of the eye. (Item 29) 30. The system of claim 28, wherein the patient interface further comprises a speculum for placement between the subject's eyelids to expose the eye to the laser beam. (Item 30) 30. The system of any one of claims 28-29, wherein the patient interface further comprises a fixation ring for a contact lens, the fixation ring comprising a resilient sealing surface, the system configured to maintain a negative pressure between the contact lens and the fixation ring to secure the patient interface to the ocular surface and substantially immobilize the subject's eye. (Item 31) 31. The system of any one of claims 28-30, wherein the negative pressure is adjustable. (Item 32) 32. The system of any one of claims 28-31, wherein the system is configured to cool the spacer and / or the fixing ring and / or the contact lens. (Item 33) 33. The system of claim 32, wherein the spacer and / or retention ring include internal fluid flow channels, and the system is configured to introduce a chilled fluid through the fluid flow channels to cool the spacer and / or retention ring and / or contact lens. (Item 34) 34. The system of any one of claims 1-33, further comprising a positioning arm for positioning the patient interface at a location relative to the surface of the subject's eye. (Item 35) 35. The system of any of items 2-34, wherein each annulus on the macula of the curvilinear treatment pattern comprises a plurality of evenly spaced, overlapping laser pulse spots delivered in succession along a perfect circle to produce an irradiated annular treatment zone within each annulus, the laser pulse spots being delivered at a common scan speed for all macular annuli. (Item 36) Item 36. The system of item 35, wherein the plurality of concentric annuli comprises a radially continuous irradiated annular treatment area on the macula. (Item 37) 37. The system according to any of items 2-36, wherein each concentric annulus has a width of 400 μm to 600 μm. (Item 38) Item 38. The system of any of items 1-37, wherein the laser source is configured to produce a laser beam with pulses at a pulse repetition period in the range of 1-3 ms, a pulse repetition rate of 1,000-333 pulses / sec, and a pulse duration in the range of 20-500 μs. (Item 39) Item 39. The system of item 38, wherein the laser source is configured to produce a laser beam with pulses at a pulse repetition period in the range of 1.5 to 2.5 ms, a pulse repetition rate of 666 to 400 pulses / sec, and a pulse duration in the range of 50 to 150 μs. (Item 40) Item 39. The system of item 38, wherein the laser source is configured to produce a laser beam with pulses at a pulse repetition period in the range of 1.8 to 2.2 ms, a pulse repetition rate of 556 to 455 pulses / sec, and a pulse duration in the range of 80 to 120 μs. (Item 41) 41. The system of any of items 2-40, wherein the annulus comprises three to five contiguous concentric annuli on the macula, each annulus having a substantially equal width, and the multiple transscleral treatment locations comprise three concentric annuli on the sclera around the limbus at radii R1, R2, and R3 corresponding to locations covering the primary aqueous outflow pathway, the ciliary body process, and the pars plana, respectively. (Item 42) 42. The system of any of items 2-41, wherein the annulus comprises five consecutive annulus on the sclera, each annulus having a width of about 500 microns, and the plurality of transscleral treatment locations comprises three concentric annulus on the sclera at distances of about 1.5, 2.5, and 3.5 mm from the corneoscleral junction. (Item 43) 43. The system of any of items 2-42, wherein the sublethal thermal increase corresponds to an increase in temperature of the target tissue within an annulus on the macula to a temperature of 47°C or less, and the laser beam increases the temperature of the target tissue within the transscleral treatment location to 57°C or less. (Item 44) 44. The system of any of items 2-43, wherein the laser source comprises a first diode laser source operable to produce a pulsed laser beam at 810 nm for directing to the transpupillary treatment location, a second diode laser source operable to produce a continuous wave laser beam at 1,475 nm for directing to the transscleral treatment location, and at least one beam splitter mounted to receive the beam at 810 nm and the beam at 1,475 nm and direct them along a common optical path for receipt by the laser scanner. (Item 45) The system of any of items 1-44, further comprising a detector optically coupled to the target ocular tissue, wherein the stored computer readable instructions cause the laser scanner to selectively direct the laser beam to the target ocular location based on changes in position of the target ocular tissue detected using the detector. (Item 46) 1. An extraocular automated method for treating an eye in a subject, the method comprising: directing laser energy having a near infrared wavelength of about 0.5-2.2 μm from a location spaced from the eye to a plurality of transscleral treatment locations for irradiation in a predetermined treatment pattern on an external surface of the eye, the transscleral treatment locations being 0-4 mm posterior to the limbal junction, the laser energy being repeatedly directed to the same irradiated transscleral treatment locations on the surface of the eye, the transscleral treatment locations being irradiated at time intervals sufficient to induce protective thermal preconditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of tissue of the eye. A method comprising: (Item 47) 47. The method of claim 46, further comprising directing laser energy having a near-infrared wavelength of about 0.5-2.2 μm to a plurality of transpupillary treatment locations from a location spaced from the eye to induce a sublethal thermal rise and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations comprising a predetermined curvilinear treatment pattern on a target ocular tissue of the eye comprising a plurality of concentric annuli on the macula surrounding but not on the foveal avascular zone. (Item 48) 48. The method of claim 46 or 47, further comprising directing laser energy having a near-infrared wavelength of about 0.5-2.2 μm from a location spaced from the eye to a plurality of transpupillary treatment locations to induce a sublethal thermal rise and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupillary treatment locations include an area that (i) surrounds the macula but is not over the foveal avascular zone, and (ii) surrounds the optic disc but is not over the optic disc or adjacent peripapillary crescent. (Item 49) 49. The method of any one of items 46-48, further comprising directing laser energy having a near-infrared wavelength of about 0.5-2.2 μm from a location spaced from the eye to a plurality of transpupillary treatment locations to induce a sublethal thermal rise and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupillary treatment locations include an area surrounding the optic disc but not on the optic disc or adjacent peripapillary crescent. (Item 50) 50. The method of any one of items 46-49, further comprising directing laser energy having a near-infrared wavelength of about 0.5-2.2 μm from a location spaced from the eye to a plurality of transpupillary treatment locations to induce a sublethal thermal rise and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupillary treatment locations include areas adjacent to the foveal avascular zone but not over an area of ​​the papillomacular bundle. (Item 51) 51. The method of any one of items 46-50, wherein directing the laser energy to the plurality of transscleral and / or transpupillary treatment locations is performed based on the subject having clinically normal intraocular pressure and / or having no glaucoma symptoms or diagnosis. (Item 52) 52. The method of any one of items 46-51, wherein directing the laser energy to the multiple transscleral treatment locations at intervals sufficient to induce protective thermal preconditioning and biostimulation of targeted structures and elicit biomechanical and biochemical responses is configured to reduce intraocular pressure in the eye. (Item 53) 53. The method of any one of items 46-52, wherein repeatedly delivering the energy to the multiple irradiated transscleral treatment locations comprises delivering the energy in a time interval that targets an increase in temperature of the outer 200-500 μm scleral layer to a temperature of about 45-57° C. (Item 54) 54. The method of any one of items 46-53, wherein directing the laser energy comprises a selected irradiance and scanning speed that increases the temperature of the outer 200 μm scleral layer to a temperature of about 43-57° C., optionally about 43-45° C. (Item 55) 55. The method of any one of items 46-54, wherein the multiple transscleral treatment locations are offset radially outwardly at a substantially uniform distance from the limbal junction or limbus to contour the treatment pattern to the target ocular anatomy. (Item 56) 56. The method of any one of items 46-55, wherein the transscleral treatment locations are within a 360° annular pattern posterior to the limbal junction, and the laser energy is directed to a set of pre-identified transscleral treatment locations on the surface of the eye during a first treatment cycle and during subsequent treatment cycles the laser energy is directed to the same pre-identified transscleral treatment locations to achieve precise cyclical thermal elevation of the scleral tissue underlying the pre-identified transscleral treatment locations in time intervals involving thermal relaxation of the irradiated tissue between treatment cycles. (Item 57) 57. The method of any one of items 46-56, wherein each treatment cycle is performed for a duration that achieves said thermal relaxation by spaced irradiation of said transcleral treatment site at sufficient time intervals to produce a targeted time-temperature history of exposure and relaxation times. (Item 58) 58. The method according to any one of items 46-57, wherein the same transscleral treatment location is irradiated at a time interval that produces a duty time rate corresponding to a ratio between active exposure on time / (active exposure + relaxation off time) in the range of 2-50%. (Item 59) 59. The method of claim 58, wherein the same transscleral treatment location is irradiated at time intervals of about 10-300 ms, optionally about 100-200 ms. (Item 60) 60. The method of any one of items 46-59, wherein the predetermined treatment pattern to which the laser energy is directed is located approximately 1.5 mm posterior to the limbal junction. (Item 61) 61. The method of any one of items 46-60, wherein the predetermined treatment pattern to which the laser energy is directed comprises a plurality of annular treatment patterns, the plurality of annular treatment patterns spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the limbal junction, and the plurality of annular treatment patterns comprise one or more of a circular, oval, elliptical, oval, non-circular, non-elliptical, or asymmetric pattern, or a pattern corresponding to a shape of the limbal junction or the limbus. (Item 62) 62. The method of any one of items 46-61, wherein the laser energy is directed in a 360° predetermined treatment pattern interrupted by 10-30° nasally and 10-30° temporally. (Item 63) The laser energy is (a) Perilibal outflow structure and (b) Ciliary process; (c) Pars plana and The method of any one of items 46-62, wherein the treatment is directed to a transscleral treatment location on a multiple annular treatment pattern targeting the. (Item 64) 64. The method of any one of items 46-63, further comprising placing a heat sink in contact with the eye across the transcleral treatment location to transfer heat away from the surface of the eye. (Item 65) Item 65. The method of item 64, wherein placing the heat sink in contact with the eye comprises placing a curved contact lens on the surface of the eye. (Item 66) Item 66. The method of item 65, wherein placing the contact lens on the eye comprises placing a cooled contact lens that substantially conforms to the surface of the eye. (Item 67) Item 67. The method of item 66, wherein the contact lens is cooled in situ on the surface of the eye. (Item 68) 68. The method according to any one of items 46-67, wherein the laser energy has a near infrared wavelength including wavelengths of 0.8 to 2.2 μm, optionally about 1 to 2.2 μm, 1.0 to 1.7 μm, 0.80 to 0.85 μm, 1.4 to 1.6 μm, and / or 1.47 μm. (Item 69) 70. The method of claim 68, wherein the laser energy has a near infrared wavelength of about 1.4 to 1.5 μm, optionally 1.47 μm. (Item 70) 70. The method of any one of items 46-69, wherein the protective thermal preconditioning and therapeutic biostimulation are controlled by one or more of the power, irradiance, scan speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle of the laser. (Item 71) 71. The method of any one of items 46-70, wherein the laser energy is directed to the treatment location in a spot having a diameter of 500 to 1,000 μm, optionally about 600 μm. (Item 72) 72. The method of any one of items 46-71, further comprising detecting the limbus and / or limbal junction of the subject using an optical imaging system. (Item 73) Item 73. The method of item 72, wherein the predetermined transscleral treatment location is determined by the shape of the limbus and / or limbal junction of the subject's eye. (Item 74) 74. The method of any one of claims 46-73, further comprising spacing the non-contact laser away from the eye with a patient interface, the patient interface comprising a spacer that maintains the eye in a substantially fixed location for imaging and treatment, the spacer maintaining a non-contact laser energy source configured to produce the laser energy spaced away from and out of contact with a surface of the eye. (Item 75) 75. The method of claim 74, wherein the patient interface further comprises a speculum for placement between the eyelids of the subject to expose the eye to the laser energy, the speculum being placed between the eyelids to expose the sclera of the subject. (Item 76) 76. The method of claim 74 or 75, wherein the patient interface further comprises a fixation ring for a contact lens, the fixation ring comprising a resilient sealing surface, the fixation ring being placed against the subject's eye and a suction force being applied between the contact lens and the eye to create a negative pressure and secure the fixation ring to the eye and substantially immobilize the subject's eye. (Item 77) Item 77. The method of item 76, wherein the negative pressure is adjustable. (Item 78) 78. The method according to any one of items 76-77, wherein the spacer and / or the retaining ring and / or the contact lens are cooled while the method is performed. (Item 79) Item 79. The method of item 78, wherein the spacer and / or retention ring are cooled by introducing a cooling fluid through internal fluid flow channels within the spacer and / or retention ring and / or contact lens. (Item 80) 81. The method of any one of claims 46-79, further comprising positioning the patient interface in a treatment location relative to a surface of the subject's eye using a positioning arm. 81. The method of any one of items 47-80, wherein the laser energy is directed in the curvilinear pattern to form continuous concentric annular treatment zones at different radii from the foveal avascular zone. (Item 82) 82. The method of any one of items 47-81, wherein the laser energy is directed in the curvilinear pattern onto the macula through all macular annuli at a common scanning speed such that, for each macular annulus, multiple evenly spaced, overlapping laser pulse spots are delivered in a continuous circular fashion to produce an irradiated annular treatment zone within each annulus. (Item 83) The laser energy is directed at the annulus and has a total laser energy in the range of 50 mJ to 12 J, with a maximum of 20 cm 2 ~30cm 2 The method according to any one of items 47-82, wherein the area is within a range of 100 mW to 2 W of peak pulse power. (Item 84) 84. The method of any one of items 47-83, wherein the laser energy is directed to three to five contiguous concentric annuli on the macula, each annulus having a substantially equal width, and the multiple transscleral treatment locations comprise three concentric annuli on the sclera around the limbus at radii R1, R2, and R3 corresponding to locations covering the primary aqueous outflow pathway, the ciliary body process, and the pars plana, respectively. (Item 85) 85. The method of any one of items 47-84, wherein the laser energy is directed to five consecutive annuli on the sclera, each annulus having a width of about 500 microns, and the plurality of transscleral treatment locations comprises three concentric annuli on the sclera at distances of about 1.5, 2.5 and 3.5 mm from the corneoscleral junction. (Item 86) 86. The method of any one of items 47-85, wherein the sublethal thermal increase corresponds to an increase in temperature of the target tissue within an annulus on the macula to a temperature of 47°C or less, and the laser beam increases the temperature of the target tissue within the transscleral treatment site to 57°C or less. (Item 87) 87. The method of any one of items 47-86, wherein the laser energy directed to the transpupillary treatment location comprises a pulsed laser beam at 810 nm and the laser energy directed to the transscleral treatment location comprises a continuous wave laser beam at 1,475 nm, and the laser energy is directed along a common optical path from at least one beam splitter. (Item 88) 88. The method of any one of claims 47-87, further comprising detecting a position of the target eye tissue, and wherein directing the laser energy is performed using a laser scanner based on the detected position. (Item 89) 89. The method of any one of items 46-88, further comprising detecting the location of the foveal avascular zone and / or optic disc of the subject. (Item 90) 89. The method of any one of claims 46-89, wherein the laser energy is directed in the curvilinear pattern at a constant circumferential scan speed of 1.5 mm / s to 2 mm / s producing a pulse-to-pulse overlap of 99% or more. (Item 91) 91. The method of any one of items 46-90, wherein the laser energy is directed transpupillarily at a pulse repetition period of 2 ms and a pulse duration of 100 μs. (Item 92) 92. The method of any one of items 46-91, wherein the curvilinear pattern is configured to target retinal pigment epithelial (RPE) cells. (Item 93) 1. A patient interface assembly for docking a laser treatment device to an eye to be treated with said laser treatment device, the patient interface system comprising: a lens holder configured to hold a contact lens heat sink against the eye, the lens holder including internal cooling channels in communication with fluid flow inlet and outlet ports; a spacer dockable with the lens holder to hold a laser output at a distance away from the contact lens heat sink; A patient interface assembly comprising: (Item 94) Item 94. A patient interface as described in item 93, further comprising a resilient sealing ring on the lens holder extending around the contact lens and creating a seal chamber between the contact lens and the eye, and retaining the lens holder against the eye when a suction force is applied to the seal chamber and the seal chamber is in communication with an aspiration input port. (Item 95) Item 95. The patient interface of item 94, comprising a contact lens with a central opening that allows air to pass into the seal chamber while still maintaining a negative pressure within the seal chamber. (Item 96) 96. A patient interface according to any one of items 93-95, further comprising a speculum, the speculum comprising jaws that hold opposing eyelid blades in a spaced apart relationship, the blades configured to fit around and retain the lens holder. (Item 97) 97. The patient interface of any one of items 93-96, further comprising a laser triangulation system for Z-focus camera viewing of the contact lens. (Item 98) 98. A patient interface as described in any one of items 93-97, further comprising an XYZ positioner for positioning the patient interface relative to the subject's eye using a sealing ring of the lens holder, and the spacer is docked to the lens holder. (Item 99) 1. A patient interface for docking a laser treatment device to an eye to be treated with the laser treatment device, the patient interface comprising: a spacer, such as a frusto-conical spacer tapering from an enlarged first surface to a smaller second surface, and a laser emission source carried by the cone and spaced from the smaller second surface; a lens holder collar, the lens holder collar tapering from a larger first surface for mating with the second surface of the spacer to a smaller second surface circumscribed by a resilient patient fixation ring and forming a seal against the eye to be treated, the collar including an internal cooling fluid passageway, an inlet port, and an outlet port for circulating a cooling fluid through the collar; a heat sink contact lens held within the collar above the fixation ring, the heat sink contact lens forming an intake chamber between the contact lens and the eye when the collar is docked against the subject's eye; and an intake port in communication with the intake chamber. A patient interface comprising: (Item 100) 99. A method of docking a laser treatment device to an eye to be treated with the laser treatment device, the method comprising: inserting a blade of the speculum into the eye to separate the eyelids and expose the sclera; holding the lens holder between the blades of the speculum and, optionally, sucking air from the seal chamber; activating the XYZ positioner to dock the spacer to the lens holder; and introducing coolant through the internal cooling channels of the lens holder by introducing coolant through the fluid inlet port and out of the fluid outlet port. (Item 101) 101. The method of claim 100, further comprising viewing the contact lens and eye with optical viewing software. (Item 102) 101. The method of claim 100, further comprising viewing the retina of the eye with optical viewing software. (Item 103) 103. The method of claim 101 or 102, further comprising administering laser treatment of the sclera and / or retina through the patient interface with a laser held in spaced relationship to the sclera. [Brief description of the drawings]

[0037] [Figure 1] FIG. 1 diagrammatically illustrates conventional prior art transcorneal laser trabeculoplasty performed using a slit lamp laser delivery system and a corneal contact gonioscopy lens to visualize and intraocularly direct the laser beam to the pigmented trabecular meshwork (TM) below the Schwalbe lines (SL) in the anterior chamber angle of the eye.

[0038] [Figure 2A] 2A and 2B diagrammatically illustrate an example of a transscleral laser trabeculoplasty method in which laser energy is directed to the surface of the eye without contacting the surface. The laser beam is directed extraocularly to the perilimbal area through the corneoscleral junction across the outflow structures. [Figure 2B] 2A and 2B diagrammatically illustrate an example of a transscleral laser trabeculoplasty method in which laser energy is directed to the surface of the eye without contacting the surface. The laser beam is directed extraocularly to the perilimbal area through the corneoscleral junction across the outflow structures.

[0039] [Diagram 3] FIG. 3 illustrates diagrammatically the anatomy of the corneoscleral junction, bounded anteriorly by the corneal limbal junction and posteriorly by the scleral limbal junction.

[0040] [Figure 4A] 4A and 4B are schematic diagrams generally showing one or more locations in an annular treatment pattern with various radii R1, R2, and R3 where a transscleral laser may be directed to the eye. OA is the optical axis of the eye. [Figure 4B] 4A and 4B are schematic diagrams generally showing one or more locations in an annular treatment pattern with various radii R1, R2, and R3 where a transscleral laser may be directed to the eye. OA is the optical axis of the eye.

[0041] [Figure 4C]4C is a front view of the eye, diagrammatically illustrating a treatment pattern of laser irradiation directed to the area of ​​the corneoscleral junction to reduce IOP. The arcuate pattern is interrupted nasally and temporally. The superior and inferior arcs shown are continuous in that they do not have any internal interruptions of the arc.

[0042] [Figure 4D] FIG. 4D is a view similar to FIG. 4C, but illustrates a treatment pattern of laser irradiation directed continuously at the perilimbal region, without nasal and temporal interruptions.

[0043] [Figure 4E] 4E is a front view of the eye similar to FIG. 4C, but showing multiple annular patterns with laser energy directed to the area of ​​the corneoscleral junction at locations R1, R2, and R3 to reduce IOP. The arcs have the optical axis as a common center of curvature, but are spaced posterior to the external limbus and therefore at different distances from the center of the optical axis.

[0044] [Figure 4F] FIG. 4F illustrates a method of applying transcleral laser energy to the eye without contacting the surface of the eye.

[0045] [Figure 4G] 4G, 4H, 4I, and 4J illustrate examples of cycles of cyclic therapy. [Figure 4H] 4G, 4H, 4I, and 4J illustrate examples of cycles of cyclic therapy. [Figure 4I] 4G, 4H, 4I, and 4J illustrate examples of cycles of cyclic therapy. [Figure 4J] 4G, 4H, 4I, and 4J illustrate examples of cycles of cyclic therapy.

[0046] [Figure 4K] FIG. 4K diagrammatically illustrates the angular locations around the right and left eyes.

[0047] [Figure 4L] FIG. 4L diagrammatically illustrates the angle between the optical axis of the eye and the incident laser beam at the surface of the eye.

[0048] [Figure 4M] FIG. 4M diagrammatically illustrates the continued movement of the laser beam as it moves through the contact lens along an annular treatment pattern and induces a heat wave in the sclera.

[0049] [Figure 4N] 4N, O, and P diagrammatically illustrate the three-dimensional heat propagation, accumulation, and relaxation within the scleral wall as a non-contact laser directed at the scleral surface moves rapidly across the sclera. [Figure 4O] 4N, O, and P diagrammatically illustrate the three-dimensional heat propagation, accumulation, and relaxation within the scleral wall as a non-contact laser directed at the scleral surface moves rapidly across the sclera. [Figure 4P] 4N, O, and P diagrammatically illustrate the three-dimensional heat propagation, accumulation, and relaxation within the scleral wall as a non-contact laser directed at the scleral surface moves rapidly across the sclera.

[0050] [Figure 4Q] Figures 4Q, R, S, T, U, V, W, and X are two-dimensional illustrations of the advancement and retreatment of the heat wave through the scleral wall. [Figure 4R] Figures 4Q, R, S, T, U, V, W, and X are two-dimensional illustrations of the advancement and retreatment of the heat wave through the scleral wall. [Figure 4S] Figures 4Q, R, S, T, U, V, W, and X are two-dimensional illustrations of the advancement and retreatment of the heat wave through the scleral wall. [Figure 4T-1] Figures 4Q, R, S, T, U, V, W, and X are two-dimensional illustrations of the advancement and retreatment of the heat wave through the scleral wall. [Figure 4T-2] Figures 4Q, R, S, T, U, V, W, and X are two-dimensional illustrations of the advancement and retreatment of the heat wave through the scleral wall. [Figure 4X] Figures 4Q, R, S, T, U, V, W, and X are two-dimensional illustrations of the advancement and retreatment of the heat wave through the scleral wall.

[0051] [Figure 4Y] 4Y and 4Z are graphs illustrating the effect of laser speed and duty cycle on peak tissue temperature. [Figure 4Z] 4Y and 4Z are graphs illustrating the effect of laser speed and duty cycle on peak tissue temperature.

[0052] [Figure 5A] FIG. 5A is a perspective view of a patient interface for stabilizing and cooling the eye during a transscleral procedure. FIG. 5B is a cross-sectional view of the patient interface illustrating a graphene contact lens held by a contact lens holder that cools the lens and allows for inhalation contact between the lens holder and the eye. Laser triangulation for Z-focus camera viewing is also illustrated. FIG. 5C is a bottom perspective view of the patient interface showing the graphene contact lens surrounded by a silicone seal member. [Figure 5B] FIG. 5A is a perspective view of a patient interface for stabilizing and cooling the eye during a transscleral procedure. FIG. 5B is a cross-sectional view of the patient interface illustrating a graphene contact lens held by a contact lens holder that cools the lens and allows for inhalation contact between the lens holder and the eye. Laser triangulation for Z-focus camera viewing is also illustrated. FIG. 5C is a bottom perspective view of the patient interface showing the graphene contact lens surrounded by a silicone seal member. [Figure 5C]FIG. 5A is a perspective view of a patient interface for stabilizing and cooling the eye during a transscleral procedure. FIG. 5B is a cross-sectional view of the patient interface illustrating a graphene contact lens held by a contact lens holder that cools the lens and allows for inhalation contact between the lens holder and the eye. Laser triangulation for Z-focus camera viewing is also illustrated. FIG. 5C is a bottom perspective view of the patient interface showing the graphene contact lens surrounded by a silicone seal member.

[0053] [Figure 6A] Figure 6A is a perspective view of a speculum, Figure 6B is a perspective view of an embodiment of a contact lens holder retained within the speculum, and Figure 6C is an isolated cross-sectional view of the contact lens holder with internal cooling channels for circulating cooling fluid to cool the contact lens. Figure 6D is an exploded view of the interface cone, contact lens holder, and speculum. Figure 6E is an enlarged side cross-sectional view of the lens holder showing the contact lens arched over the suction chamber. [Figure 6B] Figure 6A is a perspective view of a speculum, Figure 6B is a perspective view of an embodiment of a contact lens holder retained within the speculum, and Figure 6C is an isolated cross-sectional view of the contact lens holder with internal cooling channels for circulating cooling fluid to cool the contact lens. Figure 6D is an exploded view of the interface cone, contact lens holder, and speculum. Figure 6E is an enlarged side cross-sectional view of the lens holder showing the contact lens arched over the suction chamber. [Figure 6C] Figure 6A is a perspective view of a speculum, Figure 6B is a perspective view of an embodiment of a contact lens holder retained within the speculum, and Figure 6C is an isolated cross-sectional view of the contact lens holder with internal cooling channels for circulating cooling fluid to cool the contact lens. Figure 6D is an exploded view of the interface cone, contact lens holder, and speculum. Figure 6E is an enlarged side cross-sectional view of the lens holder showing the contact lens arched over the suction chamber. [Figure 6D] Figure 6A is a perspective view of a speculum, Figure 6B is a perspective view of an embodiment of a contact lens holder retained within the speculum, and Figure 6C is an isolated cross-sectional view of the contact lens holder with internal cooling channels for circulating cooling fluid to cool the contact lens. Figure 6D is an exploded view of the interface cone, contact lens holder, and speculum. Figure 6E is an enlarged side cross-sectional view of the lens holder showing the contact lens arched over the suction chamber. [Figure 6E] Figure 6A is a perspective view of a speculum, Figure 6B is a perspective view of an embodiment of a contact lens holder retained within the speculum, and Figure 6C is an isolated cross-sectional view of the contact lens holder with internal cooling channels for circulating cooling fluid to cool the contact lens. Figure 6D is an exploded view of the interface cone, contact lens holder, and speculum. Figure 6E is an enlarged side cross-sectional view of the lens holder showing the contact lens arched over the suction chamber.

[0054] [Figure 7A] Figure 7A illustrates a speculum that would be placed in a subject's eye to expose the sclera for a transscleral procedure. Figure 7B diagrammatically illustrates an assembled patient interface within the eye. Typically the interface would be inserted into the eye of a person in a recumbent position, but for illustrative purposes, a perspective view is shown. [Figure 7B] Figure 7A illustrates a speculum that would be placed in a subject's eye to expose the sclera for a transscleral procedure. Figure 7B diagrammatically illustrates an assembled patient interface within the eye. Typically the interface would be inserted into the eye of a person in a recumbent position, but for illustrative purposes, a perspective view is shown.

[0055] [Figure 8A]Figure 8A is a cross-sectional view illustrating a patient interface docked to a subject's eye in a recumbent position with laser energy directed to the eye, and Figure 8B is a schematic diagram of a 3-D scanner for imaging the front of the eye for treatment and / or patient interface positioning. [Figure 8B] Figure 8A is a cross-sectional view illustrating a patient interface docked to a subject's eye in a recumbent position with laser energy directed to the eye, and Figure 8B is a schematic diagram of a 3-D scanner for imaging the front of the eye for treatment and / or patient interface positioning.

[0056] [Figure 9A] FIG. 9A is a side view of the control box and source of coolant for the patient interface. The patient interface includes a laser cone projecting from the bottom surface of the control box and connected to the lens holder and speculum. Tubing connects the interface with the source of coolant to cool the lens. FIG. 9B is a perspective view of the control box of FIG. 9A illustrating the tubing clamp that reduces tip / angle stress on the contact lens holder, and more specifically the inlet and outlet tubing for the coolant and the suction force control tubing that communicates with the suction chamber. FIG. 9C is a perspective view of the control arm for positioning the patient interface and docking it with the subject's eye. [Figure 9B] FIG. 9A is a side view of the control box and source of coolant for the patient interface. The patient interface includes a laser cone projecting from the bottom surface of the control box and connected to the lens holder and speculum. Tubing connects the interface with the source of coolant to cool the lens. FIG. 9B is a perspective view of the control box of FIG. 9A illustrating the tubing clamp that reduces tip / angle stress on the contact lens holder, and more specifically the inlet and outlet tubing for the coolant and the suction force control tubing that communicates with the suction chamber. FIG. 9C is a perspective view of the control arm for positioning the patient interface and docking it with the subject's eye. [Figure 9C]FIG. 9A is a side view of the control box and source of coolant for the patient interface. The patient interface includes a laser cone projecting from the bottom surface of the control box and connected to the lens holder and speculum. Tubing connects the interface with the source of coolant to cool the lens. FIG. 9B is a perspective view of the control box of FIG. 9A illustrating the tubing clamp that reduces tip / angle stress on the contact lens holder, and more specifically the inlet and outlet tubing for the coolant and the suction force control tubing that communicates with the suction chamber. FIG. 9C is a perspective view of the control arm for positioning the patient interface and docking it with the subject's eye.

[0057] [Figure 10A] 10A and 10B are schematic diagrams of an automated computer controlled system for the therapeutic method. [Figure 10B] 10A and 10B are schematic diagrams of an automated computer controlled system for the therapeutic method.

[0058] [Figure 11] 11 shows an image of the eye taken by a camera after docking the patient interface and system to the eye, according to an embodiment, with an image of the limbus illustrated on the eye. The limbus location helps to identify the corneoscleral or limbal junction. The anterior border of the limbus is the limbal junction.

[0059] [Figure 12A] FIG. 12A shows an imaging scheme that can be used to estimate the shape of the limbus and the corneoscleral or limbal junction.

[0060] [Figure 12B] FIG. 12B is a flow chart of an exemplary method of imaging and determining a treatment location.

[0061] [Figure 13]13A-13D show an exemplary process for generating a treatment pattern based on one or more locations of the limbus and the corneoscleral junction.

[0062] [Figure 14] FIG. 14 is a flowchart of a method for determining a target treatment location, according to an embodiment.

[0063] [Figure 15] FIG. 15 is a perspective and partially cross-sectional schematic diagram of the human eye.

[0064] [Figure 16] FIG. 16 is a photographic image of the fundus, including the central retina, showing the macula, the foveal avascular zone (FAZ), and the foveola in the center of the image.

[0065] [Figure 17A] Figure 17A is a retinal image similar to that in Figure 16, but showing the target area for pan-macular non-damaging laser photostimulation as viewed through the pupil. A cross-section of the macula is shown below Figure 4A, illustrating the variable thickness of the macula from its center to its peripheral regions.

[0066] [Figure 17B] FIG. 17B is a schematic of a retina similar to FIG. 17A, but including an example of a circular laser beam scanning pattern.

[0067] [Figure 18A] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment. [Figure 18B] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment. [Figure 18C] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment. [Figure 18D] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment. [Figure 18E] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment. [Figure 18F] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment. [Figure 18G] 18A-18G are a series of retinal images similar to FIG. 17B illustrating the pattern of retinal illumination during subsequent pan-macular laser photostimulation treatment.

[0068] [Figure 19] FIG. 19 is a schematic showing the relative location of a laser spot to the central foveal avascular zone (FAZ) that is applied to perform central retinal photostimulation therapy.

[0069] [Figure 20] FIG. 20 is a graph illustrating an example of a retinal heating gradient during treatment.

[0070] [Figure 21] FIG. 21 is a schematic of an exemplary optical imaging and scanning system.

[0071] [Figure 22] FIG. 22 is an end view schematic of an exemplary treatment scan pattern for treating both the sclera and the retina.

[0072] [Figure 23] FIG. 23 is a flow chart of an exemplary method of treatment.

[0073] [Figure 24A] 24A-24C illustrate retinal areas and exemplary laser treatment patterns. [Figure 24B]24A-24C illustrate retinal areas and exemplary laser treatment patterns. [Figure 24C] 24A-24C illustrate retinal areas and exemplary laser treatment patterns.

[0074] [Diagram 25] FIG. 25 is a schematic of an exemplary laser treatment device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] (Detailed Description) term As used in this application and the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Additionally, the term "includes" means "comprises." Furthermore, the term "coupled" does not exclude the presence of intermediate elements between the coupled items.

[0076] The systems, devices, and methods described herein should not be construed as limiting in any way. Instead, the present disclosure is directed to all novel and non-obvious features and aspects of the various disclosed embodiments, both alone and in various combinations and subcombinations with one another. The disclosed systems, methods, and devices are not limited to any specific aspect or feature or combination thereof, and the disclosed systems, methods, and devices are not required to have any one or more specific advantages or problems solved. Any theory of operation is intended to facilitate exposition, and the disclosed systems, methods, and devices are not limited to such theory of operation.

[0077] Although some operations of the disclosed methods are described in a particular sequence for convenience of presentation, it should be understood that this mode of description encompasses permutations, unless a particular ordering is required by specific terminology set forth below. For example, operations described in sequence may, in some cases, be reordered or performed in parallel. Moreover, for purposes of simplicity, the accompanying figures may not show the various ways in which the disclosed systems, methods, and apparatus can be used in conjunction with other systems, methods, and apparatus.

[0078] With reference to the anatomy of the eye, "anterior" refers to the front of the eye, toward the anterior pole. "Posterior" refers to the back of the eye, toward the posterior pole.

[0079] A "limbic-contoured" treatment pattern refers to a treatment location on the surface of the eye that mimics the contour of the limbus of that eye. The treatment pattern may be at the limbus itself or spaced posterior to the limbal junction, but retain the limbal contour of the particular patient being treated.

[0080] "Non-contact laser source" refers to a laser source (e.g., including one or more diodes at the same or different wavelengths, beam splitting optics, beam shaping optics, optical scanner components, etc.) that produces a laser beam that is directed at an intended target and has no parts in contact with the target surface illuminated by the laser source. For example, in a non-contact laser source, the laser beam is not emitted from a probe that is in contact with the surface to be illuminated.

[0081] The "optical axis" of the eye is a straight line passing through the geometric center of the cornea and the nodal (central) point of the eye.

[0082] "Therapeutic biostimulation" refers to the stimulation of biological mechanisms to achieve a therapeutic effect (such as lowering IOP or improving trophic function within the retina).

[0083] "Thermal preconditioning" refers to preliminary mild, stepwise elevated heating of tissue to protect against thermal damage and render it more resistant to damage at more elevated temperatures. Without being bound by theory, it is believed that the initial mild heating ("hyperthermia") induces heat shock proteins that minimize folding or encourage productive refolding of stressed, but still viable, cells, such as those that are non-lethally damaged by laser irradiation.

[0084] Treatment patterns may have a variety of shapes: A circumferential pattern surrounds a curved structure, such as the limbus, for example in a curved or polygonal shape; an "annular" pattern surrounds a reference structure (such as the limbus or foveal avascular zone) and is generally a ring / oval shape.

[0085] References to dimensions of the macula, and associated fovea, foveal avascular zone (FAZ), cone processes, perifovea, parafovea, etc. refer to retinal anatomical features for a typical human eye.

[0086] Introduction The extraocular transscleral automated photothermal laser delivery system reduces intraocular pressure in a subject by irradiating the eye with a non-contact laser energy source configured to direct laser energy from a location spaced from the eye. In disclosed examples, the laser energy has a near infrared wavelength of 0.8-2.2 μm or 1-2.2 μm, such as 1.0-1.7 μm, for example, a wavelength of about 0.80-0.85 μm or a wavelength of about 1.4-1.6 μm. In some disclosed embodiments, the wavelength is 1.47 μm. A processor may be configured with instructions to direct the laser energy to a plurality of treatment locations on the external surface of the eye that are irradiated in a predetermined treatment pattern. The treatment locations may be, for example, 0-5 mm (e.g., 1-5 mm) anterior or 0-4 mm (e.g., 1-4 mm) posterior to the limbal junction, and the laser energy is repeatedly directed to the same irradiated treatment locations of the eye. The treatment site is irradiated for a time interval that induces protective thermal preconditioning and therapeutic biostimulation of one or more structures of the eye, namely the trabecular meshwork and / or the ciliary body, lowering IOP.

[0087] An energy delivery system coupled to the energy source and the processor is configured to repetitively deliver energy to multiple predetermined irradiation treatment locations on a predetermined treatment pattern at time intervals that specifically induce protective thermal preconditioning, propagation of thermal waves to targeted structures deeper within the eye, and hyperthermia and biostimulation of the targeted structures. Without being bound by theory, it is believed that these photothermal effects activate a cellular biological chain that ultimately induces biomechanical and biochemical responses, such as modification of the extracellular matrix, that reduce intraocular pressure, without photocoagulation and destruction of tissue.

[0088] In some embodiments, the processor is configured with instructions to repeatedly deliver energy to a plurality of irradiated treatment locations at time intervals that specifically target an increase in temperature of the outer 200-550 μm scleral layer to a temperature of about 43-57° C. For example, the irradiance of the laser energy and the scanning speed at which the laser energy moves around in the treatment pattern increases the temperature of the outer 200-550 μm scleral layer to a temperature of about 43-57° C. or less than 45° C. or about 43-45° C. The increase in temperature of the tissue is, for example, no more than 8 or 10° C. above the baseline temperature of the tissue. The peak temperature of the tissue is below the coagulation temperature of the irradiated tissue. The processor may be configured with instructions to receive an input corresponding to a location of the limbal junction or limbus of the target and, in response to the input, determine a plurality of treatment locations. The treatment locations are offset radially outward from the input location corresponding to the limbal junction or limbus to contour the treatment pattern to the anatomical structure of the target eye to achieve customized delivery of thermal waves to the targeted deeper structures.

[0089] In some examples, the treatment locations are in a 360° pattern posterior to the limbal junction. The treatment locations can be coextensive with the 360° treatment pattern or only along a portion of the treatment pattern (e.g., within multiple arcs or spots on the treatment pattern). The processor directs laser energy to a set of pre-identified treatment locations on the surface of the eye during a first treatment cycle, and directs laser energy to the same or a subset of the same pre-identified treatment locations during one or more subsequent treatment cycles (repeated cycles). The precise cyclical heat rise of the scleral tissue underlying the pre-identified treatment locations over a time interval induces a heat rise / relaxation cycle of the irradiated tissue, causing the propagation of heat waves to target structures deeper within the eye between treatment cycles.

[0090] In some embodiments, the processor achieves thermal relaxation by spacing the irradiation of the treatment location at time intervals that set the rate of each treatment cycle and produce a targeted time-temperature history. For example, the time intervals between irradiation of the same treatment location produce a duty cycle ratio (ratio between active exposure on time / [active exposure + relaxation off time]) in the range of 2-50%. In some examples, the time intervals between irradiation of the same treatment location are about 10-300 ms, e.g., 100-200 ms. However, the time intervals between irradiation of a specific treatment location may vary depending on other parameters.

[0091] In some examples, the predetermined treatment pattern extends through all or a portion of a 360° limbus-guided circumferential pattern or annulus located approximately 1-1.5 mm posterior to the limbal junction. Although generally reference is made to an annular treatment pattern, the energy pattern can be delivered in many configurations, such as a portion of an annulus, a polygon, or intermittent treatment along a generally circumferential pattern. In one example, the treatment pattern extends through a 120° arc. Other predetermined treatment patterns may extend through a generally annular shape approximately 2 mm-3 mm and / or 3 mm-4 mm posterior to the limbal junction. Because the limbus and limbal junction may be other than circular, a pattern spaced a fixed distance from the limbal junction through 360° will mimic the shape of the limbus and limbal junction. The limbal guidance pattern may be, for example, oval, elliptical, generally arcuate with non-arcuate segments, or irregularly shaped, but otherwise circumscribing the limbus. The treatment pattern provides a template upon which treatment locations may be located, and the treatment locations on the treatment pattern may be either continuous (in a continuous pattern) or discontinuous (spaced treatment locations, such as spots or arcs, positioned at intervals around the periphery of the treatment pattern).

[0092] The predetermined treatment pattern may be one or more treatment patterns that specifically and / or differently target aqueous humor production and outflow pathways such as the ciliary body and trabecular meshwork. In some examples, the annuli are spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the limbal junction to target the outflow pathways at 1.5 mm, the ciliary body processes at 2.5 mm, and the pars plana at 3.5 mm. The 360° pattern may be interrupted to avoid anatomical structures within the eye that may be harmed by irradiation. For example, the pattern is interrupted nasally and temporally, such as 10-30° nasally and / or 10-30° temporally. In some examples, a heat sink, such as a curved contact lens, is placed in contact with the eye over the treatment site to transfer heat outward and away from the treated surface of the eye. The lens may be a cooled lens that substantially conforms to the surface of the eye, either pre-cooled or cooled in situ while lowered horizontally onto the surface of the eye.

[0093] The protective thermal preconditioning and therapeutic biostimulation may be controlled by one or more of the laser power, irradiance, scan speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle. For example, the processor is configured to direct the laser energy to the treatment location within a spot having a diameter of 500-1,000 μm, e.g., about 600 μm. The system may also include an optical imaging system for detecting the subject's limbus and / or limbal junction. The processor may be configured to identify the predetermined treatment location as determined by the shape and size of the limbus and / or limbal junction of the subject's eye. The 360° location identified by the processor may be circular, oval, elliptical, ovoid, non-circular, non-elliptical, asymmetric, or other shape as determined by the anatomy of the individual limbus. The contoured annulus patterned by the shape of the limbus or limbal junction is, in effect, a larger (e.g., larger diameter) version of the limbus or limbal junction of the specific subject being treated.

[0094] Disclosed embodiments of the method deliver laser energy, e.g., near-infrared laser energy (such as from a 1.475 μm IR laser) with low scattering transscleral. The laser may be a continuous wave (CW) infrared laser. The laser energy interacts primarily with water-containing cells in the superficial sclera (e.g., to a depth of 200-500 μm just below the surface of the sclera) instead of interacting with pigmented cells in deeper ocular structures such as the trabecular meshwork. When intracellular water absorbs the laser energy in the superficial sclera, a heat rise is generated and cellular transduction chains in deeper ocular structures are affected. The laser energy may be applied repeatedly and specifically to the same treatment location at time intervals spaced in time by the period of the treatment cycle, generating a thermal wave at each treatment location that propagates three-dimensionally or 360° spherically into the deeper scleral layers and structures of the aqueous humor outflow tract and / or ciliary body. Energy delivery achieves phototherapy threshold through a slow photothermal rise that avoids complications such as those associated with ALT burns or cavitation interactions of SLT. The method avoids the need for gonioscopy targeting of the laser to the trabecular meshwork at the iridocorneal angle (FIG. 1) and avoids the iatrogenic disadvantages of moving a contact probe across the surface of the eye. The procedure may also be performed under local anesthesia and without a retrobulbar block.

[0095] In one disclosed embodiment, the laser is continuously illuminated in a 360° treatment pattern or portion of a pattern, starting at 0° in a clockwise direction and moving in one direction through 360° before beginning the cycle again and repeating. Such a cycle may alternatively proceed in a counterclockwise direction or in a ping-pong fashion around non-adjacent locations on the treatment pattern to complete the cycle. For example, a laser spot of a defined diameter may successively illuminate a target pattern in a ping-pong fashion at 0°, 180°, 10°, 190°, 20°, 200°, 30°, 210°, 40°, 220°, etc. throughout the entire 360° pattern, forming either a continuous or intermittent pattern. In some disclosed examples, each cycle illuminates selected treatment locations, and all treatment locations may be illuminated before proceeding to the next cycle. The multiple treatment locations on the pattern may correspond to angles within a range of about 30° to about 360° around the sclera of the eye, e.g., within a range of about 90° to about 360°, within a range of about 90° to about 150°, 160, 170, or 180°, or within a range of about 180° to about 360°. The multiple treatment locations may correspond to angles of about 30°, about 45°, about 60°, about 75°, about 90°, about 150°, about 180°, about 270°, or about 360°.

[0096] The treatment pattern may be a continuous treatment pattern, such as an annulus, forming an uninterrupted curve, or an intermittent treatment pattern with spaces between treatment "dashes" or "spots" along the treatment pattern. The treatment pattern may be multiple treatment patterns, and the multiple patterns may be overlapping or non-overlapping. For example, the multiple annuli may overlap to generate a treatment annulus with a width that exceeds the spot size of the laser energy beam. The non-overlapping annuli will have a predetermined radial distance between each of the multiple treatment patterns. For example, each non-overlapping treatment pattern may be a different fixed distance from the limbal junction, such that each of the patterns is a different circumferential limbal contour guidance pattern.

[0097] In some embodiments, the scanning speed of the circumferential movement of the laser around the treatment pattern to treat all treatment locations determines the time interval between irradiation of each treatment location on the annulus. Movement of the laser during the time interval between repeated irradiation of a particular treatment location fractionates the delivery of energy to each treatment location and allows for thermal relaxation between irradiation of each treatment location. The total energy delivered to each treatment location may be determined in part by the number of cycles, where the total energy is the product of the number of cycles times the energy applied per cycle.

[0098] Detailed Description of the Illustrated Embodiments (FIGS. 2-4) Detailed embodiments of the method and system are described with reference to the drawings. Figure 2A illustrates a schematic of a method of lowering IOP. Laser energy is emitted from a non-contact laser energy source 18 spaced from the surface of the eye and directed toward the corneoscleral junction 20, which is the transition zone between the cornea and the sclera. Figure 2B is an enlarged view of the box in Figure 2A, illustrating in more detail the corneoscleral junction, where the laser energy is directed to propagate a thermal wave to the underlying trabecular meshwork and other structures of the aqueous humor outflow pathway. Figure 3 is a further enlarged view of the corneoscleral junction 20, where the cornea 22 abuts the sclera 24. The limbus 26, which forms the corneoscleral junction, is bounded internally (within the eye) by Schwalbe's line (SL) 28 and the scleral promontory (SS) 30. The limbus 26 is bounded externally (at the surface of the eye) by the corneal limbal junction (CLJ) 32 and the scleral limbal junction (SLJ) 34. The CLJ 32 is also known as the apparent or anterior limbus, and the SLJ 34 is also known as the surgical or posterior limbus. The conjunctiva and Tenon's capsule (not shown) fuse before inserting approximately 0.5 mm posterior to the CLJ. The aqueous humor-producing inferior ciliary body 36 is divided into the ciliary process 38 and the pars plana 40. The trabecular meshwork (TM) 42 is located around the base of the cornea 22 near the ciliary body 36 and is part of the apparatus for draining aqueous humor from the eye. Schlemm's canal 44 is a circular lymphatic vessel around the base of the cornea 22 adjacent to the trabecular meshwork 42, which is also part of the aqueous humor outflow pathway. The distance from the corneal limbal junction 32 to the scleral limbal junction 34 is approximately 2 mm in a typical eye.

[0099] Irradiation of the limbus and / or perilimbal area propagates a heat wave that travels through the sclera and photostimulates most of the structures of the primary aqueous humor outflow pathway, such as the collecting duct and / or its ostium, Schlemm's canal, para-Schlemm's canal TM, corneoscleral TM, and uveal TM. All these structures are within the space directly below the limbus. In some cases, only a single treatment pattern at a distance R1 posterior to the limbal junction is used. In other cases, two treatment patterns at R1, R2 posterior to the limbal junction are used to achieve a larger spread of the heat wave to more of the structures of the aqueous humor outflow pathway and / or aqueous humor producing structures (within the ciliary body). In still other cases, three treatment patterns R1, R2, R3 posterior to the limbal junction are treated to achieve a broad spread of the heat wave to the targeted structures of aqueous humor production and outflow. In other embodiments, more than three treatment patterns can be used, such as, for example, four, five, or six treatment patterns, each at a fixed distance from the corneoscleral junction.

[0100] The distances R1, R2, R3 from the limbal junction can be custom patterns that mimic the often irregular contour of the limbal junction, such that each of R1, R2, R3 is a constant distance from the limbal junction, but a different distance from the optical axis throughout the 360° of the pattern. Alternatively, the distances R1, R2, R3 are fixed distances from the optical axis throughout the 360° of the pattern, such that the treatment pattern has a substantially constant radius. For example, in a subject with a mean corneal radius (measured from the optical axis) of 6 mm, R1 may have a fixed radius of 7.5 mm from the optical axis and space it on average 1.5 mm away from the limbal junction. R2 may have a fixed radius of 8.5 mm from the optical axis and space it on average 2.5 mm away from the limbal junction, and R3 may have a fixed radius of 9.5 mm from the optical axis and space it on average 3.5 mm away from the limbal junction.

[0101] 3, 4A, and 4B show examples of locations where the perilimbal region may be irradiated at distances R1, R2, and / or R3 posterior to the limbal junction 32. For example, R1, R2, and R3 may be approximately 0, 1.5, and 2.5 mm posterior to the limbal junction 32 or approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the limbal junction 32, respectively. In some examples, R1 may be 0-2 mm posterior to the limbal junction, R2 may be 2-3 mm posterior to the limbal junction 32, and R3 may be 3-4 mm posterior to the limbal junction 32. In other iterations, R1, R2, and R3 may be any combination of, for example, R1 = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, or 1.7 mm or more posterior to the limbal junction, R2 = 2.25, 2.5, 2.75, 3.0, or 3.25 or more posterior to the limbal junction, and R3 = 3.5, 3.75, 4.0, 4.25, 4.5, 4.75 mm or more posterior to the limbal junction. In some embodiments, R1 is about 1-2 mm from the limbal junction, R2 is about 2-3 mm posterior to the limbal junction, and R3 is about 3-4 mm posterior to the limbal junction, and R1, R2, and R3 are different distances.

[0102] In some embodiments, the ocular anatomy may be imaged, for example, using a surgical microscope, to identify the shape of the limbus for overlaying on a treatment pattern that may then be applied to the eye at the designated treatment location by automated illumination of the treatment location. In other embodiments, an image analysis software program will recognize the limbus and its anterior edge (limbal junction). The automated system may be programmed to identify a treatment pattern based on a "custom limbus" pattern, in which the treatment annulus is offset posteriorly from the limbal junction by a selected fixed distance from the limbal junction such that the treatment annulus mimics the actual shape of the patient's limbus. The shape of the limbus often varies between patients, and thus customizing the contour of the treatment pattern to the contour of the patient's limbus improves treatment outcomes and / or avoids side effects that may result from unintentional illumination of eye structures in patients with unusual eye anatomy.

[0103] For example, imaging and automated movement of the laser beam along a treatment pattern in a preprogrammed treatment pattern achieves precise irradiation of sequential treatment locations on a custom limbal pattern. The automated process allows controlled timing of the time intervals required for the laser to move through sequential treatment locations to set a preselected period of delay before subsequent irradiation of sequential treatment locations during subsequent treatment cycles of the cyclical treatment. Because the laser energy is not applied from a contact probe, the laser beam may move across the sclera or other portions of the eye at much faster speeds than can generally be achieved with a contact and indentation probe.

[0104] Optical coherence tomography (OCT) or high intensity focused ultrasound (HIFU) are examples of imaging modalities used to identify one or more of the targeted structures. For example, the 360° location of the inner and outer edges of the limbus may be imaged by OCT as disclosed in U.S. Pat. No. 9,618,322. Once the anterior edge of the limbus has been identified and mapped, a treatment location may be selected on an annulus that is offset from the anterior edge by a desired distance R1, R2, and / or R3. An automated system can then precisely deliver the treatment annulus or annuli at a reproducible location.

[0105] Locations R1, R2, and R3 irradiate the sclera covering different structures of IOP homeostasis, such as aqueous outflow pathways and production structures. In the illustrated example, R1 is positioned to irradiate the primary aqueous outflow pathway, R2 is positioned to irradiate the aqueous-producing ciliary body processes, and R3 is positioned to irradiate the pars plana and non-conventional uveoscleral outflow pathways. Tailoring the location of the treatment pattern to the specific anatomical structures of the target eye improves treatment outcomes while reducing the likelihood of complications. The operator may assess the reasons for the loss of IOP homeostasis in a particular patient and direct laser energy to targeted locations that will restore IOP homeostasis. In one example, if increased IOP is likely due to excessive aqueous production, laser energy and thermotherapy stimulation may be directed at least or exclusively to the ciliary body (such as the ciliary body processes at R2 and / or the pars plana at R3). If the increased IOP is deemed to be due to resistance within the conventional or uveoscleral outflow pathway, the laser energy and cryostimulation may be directed at least or exclusively to R1. If the increased IOP is likely due to both overproduction and impaired outflow of aqueous humor, both production and outflow pathways may be targeted, for example, at R1, R2, and R3.

[0106] In the embodiment shown in FIG. 4C, an annular treatment pattern is applied at a distance of about 1.5 mm posterior to the limbal junction, and the treatment locations are interrupted to form multiple arcs, such as superior arc 50 and inferior arc 52. Each of these illustrated arcs is uninterrupted in that the treatment locations are continuous and not spaced apart, but the arcs are separated by temporal and nasal interruptions to avoid irradiation of structures within the area. The continuous locations are treated by moving the continuous wave laser beam along the arc with the laser on. The interruptions may be formed by turning the laser off and on in pulses to form non-contiguous treatment locations. In some embodiments, the laser beam is moved circumferentially over the superior and / or inferior arcs 50, 52 with a steady and reproducible speed by a computer-driven electro-optical scanner, which ensures consistent and consistently reproducible treatment with a reliable amount of laser energy deposition. In FIGS. 4C and 4E, the laser energy is delivered in an arcuate pattern to produce two 150° arcs. The arc shown is sustained except for being interrupted at approximately the 8:30-9:30 o'clock (255°-285°) and 2:30-3:30 o'clock (75°-105°) positions to avoid the long ciliary nerve, minimize pain, and avoid the risk of anterior segment ischemia.

[0107] In FIG. 4D, an annular treatment pattern 54 is applied at a distance of about 3.5 mm posterior to the limbal junction, but in a non-intermittent pattern that is not divided into upper and lower arcs. In FIG. 4E, multiple annular treatment patterns are applied at R1, R2, and R3 within the upper and lower arcs. FIG. 4F illustrates a treatment pattern that includes an upper primary arc 56 and a lower primary arc 58, each of which is itself a series of secondary intermittent arcs that are irradiated by a laser beam whose path or shape pulses (on / off) as it moves through the arcs 56, 58, respectively. The laser beam in this case does not continuously irradiate the eye along the entire path of the upper primary arc 56 or the lower primary arc 58. The sequence of irradiating the treatment location does not have to be gradual in a circular direction around the eye at all times. For example, one of the sub-arcs in the primary arc 56 may be irradiated followed by irradiation of the sub-arcs in the lower arc 58, with the irradiation pattern ping-ponging back and forth between the arcs 56, 58. However, the sequence in which the sub-arcs are irradiated is generally the same in each treatment cycle, setting up a preselected period during which desired thermal relaxation can occur at each treatment location before the next irradiation cycle begins.

[0108] The speed of movement of the laser beam along the arc and / or the use of a pulsed laser can both affect the duty cycle, with the selection of a uniform period per cycle establishing a fixed interval between irradiation of each treatment location. The period of each cycle is the time between the start of the first cycle and the start of the next cycle. A uniform period per cycle may be achieved by moving the laser beam at a constant speed through multiple cycles. The laser beam is moved at a sufficient speed, such as 1-100 mm / sec or 1-50 mm / sec, to achieve the desired thermal preconditioning and relaxation. In some embodiments, the speed is at least 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mm / sec. In some embodiments, the speed is 200 mm / sec or less.

[0109] The period of thermal relaxation at each treatment location is also set by the period of each cycle. For example, in FIG. 4G, a single cycle is illustrated that starts irradiating the eye at the 90° location and continues clockwise around the eye through 180°, 270°, and 360° locations before returning to the 90° location. The next cycle then repeats the process. This pattern can be repeated, for example, by moving the laser beam of a continuous wave (CW) laser over the surface of the eye in a treatment pattern to set the period of thermal relaxation for each treatment location at a speed such as a preselected constant speed. For example, the treatment location at 90° will be the first location irradiated in the first cycle and the first location irradiated in the second and subsequent cycles. The time interval between irradiation of the 90° treatment location in this embodiment is equal to the period of the cycle.

[0110] In the example of FIG. 4H and FIG. 4K, the cycle begins with the laser illuminating the surface of the eye at 285° and moves along the treatment annulus to the 75° location. The laser is then turned off as the laser moves from the 75° to the 105° location, but the laser is then turned on again at the 105° to 255° location. In this case, the formation of the upper and lower arcs occurs in one cycle. In some examples, only one of the upper or lower arcs is illuminated, and in such cases the laser may start at 285° and move to 75° for the completion of one cycle. The next cycle will then start at 285° and move to 75° for the completion of the subsequent cycle, either by continuing the clockwise movement of the laser beam around the eye, or by redirecting the laser beam directly from the 75° location to the 285° location. Each movement of the laser through the 360° annular pattern (or treatment of all locations within the pattern being used) will be one treatment cycle, which can be repeated as many times as desired. The period for thermal relaxation (period of cycle) is generally fixed throughout multiple irradiation cycles by moving the laser beam at a constant speed throughout the cycle, however, variable intervals may also be used to achieve a therapeutic effect as desired.

[0111] FIGURE 4I illustrates yet another example of a treatment pattern including multiple arcs of intermediate length around a treatment annulus applied in a clockwise fashion. FIGURE 4J illustrates yet another treatment pattern in which a treatment annulus is made of multiple laser spots or arcs applied in a sequential fashion. A first cycle may constitute the completion of the sequence of arcs in FIGURE 4I or the sequence of laser spots shown in FIGURE 4J, and subsequent cycles would constitute subsequent episcleral irradiations in the same location and in the same sequence applied in the first cycle.

[0112] For illustrative purposes, the treatment patterns described are applied in a clockwise direction, but they may of course also be applied counterclockwise or in other patterns that do not move uniformly in one direction or the other around the eye. The cyclical nature of the repeated irradiation of the same location is illustrated with respect to FIG. 4K, which divides the right and left eyes into 36 equally spaced 10° sections. Treatment locations may be identified, for example, at each of the 10° locations or a subset of those locations. Treatment locations may also be located between the 10° locations. The direction of clockwise movement of the laser beam around each eye is illustrated by arrows 54, 56.

[0113] FIG. 4L diagrammatically illustrates an eye 70 having a cornea 72 and an optical axis OA that passes near the center of the cornea and is normal (perpendicular) to the surface of the cornea. A laser energy source (such as a CW diode laser) 74 is spaced outwardly from the eye 70 and directs a laser beam 76 toward the surface of the eye at an angle θ relative to the OA to generate a thermal wave that irradiates the surface of the eye and penetrates the aqueous outflow tract structures and / or the ciliary body. The laser beam does not continue into the center of the sphere, but the path of the laser is traced in dashed lines to the center of the eye to illustrate the angle between the laser beam and the OA. In this example, the angle θ is 30-50°, e.g., 35-40°, although the angle at which the beam 76 impinges on the eye may vary since the therapeutic effects of the disclosed methods are achieved by the generation of waves that propagate non-specifically through the sclera and may heat the aqueous outflow tract structures and / or the ciliary body. The laser beam therefore does not have to be aimed directly at the structure in order to take advantage of the propagating thermal waves.

[0114] FIG. 4M illustrates a laser beam 76 directed at the sclera 78 through a heat sink contact lens 80 on the surface of the sclera 78. The beam 76 has a width 82 (e.g., 600 nm), and the beam 76 travels in a travel direction 84 with a selected speed to generate a heat wave 86 that spreads three-dimensionally in the xyz directions through the superficial sclera toward the underlying target to modulate IOP homeostasis. As the beam 76 travels in the y direction along the sclera 78, the heat wave is propagated three-dimensionally along the path of the laser to the underlying tissue. For example, the laser is moved along the pattern shown in any one of FIGS. 4C-4J. The angle of impact with the sclera may be selected to minimize reflection and scattering of the laser energy and promote effective tissue penetration. In some embodiments, the laser impacts the sclera at an angle of 90±45° relative to the ocular tangent at the point of impact. As discussed below, the contact lens 80 or the sclera 78 itself can contribute to or produce the general propagation direction of the beam 76 into the sclera 78 .

[0115] The contact lens 80 (FIG. 4M) acts as a heat sink, transferring heat away from the surface of the eye. Heat sinks are fully disclosed in US2018 / 0177632, which is incorporated by reference unless inconsistent with this disclosure. In summary, the lens has suitable optical properties to allow visualization of the eye through the lens and also provide or assist in providing a selected angle of incidence on the sclera. In an exemplary embodiment, light is directed parallel to the optical axis of the objective lens to the eye using a laser scanner (such as a two-mirror galvanometer scanner) through an objective lens (such as an F-theta lens), and typically the OA of the eye is colinearly aligned with the optical axis of the objective lens. Because the sclera and eye have a refractive index (e.g., 1.3-1.5) that exceeds that of air (approximately 1.0), and the radial location of the impingement at the sclera is associated with a tangent that is not perpendicular to the OA of the eye, the incident laser beam will be refracted at an angle toward the OA of the eye, rather than parallel to it, even without the presence of contact lens 80. Contact lens 80 can also assist in this refraction with a preconfigured refractive index or curvature that produces a desired angle of incidence with respect to the sclera for the beam received at contact lens 80 propagating parallel to the OA of the eye.

[0116] Generally, the lens has optical smoothness with maximized transmission of the laser beam and low light scattering to allow visualization of the eye, for example, through a CCD or CMOS camera or through a surgical microscope. The lens may be multi-layered, for example, containing layers of graphene, to improve the heat transfer properties of the lens. The lens may also be cooled, for example, by one or both of pre-cooling and in situ cooling on the eye. A patient interface for performing in situ cooling is illustrated in Figures 5A-5C.

[0117] Three-dimensional time-dependent propagation of heat waves The propagation of the thermal wave through a section of the scleral wall over time is further illustrated in Figures 4N-P. These figures illustrate the sequential events resulting from laser illumination on an annulus, illustrated by the sliding of a series of interrupted spots from a laser beam moving across the scleral surface at a speed of 50 mm / sec. The laser energy is applied generally perpendicular to the scleral surface in Figure 4N, and as each laser spot is illuminated, heat propagates in the thermal wave toward deeper structures below the scleral surface. Figure 4O shows that the thermal wave propagates deeper into the sclera until it reaches targeted subscleral structures (inset), such as the trabecular meshwork and ciliary body. In Figure 4P, the wave again fades toward the scleral surface as thermal relaxation occurs. Although this sequence is illustrated for one such spot in Figures 4N-P, the same process occurs in each of the laser spots as the laser moves across the scleral surface.

[0118] Figures 4Q-4X similarly illustrate the propagation and decay of the thermal wave toward and away from the trabecular meshwork (TM level). In Figure 4Q, the thermal wave is propagated to the scleral surface by laser illumination. In Figures 4R, S, T, and U, the wave advances gradually over the next 1.64 seconds, penetrating and passing into the TM. Figures 4V, W, and X show a period of thermal relaxation during which the thermal wave moves away from the TM level and back toward the scleral surface.

[0119] FIG. 4Y illustrates that the peak temperature increase of the irradiated tissue can be controlled by modifying the speed of laser movement relative to the sclera. The peak tissue temperature increases as the speed of laser movement decreases because more energy is delivered to each irradiated location at constant laser power and duty cycle per unit time. The graph shows the peak temperature change of the irradiated scleral tissue at a laser power of 0.8 W and a duty cycle of 3.44% when the laser is moved at 5, 10, 25, and 50 mm / sec through a 200° arc.

[0120] 4Z illustrates that duty cycle can also be used in combination with laser speed to control peak tissue temperature. In the illustrated example, peak temperatures were compared at 0.8 W laser power moving through a 4° arc with a duty cycle of 11.5% or 172% at laser speeds of 5, 10, 25, and 50 mm / sec. Peak temperatures were substantially similar for both duty cycles at 10, 25, and 50 mm / sec, but at the slower laser speed of 5 mm / sec, the peak temperature increased from approximately 33° C. to 37° C.

[0121] Beam Size The diameter of the laser beam at the surface of the eye is large enough to direct the heat waves to the targeted aqueous humor producing and / or aqueous humor outflow structures. Beam placement refers to the location of the center of the beam relative to a reference point. For example, the diameter of the beam may be 500-1,000 μm, such as 600 μm. The 600 μm diameter laser beam may be centered on an annular treatment pattern 1.5 mm posterior to the corneal limbal junction to therapeutically stimulate most of the primary aqueous humor outflow pathway structures with generated heat and diffusing heat waves. The 600 μm diameter laser beam may also be projected in an annular pattern with the beam centered 3.5 mm posterior to the corneal limbal junction to target the non-conventional uveoscleral outflow pathways of the pars plana. In some embodiments, the 600 μm diameter laser beam may also be projected in an annular pattern with the beam centered 2.5 mm posterior to the corneal limbal junction to target the ciliary body processes.

[0122] Transscleral laser circulation irradiation with beams of this size induces a localized photothermal rise that produces a biomechanical response with movement and reorganization of the aqueous humor outflow pathways, enhancing both conventional (trabecular meshwork) and non-conventional (uveoscleral) outflow, along with fine morphological changes in the microstructure of the corneal limbus, ciliary processes, and pars plana regions, resulting in early IOP reduction. Concomitant photothermal hyperthermia (e.g., to temperatures of 43-45°C), without scleral photocoagulation, leads to thermal diffusion and attenuation in the surrounding tissues, re-equilibrating the treatment site toward or back to baseline body temperature. Without wishing to be bound by theory, it is believed that repeated irradiation and thermal attenuation induce a biochemical response with a biological cascade of cytokine expression and subsequent endogenous molecular transcriptional activity that contributes to the long-lasting IOP-lowering effect.

[0123] As an example, IR laser wavelengths of 1.475 μm provide a safe and effective time-temperature history profile that lowers IOP through one or more of increased trabecular meshwork outflow (trabeculoplasty-effect), increased uveoscleral outflow effect, and decreased aqueous humor production (ciliary process therapy effect). Different time-temperature history profiles can produce photocoagulation, photostimulation, and hyperthermia without undesirable tissue coagulation by thermally preconditioning the scleral tissue and inducing thermotolerance. Thermotolerance is a temporary state of resistance to heat-induced cell death, which is achieved by repeatedly irradiating the treatment site at spaced intervals and gradually increasing the temperature. The gradual increase in tissue temperature is believed to activate natural protective mechanisms, such as autothermoregulation and production of heat shock proteins, which ultimately increase the tissue's thermotolerance and exert repair and regenerative effects on the surrounding dysfunctional cells. Thermotolerance allows the treatment site to be repeatedly irradiated while minimizing tissue damage to the treatment site.

[0124] Irradiance, scan speed, exposure time, cycle repetition rate The combined therapeutic effect and protective thermal preconditioning are controlled by various factors that control the temperature generation-rebalancing photothermal process. These parameters are laser power (W) and irradiance (W / cm 2 ), exposure time (scanning speed in mm / sec), and cycle repetition rate (period T between two successive exposures on the same cell spot), which determines the duty time percentage, i.e., on-time / period T (%) and the number of cycle repetitions (total treatment duration). The laser beam is projected through a limbus-guided scanning computer-controlled electro-optical delivery system to irradiate the sclera in different arc patterns, at different distances posterior to the limbus, at programmed scan speeds (exposure times) and other selected variables, and may generate unique time-temperature histories with photothermal rise that concomitantly produce IOP-lowering biomechanical and biochemical responses.

[0125] Laser irradiance (W / cm 2 The power per unit of area in mm (power per unit of area in mm / sec) and scanning circular speed (mm / sec) may be selected to produce a temperature rise of 8-20°C above the 37°C body temperature in the sclera when illuminated by a scanning laser beam, e.g., a 0.6 mm diameter laser beam. -1 ), the temperature of the first 200 μm deep scleral layer (160–200 μm from the conjunctiva through the scleral depth) is a function of the laser irradiance (W / cm 2By controlling the laser power (e.g., 50%, 40%, 30%, or 20%) and exposure duration (determined by the scanning speed in mm / sec as well as the number of repetitions), the laser power for the first treatment cycle may be set to start at a certain fraction of the threshold power (e.g., 50%, 40%, 30%, or less than 20%) that would cause an immediate coagulation response, in order to reduce the risk of cumulative thermal damage to the superficial first absorbing layers of the conjunctiva and sclera. At the completion of the first cycle, the laser power is automatically increased stepwise in each successive cycle (e.g., 25% in the second cycle, 30% in the third cycle, and up to 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% in each successive cycle), reaching 100% in the 17th cycle without causing any visible coagulation effect due to a thermal conditioning process that increases heat tolerance or resistance to thermal cell death. In an alternative embodiment, the targeted peak temperature may be rapidly reached and then decreased to maintain a dwell period at the peak temperature rise.

[0126] When an electro-optical scanner moves the beam at a constant circular speed of 50 mm / sec around the treatment annulus, each portion of the scleral annulus illuminated by the 0.6 mm diameter beam receives an exposure duration of 12 ms (0.6 mm÷50 mm / sec=0.012 s), increasing the local temperature. As the laser beam moves away, the exposure and heat production is terminated, but the generated heat diffuses and attenuates towards the adjacent surrounding cooler tissue in a thermal relaxation process, eventually re-equilibrating with the body baseline temperature (37° C.). This thermal relaxation process is interrupted when the laser beam is returned to the same spot after completing a 360° cycle and beginning the next cycle, converting the thermal relaxation into a new temperature increase. In one example, using treatment in a circular pattern with a 13 mm diameter and 40 mm circumference, each cycle would take approximately 800 ms (40 mm ÷ 50 mm / sec = 0.8 s) to deliver with a 1.5% duty cycle (12 ÷ 800 = 0.015 or 1.5%).

[0127] In some embodiments, the duration of exposure of each portion of the scleral annulus is about 2-120 ms, e.g., 2-20, 10-20, 10-15, 12, 24, 60, or 120 ms. In some embodiments with a constant 0.6 mm (600 μm) beam diameter spot size, the duration of illumination at each point within the center of the annulus width can depend on the beam circular scan speed. That is, at 1.0 mm / sec, the exposure time in each cycle is 0.6 s or 600 ms, at 5.0 mm / sec, the exposure time in each cycle is 0.12 s or 120 ms, at 10.0 mm / sec, it is 60 ms, at 15.0 mm / sec, it is 40 ms, at 20.0 mm / sec, it is 30 ms, at 25.0 mm / sec, it is 24 ms, at 30.0 mm / sec, it is 20 ms, at 50.0 mm / sec, it is 12 ms, at 100.0 mm / sec, it is 6 ms, and at 300.0 mm / sec, it is 2 ms.

[0128] The process continues for N cycles to withstand the heat rise for the programmed time-temperature history. In addition to the thermal preconditioning, which improves the heat resistance of the first energy absorbing layer of the sclera, heat may also be continuously withheld from the conjunctival / scleral superficial layers by a heat sink, such as a deep-cooled contact lens, which cools, protects, and spares those superficial layers from cumulative heat damage. The heat sink allows the duration of the temperature rise to be extended for the time required to allow the attenuating heat wave to reach the deep target at the selected photothermal stimulation temperature, and to withstand the propagation of the heat wave for the duration required for effective hyperthermia therapy, for example, 25 seconds or more.

[0129] The system described herein can thus induce therapeutic photothermal effects without the use of a contact probe with a projected fiber optic tip that is pulled along the eye, potentially causing discomfort and scratching the sclera. The non-contact laser source may also be moved at a faster rate through the treatment pattern than can be achieved by moving a contact probe relative to the eye. The automated or computer-implemented features of the present system also help achieve a more consistent treatment that avoids subjective variations in precisely positioning and controlling the rate of laser energy delivery. Transscleral cyclic laser therapy does not require retrobulbar block. It is also more efficient because it converts electromagnetic energy into heat nonspecifically, not only in pigmented cells, but also in cellular water. Cyclic laser therapy also produces beneficial photothermal stimulation / heating therapy by modulating the time-temperature history of the tissue, for example, through computer-controlled laser power, beam movement speed (laser "on" exposure time), and cycle repetition time (period T and duty time rate) and the number of cycles repeated (duration of sustained heating therapy).

[0130] Patient Interface In some examples, the system includes a patient interface for docking the non-contact laser energy source at a distance from the eye. The patient interface may include a spacer that maintains the eye at a substantially fixed location and / or focal distance for imaging and treatment. The spacer may, for example, be in soft contact with the surface of the eye and maintain the laser energy source at a distance (without contact) from the surface of the eye. The patient interface may further include a speculum for placement between the subject's eyelids to hold the eye open and better expose the eye (particularly the sclera) to the laser energy. In some embodiments, the patient interface includes a lens holder that stably positions a contact lens over the surface of the eye and acts as a heat sink to transfer heat outwardly away from the eye. For example, the lens may be a scleral contact lens that contacts the sclera at the treatment site. In disclosed embodiments, the contact lens holder may also include a fixation ring having a resilient sealing surface for seating against the eye, and the system may be configured to maintain an adjustable negative pressure within the fixation ring between the eye and the contact lens to secure the patient interface to the surface of the eye and substantially immobilize the subject's eye during the procedure.

[0131] In some examples, a positioning arm positions the patient interface in a treatment orientation relative to the surface of a subject's eye in a selected treatment orientation. The positioning arm may be driven by an XYZ controller that precisely aligns and positions the spacer and ring in contact with the eye and precisely applies laser energy to the eye.

[0132] The spacer and / or the retention ring may be cooled to protect the superficial layers of the sclera from thermal damage during laser irradiation of the eye. For example, internal flow channels are present in the spacer and / or the lens holder, and the system is configured to introduce a chilled fluid (such as water or a saline solution) through the fluid flow channels to cool the spacer and / or the retention ring and / or the contact lens.

[0133] The spacer can be docked to the lens holder to hold the laser output at a spaced distance from the contact lens heat sink. A resilient seal ring on the lens holder, which extends around the contact lens and creates a seal chamber between the contact lens and the eye, holds the lens holder against the eye and substantially immobilizes the eye, or at least disables differential movement of the eye relative to the laser, when a suction force is applied to the seal chamber. The seal chamber below the lens communicates with a suction input port through which negative pressure can be selectively and / or adjustably applied to the seal chamber to optionally secure the lens holder to the eye and control eye movement during the procedure. A laser triangulation system provides Z-focus camera viewing of the contact lens, and an XYZ positioner positions the patient interface with the seal ring of the lens holder relative to the subject's eye with the spacer docked to the lens holder.

[0134] In some embodiments, the patient interface assembly includes a spacer cone, such as a frusto-conical spacer, tapering from an enlarged first surface to a smaller second surface. The laser emission source (such as an objective lens) is carried by the cone and spaced from the smaller second surface. The lens holder is a collar that tapers from a larger first surface of similar shape and size to the second surface of the spacer to which it docks, to a smaller second surface of the lens holder collar, circumscribed by a resilient patient fixation ring and forming a seal against the eye to be treated. The lens holder collar includes an internal cooling fluid passage, an inlet port, and an outlet port for circulating cooling fluid through the collar. A heat sink contact lens is retained within the fixation ring, and the collar is docked against the subject's eye, forming an inhalation chamber between the contact lens and the eye when air in the inhalation chamber is evacuated from the chamber. The suction force applied by the inhalation chamber can be varied depending on the clinical situation. For example, very low or no vacuum may be used at all to avoid any potentially damaging IOP elevation in the patient's eye.

[0135] In a method using a patient interface, a speculum blade is inserted into the eye, separating the eyelids and exposing the sclera. A lens holder is held between the speculum blades and air is optionally aspirated from a seal chamber. The XYZ positioner is adjusted to dock the spacer to the lens holder and coolant is introduced through the lens holder's internal cooling channels via fluid inlet and outlet ports. The contact lens and eye are viewed with optical viewing software and laser treatment of the eye may be performed through the patient interface with the laser held in spaced relationship to the sclera.

[0136] The spacer allows therapeutic laser energy to be applied to the eye from a laser energy source spaced from the ocular surface. A specific example of such a device is shown in Figures 5A, 5B, and 5C, where a patient interface 100 docks a laser treatment device to the eye to be treated. The interface 100 includes a spacer 102 and a lens holder 104. The lens holder 104 is configured to hold a heat sink, such as an ophthalmic contact lens 106, against the ocular surface to be irradiated. In the illustrated embodiment, the lens has a radius of curvature of about 11.5 mm and a diameter of about 15-20 mm. The lens may be a scleral lens with a corneal apex curvature space (e.g., 1 mm apex curvature space), with the peripheral edge of the lens seated against the sclera. The lens arches across the eye to form an intake chamber.

[0137] As shown in FIG. 5B, a resilient seal ring 120 surrounds the peripheral edge of the contact lens 106, establishing a seal between the contact lens 106 and the surface of the eye to which the contact lens 106 is applied. The radius of curvature of the lens 106 may exceed the radius of curvature of the cornea on which it is placed, so that the lens 106 arches across the eye, forming an aspiration chamber 123 within the seal ring 120 between the contact lens 106 and the surface of the eye to which the contact lens 106 is applied. A small central hole 122 in the contact lens 106, for example having a diameter of 0.5 mm to 2 mm or 0.5 to 1 mm, allows air and tear fluid to move through the lens 106. As shown in FIG. 5B, a suction input passage 124 extends through the wall of the lens holder 104 and communicates with an external suction input port 126. The hole 122 in the lens 106 allows air to pass into the seal chamber while still maintaining a negative pressure in the seal chamber. A video camera indicates docking contact proximity by triangulating on hole 122 with two low power laser spots as they focus on the patient's eye indicating proximity sensing of the conical contact lens. The triangulation laser spots generated by laser emitter 128 coincide at the contact lens center in the treatment eye focal plane.

[0138] The inner surface of the contact lens 106, which is placed against the eye, may be a graphene surface to improve the heat sink properties of the lens, as disclosed in more detail in US2018 / 0177632. Within the lens holder 104 is an internal cooling channel 108 (FIG. 5B) that communicates with a fluid flow inlet port 110 and an outlet port 112 and circulates a cooling fluid (such as chilled moisture) from an inlet line 114, through the channel 108, and into an outlet line 116. The spacer 102 is affixed to a control box 118 that contains a laser source that is controllable to target a laser beam 82 (FIG. 4M) through a chamber within the spacer 102 toward the contact lens 106. The laser beam 84 may be controlled to move it through an arcuate path 84 (FIGS. 4M and 8A), for example, that directs laser energy toward the eye and irradiates the eye in an annular treatment pattern. The laser beam 84 passes through the contact lens 106 and induces targeted hyperthermia in the sclera and / or retina of the treated eye with a selected time-temperature history response that propagates heat waves to adjacent tissues within the eye. The angle of incidence may depend on the selected treatment location. For example, the impingement of the treatment beam at the sclera may be normal to the tangent of the sclera (or at an angle that is otherwise not parallel to the optical axis of the eye), and the impingement of the treatment beam passing transpupillarily through the pupil will generally propagate parallel (or close to parallel) to the optical axis to treat the pan-macular annulus concentric to the foveal avascular zone or other fundus feature. A common lens may be used for beam delivery, or alternative lenses may be used in some embodiments to provide a larger angle of incidence to the scleral treatment location. In a further embodiment, a mirrored surface, similar to a gonioscopy lens delivery configuration, may be used to provide extraocular delivery to the sclera, such as by having a conical reflective inner surface of the patient interface 100 (such as using a conical spacer 154 discussed below).

[0139] The interface 100 may also include an ophthalmic speculum 132 (FIGS. 6A and 6B) including a pair of opposed plastic arms 134, 136 joined at a flexible pivot point 142 that biases the arms 134, 136 to the open position shown in FIGS. 6A and 6B. The unjointed open ends of the arms 134, 136 each carry a curved speculum blade 138, 140 configured to fit within the palpebral fissure of the eye. The speculum 132 is sufficiently flexible about the pivot point 142 such that the speculum arms 134, 136 may be moved toward one another to narrow the distance between the blades 138, 140, facilitating insertion of the speculum into the eye and better exposing the sclera to be irradiated. An outward bias of the arms 134, 136 will return the arms to the open position shown in FIGS. 6A and 6B, maintaining exposure of the targeted ocular tissue to be treated. Different size speculums may be used to open the eyelids to a preselected distance, for example 20 mm, 22 mm, or 24 mm, at the maximum separation point between the eyelids.

[0140] The speculum 132 is also configured to conform and secure to the collar 104 between the blades 138, 140. As shown in FIG. 6C, the collar 104 includes a generally cylindrical upper portion 144 and a generally cylindrical lower portion 146 joined by an angled shoulder 148 that narrows the inner diameter of the collar 104 from the top portion to the bottom portion. An internal fluid passageway 108 extends circumferentially around the upper portion 144. A resilient seal ring 120 seats within a circumferential recess on the inner surface of the lower portion 146 to hold the heat sink contact lens 106 centered within the lower open surface of the collar 104 with the central hole 122 of the contact lens substantially centered on the surface. FIG. 6D is an exploded view of the interface 100 showing how the spacer 102, collar 104, and speculum 132 are assembled. The collar 104 is placed between the blades 138, 140 of the speculum 132, with the inner surface of the speculum blade conforming to the outer cylindrical surface of the lower portion 146 of the collar, engaging and retaining the collar between the blades. The spacer 102 may then be docked against the collar 104.

[0141] The embodiment of spacer 102 in Figure 6D has a shape that tapers from an open top surface circumscribed by a circular edge 150 to a narrower bottom surface circumscribed by a circular edge 152 that mates with upper portion 144 of collar 104. Spacer 102 includes an upper generally cylindrical collar 152 that is joined to a frusto-conical central section 154 that tapers to a docking section 156 from which a snap-fit ​​member 158 depends and engages an inner surface of portion 144 of collar 104 to selectively engage and retain spacer 102 with collar 104. Snap-fit ​​member 158 is coupled to a complementary member on the inside of collar 104 for releasably interconnecting spacer 102 and collar 104 with a compression joint that conveniently connects and disconnects from the spacer and collar. In other embodiments, a snap-fit ​​connection between the spacer 102 and the collar 104 is not used, and the spacer 102 is instead soft-docked to the collar 104 using an XYZ positioning system and an imaging system.

[0142] 6E is an enlarged view of the collar 104 with the peripheral edge of the contact lens 106 seated within the inner edge of the collar 104 with the central bore 122 centered within the collar 104. An suction chamber 123 is formed below the contact lens 106 and communicates with a suction input line 124 through an opening in the collar 104 below the peripheral edge of the contact lens 106. An external suction input port 126 draws suction force through line 124, establishing a suction force between the contact lens 106 and the surface of the eye, holding the collar 104 and patient interface 100 relatively stationary relative to the eye.

[0143] FIG. 7A illustrates the speculum 132 positioned in the palpebral fissure 158 of the subject to expose the sclera 24 for treatment. FIG. 7B shows the assembled interface 100 with the spacer 102 docked against the collar 104, itself retained between the blades 138, 140 of the speculum 132, with the contact lens 106 placed against the surface of the eye (e.g., the cornea and / or sclera). The interface 100 substantially immobilizes the subject's eye being treated and prevents differential movement of the eye relative to a laser beam directed toward the eye from a laser energy source 74 spaced outwardly from the surface of the eye. Control of eye movement is effectively achieved, inter alia, by sucking air from an inhalation chamber in the seal ring 120 below the contact lens 106. The inhalation force may be dictated by the clinical situation. For example, the procedure may be performed without or with inhalation force. When suction force is applied, the negative pressure in the inhalation chamber is controlled, for example, below 35 mmHg. A gentle level of inhalation force that does not increase IOP, not exceeding 5 mmHg, is preferred. The central hole 122 of the contact lens 106 allows the inflow of air into the inhalation chamber, which, in combination with the outflow of air from the chamber induced by the applied inhalation force, helps to regulate the pressure in the inhalation chamber.

[0144] The patient interface 100 improves detection of the limbus and / or limbal junction using an optical imaging system. Differential movement of the eye relative to the laser beam can also be minimized by controlling the relative movement of the eye using the patient interface 100 (FIG. 8A) to avoid interference with the targeted delivery of laser energy. The resilient sealing surface of the sealing ring 120 is seated against the eye and a suction force is drawn between the lens 106 and the eye 70, minimizing differential eye movement. The patient interface 100 also maintains the non-contact laser energy source or optics 74 at a predetermined distance from, and not in contact with, the surface of the eye 70.

[0145] Laser energy may be delivered transsclerally by a patient interface under spatial and temporal processor control while cooling the surface. For example, the method is performed using a computer-driven electro-optical scanning beam delivery system 200 (FIG. 8B) designed for limbal-guided non-contact transscleral circulatory deposition of infrared (IR) electromagnetic energy (e.g., 1.475 μm laser energy) in an arcuate or circumferential arc pattern at selectable scleral meridian locations posterior to the anterior (apparent) limbus over i) perilimbal outflow structures (collecting canal, Schlemm's canal, trabecular meshwork), ii) ciliary processes, and iii) pars plana uveoscleral regions. The scanning speed is adjustable, e.g., in the range of 0.1-50 mm / sec.

[0146] The amount of infrared laser energy delivered is called the laser irradiance (W / cm 2 ) and exposure duration (by controlling the cyclic scanning rotation speed in mm / sec) can produce a titrated and localized photothermal rise that is non-coagulative but induces a biomechanical response with microscopic morphological changes in the microstructures of the perilimbal, ciliary processes, and pars plana regions that results in a reorganization of the aqueous humor (AH) outflow tract, enhancing both conventional (trabecular meshwork) and non-conventional (uveoscleral) outflow tracts. The method also induces a biochemical response, elicited by the concomitant photohyperthermia (43-45°C), as the heat diffuses and attenuates in the surrounding tissues, re-equilibrating and returning to baseline body temperature, which induces a biological cascade of cytokine expression and subsequent endogenous molecular transcriptional activity that contributes to the long-term IOP-lowering effect.

[0147] FIG. 8B shows the laser treatment optical system. 8B shows an exemplary optical system 200 configured to direct a laser beam to a targeted surface of the eye 70 and rapidly move the beam in a rotation or other cycle about the eye's optical axis OA (as in FIG. 4M or 8A). For example, the optical system may be a digital galvanometer scanner system such as that made by Canon, in which an LED optical encoder (digital position sensor) and a high-speed digital servo controller scan the laser beam across the eye with high precision and accuracy. The movement of the scanned beam may be, for example, a clockwise or counterclockwise movement inside the interface 100.

[0148] The optical system 200 of FIG. 8B produces an optical beam 202 from an optical beam source 206. The optical beam source 206 includes one or more laser sources, such as one or more semiconductor diode lasers, fiber lasers, solid-state lasers, frequency-changing nonlinear optical materials (e.g., frequency doubled), and the like. In an exemplary embodiment, the optical beam 202 has a predetermined wavelength (corresponding to one or more specific wavelengths and / or wavelength ranges) selected to be within the infrared region of the optical spectrum, between 1,000-1,700 nm or 875 nm to about 2,100 nm, e.g., between about 800-2,200 nm or 1,000-2,200 nm, such as 1,000-2,100 nm. In general, the predetermined wavelength of the optical beam 202 is selected to produce the transscleral therapeutic hyperthermia therapy previously described. For example, the predetermined wavelength may be selected to be long enough that the optical beam 202 is absorbed by water in the scleral cells of the eye 104 to a greater extent than would occur at shorter wavelengths, such as 808 nm, 650 nm, 532 nm, 355 nm, etc. In one embodiment, the optical beam 202 has a wavelength at 1,475 nm and is generated in the optical beam source 206 with a 14,75 nm diode laser. The increased absorption at the longer predetermined wavelength can allow the optical beam 202 to be directed to the eye target 70 through an offset 208 (e.g., free space) between the focusing lens 220 of the optical system 200 and the target eye 70. The distance of the offset 208 is, for example, at least 45 mm, such as 45-55 mm. In a disclosed embodiment, the offset is 35-45 mm, such as 40 mm.

[0149] In an exemplary embodiment, the optical beam 202 is emitted from the optical beam source 206 as a collimated beam propagating along an optical axis 210. A lens group 212 is configured to adjust beam characteristics such as beam area, divergence, convergence, etc. For example, the beam width, generally shown in relation to side rays 213a, 213b, can be adjusted using the lens group 212. The optical beam 202 is received by an optical scanner 214, which is configured to vary the direction of the optical beam 202, for example, to move the beam in a rotational movement within the interface 100. For illustrative purposes, the optical scanner 214 is shown to deflect the optical beam 202 along three optical beam paths 216a, 216b, 216c. A reflective element 218 is mounted to redirect the beam paths 216a-216c of the optical beam 202. A beam splitting element 219 is mounted to receive the optical beam 202 and pass the optical beam 202 to a focusing lens 220, which may include one or more lens elements. A camera 222 is also coupled to the optical system 200 by the beam splitting element 219. A surface 224 of the beam splitting element 219 may include a wavelength selective coating configured to receive illumination from the eye target 70 through the focusing lens 220 and direct the illumination to a reflective element 226, which directs the illumination to the camera 220 and images the eye target 70.

[0150] The optical scanner 214 can be of various types suitable for scanning the optical beam over the eye target 70, including an XY galvanometer scanner, a 3D scanner, an electro-optical scanner, or an acousto-optical scanner. A controller 228 is coupled to the optical beam source 206, the optical scanner 214, and / or the camera 222 and can coordinate and control the emission of the optical beam 202 from the optical beam source 206, the scanning of the optical beam 202 with the optical scanner 214, and the alignment of the optical scanner 214 over the eye target 70, or other processes for monitoring the eye target 104. The controller 228 typically includes a processor and memory that can store scan files, laser parameters, and software for aligning and / or laser processing the eye target. The controller 228 can be of various types including one or more computing devices, computing units, PLCs, PALs, ASICs, etc. The memory can include volatile memory such as registers, caches, and RAMs, as well as non-volatile memory, or a combination. The memory can store software in the form of computer-executable instructions that can be accessed and executed by the processor (or processors) of the controller. In some embodiments, the controller 228 can be distributed among different components (such as between the optical beam source 206 and the optical scanner 214), and in some embodiments, communication is not required between all components.

[0151] In an exemplary embodiment, the optical beam 202 is a continuous wave beam that is focused or defocused to a selected spot size at a predetermined location radially spaced outward from the limbus or corneoscleral junction of the eye 70. For example, the optical beam 202 is directed along optical beam paths 216a, 216c to a location at the eye target 70 radially spaced outward from the limbus or corneoscleral junction, and optical beam path 216b at the eye target 70 may also be understood to be radially spaced outward from the limbal junction if the location is sufficiently below or above the plane of the figure. In an exemplary embodiment, the controller 228 controls the optical scanner 214 to scan the optical beam 202 in a circular annular pattern radially spaced outward from the corneoscleral junction. The scanning of the optical beam 202 produces a selected duty cycle of heating at sequential azimuthal locations of the annular pattern at the eye target 70 such that thermal relaxation can occur between scan cycles.

[0152] Unexpected lens slippage and / or eye movement may be detected by the camera software. The camera display at Z-focus provides additional alignment assurance.

[0153] Control Box and Positioning Arm As illustrated in FIG. 9A, the interface 100 may be suspended from and positioned by a control box 118, which includes a handle 172 on one side of the box for manually moving or positioning the unit, tubing clamps 174 for suspending tubing without inducing torque on the interface 100, and a peristaltic pump 176 (such as a Welco Ultra pump) for controlled movement of coolant from a source 178 of chilled liquid, such as sterile saline or water, e.g., phosphate buffered saline (PBS). The illustrated pump 176 may move cooling fluid at up to 100 ml / min, but typically the peristaltic flow rate is controlled at about 50 ml / min, cooling the contact lens 106 in the holder 104 as the chilled liquid moves from the source 178 through the tubing 180 and pump 176. Contact lens fogging can be minimized with the coolant liquid temperature set at about -10°C. The lens thermal capacity requirements are determined by the thermal profile of the lens material, such as a PMMA or BK7 lens.

[0154] 9B, pump 176 moves chilled liquid from control box 118 to interface 100 through inlet line 182, which communicates with inlet port 110, and moves the chilled liquid through channels 108 in lens holder 104 to cool lens 106 in situ. The liquid then passes through outlet port 112 and outlet line 184. Suction input line 186 communicates with suction input port 126 to draw suction force underneath lens 106 to improve contact between resilient sealing ring 120 and the ocular surface during the laser mounting procedure.

[0155] The control box 118 may include a laser support structure (not shown), such as that disclosed in US2018 / 0177632. The laser support structure may include one or more channels that house one or more optical fibers or light source cables. The optics tray may support one or more optical components that direct one or more lasers to the surface of the eye 70, for example, as described with respect to FIG. 8B. One or more optical components may also be contained within the interface 100 to illuminate the eye.

[0156] The control box 118 may be suspended from a positioning arm, such as an XYZ positioning arm 186 (FIG. 9C), which may be computer controlled for precise positioning of the control box 118 and the interface 100. The arm 186 is secured to the box 118 by a flange 188 having a positioning knob 190 that can be relaxed to move the flange 188 in a horizontal plane.

[0157] Patterned energy delivery system and processor For any of the desired treatment patterns, a processor may be coupled to the laser energy source and the scanner and configured with instructions to provide an automated or computer-implemented treatment method that heats tissue at multiple treatment locations and delivers energy more precisely to preselected treatment locations. The multiple treatment locations, e.g., the first annular treatment pattern and the second annular treatment pattern, may avoid underlying anatomical structures such as intraocular muscle attachment points. In some embodiments, the computer implementation of the automated treatment pattern may achieve controlled heating of specific locations to achieve a desired treatment outcome.

[0158] FIG. 10A illustrates a system 600 for patterned delivery to an eye 602, according to an embodiment. The system 600 includes a processor 604 having a tangible medium 606 (e.g., RAM). The processor 604 is operatively coupled to a first light source 608, an optional second light source 610, and an optional third light source 612. The first light source 608 emits a first beam of light 614 that is scanned by an XY scanner 616 through an optional mask 618 and an optional heat sink 620 onto the eye 602. A mirror 622 directs light energy from the eye 602 to a viewing camera 627 that is coupled to a display 628. For example, a separate non-therapeutic light source for the optional viewing camera can be provided. The mirror 622 may direct a portion of the light beam returning from the eye 602 to, for example, the camera 627. The second light source 610 emits a second beam of light 630 that is combined with the first beam of light 614 by a first beam combiner 632 prior to passing through the XY scanner 616. The third light source 612 emits a third beam of light 634 that is combined with the second beam of light 630 by a second beam combiner 636 prior to passing through the first beam combiner 632.

[0159] The processor may be configured with one or more instructions for performing any of the methods and / or any one of the steps and sub-steps of the methods or treatments described herein. The processor may comprise a memory having instructions for performing the methods, and the processor may comprise a processor system, for example, configured to perform the methods. In many embodiments, the processor comprises array logic, such as, for example, a programmable array logic ("PAL"), configured to perform one or more steps of any of the methods or treatments described herein. The processor may be embodied on a tangible medium, such as a computer memory or a gate array, and may comprise one or more instructions of a treatment program to perform one or more steps of a treatment method as disclosed herein. The processor may comprise instructions for treating a patient according to the embodiments described herein.

[0160] The processor may be configured with instructions to determine one or more locations of the limbus and / or one or more locations of the limbal junction. In response to the determined location of the limbus, for example, one or more locations of the limbal junction may be determined. The processor may be configured with instructions to determine a treatment pattern based on the one or more locations of the limbus and / or one or more locations of the limbal junction. The treatment pattern may comprise, for example, a treatment pattern spaced one or more of 1.5 mm, 2.5 mm, and 3.5 mm from the limbal junction. The processor may be configured to deliver non-coagulating energy to the treatment location on the treatment pattern to induce a thermal effect as described herein.

[0161] The optical delivery system may comprise one or more of a first light source, a second light source, a third light source, an XY scanner, an optional mask, or a heat sink. Energy is directed by an automated optical energy delivery system to achieve reproducible heating of the same location during repeated cycles of heating. In some embodiments, beams of light 614, 630, and 634 can be scanned by an XY scanner 616 on the eye 602 at defined X and Y positions to treat the eye 602. An optional mask 618 can be used to mask the light applied to the eye 602, e.g., to protect the masked portion of the eye 602 while treating other portions, as described herein. An optional heat sink 620 can be placed on the eye 602 during treatment to avoid heating of the defined portion of the eye 602, as described herein.

[0162] The system 600 can be used to apply light energy to the eye 602 according to any suitable treatment procedure, such as the embodiments described herein. In many embodiments, the first light beam 614 has a first wavelength, the second light beam 630 has a second wavelength, and the third light beam 634 has a third wavelength. Each wavelength can be the same or a different wavelength of light. A processor is coupled to each of the light sources and can selectively illuminate the eye with light having a wavelength within a desired range of wavelengths. The software can include instructions for a treatment table to scan the laser beam to a desired treatment location, for example, as described herein.

[0163] The laser system 600 may include an OCT system 625, such as a commercially available OCT system. The OCT system may be, for example, a CASIA2 or CASIA SS-100 OCT scanner (TOMEY). The OCT system may be, for example, a commercially available OCT system, such as those sold by Tomey, Heidelberg, Visante, or Optovue. The OCT system may be coupled to a laser delivery system with viewing optics and a beam splitter 626. The viewing optics may include, for example, a surgical microscope (such as those sold by Zeiss, Haag Streit, Leica, or Moller Weidel), a slit lamp, or other custom optics. The OCT system may be used to measure the eye in situ during treatment. For example, the OCT system may be used to generate OCT images as described herein to generate tomography of the eye and determine the location of the target tissue, the movement of the target tissue, and the extension of the target tissue, as described herein. The OCT system 625 is coupled to the processor 604 and can be used to control the laser system, for example, using a feedback loop. An ophthalmoscope or other suitable ocular imaging device can be used to generate images of the exterior and / or interior of the eye and can include an imaging detector such as a CCD or CMOS detector.

[0164] The processor can be configured with instructions to scan the laser beam on the eye according to treatment patterns and parameters as described herein.

[0165] FIG. 10B shows another embodiment of a treatment system that can be used for any of the treatment methods described herein. The system may include a laser scanner (such as that shown in FIG. 8B) that directs and scans laser energy from a continuous wave or pulsed laser to one or more locations on or inside the eye. The scanner may be coupled to a patient interface or patient coupling structure as described herein. The scanner may further be coupled to an imaging system, such as a camera, OCT, UBM, ophthalmoscope, etc., as described herein. The imaging system may be used to capture one or more images of the eye before, during, or after treatment, as described herein.

[0166] A processor or controller may be coupled to the energy source (such as a laser) and the imaging system and configured with instructions to scan the energy beam to multiple locations or in one or more patterns and image the tissue during treatment. The system may also include a display coupled to the processor that allows a user to visualize the tissue prior to, before, or after treatment. The display may show images that allow a user to review tissue treatment and plan treatment. The images shown on the display may be provided in real time and can be used prior to treatment to allow a user to align tissue and / or select a treatment area or pattern to target. The identified target treatment area may be input by the user in response to the images shown on the display to program the treatment depth, location, and pattern. The imaging system can be used to visualize the movement of ocular structures during treatment to detect beneficial treatment effects.

[0167] The glaucoma treatment systems described herein may simultaneously provide imaging guidance, quantitative characterization of tissue (e.g., measuring mechanical properties such as elasticity or the presence of tissue clots), and / or perform therapy tasks.

[0168] In some embodiments, the treatment system described herein may include two or more lasers. The processor may be configured with instructions to treat the eye at a first location (or locations) with light of a first wavelength and at a second location (or locations) with light of a second wavelength. The treatment system described herein may include one or more lasers in the range of about 1.0 μm to about 2.2 μm, about 1.4 μm to about 1.5 μm, for example, about 1.47 μm.

[0169] FIG. 11 shows an image of an ex vivo porcine eye taken with a camera after docking the patient interface and system to the eye. The limbus was clearly visible for use in patterning glaucoma treatment relative to the location of the limbus or limbal junction. The patterning may be manually selected by a user (e.g., a medical professional) or the pattern may be automatically (or semi-automatically) determined by the system based on the estimated location of the limbus or other criteria of interest. The location of the limbus may be manually estimated by the user or automatically determined through imaging and feature detection. The location of the limbus may be automatically "tracked" by the system using a camera and / or other imaging system such as OCT, for example, as described herein. The location of the limbus may comprise a perfect annular contour of the limbus, or may comprise multiple locations along the limbus (i.e., an incomplete contour of the limbus) that may be used as a reference point to determine the shape of the limbus and / or where treatment should occur.

[0170] Identification of one or more locations of the limbus as described herein may be used to estimate one or more treatment locations. The anterior border of the limbus may be used as a proxy for the limbal junction 32. Alternatively, or in combination, one or more locations of the limbal junction 32 may be estimated from one or more OCT slices. For example, a single OCT image taken through the center of the eye may be used to identify two locations of the limbal junction (one on each side of the eye), and a treatment location / pattern may be determined in response to the two identified limbal junction locations. In some cases, multiple OCT images may be taken at different angles relative to the center of the eye, and multiple limbal junction locations may be identified and used to estimate the shape of the limbal junction. FIG. 12A illustrates one such imaging scheme, which may be used to estimate the shape of the limbal junction. Multiple OCT images may be taken across the center of the eye at varying angles, and one or more locations of the limbal junction may be estimated from each image. The locations (optionally images as shown) may then be used to estimate the shape of the limbal junction using partial 3-D reconstruction.

[0171] In some cases, the location and / or shape of the limbal junction may be estimated in response to multiple limbal locations of the eye. As an example, an image (e.g., an anterior image of the eye) including the limbus may be obtained (e.g., as shown in FIG. 11). The limbal location or multiple limbal locations may be determined based on the image of the eye. For example, by detecting a change in intensity in the anterior image (e.g., across images over a series of images, etc.), the location of multiple limbal locations may be determined. In some cases, one or more processors may be utilized to analyze the image and determine the limbal location. Based on the multiple limbal locations, multiple limbal junction locations may be estimated, as substantially described throughout. Suitable techniques for automated image analysis include automated digital image processing techniques, including machine learning, object identification algorithms, pattern recognition algorithms, video tracking algorithms, convolutional neural networks, and the like. FIG. 12B illustrates an example of an automated process 1200 for determining a treatment location. At 1202, an image of the eye is acquired using a suitable imaging device, and at 1204, image features in the image are analyzed using digital image processing techniques, such as through any of the digital image processing techniques described herein. At 1206, a suitable treatment location is determined for the features in the image. For example, if an anatomical feature is found, such as the limbal junction in a transscleral treatment embodiment or a fundus feature such as the macula or optic disc in a transpupillary embodiment, a suitable treatment location can be determined for and based on the found feature. At 1208, the treatment location can be converted to suitable laser scanner commands for a matched and calibrated laser scanner and a scanner command table that maps scanner command values ​​to one or more scan planes, surfaces, or volumes.

[0172] 13A-13D show an example of a process for generating a treatment pattern based on one or more locations of the limbus. FIG. 13A shows an anterior image of the eye taken with a front camera of the CASIA2 OCT system. The anterior image of the eye may be transferred to a processor for detection of the limbus edge. FIG. 13B shows the image after processing to determine the limbus boundary (edge). The portion of the eye within the limbus is colored white, while the portion of the eye outside the limbus is colored black. This black and white image may then be used to generate the XY coordinates of the limbus edge. The processor may then use the XY coordinates to generate a limbus contour, which may be overlaid on the real-time image of the eye shown on the display, as shown in FIG. 13C. The XY coordinates may be aligned with the real-time image of the eye such that the limbus shown on the display and the XY coordinate generated limbus contour are co-registered. A treatment pattern can also be automatically generated based on the contour. If an arc is formed, the treatment pattern can be generated using the patient's orientation to align the arc in the superior / inferior direction or to a selected azimuth angle. In some embodiments, posterior transpupillary images can be taken using a CASIA2 OCT system or another camera, and anatomical feature boundaries can be determined such that laser scan coordinates can be generated relative to the anatomical feature boundaries.

[0173] The image may also display a fiducial referenced to the center of the eye to aid in centration of the treatment, e.g., circles displayed radially outward every 5 mm from the center of the eye. The processor may further use the XY coordinates of the limbus and / or the generated contour to determine a treatment pattern, e.g., a series of limbus-guided treatment locations. It will be understood by those skilled in the art that during use, the limbus contour and / or treatment pattern may be aligned (i.e., co-registered) with respect to one another such that the limbus contour and real-time location overlap or are offset by a preselected amount to space the limbus-guided treatment pattern a desired distance from the limbal junction.

[0174] FIG. 14 illustrates a method for determining a target treatment location. The method may use one or more of the systems described herein. In a first step, an anterior image of the eye may be acquired by a camera or video recorder. In some embodiments, a posterior image may be photographed. In a second step, an image of the eye may be displayed to a user as described herein, although in some embodiments, no image display for the user or user intervention based on the acquired image is required. In a third step, one or more images of the eye, such as a video or OCT image, may be optionally acquired. In a fourth step, multiple locations of the limbal junction (or limbus or other criteria described herein) may be determined from an anterior image of the eye, one or more OCT images of the eye, or any combination thereof. In some embodiments, multiple locations of macular features, such as foveal avascular zone, optic nerve, etc., are determined from a posterior image, an OCT image, or a combination. Multiple locations of the limbal junction or macula may be estimated manually by a user or automatically by a processor. The limbal junction locations may optionally be aligned with corresponding anterior or posterior image locations. In a fifth step, multiple treatment locations for the eye may be determined in response to the limbal junction or macular feature locations. The multiple treatment locations may be determined manually by a user or automatically by a processor. In a sixth step, the treatment locations may be overlaid on the anterior image shown on a display, although such a display may be omitted in automated or streamlined processing. The treatment locations may optionally be adjusted or authenticated by a user. In a seventh step, treatment energy may be directed to the treatment locations displayed on the image by a laser source and a scanner as described herein. Typically, the laser source includes multiple lasers suitable for operating at different wavelengths or in a selected mode (such as pulsed, continuous wave, or selected pulsed characteristics such as repetition rate, pulse duration, power, pulse energy, etc.).In an eighth step, the treatment may be visually and / or automatically monitored in real time at the treatment site and the treatment adjusted or stopped if eye movement occurs.

[0175] A processor may be provided that is configured with instructions to perform the sequence of steps illustrated in FIG. 14. In some cases, the processor may provide instructions to acquire anterior and / or posterior images of the eye. For example, the images of the eye may be acquired using a camera with the assistance of the processor. In some cases, the processor may be configured with instructions to receive the images of the eye.

[0176] The processor may provide instructions for displaying one or more of the images of the eye. In some cases, the processor may provide instructions for acquiring an OCT image of the eye. In some cases, the processor may provide instructions for determining a plurality of locations of the limbal junction of the eye. The processor may, in some cases, estimate a plurality of limbal junction canal locations in response to an anterior image of the eye, and / or a plurality of retinal locations in response to a posterior image of the eye. Alternatively or in addition, the processor may estimate a plurality of Schlemm's canal locations, retinal locations, or other ocular locations in response to a plurality of OCT images of the eye.

[0177] In some cases, the processor may be configured with instructions to generate multiple treatment locations. Optionally, the processor may be configured with instructions to generate multiple treatment locations for the eye in response to multiple limbal junction locations.

[0178] In some cases, the processor may provide instructions for overlaying the treatment locations onto the anterior and / or posterior images of the eye. The processor may be configured with instructions for overlaying a plurality of treatment locations and a plurality of limbal junction locations onto the anterior image of the eye. Optionally, the processor may be further configured to register a plurality of anterior image locations corresponding to a plurality of limbal junction locations. Optionally, the processor may be further configured with instructions for overlaying a plurality of treatment locations and a plurality of retinal locations onto the posterior image of the eye, and the processor may be further configured to register a plurality of posterior image locations corresponding to a plurality of retinal locations.

[0179] The processor may provide instructions for directing treatment energy to the treatment locations on the display. In some cases, the processor may be configured with instructions for alternating treatment at a first plurality of treatment locations with treatment at a second plurality of treatment locations. Optionally, the processor may be configured with instructions for generating a treatment table including a plurality of coordinate reference locations corresponding to the plurality of treatment locations overlaid on the anterior and / or posterior images. Optionally, the energy source directed to the eye may comprise a pulsed laser source, with each of the plurality of coordinate references corresponding to a pulse from the laser source. In some cases, the processor may provide instructions for displaying the treatment at the treatment locations in real time.

[0180] Although the steps described above show obtaining an image of the eye and treating tissue in a user-selected treatment area, one of ordinary skill in the art will recognize many variations based on the teachings described herein. The steps may be completed in a different order. Steps may be added or deleted. Some of the steps may include sub-steps. Many of the steps may be repeated as many times as necessary to treat tissue, as desired. The steps may be applied using any suitable device herein and are not limited to transcleral treatment examples.

[0181] Examples herein include devices and methods for performing selected transpupillary retinal treatments and combined transscleral-transpupillary treatments.

[0182] FIG. 15 shows a schematic of an example of a human eye, including the cornea, lens, iris, and pupil structures near the anterior surface of the eye, and the retina, macula, and optic nerve toward the posterior pole of the eye. FIG. 16 shows the central retina of FIG. 15 within the vascular arcade, including the darker macular portion near the center. In a representative example herein, the sclera of the eye (adjacent to the cornea) is targeted for irradiation with a 1,475 nm transscleral laser beam with a selected set of transscleral lasers and scanning parameters for IOP-lowering therapy, and / or the retina of the eye, e.g., the macula, is targeted for irradiation with a separate set of 810 nm transpupillary lasers and scanning parameters for pan-macular neuroprotective therapy, thereby inducing sublethal and therapeutically beneficial biomodulation or biostimulation of ocular tissues in one or both locations, e.g., during a complete therapeutic window or instance. Therapeutic benefits can include reduced intraocular pressure (IOP), neuroprotection, and comprehensive management of glaucoma, such as open-angle glaucoma.

[0183] Biological Mechanism According to representative embodiments herein, the central retina of the eye can receive sublethal laser photostimulation for the treatment of chronic progressive neurodegenerative vascular retinopathies and other disorders such as POAG, which share similar common characteristics. Sublethal non-damaging laser photostimulation of the central retina targets retinal pigment epithelial (RPE) cells using subthreshold laser energy to induce a stress response. Using carefully selected laser parameters and / or scanning patterns, the stress response can be configured to activate a cascade of molecular, cellular, and biochemical activities that may rebalance the pathological retinal vascular neurotrophic deficiency and prevent and potentially reverse the progressive apoptotic process (i.e., retinal ganglion cell loss in POAG). Thus, in representative embodiments, laser parameters are selected such that energy is delivered in a pattern configured to produce a biological effect within the photothermal therapy window that is above the activation threshold but below the lethal threshold (e.g., 44°C-50°C). In general, various parameters (laser pulse energy, duration, fluence, irradiance, pattern, etc.) are selected to recruit and activate a large number, preferably the highest number of possible RPE cells for the biological photostimulation process in a pathology-selective manner. Such photothermal stimulation can be configured to activate endogenous repair and / or regeneration processes that do not harm or affect normal healthy RPE cells, but selectively affect and improve only dysfunctional RPE cells according to their specific dysfunction. The primary response to RPE sublethal photostimulation is understood to be the activation of heat shock proteins (HSPs) and cytokine expression, which induces a cascade of events that leads to RPE cell repair, replacement, and regeneration. These events can result in improved transport function, normalized retinal autoregulation, reduced biomarkers of chronic inflammation, repair acute inflammation, and immune modulation. Such effects can provide neuroprotection, neurotrophic enhancement, along with recovery and / or regeneration of diseased dysfunctional cells, reducing, slowing, or preventing vision loss, and restoring visual function in, for example, various chronic progressive degenerative retinal disorders and POAG, which may share similarities.

[0184] The effect of sub-threshold laser central retinal sublethal photostimulation with indistinguishable retinal damage is completely "homeotropic" and can normalize retinal function and reduce the risk of disease progression and vision loss. Normalization of retinal cytokine expression can be neuroprotective in POAG in the same way that it is retinoprotective in diverse chronic progressive retinopathies that are pathogenetically heterogeneous, exhibit very different drug response profiles (such as diabetic macular edema (DME) and central serous retinopathy (CSR)), and respond in a manner unique to the particular disease process and its characteristics. Sublethal RPE laser photostimulation can be a non-specific trigger of disease-specific RPE HSP activation and cellular repair. Moreover, sublethal RPE laser photostimulation is also pathoselective, as it can normalize only the function of dysfunctional cells, affecting abnormal cells while having negligible effects on healthy cells, as significantly superior improvements have been observed clinically in eyes with the worst pre-treatment conditions.

[0185] Disease-specific responses can be further demonstrated by characteristically different pattern electroretinogram (PERG) responses in dry AMD compared to PERG responses in hereditary retinopathies after subthreshold laser central retinal sublethal photostimulation treatment. In both cases, retinal abnormalities are present. Thus, a therapy response to the non-specific trigger of sublethal laser photostimulation is observed. In both cases, the retinal abnormalities are different. Thus, the therapy response is always homeotropic, but different and reflects the nature of the underlying retinal abnormalities (disease-specific repair response). POAG may represent, at least in part, a manifestation of primary optic neuropathy or central nervous system disease. Electrophysiological tests such as PERG and visual evoked potential (VEP) tests can objectively measure and monitor electrophysiological indices of ganglion cell and optic nerve functionality. Thus, by treating the retina, a unique disease-specific therapy response in the glaucomatous optic nerve can be elicited. Thus, there may be an as yet unidentified retinal abnormality underlying at least some cases of POAG, which may help explain the progressive optic nerve atrophy observed in "normal" or "low" tension glaucoma despite IOP reduction. It is also possible that retinal loss of neurotrophic function may be a separate and unique retinal disease entity that may underlie some or all cases of OAG, although further study is required.

[0186] Subliminal pan-macular micropulse laser photostimulation therapy has been disclosed in Luttrull et al., Chapter 20-Glaucoma research and Clinical Advances: 2018 to 2020: Samples JR and Klepper PA, Eds. Kugler Publications: Amsterdam, Neederlands (incorporated herein by reference) as a neuroprotective treatment for patients with primary open-angle glaucoma. Subliminal pan-macular micropulse laser can restore RPE cell trafficking and gene expression function, improve retinal trophic deficiencies, and result in increased ganglion cell electrophysiological functionality on pattern electroretinograms (PERG) and improved visual function on automated visual field testing. These improvements indicate that sublethal laser photostimulation can rescue dysfunctional, but still viable, retinal elements, promote long-term survival, and improve functionality of ganglion cells and other neurons, potentially through endogenous neurostrengthening and upregulation of neuroprotective neurotrophic factors. POAG shares most of the common characteristics found in all chronic progressive degenerative retinopathies (AMD, DR, CSC, RP, etc.), and POAG may similarly benefit from the same sublethal laser photostimulation of the RPE.

[0187] Theoretically, the primary mechanism of action of sublethal light stimulation of the RPE is a reparative acute inflammatory response that promotes the activation of heat shock proteins (HSPs), which induces a cellular cascade that results in a restorative immunomodulatory response, including cytokine expression, upregulation of pigment epithelium-derived factor (PEDF), intracellular repair, replacement, regeneration, improved RPE cell function, normalized retinal homeotropic autoregulation, inhibition of apoptosis, reduction of chronic inflammatory biomarkers, and recruitment of bone marrow-derived hematopoietic stem cells capable of differentiating into epithelial and / or endothelial cells to the retina. In vivo studies have shown that improvements in retinal electrophysiological indices on PERG and mesopic visual function on automated visual field testing can be demonstrated within 24 hours of sublethal treatment. The absence of discernible iatrogenic damage makes neuroprotective homeotropic sublethal laser photostimulation therapy a natural, renewable physiological process, with the potential for early POAG treatment, preventative treatment, and periodic retreatment to maintain the homeotropic effect, slow disease progression, and reduce the risk of visual loss.

[0188] The use of laser transpupillary thermotherapy (TTT) to deliver sublethal thermotherapy light stimulation treatment and elicit retinal biochemical responses accompanied by expression of endogenous neuroprotective heat shock proteins (HSPs) has also been reported by Kim et al. (Neuroprotective effect of trans-pupillary thermotherapy in the optic nerve crush of the rat. Eye (2009);23:727-733) and MaJ et al. (Neuroprotective effect on retinal ganglion cells by trans-pupillary laser irradiation of the optic nerve head. Neurosci. Lett. (2010), doi:10.1016 / j.neulet.2010.01.001). Heat shock proteins are a group of proteins that are upregulated by hyperthermia or other types of physiological and environmental stress. HSPs can improve cell survival even under conditions of more severe stress. Some of the HSPs are constitutively expressed, while others are inducible in response to different types of stress. In the nervous system, the HSP70 system, which consists of Hsc70 or the constitutive form and HSP72 or the inducible form, can have protective effects against ischemia, stroke, and axotomy. Also, retinal ganglion cells (RGCs) can be protected against intraocular pressure elevation or axonal transection by induction of HSP72 by hyperthermia, zinc, and drugs such as geranylgeranylacetone. RGC death is one of the main pathological events in glaucoma, and therefore protection of RGCs by induction of HSPs can be used to treat glaucoma. However, several methods have been shown to increase HSP expression with neuroprotective effects, and a non-invasive and safe method to induce HSPs without any systemic effects is worthy of further investigation.

[0189] TTT is a treatment modality in which infrared radiation energy is delivered directly to the posterior compartment of the eye, for example by an 810 nm diode laser, to generate hyperthermia. TTT can be performed using a broad beam and long exposure time. Mainster (Mainster MA, Reichel E., Trans-pupillary thermotherapy for age-related macular degeneration: long-pulse photocoagulation, apoptosis, and heat shock proteins. Ophthalmic Surg Lasers 2000; 31: 359-373) has shown that TTT increases the temperature in the treated tissue by up to 10°C above baseline levels. Using this hyperthermia, TTT has been attempted for the treatment of various intraocular tumors (i.e., choroidal malignant melanoma, hemangioma, and retinoblastoma) and choroidal neovascularization in age-related macular degeneration. TTT increases the temperature in the treated tissue, and therefore TTT can stimulate the expression of HSPs. TTT performed on the optic nerve head, the primary site of glaucomatous optic nerve injury, effectively induced HSP72 expression in the treated tissue. The optimal parameters of TTT for maximal HSP72 expression in the optic nerve head without damage to the ocular tissues were determined to be 100 mW for 60 s by Kim et al. (Kim JM, Park KH, Kim YJ, Park HJ, Kim DM. Thermal injury induces heat shock protein in the optic nerve head in vivo. Invest Ophthalmol Vis Sci 2006;47:4880-4894). At this setting, no tissue damage was detected using confocal scanning laser ophthalmoscopy, light microscopy, and scanning electron microscopy as well as fundus examination. In the next step, TTT was applied to a rat optic nerve crush injury model to investigate the neuroprotective effect, and it was found that the use of TTT increased the survival rate of RGCs in the retinal area close to the optic nerve head in a rat optic nerve crush injury model.

[0190] In the exemplary embodiment herein, many patients may require or benefit from IOP-lowering treatments supplemented with neuroprotective therapy. In these cases, the transpupillary sublethal photothermal therapy method is optionally performed in conjunction with a system configured for transscleral laser therapy for IOP reduction. Thus, the system embodiment is operable to perform central retinal neuroprotective transpupillary sublethal photothermal therapy that may elicit a biochemical response that may result in neuroprotection, neurostrengthening, and possibly regeneration of retinal ganglion cells (RGCs), including, by way of example, "missing, diseased, but not yet dead" RGCs, with the goal of delaying, preventing, or even restoring intraocular visual function loss associated with POAG and other retinal angiotrophic neuropathy. According to examples herein, retinal sublethal photostimulation is achieved using annular (e.g., circular) treatments that produce advantageous temperature distribution profiles with flat-top histogram characteristics over the pan-macular area (including the central fovea, if required) that do not exceed 45-47 degrees Celsius, thereby avoiding a central cumulative heat peak rise with a Gaussian-like heat peak profile. In some examples, a diode laser operating at a selected wavelength, e.g., 810 nm, in a repetitive micropulse emission mode (for fine control of the laser-induced heat rise at the RPE level) is directed in a circular pattern that irradiates the annulus, avoiding irradiation of a 1.0-2.0 mm central hole centered over the fovea, and extending the outer edges to a predetermined distance, such as up to about 3 disc diameters (4.5-5.0 mm). In this way, the pan-macular area of ​​the eye can receive a safe warming stimulus, including the central foveal region (which would be heated by indirect conductive heating, not by direct laser-induced heating).

[0191] Exemplary Systems and Methods for Transpupillary and / or Transscleral Treatments 8A can be used to couple a non-contact laser system 74 (with the scanning optics portion of the laser system shown for convenience) to an eye 70 receiving biostimulation therapy in accordance with method embodiments herein. In a transpupillary method embodiment, a laser beam 71 is directed by the non-contact laser system (e.g., using a laser scanner) through the pupil of the eye 70 to the macular region of the retina of the eye 70.

[0192] The exemplary optical scanning system 200 shown in FIG. 8B can be configured to direct a beam transscleral and transpupillary. The optical beam source 206 emits an optical beam 202, which is directed through an optical system to the eye 70 using a laser scanner 214 (e.g., a two-axis or three-axis galvanometer scanner) and focusing optical system 220. In a representative embodiment, for transscleral treatment, the optical beam 202 can have a wavelength of about 1,475 nm based on emission from a 1,475 nm diode laser of the optical beam source 206, and for transpupillary treatment, the optical beam 202 can have a wavelength of about 810 nm based on emission from an 810 nm diode laser of the optical beam source 206. It should be understood that other wavelengths can also be used. In general, the wavelength can be selected based on the location and absorptivity (such as absorbing chromophores) of the targeted ocular tissue. In some embodiments, the optical scanning system 200 is configured to direct the optical beam 202 at least one of transscleral (e.g., 1,475 nm) or transpupillary (e.g., 810 nm) as well as both.

[0193] In FIG. 17A, the macula of the retina is divided into multiple circular (or oval) regions concentric around the cone protrusion, including the foveola, foveal avascular zone (FAZ), fovea, parafovea, and perifovea, in the order of increasing diameter and radial distance from the center of the cone protrusion. Typical dimensions of the illustrated regions are shown. FIG. 17B shows multiple concentric paths for the laser beam to be directed to the macula for biostimulation therapy. Using a spot size of about 0.5 mm, five adjacent concentric paths can span an area starting radially from the FAZ and extending radially outward to the outer radius of the perifovea (e.g., from 0.25 mm from the center of the cone protrusion to 2.75 mm from the center of the cone protrusion). In some embodiments, the predetermined values ​​for spot size and scan pattern radius can be based on average or typical dimensions of the macula, and in further embodiments, the radius and / or spot size can be adjusted or selected after imaging and examining the patient's macula (e.g., through anatomical estimation of dimensional differences such as color relative to a typical macula, by an expert or using machine learning image identification software tools).

[0194] 18A-18G depict an exemplary transpupillary treatment method at different times during the treatment process. In FIG. 18A, at an initial time 500a, a spot 502 of a pulsed laser beam is directed through the pupil of a human eye to impinge on a location outside the macula 504 of the eye (e.g., in or adjacent to the perifovea). The macula 504 is shown on-axis through the pupil, and a cross-sectional depiction is projected below the on-axis view. FIG. 18B depicts a time 500b immediately following the initial time 500a as the spot 502 is scanned in a clockwise direction along an untreated first annulus 506a of a curvilinear scan path 508 centered on the macula 504. Untreated second, third, fourth, and fifth annuli 506b-506e are also shown adjacent to each other at their neighboring beam boundaries to form a continuous area for treatment that excludes the FAZ, foveola, and cone projection. In an exemplary embodiment, the beam boundary is defined as a pulse of a pulsed laser beam having an intensity that is greater than or equal to a full width at half maximum (FWHM), 1 / e, or 1 / e 2, zero. The beam intensity is preferably uniform across the spot to avoid uneven heating or temperature spikes toward the spot center. Uniform intensity can be achieved through a variety of methods, such as homogenizing light pipes, lens arrays, diffusers, etc. The spot size can be fixed in some embodiments or adjusted, for example, using a beam expander or other optics. FIG. 18C depicts a time 500c after the spot 502 has completed treatment of the untreated first annulus 506a and formed a treated first annulus 510a. The spot 502 travels on a curved scan path 508, where it scans clockwise along the untreated second annulus 506b. FIG. 18D illustrates a time 500d during laser treatment after a pulse of the pulsed laser beam has scanned and completed the treated second annulus 510b. The spot 502 is then directed to begin scanning along a curved scan path 508 around the untreated third annulus 506c. At time 500e shown in FIG. 18E, the treatment process has formed the treated third annulus 510c and the laser spot 502 is directed along the curved scan path 508 to begin treatment of the untreated fourth annulus 506d with pulses of the pulsed laser beam. FIG. 18F shows a time 500f during the laser treatment after which the treated annulus 506a-506d is completed and scanning of the untreated annulus 506e begins. FIG. 18G shows a time 500g after the spot 502 has been directed and sequentially directed through each of the untreated annuluses 506a-506e to form the treated annuluses 510a-510e. In selected embodiments, more or less than five annuli may be used, typically with different or variable beam spot diameters.

[0195] 19 shows a dimensional representation 1900 of the positions of beam spots 1902a-1902e at different distances from a central conical projection location 1904 and the positions of beam spots 1906a-1906e arranged at opposing locations, the distance corresponding to the diameter length of individual concentrically arranged treatment annuli, such as annuli 506a-506e shown in FIGS. 18A-18F. In an exemplary embodiment, the FAZ is approximately 0.5 mm wide, and thus the radially inner positions of the beam boundaries of beam spots 1902e, 1906e define a distance 1908, corresponding to the circular area between the treatment annuli where laser beam treatment does not occur through direct irradiation. In an embodiment in which the size of the beam spots 1902a-1902e, extending radially outward from the central conical projection location 1908, is the same for each annulus, and the boundaries of adjacent ones of the beam spots 1902a-1902e are adjacent to one another, the cumulative radial lengths 1912a, 1912b can be defined as 2.5 mm, etc., for a common spot size of 0.5 mm. Thus, an overall length 1914 can be defined for the outer treatment diameter, and the outer annulus diameter 1916 (aligned with the beam spot center) can be smaller by one radially extending spot size.

[0196] In FIG. 20, graph 2000 shows a prediction of a time course temperature profile 2002 treating a macular region centered on the cone protrusion at r=0 mm using an exemplary set of parameters for the laser beam and scanning pattern. Profile 2002 is produced with an annular pattern of a pulsed laser beam scanned around five annuli, the first ring having a beam center radius of 2.5 mm, the second ring having a 2.0 mm radius, the third ring having a 1.5 mm radius, the fourth ring having a 1.0 mm radius, and the fifth ring having a 0.5 mm radius. A circular beam spot with a diameter of 0.5 mm at the macula defines an illumination beam boundary that avoids direct illumination of the FAZ, fovea, and cone protrusion of the macula. The spot size in the radial direction of the annulus and the annulus radius define the continuous laser treatment area.

[0197] In a particular embodiment, the laser beam and scanning parameters further include a constant scanning speed of 1.66 mm / sec during scanning of one or more of the annuli, thereby providing a 300 ms exposure time to each RPE cell that is irradiated by the beam spot diameter within the scanning annulus. It should be understood that other speeds can be selected to produce a range of exposure times, such as 10 ms, 50 ms, 100 ms, 200 ms, 500 ms, etc., in additional embodiments. A series of processing pulses are generated and directed to the macula according to an annular pattern of five annuli at a constant scanning speed. The processing pulses for the pulsed laser beam can have a pulse period of 2 ms (0.5 kHz pulse repetition rate) with a 5% duty cycle, corresponding to a processing pulse duration (FWHM or other suitable measurement) of 100 μs. At a 1.66 m / sec scanning rate and a 0.5 mm beam spot diameter, a pulse-to-pulse area overlap in the macula of greater than 99% is achieved, with an irradiation area density in the macula of greater than 99%. When the peak power of the micropulse is set to 100 mW (e.g., with a 5% duty cycle--0.1 ms "on" and 2 ms period), this may correspond to an average power of 5 mW for a continuous wave (CW) equivalent setting. The power density (irradiance) for the laser micropulse at the macula is approximately 50 W / cm 2 (without considering absorption / scattering losses in the intermediate medium). In another example, the peak power of the micropulse is set to 1,000 mW with the same 5% duty cycle, producing an average power of 50 mW for the CW equivalent setting, resulting in a power of 510 W / cm. 2 According to different embodiments, the laser and scanning treatment parameters can be varied by selected amounts to achieve a similar treatment effect, such as by varying the values ​​by 1%, 2%, 5%, 10%, 50%, 100%, etc.

[0198] Using the aforementioned spot size and five annular radii, which define a continuous scan area through the inner radial beam boundary of each annulus adjacent the outer radial beam boundary of the adjacent smaller annulus, a scan area of ​​approximately 23.5 mm is obtained. 2Total area of ​​600mJ / cm using 100mW micropulse peak power 2 The treatment is performed with a treatment pulse resulting in the delivery of a total energy of 141 mJ at a fluence of approximately 760 mJ / cm2 delivered directly to the RPE cells with 150 micropulses of 1 mJ each over a duration of 300 ms. 2 fluence of 1000 nm may be similar to that of 1000 nm. At peak power for micropulses in the range of 1.0-2.0 W, each 0.5 mm diameter area receives 15-30 mJ of total energy. In general, repetitive pulsing at low duty cycles can reduce the significance of the total process fluence depending on the therapy efficacy since the time-based characteristics carry increased significance. Scanning interruptions or pauses may occur between annuli or between annular treatments and can be selected to be repetitive or periodic based on the characteristics of the laser source generating the pulsed laser beam, such as the duty cycle defined for the CW pulses, and the treatment pulses are generated by modulating or aborting the CW pulses. As shown in profile 2002 without scanning interruptions or pauses, the first ring can be completed after about 9 s, the second ring at about t=17 s, the third ring at about t=23 s, the fourth ring at about t=26 s, and the fifth ring at about t=28 s. By processing sequentially through the annulus, the temperatures within the FAV, pits, and cone projections can be controlled without exceeding the range, e.g., T LOWER ~T UPPER (e.g., by avoiding a temperature profile as depicted with the "over-treatment" line). Thus, temperature uniformity across the macular treatment area can be improved and Gaussian thermal spikes associated with central macular areas can be avoided or reduced.

[0199] FIG. 21 shows an example of an apparatus 2100 that may be used to treat the retina 2102 and / or sclera 2104 of a treated (typically human) eye 2106 as well as other target tissues of the eye 2106. The apparatus 2100 includes a patient interface device 2108 that couples the apparatus 2100 to the eye 2106. The apparatus 2100 includes a light source that includes multiple laser sources such as a transpupillary laser source 2110 that may generate laser pulses at a wavelength of 810 nm with a predetermined duration, repetition frequency, power, duty cycle, etc., and a transscleral laser source 2112 that may generate a continuous wave laser beam at 1,475 nm. In different examples, other additional laser sources may be used and other laser source characteristics including continuous wave or pulsed, wavelength, power, etc. may be selected based on the type of ocular tissue being targeted and the type of laser treatment process being used for the targeted ocular tissue.

[0200] The multiple laser sources can be directed to propagate along a common optical path 2113 using a beam splitter 2114. An optical beam scanner 2116, such as a two-axis or three-axis galvanometer scanner, is coupled to the common optical path 2113 to receive the laser beams from the multiple laser sources and direct the beams toward a predetermined location on the eye 2106 according to a predetermined scanning pattern depending on the selected treatment process. In an exemplary embodiment, a detector 2118, such as a camera, photodiode, CCD, CMOS, imaging system, etc. (such as an OCT system), is optically coupled to the eye 2106, for example through a beam splitter 2120. As shown, the optical coupling for the detector 2118 is between the optical beam scanner 2116 and the patient interface device 2108, although other locations are possible, including between the beam splitter 2114 and the optical beam scanner 2116. The detector 2118 can be used, for example, to monitor the location of ocular tissue that will be or is being treated so that the optical beam scanner 2116 can direct a laser beam or beams from multiple laser sources to a targeted location of the eye 2106. In some examples, the working distance of the laser beam or beams is substantially greater than the propagation distance difference between the scleral and retinal tissues such that the commanded focal plane does not change while treating different portions of the eye 2106. In further examples, the commanded focal point can vary, for example, between scleral and retinal locations or at different locations of the sclera or retina.

[0201] The multiple laser sources, such as laser sources 2110, 2112, the optical beam scanner 2116, and the detector 2118 can be coupled to a computing unit 2122. The computing unit 2122 includes a processor 2124 and a memory 2126 storing instructions executable by the processor 2124 to control laser treatment, such as, by way of example, laser beam characteristics, laser wavelength selection, pulse repetition rate, duty cycle, beam initiation, scan pattern commands, and eye alignment and / or scan calibration. The memory 2126 can be configured with one or more pattern command files that define scan positions and paths for directing the laser beam using the optical beam scanner 2116 in relation to the patient interface 2108 with the eye 2106 in position. In some examples, the computing unit 2122 can also receive signals from the detector 2118 before, during, and / or after treatment and use the received signals to generate images of the eye 2106. In some examples, the detector 2118 can provide location information regarding the eye 2106 such that a scan can be performed in relation to the detected location information and the pattern command file can be updated. Suitable location information can include anatomical reference features, color variations, reflectance variations, etc. In some examples, the detector 2118 can be configured to detect the temperature of the target ocular tissue, for example, using a pyrometer, and the detected temperature can be used to adjust the laser beam characteristics, such as pulse duration, peak power, repetition rate, including in situ during treatment. In some examples, the memory 2126 can control the processor 2124 to control delivery to the macular annulus and to adjust the delivery to the retina at a frequency of 20 mm. 2 ~30mm 2 (For example, 23.5 mm 2) within an annulus treatment area surrounding the foveal avascular zone, with a peak pulse power within the range of 1W-2W, with total laser energy within the range of 1J-3J, delivered to the annulus on the sclera at a constant scanning speed within the range of 5mm / sec-200mm / sec, at the scleral radius, along the circumferential arc length, with a temperature rise within the range of 8°C-20°C and a proportionally reduced exposure time, in the form of N continuous wave cycles, corresponding to a cycle duty time ratio for the annulus within the range of 0.5%-50%, that does not produce a photocoagulation effect. Suitable values ​​can be determined from clinical practice for specific patient cohorts. For example, providing subthreshold non-damaging pan-macular laser photothermal stimulation for a variety of patients, treatment parameters may vary with different ethnicities, pigmentation, morphology, ocular characteristics, and glaucomatous conditions. In particular, non-uniformity or significant variability in the distribution of melanin (the primary absorbing chromophore) in human retinal pigment epithelial cells RPE tends to modify the photothermal effect more than the laser pulse fluence parameters. Energy values ​​may be determined from or varied based on the selected wavelength, including pigmentation variations between patients, which may affect and determine the preferred heat rise. Such delivery to the macular annulus may be achieved with 150 micropulses over each successive 300 ms period, a laser spot diameter of 500 μm, and a fluence of 0.00196 cm. 2 Laser spot area: 510~1,020W / cm 2 irradiance range of 1000 nm, single micropulse duration of 0.1 ms in the energy range of 0.1-0.2 mJ producing 150 pulse exposure energy range of 15-30 mJ, and 51-102 mJ / cm 2 This may correspond to the delivery of a repetitive pulse train of a single micropulse fluence of 100 .mu.m.

[0202] For example, in clinical validation and validation studies, laser parameters using other retinal laser devices have performed successful and effective non-damaging pan-macular photostimulation retinal treatments, and the exemplary devices herein can be controlled to deliver laser exposures similar to such clinically validated procedures. Laser parameters include a 5% duty cycle (0.1 ms on + 1.9 ms off) and 500 pps repetition rate with a 2.0 ms period, a 300 ms exposure duration (delivering a train of 150 micropulses), a 500 μm laser spot diameter, and a 0.00196 cm 2 Laser spot area, laser power of 1.7W, 867W / cm 2 irradiance of 0.17 mJ, single micropulse (0.1 s) energy of 0.17 mJ, 150 pulse exposure total energy of 25.5 mJ, and 86.7 mJ / cm 2 The laser consisted of an 810 nm diode laser operated in micropulse emission mode at a single micropulse fluence of 0.00196 cm of a 500 μm diameter spot. 2 Area targeted: 10-14 μm diameter and approximately 4,220 ± 727 cells / mm 2Each single RPE cell with a macular area density of 100 nm (Songhomitrapanda-Jonasm D. et al., Retinal Pigment Epithelial Cell Count, Distribution, and Correlations in Normal Human Eyes. AJO Volume 121, Issue 2,February 1996, Pages 181-189) was irradiated with 150 consecutive micropulse trains using the above parameters. In the exemplary annular macular treatment pattern described herein without overlap, the RPE cells at the edge of the selected annulus may be exposed to laser energy for a shorter duration than the central portion by the selected annulus (due to the circular shape of the spot) and will receive less energy (e.g., less than 150 pulses). However, this reduction can be compensated for by the proximity of the photothermal stimulation effect from adjacent treatment annuli. In some embodiments, radial overlap of adjacent annuli can be provided to reduce fluence variation in the radial direction.

[0203] In a representative treatment example combining scleral and retinal treatments, the one or more pattern command files may include a first set of pattern commands for transscleral treatments, a second set of pattern commands for transpupillary treatments proximate to the macula, and a third set of pattern commands for transpupillary treatments proximate to the optic disc. In particular, some treatments may be applied prophylactically, such as before the onset of glaucoma or without any indication of glaucoma, to reduce the probability of glaucoma occurring or to delay the onset of glaucoma. For example, it may be determined from the patient's family history, genetics, or population, whether there is a higher likelihood of a predisposition to certain eye diseases, and whether a treatment may be applied based on a positive determination. Alternatively, other treatments may be applied with any indication or with few indications of predisposition to provide neuroprotective therapy that may slow, stop, and / or reverse neurodegenerative progression. The diagram of the eye shown in FIG. 22 shows an example of a transscleral treatment annular scan path and a transpupillary treatment annular scan path overlaid on the eye. The transscleral pattern commands can be configured to control the beam characteristics and direct the beam to multiple treatment locations 0-4 mm posterior to the limbal junction on the external surface of the sclera 2104. At least one (and typically all) of the treatment locations can include a curved or arcuate scan path segment (e.g., a perfect circle or an arcuate portion thereof) of a predetermined length, and the laser beam, operating in a continuous wave mode (although in some embodiments, a sustained series of pulses can be used), is repeatedly directed to scan along the same scan path segment at a predetermined scan speed. The length and scan speed can define a duty time rate for the repetitions that is sufficient to induce protective thermal preconditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body of the eye.In some examples, the multiple transscleral treatment locations are defined by three concentric circular scan paths at different diameters within a range of 0-4 mm (e.g., 1 mm, 2 mm, and 3 mm, 1.5 mm, 2.5 mm, and 3.5 mm, etc.) posterior to the limbal junction on the external surface of the eye, each circular scan path including a single scan path arc segment forming a perfect circle or a near perfect circle, or including multiple arc-like segments including consecutive, spaced, and / or overlapping segments. In certain examples, the circular scan paths each include a superior 150° arc from 9:30 to 2:30 o'clock and a inferior 150° arc from 3:30 to 8:30 o'clock, while avoiding the nasal and temporal 30° arcs.

[0204] The second set of transpupillary treatment commands can be configured to control the beam characteristics and direct the beam to multiple treatment locations in the macular region of the retina 2102, excluding the FAZ, foveola, and cone projection. In an exemplary embodiment, the multiple treatment locations include five annular scan paths concentric about the FAZ, scanned in sequence from the outermost larger diameter annulus to the innermost smallest diameter annulus. The innermost annulus has an inner beam boundary adjacent or contiguous to the FAZ to avoid direct irradiation of the FAZ, and starting with the innermost annulus, each outer beam boundary is adjacent or contiguous (or in some embodiments overlaps) to the next larger diameter annulus to form a continuous treatment area. Using a beam dimension of 0.5 mm radially outward from the FAZ, and using adjacent annuli with adjacent boundaries of the outermost annulus of the five annuli, an outer beam boundary can be at a radius of 2.75 mm for the macula of a typical human eye. In other embodiments, fewer or more than five annuli can be scanned and different beam spot sizes in the radial direction can be used. In an exemplary embodiment, the beam spot is circular resulting in a common value for the beam spot size along the scanning direction and the beam spot size in the radial direction from the cone projection, and in further embodiments, oval, square, rectangular, or other non-circular beam spot shapes can also be used. The treatment annuli can be scanned in a sequence from maximum diameter to minimum, and the sequence can be associated with a suitable temperature increase of the FAZ, pits, and cone projection to within a therapeutic temperature range, such as 37-47°C. In some embodiments, the thickness of the different annuli can be different.

[0205] Beam characteristics for the laser beam targeting the macular region can include pulsed operation with selectable pulse characteristics. For example, pulse repetition rate and curvilinear scanning speed can be selected so that each individual retinal pigment epithelial (RPE) cell in the laser treatment area receives about 150 pulses. To achieve such delivery for a circular beam spot with a diameter of 0.5 mm in the macula, a scanning speed of 1.666 mm / sec and a pulse repetition rate of 0.5 kHz (2 ms pulse period) can be used, thereby delivering about 150 pulses over 300 ms. With a suitable pulse duration and peak power selected (e.g., 100 μs and 100 mW), a time-temperature history of 150 consecutive small non-lethal temperature spikes can be generated for each RPE cell, each spike producing a very high temperature change rate that elicits a biological stress response but does not kill the RPE cell. In generating a non-lethal 7° C. gradient with a 0.1 ms rising front, each spike can inflict heat shock on cells at a rate of approximately 70,000° C. / sec.

[0206] The third set of transpupillary treatment commands can be configured to control the beam characteristics and direct the beam to multiple treatment locations proximate the optic disc region of the retina 2102, but excluding the optic disc and underlying optic nerve (e.g., by having the illuminated laser light avoid substantial impingement on the area bounded by the dura of the optic nerve). The multiple treatment locations can include a scan pattern similar to the second set of transpupillary treatment commands, but instead navigates around the optic disc. For example, the multiple treatment locations can include five annular scan paths concentric with the optic disc center, scanned in sequence from an outermost larger diameter annulus to an innermost smallest diameter annulus. The innermost annulus has an inner beam boundary adjacent or adjacent to the optic disc to avoid direct irradiation of the optic nerve, and starting with the innermost annulus, each outer beam boundary is adjacent or adjacent (or in some examples overlaps) to the next larger diameter annulus to form a continuous treatment area. By using a beam size of 0.5 mm radially outward from the major diameter (approximately 1.92 mm) of the optic disc, and by using adjacent annuli with adjacent boundaries, the outermost annulus of the five annuli can have an outer beam boundary at a radius of 3.46 mm for the optic disc of a typical human eye. By using an oval shaped path that matches the oval shape of the optic disc, the five annuli can be oval shaped, for example, with the outer beam boundary at a radius of 3.38 mm for the optic disc of a typical human eye along the minor diameter (approximately 1.76 mm). In other embodiments, fewer or more than five annuli can be scanned, and different beam spot sizes in the radial direction can be used. In an exemplary embodiment, the beam spot is circular, resulting in a common value for the beam spot size along the scanning direction and the beam spot size in the radial direction from the optic disc center, and in further embodiments, oval, square, rectangular, or other non-circular beam spot shapes can also be used. The treatment annulus can be scanned in a sequence from maximum diameter to minimum diameter, and the sequence can be associated with a suitable temperature increase of the retina in an area having retinal cells surrounding the optic disc to within a therapeutic temperature range, such as 37 to 47°C.In some embodiments, the thicknesses of different annuli may be different.

[0207] Due to the proximity between the macula and the optic disc at the fundus of a typical human eye, the annular example formed with the second and third sets of transpupillary treatment commands can be overlapped at the fundus to produce a dual stimulation treatment of a selected area. Examples herein can also include avoidance of dual treatment by varying the scan pattern associated with the second and / or third sets of transpupillary treatment commands such that a beam spot delivered along one beam scanning path (such as a path that encompasses the macula) does not substantially overlap a beam spot delivered along an adjacent beam scanning path (such as another path that encompasses the optic disc). Additional treatment pattern options are shown in Figures 24A-24C. In Figure 24A, the transpupillary treatment commands produce an exemplary laser scanning path that is in close proximity to the optic disc, generally following the oval contour of the optic disc. If a transpupillary macular treatment command is provided, to avoid over-treatment of the treated area adjacent to the macula (or within the foveal avascular zone), the scan path can be adjusted to terminate to prevent overlap, such as with the interrupted scan oval shown. FIG. 24B shows a transpupillary treatment area that surrounds and avoids the optic disc and foveal avascular zone. In some examples, the scan path or paths that define the transpupillary treatment area can include outlined circles and ovals (similar to those shown in FIG. 24A), although other scan paths can be selected to "fill in" the selected treatment area adjacent to the optic disc and macula as well. In an exemplary embodiment, the scan path of the laser beam treats the area without overlapping scan path segments in a single pass, although additional exemplary paths can be retraced. As discussed herein, treatment parameters are selected to produce sub-threshold, sublethal laser light stimulation of the retina that induces a stress response by targeting retinal pigment epithelial (RPE) cells through sustained scanning of the laser beam according to a predetermined scanning pattern and using selected CW or pulsed laser parameters and laser scanning parameters.24C illustrates another exemplary treatment pattern in which an area of ​​the retina is targeted for subthreshold sublethal laser light stimulation, but an area corresponding to the location of the papillomacular nerve bundle is avoided. As shown, macular areas including the perifovea and other macular areas outside the FAZ are avoided, but in some examples, macular areas excluding or including the papillomacular nerve bundle can be treated.

[0208] In some embodiments, the second and third sets can also be combined to form a single set of treatment commands. By using OCT or another imaging device, the macula and optic disc can be located and their locations determined, and the second and third treatment locations and corresponding sets of treatment commands can be defined relative to the determined locations. Although the locations can be found by a trained person performing the treatment, a representative embodiment can use a coupled control device to compare detected features of the patient's fundus with images or outlines depicting the macula and optic disc. For example, the detected features can be processed through one or more image identification or pattern recognition algorithms (deep learning, convolutional neural networks, circle Hough transform, etc.) to determine the centroid location, boundaries, orientation, relative position, distance, etc. for the patient's macula and optic disc (or corneal / scleral features in transscleral treatments), and the treatment commands can be updated so that the laser beam is scanned to the correct location of the patient's eye.

[0209] The treatment or treatments can be performed using a calibrated system. For example, in the method 2300 shown in FIG. 23, the laser power of the system can be calibrated in 2302 using a detector to compare the commanded peak and / or average power with the actual power. The commanded location for laser beam delivery using an optical beam scanner and patient interface device can be compared to the actual location of beam delivery at one or more predefined working planes or surfaces (e.g., aligned with the expected scleral or retinal surface) using a spatial calibration device such as a laser test surface and / or a coordinate measuring machine or probe. In 2304, with the calibrated device, one or more sets of treatment pattern commands can be produced using software that are for a specific patient and correspond to a pre-planned or custom-generated nomogram. At 2306, the patient is prepared for supine position treatment and anesthetic can be applied, including pre-instilling Duo eye drops (Thealose 3% API-Thea Pharma) at 2 drops / min, on the eye selected to receive treatment prior to anesthetic instillation for 10 minutes or longer, if appropriate. Topical proparacaine eye drops can be instilled when treatment is ready to begin. At 2308, a speculum can be placed in the eye and the patient interface device can be centered on the cornea. Suction force can be applied and the cone of the speculum can be docked to the PID. At 2310, eye position can be detected through the laser treatment system and any changes to the treatment pattern that may improve accuracy, such as XY centering or annulus diameter or shape, can be applied using software. The transscleral and / or transpupillary treatment can then proceed at 2312, and after completion at 2314, the aspiration force can be disengaged and the PID can be removed.

[0210] FIG. 25 illustrates an exemplary laser therapy device 2500 that may be used to deliver laser therapy according to various embodiments described herein. The device 2500 includes a laser head 2502 that is slidably coupled to rails 2504a, 2504b such that the laser head 2502 may be fixed in a predetermined orientation relative to a headrest 2506 and may slide toward the headrest 2506. The rails 2504a, 2504b are arranged in a fixed relationship relative to the headrest 2506, but may be adjustable, including relative to each other. For example, the rails 2504a, 2504b may be attached to a body support 2508, such as a recliner (e.g., a dental chair) that leans back and has a back and / or footrest that may be finely adjusted through electrical controls. The patient may also be positioned in a supine position on a gurney. In additional embodiments, the patient may be upright, as viewed from the patient's head downward in the view in FIG. 25. The head rest 2506 can be fixedly attached to and adjustable relative to the body support 2508 through one or more pivoting support members 2510a-2510d. The head rest 2506 can be configured as a horseshoe shaped head rest including opposing adjustable pads 2512a, 2512b coupled to support members 2410a, 2510b. In an exemplary embodiment, the head rest 2506 can be adjusted to accommodate different head sizes.

[0211] The laser head 2502 can be coupled to the end of an articulating support arm and stand 2514 including pivoting support members 2516a-2516c configured to allow movement and rotation of the laser head 2502 and to allow the laser head 2502 to be brought into close proximity with the body support 2508 and headrest 2506. In an exemplary embodiment, the laser head 2502 can be removably coupled to rails 2504a, 2504b such that the laser head 2502 can be fixedly and slidably translated along the rails 2504a, 2504b. Once mechanically mounted or "click-fit" to the rails 2504a, 2504b, the laser head 2502 can also be adjusted in various directions using an internal translation stage for fine adjustment and to center the optical components of the laser head 2502 in relation to the patient's eye. In some embodiments, once the laser head 2502 is attached to the rails 2504a, 2504b, a physician can be seated adjacent to the patient's head and be enabled to control the coupling of the laser head 2502 to one or both of the patient's eyes through a patient interface device (PID) 2518 (such as, for example, the patient interface device 100 shown in FIGS. 5A-5C). The PID 2518 can be affixed to the laser head 2502 and in contact with the patient's face and eyes. The PID 2518 can include a coolant intake ring configured to provide a coolant solution (such as a PBS saline solution) to the patient's cornea. The PID 2518 and laser head 2502 can be aligned with the patient's eyes with the patient's head resting on the head rest 2506. A foot pedal can be used by the physician for manual laser application, imaging control, or mechanical adjustment.

[0212] The laser head 2502 typically includes multiple laser sources, such as two laser sources, three laser sources, four laser sources, or more, and a laser scanner, such as a two-mirror galvanometer scanner or two double wedge prisms. In an embodiment, the laser head 2502 includes a laser source configured to generate a laser beam at about 1,470 nm, which may be used in transscleral treatments described herein, such as to reduce intraocular pressure or provide prophylactic treatment. In an embodiment, the laser head 2502 further includes a laser source configured to generate a laser beam at about 810 nm, which may be used in transpupillary treatments described herein, such as for retinal neuroprotection applications. In some embodiments, the laser source at 810 nm (or another laser source) can generate a laser beam configured for standard glaucoma treatment modalities, such as diode laser trabeculoplasty (DLT), micropulse diode laser trabeculoplasty (MDLT), and laser cyclophotocoagulation (LCP). In some embodiments, the laser head 2502 further includes a laser source configured to generate a laser beam at about 635 nm, which may be used to aim and align other laser beams generated and scanned with the laser head 2502. The laser scanner of the laser head 2502 may be used to direct one or more laser beams through the PID 2518 and / or a contact lens coupled to the patient's eye. In an exemplary embodiment, a fixed objective lens (such as an F-theta lens or other scanning optics) is mounted to receive the beam scanned to a selected location using a scanning mirror and focus (or otherwise direct) the received beam to a targeted treatment location. In some embodiments, a rotatable lens fixture may be provided such that an alternative objective lens (or no objective lens) may be coupled between the laser scanner and the PID 2518.In an exemplary embodiment, the laser beams emitted from the laser sources each can have a fixed spot size, although some embodiments can include a variable spot size, for example, using an in-line beam expander or a zoom lens. The laser beams typically have a uniform "top hat" intensity profile provided by suitable homogenizing optics, such as a homogenizing waveguide and / or lens array.

[0213] The laser head 2502 can also include one or more imaging devices, such as a camera, coupled through the PID 2518, for example, through a laser scanner and / or objective lens, that can image the patient's eye. If there is an insufficient form factor to accommodate a more complex imaging device, such as an OCT machine 2520, it can be placed separately and coupled to the laser head 2502, for example, along the support members 2516a-2516c. A display 2522 can be coupled to the stand 2514 to show an image of the eye and / or provide a graphical user interface for control of the laser treatment. The display 2522 and the laser head 2502 can be coupled to a laser controller 2524 (such as a PC or other computing device), which can include a processor and a memory that stores instructions for controlling the laser treatment. As shown, the laser source is mounted in the laser head 2502 at the end of the support member 2516c, but in other embodiments, the laser source can be coupled to the articulating support arm and stand 2514 at other locations and coupled through suitable waveguides, such as optical fibers, along the support members 2516a-2516c. The physician can align the patient's eye with the laser beam emitted by the laser head 2502 through the optics and PID 2518 by using an aiming beam, a camera, and / or an imaging device. The laser controller 2524 can include an input interface configured with user controls to activate one or more treatment routines. For example, existing treatment patterns can be preloaded into the laser controller 2524, or additional routines, such as patient-specific ones, can be loaded from an external device.

[0214] Although the principles of the disclosed technology have been described and illustrated with reference to the illustrated embodiments, it will be recognized that the illustrated embodiments can be modified in arrangement and detail without departing from such principles. For example, elements of the illustrated embodiments shown in software may be implemented in hardware, and vice versa. Also, techniques from any embodiment can be combined with techniques described in any one or more of the other embodiments. It should be understood that procedures and functions such as those described with reference to the illustrated embodiments can be implemented in a single hardware or software module, or separate modules can be provided. The particular arrangements above are provided for convenient illustration, and other arrangements can also be used.

[0215] In light of the many possible embodiments to which the principles of the disclosed technology may be applied, it should be recognized that the illustrated embodiments are merely representative examples and should not be taken as limiting the scope of the present disclosure. The alternatives specifically mentioned in these sections are merely exemplary and do not constitute every possible alternative to the embodiments described herein. For example, the various components of the systems described herein may be combined in function and use. Accordingly, everything that falls within the scope of the appended claims is claimed.

Claims

1. 1. An automated extraocular laser treatment system for treating an eye in a subject, comprising: the extraocular automated laser treatment system comprises a processor and a memory, the memory including stored computer readable instructions which, in response to execution by the processor, cause the extraocular automated laser treatment system to direct a laser beam to a plurality of perilimbal scleral treatment locations posterior to a limbal junction to be irradiated in a predetermined treatment pattern on an external surface of the eye, the plurality of perilimbal scleral treatment locations being between 0 mm and 4 mm posterior to the limbal junction, such that laser energy is absorbed by water-containing cells in the superficial sclera to generate a thermal rise such that cellular transduction chains in deeper ocular structures are affected, and directing the laser beam includes repetitively directing the laser beam to the irradiated plurality of perilimbal scleral treatment locations on the external surface of the eye at periodically repeating time intervals sufficient to induce protective thermal preconditioning and therapeutic biostimulation of one or more of the trabecular meshwork, the uveoscleral meshwork, and / or the ciliary body without photocoagulation of tissues of the eye; wherein laser parameters are configured to provide an irradiance of the laser beam and scanning parameters are configured to move the laser beam according to the predetermined treatment pattern, the laser parameters and the scanning parameters are adapted to increase a temperature of one or more of the trabecular meshwork, the uveoscleral meshwork, and / or the ciliary body to a temperature of about 43° C. to about 45° C.; The laser beam has a wavelength between 0.8 μm and 2.2 μm.

2. The extraocular automated laser treatment system comprises: a non-contact laser source configured to treat the eye by generating the laser beam having at least one wavelength and directing the laser beam from a location spaced apart from the eye, the at least one wavelength being a near infrared wavelength of 1.475 μm; a laser scanner optically coupled to the non-contact laser source to receive the laser beam from the non-contact laser source and scan the laser beam relative to the eye; The automated extraocular laser treatment system of claim 1 , further comprising:

3. The non-contact laser source is further configured to generate a transpupillary laser having a wavelength different from 1.475 μm, and the memory includes stored computer readable instructions that cause the extraocular automated laser treatment system to direct the transpupillary laser to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in a target ocular tissue of the eye within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations being located at a yelloW region around but not on a foveal avascular zone. and / or the memory includes stored computer readable instructions that cause the extraocular automated laser treatment system to direct the transpupillary laser to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations (i) surrounding the macula but not over the foveal avascular zone, and (ii) and / or the memory includes stored computer readable instructions that cause the extraocular automated laser treatment system to direct the transpupillary laser to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including areas surrounding the optic disc but not on the optic disc or adjacent optic nerve crescent.

3. The extraocular automated laser treatment system of claim 2, wherein the memory includes stored computer readable instructions that cause the extraocular automated laser treatment system to direct the transpupillary laser to a plurality of transpupillary treatment locations, induce a sublethal thermal rise, and elicit therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations including areas adjacent to the foveal avascular zone but not over an area of ​​the papillomacular bundle.

4. 4. The extraocular automated laser treatment system of claim 3, wherein the stored computer readable instructions cause the extraocular automated laser treatment system to direct the laser beam to the multiple perilimbal scleral treatment locations at cyclic repeat time intervals sufficient to induce protective thermal preconditioning and biostimulation of targeted structures and elicit a biomechanical and biochemical response to lower intraocular pressure, and / or the processor is configured with instructions to receive input corresponding to a location of the target limbal junction or limbus, the processor being configured to determine the multiple perilimbal scleral treatment locations in response to the input, the multiple perilimbal junction or limbus being offset radially outward from an input location corresponding to the limbal junction or limbus, and contouring the predetermined treatment pattern to the target ocular anatomical structure.

5. 5. The extraocular automated laser treatment system of claim 4, wherein the plurality of perilibal scleral treatment locations are in a 360° annular pattern posterior to the limbal junction, and the processor is configured to direct the laser beam to a set of pre-identified scleral treatment locations on the external surface of the eye during a first treatment cycle and to direct the laser beam to a set of pre-identified scleral treatment locations during a subsequent treatment cycle to achieve precise cyclical thermal elevation of scleral tissue underlying the set of pre-identified scleral treatment locations during time intervals involving thermal relaxation of the irradiated tissue between treatment cycles.

6. The extraocular automated laser treatment system of any one of claims 1 to 5, wherein the time intervals between irradiation of the multiple perilimbal scleral treatment locations produce a duty cycle corresponding to a ratio between active exposure on time / (active exposure + relaxation off time) in the range of 2% to 50%.

7. 6. The extraocular automated laser treatment system of claim 5, wherein the predetermined treatment pattern is located approximately 1.5 mm posterior to the limbal junction, and / or the predetermined treatment pattern comprises a plurality of annular treatment patterns, the plurality of annular treatment patterns being spaced approximately 1.5 mm, 2.5 mm, 3.5 mm posterior to the limbal junction, the plurality of annular treatment patterns comprising one or more of a circular, oval, elliptical, oval, non-circular, non-elliptical or asymmetric pattern or a pattern corresponding to a shape of Schlemm's canal or the limbus, and / or the 360° annular pattern is interrupted 10-30° nasally and 10-30° temporally.

8. The extraocular automated laser treatment system of any one of claims 1 to 7, further comprising a heat sink, the heat sink being placed in contact with the eye across the plurality of perilimbal scleral treatment locations to transfer heat away from the external surface of the eye.

9. 5. The extraocular automated laser treatment system of claim 4, wherein the protective thermal preconditioning and therapeutic biostimulation are controlled by one or more of laser power, irradiance, scan speed, cycle repetition rate, number of cycle repetitions, spot size, duty cycle, and / or the processor is configured to direct the laser to the multiple perilimbal scleral treatment locations within a spot having a diameter of 500 μm to 1,000 μm.

10. The extraocular automated laser treatment system of any one of claims 2 to 5, 7 and 9, further comprising a patient interface for docking the non-contact laser source away from the eye, the patient interface comprising a spacer for maintaining the eye in a substantially fixed location for imaging and treatment, the spacer maintaining the non-contact laser source away from and without contacting an external surface of the eye.

11. 5. The extraocular automated laser treatment system of claim 3 or claim 4, wherein each annulus on the macula of the predetermined curvilinear treatment pattern comprises a plurality of uniformly spaced and overlapping laser pulse spots, the plurality of laser pulse spots being delivered sequentially along a perfect circle to generate an irradiated annular treatment zone within each annulus, and the plurality of laser pulse spots being delivered at a common scan speed for all macular annuli.

12. The extraocular automated laser treatment system of any one of claims 2 to 5, 7, 9 to 11, wherein the non-contact laser source is configured to generate a laser beam having pulses at a pulse repetition period in the range of 1 ms to 3 ms, a pulse repetition rate of 1,000 pulses / sec to 333 pulses / sec, and a pulse duration in the range of 20 μs to 500 μs.

13. The plurality of concentric annuli includes three to five contiguous concentric annuli on the macula, each annulus having a substantially equal width, and the plurality of perilimbal scleral treatment locations each have a radius R corresponding to a location covering the primary aqueous humor outflow pathway, the ciliary body process, and the pars plana. １ , R ２ , R ３ 5. The extraocular automated laser treatment system of claim 4, comprising three concentric annuli on the superficial sclera around the limbus at

14. 8. The extraocular automated laser treatment system of claim 5 or claim 7, wherein the plurality of concentric annuli comprises five consecutive annuli on the superficial sclera, each having a width of about 500 microns, and the plurality of perilibal scleral treatment locations comprises three concentric annuli on the superficial sclera at distances of about 1.5 mm, about 2.5 mm, and about 3.5 mm from the corneoscleral junction. Tem.

15. The extraocular automated laser treatment system of any one of claims 3-5, 7, 9, 11, 13-14, wherein the non-contact laser source comprises a first diode laser source operable to generate a pulsed laser beam at 810 nm for directing to the plurality of transpupillary treatment locations, a second diode laser source operable to generate a continuous wave laser beam at 1,475 nm for directing to the plurality of perilibal scleral treatment locations, and at least one beam splitter mounted to receive the pulsed laser beam at 810 nm and the continuous wave laser beam at 1,475 nm and direct them along a common optical path for receipt by the laser scanner.

16. The extraocular automated laser treatment system of claim 3 or claim 4, further comprising a detector optically coupled to the target ocular tissue, and the stored computer readable instructions cause the laser scanner to selectively direct the laser beam to a target location on the target ocular tissue based on a change in position of the target ocular tissue detected using the detector.

17. 6. The extraocular automated laser treatment system of claim 5, wherein the processor is configured to set a speed for each treatment cycle and achieve the thermal relaxation by spaced irradiation of the multiple perilimbal scleral treatment sites at intervals of sufficient time such that exposure and relaxation times produce a targeted time-temperature history.

18. 7. The extraocular automated laser treatment system of claim 6, wherein the time interval between irradiation of the multiple perilimbal scleral treatment sites is between about 10 ms and about 300 ms.

19. 20. The extraocular automated laser treatment system of claim 18, wherein the time interval between irradiation of the multiple perilimbal scleral treatment locations is between about 100 ms and about 200 ms.

20. The plurality of annular treatment patterns include: (a) perilimbal outflow structure; (b) ciliary processes; (c) the pars plana of the ciliary body; The extraocular automated laser treatment system of claim 7 , which targets

21. The extraocular automated laser treatment system of claim 8 , wherein the heat sink comprises a curved contact lens placed on the external surface of the eye.

22. 22. The extraocular automated laser treatment system of claim 21, wherein the curved contact lens comprises a cooled contact lens that substantially conforms to the external surface of the eye.

23. 10. The extraocular automated laser treatment system of claim 9, wherein the diameter is approximately 600 μm, and / or the extraocular automated laser treatment system further comprises an optical imaging system for detecting the limbus and / or limbal junction of the subject, and / or the processor is configured to identify a predetermined scleral treatment location at a location determined by the shape of the limbus and / or limbal junction of the subject's eye.

24. the patient interface further comprises a speculum for placement between the eyelids of the subject to expose the eye to the laser beam, and / or the patient interface further comprises a fixation ring for a contact lens, the fixation ring comprising a resilient sealing surface, the extraocular automated laser treatment system configured to maintain a negative pressure between the contact lens and the fixation ring to secure the patient interface to an external surface of the eye and substantially immobilize the subject's eye, and / or the negative pressure is adjustable, and / or the extraocular automated laser treatment system ... spacer and 11. The extraocular automated laser treatment system of claim 10, wherein the spacer and / or the fixation ring are configured to cool the spacer and / or the fixation ring and / or the contact lens, and / or the spacer and / or the fixation ring include an internal fluid flow channel, the extraocular automated laser treatment system configured to introduce cooled fluid through the fluid flow channel to cool the spacer and / or the fixation ring and / or the contact lens, and / or the extraocular automated laser treatment system further includes a positioning arm for positioning the patient interface at a location relative to an external surface of the eye of the subject.

25. The extraocular automated laser treatment system of claim 11, wherein the plurality of concentric annuli comprises a radially continuous irradiated annular treatment area on the macula and / or each concentric annulus has a width of between 400 μm and 600 μm.

26. 13. The extraocular automated laser treatment system of claim 12, wherein the non-contact laser source is configured to generate a laser beam having pulses at a pulse repetition period in a range of 1.5 ms to 2.5 ms and a pulse repetition rate of 666 pulses / sec to 400 pulses / sec and a pulse duration in a range of 50 μs to 150 μs, or the laser source is configured to generate a laser beam having pulse repetition period in a range of 1.8 ms to 2.2 ms and a pulse repetition rate of 556 pulses / sec to 455 pulses / sec and a pulse duration in a range of 80 μs to 120 μs.

27. The extraocular automated laser treatment system of claim 1 , wherein the laser parameters are configured to maintain a temperature of about 43° C. to about 45° C. for at least about 25 seconds.

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