Laser therapy for the treatment and prevention of eye diseases

Abstract

To provide a laser therapy for treatment and prevention of eye diseases.SOLUTION: An ab externo 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 to 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 about 0.5-2.2 μm; a laser scanner optically coupled to the non-contact laser source to receive the laser beam from the non-contact laser source and to scan the laser beam relative to the eye; and a processor and a memory, the memory including stored computer-readable instructions that, responsive to execution by the processor, cause the laser treatment system to direct the laser beam to a plurality of trans-scleral treatment locations so as to be radiated in a predetermined treatment pattern on an external surface of the eye.SELECTED DRAWING: Figure 4J

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application relates to U.S. Provisional Application No. 62 / 755,298, filed on 2 November 2018, and U.S. Provisional Application No. 62 / 888,153, filed on 16 August 2019, respectively, which are incorporated together by reference.

[0002] (Field) Transscleral extraocular IOP reduction and transpupillary nerve protection laser therapy is disclosed for the clinical management of patients with ocular hypertension and / or glaucoma, as well as for the treatment and / or prevention of related diseases. [Background technology]

[0003] (background) Glaucoma is an optic neuropathy characterized by increased intraocular pressure (IOP), which damages retinal ganglion cells and nerve fibers within the optic disc. Aqueous humor is produced from the ciliary process and flows through the pupil into the anterior chamber, from where it travels through the trabecular meshwork, Schlemm's canal, and uveoscleral outflow pathway. Increased IOP arises 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. If left untreated in a timely manner, nerve damage causes progressive peripheral vision loss, followed by central vision loss and irreversible blindness. The goal of current glaucoma treatment is to halt or slow disease progression by reducing IOP, the only known modifiable risk factor. The majority of common treatments for glaucoma involve lifelong use of IOP-reducing medications, such as eye drops, containing prostaglandin analogs, beta-adrenergic receptor antagonists, alpha-2-adrenergic agonists, and miotics. While these medications improve 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 expensive. Poor compliance with medication use is a leading cause of blindness in glaucoma patients.

[0004] Glaucoma surgeries such as trabeculotomy and canal shunts with antifibrosis avoid some of these problems. Laser-based therapies such as laser trabeculoplasty (LT) and laser ciliary photocoagulation are also performed to reduce 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 to the angle of the anterior chamber of the eye, directly irradiating the trabecular meshwork. ALT was the first type of LT introduced in the 1970s and has since been practiced using various lasers, wavelengths, and treatment techniques. Some of these techniques include 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 typically performed transcorneal using a slit-lamp delivery system and a corneal contact gonioscope lens. It visualizes the anterior chamber angle of the eye and precisely directs a laser beam from within it, below the Schwalbe lines (SL), to the pigmented trabecular meshwork, where the laser energy is absorbed and converted into heat. Laser wavelengths in the 488-810 nm range are used for these procedures, as they specifically interact with the darkly pigmented cells in the TM. Transcorneal LT procedures are difficult, and contact between the gonioscope lens and the eye can induce iatrogenic corneal lesions such as punctate keratopathy and infections.

[0006] LT has also been performed extraocularly using a transscleral approach with a 532nm SLT frequency dual Q-switching 3-nsNd:YAG laser beam (Geffen et al., J.Glaucoma26:201-207,2017) or an 810nm MDLT micropulsed laser beam (see Aquino MC and Chew PK, External Micropulse Diode Laser Trabeculoplasty (EMDLT) for Primary Open Angle Glaucoma: apilotstudy.P4-097 European Glaucoma Society 2018 Annual Congress, Firenze, Italy, and U.S. Patent No. 8,945,103). The SLT or EMDLT laser beam is applied extraocularly across the peri-corneal area through the cornoscleral junction, affecting the conventional outflow pathway structures (collecting ducts, Schlemm's canal, para-Schlemm's canal, cornosclera, and uvea™). Transscleral procedures generally did not use infrared wavelengths known to be absorbed by water in superficial scleral cells, as superficial absorption would prevent the laser energy from reaching deeper, targeted structures such as the trabecular meshwork. U.S. Patent No. 6,319,274 describes using longer wavelength laser energy directed transsclerally from a probe that penetrates the surface of the eye and facilitates laser energy penetration through the scleral thickness (750-950 μm) to reach the trabecular meshwork.

[0007] Manual guidance of a physical probe into the eye can irritate the ocular surface and produce variable, operator-dependent outcomes. Scleral indentation can also induce intraocular pressure spikes and cause glaucomatous damage to the eye. Laser energy within the probe-conjunctival interface can cause contact burns, and the probe touching the eye is a potential infectious disease vector. Despite these problems, 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, exposing water from the underlying scleral cells and reducing both the absorption and scattering of light energy by water molecules within the superficial sclera. However, manual movement of the laser probe into the eye limits the laser movement speed, as high-speed movement can 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 unreproducible and macroscopically variable laser energy deposition for each treatment.

[0008] Reducing and controlling IOP has been, and remains, the primary goal in the management of patients with glaucoma. Unfortunately, even when IOP is well controlled, nearly 60% of glaucoma patients experience progressive visual field loss due to a continuing neurodegenerative process involving loss of retinal ganglion cells and thinning of optic 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 retinopathy, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), as well as in patients with POAG. Glaucoma is associated with reduced blood perfusion in the retina, and the presence of capillary hypoperfusion correlates with measurements after nerve fiber thinning and visual field defect progression. Concerns that IOP reduction treatment alone may not be sufficient to prevent the progression of visual loss have led to increased interest in neuroprotective therapies to improve neurotrophic balance, and therefore the health and function of the optic nerve and retina. For example, US Patent No. 9,962,291 discloses the use of subliminal photocoagulation of the retina in a grid or rotational line pattern. However, there remains a need for improved systems and methods to treat glaucoma by reducing / controlling IOP and administering effective neuroprotective therapies to slow, halt, or potentially reverse the progression of neurodegeneration. [Prior art documents] [Patent Documents]

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

[0011] (summary) To irradiate the ocular structure, the laser beam 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 remainder of the cycle until the tissue is irradiated again 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 with different refractive indices. The wavelength of the laser can also be selected to improve the delivery of laser energy to the targeted ocular structure. The laser beam can be directed transscleral and / or transpupillary, and the wavelength of the laser beam may vary for different targeted ocular structures. The transpupillary beam can be continuously scanned at a selected scanning speed while delivering sustained wave and / or pulsed laser energy to the treatment site pattern. The embodiment may irradiate the laser beam in the absence of specific glaucoma indicators to provide prophylactic treatment for various ocular diseases.

[0012] In one embodiment, transscleral IOP reduction laser therapy is performed without the laser probe touching the eye. The laser beam does not directly irradiate the deep sclera and subscleral target structures such as the trabecular meshwork or ciliary process, but instead indirectly thermally stimulates them using heat generated by the absorption of laser energy within the more superficial layers of the eye. The laser beam is projected across the eye, rapidly moved, and induces a heat wave that propagates from surface structures to targeted subscleral or intraocular structures. The high-speed laser movement repeatedly irradiates the same treatment site on the sclera at spaced time intervals during sequential cycles of treatment. For example, the laser may move through 360° in a cycle and repeatedly return to the previous treatment site in subsequent cycles, irradiating that same treatment site throughout the subsequent cycles. In some embodiments, the laser irradiates the scleral surface continuously or at spaced locations around the 360° path, inducing a heat wave into the tissues beneath the scleral surface throughout the entire path of irradiation. The heat wave propagates three-dimensionally in 360° through conduction via the subscleral tissue, without direct laser irradiation, reaching targeted subscleral structures (such as the trabecular meshwork, ciliary body, and / or other targets for aqueous humor production and outflow).

[0013] A patient interface docked to the eye can hold a laser emission source at a position spaced apart from the eye. The laser wavelength can be within a range that targets the selected tissue, for example, penetrates the episcleral surface and interacts with the cellular moisture of the episcleral surface. In some embodiments, the wavelength can be 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 of the disclosed embodiments, the wavelength is 1.47 μm. The laser energy directly reaches deeper scleral structures (such as structures deeper than 700 μm) and thereby heats the episcleral surface at the treatment site over a short period without being absorbed (for example, 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 pores, and / or the ciliary body.

[0014] After the episcleral surface is heated, a period of heat relaxation follows, during which the heat is transmitted deeper into the sclera towards the trabecular meshwork and / or the ciliary body. The repeated cycles of heating and heat relaxation are intended to achieve preconditioning of the protective heat of the intended targets such as the trabecular meshwork, the uveoscleral outflow network, and / or the ciliary body, thermotherapy, and biostimulation for therapy. In the disclosed examples, the repeated heating cycles are specifically targeted at the same location on the scleral surface by an imaging system that repeatedly targets the same treatment site throughout multiple cycles of heating, heat relaxation, and heat wave propagation to deeper target tissues. The treatment site can be 0 - 4 mm (for example, 1 - 4 mm) behind the corneal limbus junction.

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

[0016] According to one aspect of the disclosed technology, an extracorporeal automated laser therapy system for treating an eye in a subject is 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 apart from the eye, wherein the at least one wavelength is a near-infrared wavelength within the range of about 0.5 to 2.2 μm, a laser scanner optically coupled to the non-contact laser source, receiving the laser beam from the non-contact laser source, and scanning the laser beam across the eye, a processor, and a memory including stored computer-readable instructions that, responsive to execution by the processor, direct the laser beam to a plurality of trans-scleral treatment sites to be irradiated on an external surface of the eye in a predetermined treatment pattern, wherein the trans-scleral treatment sites are located 0 to 4 mm behind the limbal junction, the laser beam is repeatedly directed to the same trans-scleral treatment site on the surface of the eye, and the trans-scleral treatment sites are irradiated at time intervals sufficient to induce protective thermal preconditioning and biostimulation for therapy of one or more of the trabecular meshwork and / or ciliary body without causing photocoagulation of the eye tissue, comprising the processor and the memory.

[0017] In some embodiments, the memory includes stored computer-readable instructions that direct the laser therapy system to direct the laser beam to a plurality of trans-pupillary treatment sites to induce a sub-lethal temperature rise and to elicit a therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, wherein the plurality of trans-pupillary treatment sites include various singular or combinations thereof of (a) a predetermined curvilinear treatment pattern on the target eye tissue of the eye comprising a plurality of concentric annuli on the macula that surround but are not on the foveal avascular zone, (b) an area that (i) surrounds the macula but is not on the foveal avascular zone and (ii) surrounds the optic nerve head but is not on the optic nerve head or the adjacent peripapillary crescent, (c) an area that surrounds the optic nerve head but is not on the optic nerve head or the adjacent peripapillary crescent, or (d) an area that is adjacent to the foveal avascular zone but is not on the area of the papillomacular bundle.

[0018] In some embodiments, stored computer-readable instructions direct a laser treatment system to direct a laser beam to multiple transscleral and / or transpupil treatment sites, where the subject has clinically normal intraocular pressure and / or does not have glaucoma symptoms or a diagnosis.

[0019] In selected embodiments, stored computer-readable instructions direct the laser treatment system to direct a laser beam to multiple transscleral treatment sites at sufficient time intervals to induce protective thermal pre-conditioning and biostimulation of targeted structures, thereby reducing the intraocular pressure of the target eye. In some embodiments, the processor is configured with instructions to repeatedly deliver the laser beam to multiple irradiated transscleral treatment sites at time intervals, targeting an increase in the temperature of the outer 200-500 μm scleral layer to a temperature of approximately 45-57°C. Embodiments may include laser parameters configured to provide the irradiance of the laser beam, the scanning speed which moves the laser beam in a predetermined treatment pattern, and which increases the temperature of the outer 200 μm scleral layer to approximately 43-57°C, optionally to approximately 43-45°C.

[0020] In some embodiments, the processor is configured with instructions for receiving inputs corresponding to the location of the corneal marginal junction or limbal region of a target, and in response to the inputs, the processor is configured to determine a plurality of transscleral treatment sites, which are radially offset outward from the input locations corresponding to the corneal marginal junction or limbal region, and contour the treatment pattern to the anatomical structure of the target eye. In some embodiments, the transscleral treatment sites are located within a 360° ring-shaped pattern posterior to the corneal marginal junction, and the processor is configured to direct the laser beam to a set of pre-identified transscleral treatment sites on the surface of the eye during a first treatment cycle, and to direct the laser beam to the same pre-identified transscleral treatment sites during subsequent treatment cycles, thereby achieving precise circulating heat rise of the scleral tissue beneath the pre-identified transscleral treatment sites over the time interval between treatment cycles to achieve thermal relaxation of the irradiated tissue. In some embodiments, the processor is configured to achieve thermal relaxation by spaced irradiation of transscleral treatment sites at sufficient time intervals, setting the speed of each treatment cycle and producing a targeted time-temperature history of exposure and relaxation times. In some embodiments, the time interval between irradiations of the same transscleral treatment site produces a load time rate corresponding to the ratio of active exposure on time / (active exposure + relaxation off time) in the range of 2-50%. Exemplary time intervals between irradiations of the same transscleral treatment site can be approximately 10-300 ms, and optionally approximately 100-200 ms. In some embodiments, a given treatment pattern is located approximately 1.5 mm posterior to the corneal marginal junction. In certain embodiments, a given treatment pattern comprises multiple annular treatment patterns, which are spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the corneal marginal junction, and the annular treatment patterns comprise one or more of the following patterns: circular, oval, elliptic, egg-shaped, non-circular, non-elliptic, or asymmetrical, or corresponding to the shape of Schlemm's canal or the corneal limbus. In further embodiments, the 360° pattern is interrupted 10–30° nasally and 10–30° temporally. In some embodiments, the multiple annular treatment patterns target the peri-corneal outflow structures, ciliary processes, and ciliary flaccids.

[0021] Some embodiments further include a heat sink that is placed in contact with the eye across the transscleral treatment site 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 embodiments, the laser beam has near-infrared wavelengths 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 approximately 1.4–1.5 μm, optionally 1.47 μm. In some embodiments, protective thermal pre-conditioning and therapeutic biostimulation are controlled by one or more of the following: laser power, irradiance, scanning speed, cycle repeat rate, number of cycle repeats, spot size, and duty cycle. In some embodiments, the processor is configured to direct a laser beam to a transscleral treatment site within a spot having a diameter of 500 to 1,000 μm, optionally, about 600 μm. Some embodiments further include an optical imaging system for detecting the limbus and / or corneal marginal junction of the target eye. In some embodiments, the processor is configured to identify a predetermined transscleral treatment site at a location determined by the shape of the limbus and / or corneal marginal junction of the target eye.

[0022] In some embodiments, the patient interface further includes a patient interface for docking a non-contact laser source in a state separated from the eye, the patient interface comprising a spacer that maintains the eye in a substantially fixed position for imaging and treatment, the spacer maintaining the non-contact laser source separated from the surface of the eye and without contact. In some embodiments, the patient interface further includes a microscope for placement between the eyelids of the subject for exposure of the eye to the laser beam. In further embodiments, the patient interface further comprises a retaining ring for a contact lens, the retaining ring comprising a resilient sealing surface, the system configured to maintain negative pressure between the contact lens and the retaining ring, fixing the patient interface to the surface of the eye and substantially immobilizing 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 retaining ring and / or the contact lens. In some embodiments, the spacer and / or the retaining ring comprises an internal fluid flow channel, the system configured to introduce cooled fluid through the fluid flow channel to cool the spacer and / or the retaining ring and / or the contact lens. Some embodiments further include a positioning arm for locating the patient interface at a specific point relative to the surface of the target eye.

[0023] In some embodiments, each ring shape on the macula of the curved treatment pattern comprises multiple uniformly spaced and overlapping laser pulse spots, delivered continuously along a perfect circle, producing an irradiated annular treatment area within each ring, with the laser pulse spots delivered at a common scanning speed for all macular rings. In some embodiments, multiple concentric ring shapes provide a radially continuous irradiated annular treatment area on the macula. In some embodiments, each concentric ring shape has a width of 400 μm to 600 μm. In various embodiments, the laser source is configured to produce a laser beam with pulses in the range of pulse repetition period in the range of 1 to 3 ms, pulse repetition rate of 1,000 to 333 pulses / second, and 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 in the range of pulse repetition period in the range of 1.5 to 2.5 ms, pulse repetition rate of 666 to 400 pulses / second, and 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 in the range of 1.8–2.2 ms, a pulse repetition rate of 556–455 pulses / second, and a pulse duration of 80–120 μs. In some embodiments, the rings comprise 3–5 consecutive concentric rings on the macula, each ring having substantially equal width, and the multiple transscleral treatment sites comprise 3 concentric rings on the sclera around the limbus at radii R1, R2, and R3, respectively, corresponding to the primary aqueous humor outflow pathway, the ciliary process, and the ciliary body, and the ciliary body planus. In some embodiments, the rings comprise 5 consecutive rings on the sclera, each ring having a width of approximately 500 microns, and the multiple transscleral treatment sites comprise 3 concentric rings on the sclera at distances of approximately 1.5, 2.5, and 3.5 mm from the cornoscleral junction. In some embodiments, the sublethal fever rise corresponds to an increase in the temperature of the target tissue within the annular region on the macula to a temperature of 47°C or lower, while the laser beam raises the temperature of the target tissue within the transscleral treatment site to 57°C or lower.

[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 a transpupil treatment site, a second diode laser source operable to produce a sustained-wave laser beam at 1,475 nm for directing to a transscleral treatment site, and at least one beam splitter that receives the 810 nm and 1,475 nm beams and is mounted to direct them along a common optical path for reception by a laser scanner. Some embodiments further include a detector optically coupled to the target eye tissue, and stored computer-readable commands cause the laser scanner to selectively direct the laser beam to the target eye location based on changes in the position of the target eye tissue detected using the detector.

[0025] According to another aspect of the disclosed technology, an extraocular automated method for treating the eye in a subject includes the step of directing laser energy having a near-infrared wavelength of about 0.5 to 2.2 μm to multiple transscleral treatment sites from a location spaced away from the eye to be irradiated on the external surface of the eye in a predetermined treatment pattern, wherein the transscleral treatment sites are located 0 to 4 mm posterior to the corneal marginal junction, and the laser energy is repeatedly directed to the same irradiated transscleral treatment sites on the surface of the eye, wherein the transscleral treatment sites are irradiated at sufficient time intervals to induce protective thermal pre-conditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of the tissues of the eye.

[0026] Some embodiments further include the step of directing laser energy having a near-infrared wavelength of approximately 0.5–2.2 μm from a location separated from the eye to multiple transpupillar treatment sites to induce a sublethal fever and induce therapeutic biomodulation in the target ocular tissue within a predetermined therapeutic temperature range, wherein the multiple transpupillar treatment sites include a predetermined curved treatment pattern on the target ocular tissue of the eye comprising multiple concentric rings on the macula surrounding but not on the foveal avascular area, (b) an area surrounding the macula but not on the foveal avascular area, (ii) an area surrounding the optic disc but not on the optic disc or adjacent peripapillary crescent, (c) an area surrounding the optic disc but not on the optic disc or adjacent peripapillary crescent, or (d) an area adjacent to the foveal avascular area but not on the area of ​​the optic disc-macular bundle, either one or a combination thereof.

[0027] In some embodiments, the step of directing laser energy to multiple transscleral and / or transpupil treatment sites is performed on the basis that the subject has clinically normal intraocular pressure and / or does not have glaucoma symptoms or a diagnosis.

[0028] In some embodiments, the step of directing laser energy to multiple transscleral treatment sites at time intervals sufficient to pre-condition the targeted structures for protective thermal effects and induce biostimulation, thereby eliciting biomechanical and biochemical responses, is configured to reduce the intraocular pressure of the eye. In some embodiments, the step of repeatedly delivering energy to multiple irradiated transscleral treatment sites includes a step of delivering energy at time intervals that target an increase in the temperature of the outer 200–500 μm scleral layer to a temperature of approximately 45–57°C. In some embodiments, the step of directing laser energy includes a selected irradiance and scanning speed that increases the temperature of the outer 200 μm scleral layer to approximately 43–57°C, optionally to approximately 43–45°C.

[0029] In some embodiments, multiple transscleral treatment sites are offset radially outward at substantially uniform distances from the corneal marginal junction or limbal region, contouring the treatment pattern to the anatomical structure of the target eye. In some embodiments, the transscleral treatment sites are located within a 360° annular pattern posterior to the corneal marginal junction, and laser energy is directed to a set of pre-identified transscleral treatment sites on the surface of the eye during the first treatment cycle, and to the same pre-identified transscleral treatment sites during subsequent treatment cycles, achieving precise circulating thermal rise of the scleral tissue beneath the pre-identified transscleral treatment sites during the time intervals between treatment cycles to achieve thermal relaxation of the irradiated tissue. In some embodiments, each treatment cycle is performed for a duration that achieves thermal relaxation by spaced irradiation of transscleral treatment sites at sufficient time intervals between exposure and relaxation times to produce a targeted time-temperature history. In some embodiments, the same transscleral treatment site is irradiated at time intervals that produce a loading time rate corresponding to the ratio of active exposure on time to (active exposure + relaxation off time) within the range of 2-50%. In some embodiments, the same transscleral treatment site is irradiated at time intervals of approximately 100-200 ms, optionally, for approximately 10-300 ms. In some embodiments, a predetermined treatment pattern to which the laser energy is directed is located approximately 1.5 mm posterior to the corneal marginal junction. In some embodiments, a predetermined treatment pattern to which the laser energy is directed comprises multiple annular treatment patterns, which are spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the corneal marginal junction, and which comprises one or more of the following patterns: circular, oval, elliptic, egg-shaped, non-circular, non-elliptic, or asymmetrical patterns, or patterns corresponding to the shape of the corneal marginal junction or limbus. In some embodiments, the laser energy is directed to a predetermined 360° treatment pattern, interrupted 10–30° nasally and 10–30° temporally. In some embodiments, the laser energy is directed to transscleral treatment sites on multiple annular treatment patterns, targeting the peri-corneal outflow structures, ciliary processes, and ciliary flaccids.

[0030] Some embodiments further include the step of placing a heat sink so as to be in contact with the eye across the transscleral treatment site to transfer heat away from the surface of the eye. In some embodiments, the step of placing the heat sink in contact with the eye includes the step of placing a curved contact lens on the surface of the eye. In some embodiments, the step of placing the contact lens on the eye includes the step of 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 near-infrared wavelengths 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 near-infrared wavelengths of about 1.4–1.5 μm, optionally 1.47 μm. In some embodiments, protective thermal pre-conditioning and therapeutic biostimulation are controlled by one or more of the following: laser power, irradiance, scanning speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle. In some embodiments, the laser energy is directed to the treatment site within a spot having a diameter of 500–1,000 μm, optionally, about 600 μm. Some embodiments further include the step of detecting the limbus and / or corneal marginal junction of the target using an optical imaging system. In some embodiments, a predetermined transscleral treatment site is determined by the shape of the limbus and / or corneal marginal junction of the target eye.

[0031] In some embodiments, the patient interface further includes a step of spacing a non-contact laser away from the eye using a patient interface, the patient interface comprising a spacer that maintains the eye in a substantially fixed position for imaging and treatment, the spacer maintaining a non-contact laser energy source, configured to produce laser energy, away from the surface of the eye and free from contact. In some embodiments, the patient interface further comprises a microscope for placement between the eyelids of a subject for exposing the eye to laser energy, the microscope is placed between the eyelids and exposes the sclera of the subject. In some embodiments, the patient interface further comprises a retaining ring for a contact lens, the retaining ring comprising a resilient sealing surface, the retaining ring being placed against the subject's eye, and an insulated force being applied between the contact lens and the eye to generate negative pressure, fixing the retaining ring to the eye and substantially immobilizing the subject's eye. In some embodiments, the negative pressure is adjustable. In some embodiments, the spacer and / or the retaining ring and / or the contact lens are cooled while the method is being carried out. In some embodiments, the spacer and / or retaining ring are cooled by introducing a cooling fluid through internal fluid flow channels within the spacer and / or retaining ring and / or contact lens. Some embodiments further include the step of using a positioning arm to position the patient interface within the treatment location relative to the surface of the eye in question.

[0032] In some embodiments, the laser energy is directed within a curved pattern, forming a continuous concentric ring-shaped treatment area at a different radius from the foveal avascular area. In some embodiments, the laser energy is directed in a curved pattern over the macula through all macular rings at a common scanning speed, so that multiple uniformly spaced and overlapping laser pulse spots are delivered continuously along a perfect circle for each macular ring, producing an irradiated ring-shaped treatment area within each ring. In various embodiments, the laser energy is directed in a ring shape, with a total laser energy in the range of 50 mJ to 12 J delivered over 20 cm². 2 ~30cm 2Within this area, the laser energy is delivered with a peak pulse power in the range of 100 mW to 2 W. In some embodiments, the laser energy is directed to 3 to 5 consecutive concentric rings on the macula, each ring having substantially equal width, and the multiple transscleral treatment sites comprise three concentric rings on the sclera around the limbus at radii R1, R2, and R3, respectively, corresponding to the primary aqueous humor outflow pathway, the ciliary process, and the ciliary body, and the ciliary body planus. In some embodiments, the laser energy is directed to 5 consecutive rings on the sclera, each ring having a width of approximately 500 microns, and the multiple transscleral treatment sites comprise three concentric rings on the sclera at distances of approximately 1.5, 2.5, and 3.5 mm from the cornoscleral junction. In some embodiments, the sublethal fever rise corresponds to an increase in the temperature of the target tissue within the annular region on the macula to a temperature of 47°C or lower, while the laser beam raises the temperature of the target tissue within the transscleral treatment site to 57°C or lower.

[0033] In some embodiments, the laser energy directed to the transpupillary treatment site comprises a pulsed laser beam at 810 nm, and the laser energy directed to the transscleral treatment site comprises a sustained-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 a step of detecting the location of the target ocular tissue, and the step of directing the laser energy is performed using a laser scanner based on the detected location. Some embodiments further include a step of detecting the location of the foveal avascular area and / or optic nerve disc of the target. In some embodiments, the laser energy is directed in a curved pattern at a constant circumferential scanning speed of 1.5 mm / sec to 2 mm / sec, producing 99% or more inter-pulse overlap. In some embodiments, the laser energy is directed transpupillarily with a pulse repetition period of 2 ms and a pulse duration of 100 μs. In a typical embodiment, the curved pattern is configured to target retinal pigment epithelial (RPE) cells.

[0034] According to further aspects of the disclosed technology, a patient interface assembly for docking a laser treatment device to an eye to be treated with the laser treatment device includes a lens holder configured to retain a contact lens heat sink against the eye, and including an internal cooling channel communicating with fluid flow inlet and outlet ports, and a spacer dockable to the lens holder to keep the laser output at a distance spaced apart from the contact lens heat sink. Some embodiments further include an elastic sealing ring on the lens holder that extends around the contact lens, creating a seal chamber between the contact lens and the eye, and when an inhalation force is applied to the seal chamber, and the seal chamber communicates with an inhalation port, it retains the lens holder against the eye. In some embodiments, the contact lens comprises a contact lens with a central opening that still allows air to pass into the seal chamber while maintaining negative pressure within the seal chamber. Some embodiments further include a microscope, which comprises jaws that hold opposing eyelid blades in a spaced-apart relationship, and the blades are configured to fit around and retain the lens holder. Some embodiments further include a laser triangulation system for Z-focus camera visualization of the contact lens. Some embodiments further include an XYZ positioner for positioning the patient interface relative to the target eye using a sealing ring of the lens holder, and the spacer is docked to the lens holder.

[0035] According to further aspects of the disclosed technology, the patient interface for docking the laser treatment device to the eye to be treated with the laser treatment device includes a spacer such as a frustoconical spacer tapering from an enlarged first surface to a smaller second surface, and a laser emission source supported by a cone and spaced apart from the smaller second surface; a lens holder collar tapering from a larger first surface for engaging with the second surface of the spacer to a smaller second surface circulated by a resilient patient retention ring and forming a seal to the eye to be treated, the collar having an internal cooling fluid passage, 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 retention ring and forming an inhalation chamber between the contact lens and the eye when the collar is docked to the eye of interest, and an inhalation port communicating with the inhalation chamber. According to further aspects of the disclosed technology, a method for docking a laser treatment device to an eye to be treated with the laser treatment device includes the steps of inserting the blades of the microscope into the eye, separating the eyelids and exposing the sclera; holding a lens holder between the blades of the microscope and optionally drawing air from a seal chamber; activating an XYZ positioner and docking a spacer to the lens holder; and introducing a coolant through an internal cooling channel of the lens holder by introducing a coolant through a fluid inlet port and out through a fluid outlet port. Some embodiments further include the step of visualizing the contact lens and the eye using optical visualization software. Some embodiments further include the step of visualizing the retina of the eye using optical visualization software. Some embodiments further include the step of performing laser treatment of the sclera and / or retina through a patient interface using a laser held in a separated relationship with respect to the sclera.

[0036] The foregoing description illustrates various aspects of the systems, devices, and methods, which will be disclosed in more detail throughout this specification. The description is provided for the convenience of the reader and is not a limitation on the scope of any claim. The aforementioned and other purposes, features, and advantages of the disclosed technology will become more apparent from the following modes for carrying out the invention, which will proceed with reference to the accompanying drawings. The present invention provides, for example, the following: (Item 1) An extraocular automated laser treatment system for treating the eye in a subject, A non-contact laser source is 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 away from the eye, wherein the at least one wavelength is a near-infrared wavelength in the range of about 0.5 to 2.2 μm. A laser scanner comprising: a laser scanner optically coupled to a non-contact laser source, receiving the laser beam from the non-contact laser source, and scanning the laser beam toward the eye; A processor and memory comprising the memory containing stored computer-readable instructions, which, in response to execution by the processor, directs the laser beam to a plurality of transscleral treatment sites such that the laser treatment system irradiates the outer surface of the eye in a predetermined treatment pattern, the transscleral treatment sites being located 0-4 mm behind the corneal marginal junction, the laser beam being repeatedly directed to the same irradiated transscleral treatment sites on the surface of the eye, and the transscleral treatment sites being irradiated at sufficient time intervals to induce protective thermal pre-conditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of the tissues of the eye, and A system equipped with these features. (Item 2) The system according to item 1, wherein the memory includes stored computer-readable instructions for directing the laser treatment system to a plurality of transpupillary treatment locations, inducing a sublethal fever and causing therapeutic biomodulation to be induced in the target ocular tissue within a predetermined therapeutic temperature range, the plurality of transpupillary treatment locations comprising a predetermined curved treatment pattern on the target ocular tissue of the eye, comprising a plurality of concentric rings on the macula surrounding but not on the foveal avascular area. (Item 3) The memory includes stored computer-readable instructions for directing the laser treatment system to a plurality of transpupillary treatment locations, inducing a sublethal fever, and inducing therapeutic biomodulation in the target eye 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 on the foveal avascular area, and (ii) surrounds the optic disc but is not on the optic disc or an adjacent peripapillary crescent, according to item 1 or 2. (Item 4) The system according to any one of items 1-3, wherein the memory includes stored computer-readable instructions for directing the laser beam to a plurality of transpupil treatment locations, inducing a sublethal fever, and inducing therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, the plurality of transpupil treatment locations including an area surrounding the optic nerve disc but not on the optic nerve disc or adjacent peripapillary crescent. (Item 5) The system according to any one of items 1-4, wherein the memory includes stored computer-readable instructions for directing the laser beam to a plurality of transpupil treatment locations, inducing a sublethal fever, and inducing therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, the plurality of transpupil treatment locations including areas adjacent to the foveal avascular area but not on the area of ​​the papillomacular bundle. (Item 6) The stored computer-readable instructions cause the laser treatment system to direct the laser beam to the plurality of transscleral and / or transpupil treatment sites, wherein the subjects have clinically normal intraocular pressure and / or do not have symptoms or a diagnosis of glaucoma, as described in any one of items 1-5. (Item 7) The system according to any one of items 1-6, wherein the stored computer-readable instructions direct the laser treatment system to direct the laser beam to the plurality of transscleral treatment sites at sufficient time intervals to induce protective thermal pre-conditioning and biostimulation of the targeted structures and to elicit biomechanical and biochemical responses to lower intraocular pressures. (Item 8) The system according to any one of items 1-7, wherein the processor is configured with instructions for repeatedly delivering the laser beam to the plurality of irradiated transscleral treatment sites at time intervals that target an increase in the temperature of the outer 200-500 μm scleral layer up to a temperature of approximately 45-57°C. (Item 9) The system according to any one of items 1-8, wherein the laser parameters are configured to provide the irradiance of the laser beam, and the scanning speed at which the laser beam moves in the predetermined treatment pattern increases the temperature of the outer 200 μm sclera layer to approximately 43-57°C, optionally to approximately 43-45°C. (Item 10) The system according to any one of items 1-9, wherein the processor is configured with instructions for receiving inputs corresponding to the location of the corneal marginal junction or limbal cornea of ​​the subject, the processor is configured to determine the plurality of transscleral treatment locations in response to the inputs, the plurality of transscleral treatment locations being offset radially outward from the input locations corresponding to the corneal marginal junction or limbal cornea, and the treatment pattern contours the anatomical structure of the eye of the subject. (Item 11) The system according to any one of items 1-10, wherein the transscleral treatment sites are located within a 360° annular pattern posterior to the corneal marginal junction, and the processor is configured to direct the laser beam to a set of pre-identified transscleral treatment sites on the surface of the eye during a first treatment cycle, and to direct the laser beam to the same pre-identified transscleral treatment sites during subsequent treatment cycles, thereby achieving precise circulating heat rise of the scleral tissue beneath the pre-identified transscleral treatment sites during the time intervals between treatment cycles. (Item 12) The system according to item 11, wherein the processor is configured to set the speed of each treatment cycle and to achieve thermal relaxation by spaced irradiation of the transscleral treatment sites at sufficient time intervals to produce a targeted time-temperature history of exposure time and relaxation time. (Item 13) The time interval between irradiations at the same transscleral treatment site produces a load time rate corresponding to the ratio of active exposure on time to (active exposure + relaxation off time) within the range of 2-50%, as described in any one of items 1-12. (Item 14) The time interval between irradiations at the same transscleral treatment site is approximately 10-300 ms, or optionally approximately 100-200 ms, as described in item 13. (Item 15) The predetermined treatment pattern is a system located approximately 1.5 mm posterior to the corneal margin junction, as described in any one of items 1-14. (Item 16) The system according to any one of items 1-15, wherein the predetermined treatment pattern 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 corneal marginal junction, and the annular treatment patterns comprise one or more of the following: circular, oval, elliptic, egg-shaped, non-circular, non-elliptic, or asymmetrical patterns, or patterns corresponding to the shape of Schlemm's canal or the corneal limbus. (Item 17) The 360° pattern is interrupted by 10–30° nasally and 10–30° temporally, as described in any one of items 11–16. (Item 18) The aforementioned multiple ring-shaped treatment patterns are, (a) Pericorneal outflow structure, (b) Ciliary process and, (c) Flattened part of the ciliary body and A system that targets the following, as described in item 16 or 17. (Item 19) The system according to any one of items 1-18, further comprising a heat dissipation plate positioned in contact with the eye across the transscleral treatment site to transfer heat away from the surface of the eye. (Item 20) The system according to item 19, wherein the heat sink comprises a curved contact lens placed on the surface of the eye. (Item 21) The system according to item 20, wherein the contact lens comprises a cooled contact lens that substantially conforms to the surface of the eye. (Item 22) The system according to any one of items 1-21, wherein the laser beam has near-infrared wavelengths 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. (Item 23) The system described in item 22, wherein the laser beam has a near-infrared wavelength of approximately 1.4 to 1.5 μm, and optionally 1.47 μm. (Item 24) The protective thermal pre-conditioning and therapeutic biostimulation are controlled by one or more of the laser power, irradiance, scanning speed, cycle repeat rate, number of cycle iterations, spot size, and duty cycle, as described in any one of items 1-23. (Item 25) The system according to any one of items 1-24, wherein the processor is configured to direct the laser beam to the transscleral treatment site within a spot having a diameter of 500 to 1,000 μm, optionally about 600 μm. (Item 26) The system according to any one of items 1-25, further comprising an optical imaging system for detecting the limbus and / or corneal margin junction of the subject. (Item 27) The system according to item 26, wherein the processor is configured to identify the predetermined transscleral treatment site at a location determined by the shape of the anterior limbus and / or corneal marginal junction of the eye in question. (Item 28) The system according to any one of items 1-27, further comprising a patient interface for docking the non-contact laser source in a manner separated from the eye, the patient interface comprising a spacer for maintaining the eye in a substantially fixed position for imaging and treatment, the spacer for maintaining the non-contact laser source separated from the surface of the eye and without contact. (Item 29) The patient interface further comprises a microscope for placement between the eyelids of the target eye to expose the eye to the laser beam, as described in item 28. (Item 30) The system according to any one of items 28-29, wherein the patient interface further comprises a retaining ring for a contact lens, the retaining ring having an elastic sealing surface, and the system is configured to maintain negative pressure between the contact lens and the retaining ring, to fix the patient interface to the surface of the eye, and to substantially immobilize the eye of the subject. (Item 31) The negative pressure is adjustable, as described in any one of items 28-30. (Item 32) The system described in any one of items 28-31 is configured to cool the spacer and / or the retaining ring and / or the contact lens. (Item 33) The system according to item 32, wherein the spacer and / or retaining ring comprises an internal fluid flow channel, and the system is configured to introduce a cooled fluid through the fluid flow channel to cool the spacer and / or retaining ring and / or contact lens. (Item 34) The system according to any one of items 1-33, further comprising a positioning arm for positioning the patient interface in relation to the surface of the eye of the subject. (Item 35) The system according to any of items 2-34, wherein each ring on the macula of the curved treatment pattern comprises a plurality of uniformly spaced and overlapping laser pulse spots, which are delivered continuously along a perfect circle and produce an irradiated ring-shaped treatment area within each ring, and the laser pulse spots are delivered at a common scanning speed for all macular rings. (Item 36) The system according to item 35, wherein the plurality of concentric ring shapes provide a radially continuous irradiation ring-shaped treatment area on the macula. (Item 37) Each concentric ring has a width of 400 μm to 600 μm, according to any of the systems described in item 2-36. (Item 38) The laser source is configured to produce a pulsed laser beam with a pulse repetition period in the range of 1 to 3 ms, a pulse repetition rate of 1,000 to 333 pulses / second, and a pulse duration in the range of 20 to 500 μs, as described in any of items 1-37. (Item 39) The system according to item 38, wherein the laser source is configured to produce a pulsed laser beam with a pulse repetition period in the range of 1.5 to 2.5 ms, a pulse repetition rate of 666 to 400 pulses / second, and a pulse duration in the range of 50 to 150 μs. (Item 40) The system according to item 38, wherein the laser source is configured to produce a pulsed laser beam with a pulse repetition period in the range of 1.8 to 2.2 ms, a pulse repetition rate of 556 to 455 pulses / second, and a pulse duration in the range of 80 to 120 μs. (Item 41) The system according to any of items 2-40, wherein the ring shape comprises 3 to 5 consecutive concentric ring shapes on the macula, each ring shape having substantially equal width, and the plurality of transscleral treatment sites each comprises 3 concentric ring shapes on the sclera around the limbus at radii R1, R2, and R3, corresponding to the locations covering the primary aqueous humor outflow tract, the ciliary process ciliary body, and the ciliary body flattening. (Item 42) The system according to any of items 2-41, wherein the ring shape comprises five consecutive ring shapes on the sclera, each ring shape having a width of approximately 500 microns, and the plurality of transscleral treatment sites comprises three concentric ring shapes on the sclera at distances of approximately 1.5, 2.5, and 3.5 mm from the cornoscleral junction. (Item 43) The system according to any of items 2-42, wherein the sublethal fever rise corresponds to a rise in the temperature of the target tissue within the annular region on the macula to a temperature of 47°C or less, and the laser beam raises the temperature of the target tissue within the transscleral treatment site to 57°C or less. (Item 44) The system according to any one 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 transpupil treatment site, a second diode laser source operable to produce a sustained-wave laser beam at 1,475 nm for directing to the transscleral treatment site, and at least one beam splitter that receives the 810 nm beam and the 1,475 nm beam and is mounted to direct them along a common optical path for reception by the laser scanner. (Item 45) The system according to any one of items 1-44, further comprising a detector optically coupled to the target eye tissue, wherein the stored computer-readable command causes the laser scanner to selectively direct the laser beam to the target eye location based on a change in the position of the target eye tissue detected using the detector. (Item 46) An automated extraocular method for treating the eye in a subject, wherein the method is Laser energy having a near-infrared wavelength of approximately 0.5 to 2.2 μm is directed from a location spaced away from the eye to multiple transscleral treatment sites in order to irradiate the outer surface of the eye in a predetermined treatment pattern, wherein the transscleral treatment sites are located 0 to 4 mm behind the corneal marginal junction, the laser energy is repeatedly directed to the same irradiated transscleral treatment sites on the surface of the eye, and the transscleral treatment sites are irradiated at sufficient time intervals to induce protective thermal pre-conditioning and therapeutic biostimulation of one or more of the trabecular meshwork and / or ciliary body without photocoagulation of the eye tissue. Methods that include... (Item 47) The method according to item 46, further comprising directing laser energy having a near-infrared wavelength of approximately 0.5 to 2.2 μm from a location separated from the eye to a plurality of transpupil treatment sites to induce a sublethal fever and induce therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupil treatment sites include a predetermined curved treatment pattern on the target eye tissue of the eye, comprising a plurality of concentric ring shapes on the macula surrounding but not on the foveal avascular area. (Item 48) The method according to item 46 or 47, further comprising directing laser energy having a near-infrared wavelength of approximately 0.5 to 2.2 μm from a location separated from the eye to a plurality of transpupil treatment sites to induce a sublethal fever and induce therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupil treatment sites include an area that (i) surrounds the macula but is not on the foveal avascular area, and (ii) surrounds the optic disc but is not on the optic disc or an adjacent peripapillary crescent. (Item 49) The method according to any one of items 46-48, further comprising directing laser energy having a near-infrared wavelength of approximately 0.5 to 2.2 μm from a location spaced away from the eye to a plurality of transpupil treatment sites to induce a sublethal fever and induce therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupil treatment sites include an area surrounding the optic nerve disc but not on the optic nerve disc or adjacent peripapillary crescent. (Item 50) The method according to any one of items 46-49, further comprising directing laser energy having a near-infrared wavelength of approximately 0.5-2.2 μm from a location separated from the eye to a plurality of transpupil treatment sites to induce a sublethal fever and induce therapeutic biomodulation in the target eye tissue within a predetermined therapeutic temperature range, wherein the plurality of transpupil treatment sites include areas adjacent to the foveal avascular area but not on the area of ​​the pacifopalacular bundle. (Item 51) The method according to any one of items 46-50, wherein the laser energy is directed to the plurality of transscleral and / or transpupil treatment sites, provided that the subjects have clinically normal intraocular pressure and / or do not have glaucoma symptoms or a diagnosis. (Item 52) The method according to any one of items 46-51, wherein the laser energy is directed to the plurality of transscleral treatment sites at a time interval sufficient to protect the targeted structure, pre-condition the target structure with thermal pre-conditioning and induce biostimulation, and to elicit biomechanical and biochemical responses, thereby reducing the intraocular pressure of the eye. (Item 53) The method according to any one of items 46-52, wherein the repeated delivery of the energy to the plurality of irradiated transscleral treatment sites is carried out at time intervals that target an increase in the temperature of the outer 200-500 μm scleral layer up to a temperature of approximately 45-57°C. (Item 54) The method according to any one of items 46-53, wherein the directing of the laser energy includes a selected irradiance and scanning speed that increases the temperature of the outer 200 μm sclera layer to approximately 43-57°C, optionally to approximately 43-45°C. (Item 55) The method according to any one of items 46-54, wherein the plurality of transscleral treatment sites are offset radially outward at substantially uniform distances from the corneal marginal junction or limbal cornea, and the treatment pattern contours to the anatomical structure of the eye in question. (Item 56) The method according to any one of items 46-55, wherein the transscleral treatment sites are located within a 360° ring-shaped pattern posterior to the corneal marginal junction, the laser energy is directed to a set of pre-identified transscleral treatment sites 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 sites, thereby achieving precise circulating heat rise of the scleral tissue beneath the pre-identified transscleral treatment sites during the time intervals between treatment cycles. (Item 57) The method according to any one of items 46-56, wherein each treatment cycle is carried out for a duration to achieve thermal relaxation by spaced irradiation of the transscleral treatment sites at sufficient time intervals to produce a targeted time-temperature history of exposure and relaxation time. (Item 58) The same transscleral treatment site is irradiated at time intervals that produce a loading time rate corresponding to the ratio of active exposure on time to (active exposure + relaxation off time) in the range of 2-50%, according to any one of items 46-57. (Item 59) The same transscleral treatment site is irradiated at intervals of approximately 100 to 200 ms, as optional, for approximately 10 to 300 ms, according to the method described in item 58. (Item 60) The predetermined treatment pattern to which the laser energy is directed is located approximately 1.5 mm posterior to the corneal margin junction, as described in any one of items 46-59. (Item 61) The method according to 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 are spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the corneal marginal junction, and the plurality of annular treatment patterns comprises one or more of the following: circular, oval, elliptic, egg-shaped, non-circular, non-elliptic, or asymmetrical patterns, or patterns corresponding to the shape of the corneal marginal junction or the corneal limbus. (Item 62) The method according to any one of items 46-61, wherein the laser energy is directed to a predetermined 360° treatment pattern interrupted by 10-30° nasally and 10-30° temporally. (Item 63) The aforementioned laser energy is (a) Pericorneal outflow structure, (b) Ciliary process and, (c) Flattened part of the ciliary body and The method according to any one of items 46-62, directed to transscleral treatment sites on multiple annular treatment patterns that target a particular area. (Item 64) The method according to any one of items 46-63, further comprising placing a heat dissipation plate so as to be in contact with the eye across the transscleral treatment site to transfer heat away from the surface of the eye. (Item 65) The method of item 64, wherein the heat sink is placed in contact with the eye, and the curved contact lens is placed on the surface of the eye. (Item 66) The method of item 65, wherein placing the contact lens on the eye involves placing a cooled contact lens that substantially conforms to the surface of the eye. (Item 67) The method according to item 66, wherein the contact lens is cooled in situ on the surface of the eye. (Item 68) The method according to any one of items 46-67, wherein the laser energy has near-infrared wavelengths 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. (Item 69) The laser energy has a near-infrared wavelength of approximately 1.4 to 1.5 μm, optionally 1.47 μm, as described in item 68. (Item 70) The method according to any one of items 46-69, wherein the protective thermal pre-conditioning and therapeutic biostimulation are controlled by one or more of the laser power, irradiance, scanning speed, cycle repetition rate, number of cycle repetitions, spot size, and duty cycle. (Item 71) The method according to any one of items 46-70, wherein the laser energy is directed to the treatment site within a spot having a diameter of 500-1,000 μm, optionally, about 600 μm. (Item 72) The method according to any one of items 46-71, further comprising detecting the limbus and / or corneal margin junction of the subject using an optical imaging system. (Item 73) The method according to item 72, wherein the predetermined transscleral treatment site is determined by the shape of the limbus and / or corneal marginal junction of the eye in question. (Item 74) The method according to any one of items 46-73, further comprising using a patient interface to space the non-contact laser away from the eye, the patient interface comprising a spacer that holds the eye in a substantially fixed position for imaging and treatment, the spacer holding a non-contact laser energy source configured to produce the laser energy away from and out of contact with the surface of the eye. (Item 75) The patient interface further comprises a microscope for placement between the eyelids of the subject to expose the eye to the laser energy, the microscope being placed between the eyelids and exposing the sclera of the subject, according to the method of item 74. (Item 76) The patient interface further comprises a retaining ring for a contact lens, the retaining ring having an elastic sealing surface, the retaining ring being positioned relative to the eye of the subject, and an inhalation force being applied between the contact lens and the eye, generating negative pressure, fixing the retaining ring to the eye, and substantially immobilizing the eye of the subject, according to item 74 or 75. (Item 77) The negative pressure is adjustable, as described in item 76. (Item 78) The method according to any one of items 76-77, wherein the spacer and / or retaining ring and / or contact lens are cooled while the method is being carried out. (Item 79) The method according to item 78, wherein the spacer and / or retaining ring is cooled by introducing a cooling fluid through internal fluid flow channels within the spacer and / or retaining ring and / or contact lens. (Item 80) The method according to any one of items 46-79, further comprising using a positioning arm to position the patient interface within the treatment area relative to the surface of the eye of the target. (Item 81) The method according to any one of items 47-80, wherein the laser energy is directed within the curved pattern, forming a continuous concentric therapeutic area at a radius different from that of the foveal avascular area. (Item 82) The method according to any one of items 47-81, wherein the laser energy is directed in the curved pattern over the macula through all macular rings at a common scanning speed, so that multiple uniformly spaced and overlapping laser pulse spots are delivered in succession along a perfect circle for each macular ring, producing an irradiated ring-shaped treatment area within each ring. (Item 83) The laser energy is directed in the ring shape, and the total laser energy in the range of 50 mJ to 12 J is directed at 20 cm. 2 ~30cm 2 The method according to any one of items 47-82, which delivers a peak pulse power in the range of 100mW to 2W within the area. (Item 84) The method according to any one of items 47-83, wherein the laser energy is directed to 3 to 5 consecutive concentric rings on the macula, each ring having substantially equal width, and the plurality of transscleral treatment sites each comprise three concentric rings on the sclera around the limbus at radii R1, R2, and R3, corresponding to the locations covering the primary aqueous humor outflow tract, the ciliary process ciliary body, and the ciliary body flattening. (Item 85) The method according to any one of items 47-84, wherein the laser energy is directed to five consecutive ring shapes on the sclera, each ring shape having a width of about 500 microns, and the plurality of transscleral treatment sites comprise three concentric ring shapes on the sclera at distances of about 1.5, 2.5, and 3.5 mm from the cornoscleral junction. (Item 86) The method according to any one of items 47-85, wherein the sublethal fever rise corresponds to a rise in the temperature of the target tissue within the annular region on the macula to a temperature of 47°C or less, and the laser beam raises the temperature of the target tissue within the transscleral treatment site to 57°C or less. (Item 87) The method according to any one of items 47-86, wherein the laser energy directed to the transpupil treatment site comprises a pulsed laser beam at 810 nm, and the laser energy directed to the transscleral treatment site comprises a sustained-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) The method according to any one of items 47-87, further comprising detecting the location of the target eye tissue and directing the laser energy, which is performed using a laser scanner based on the detected location. (Item 89) The method according to any one of items 46-88, further comprising detecting the location of the foveal avascular area and / or optic disc of the subject. (Item 90) The laser energy is directed in the curved pattern at a constant circumferential scanning speed of 1.5 mm / sec to 2 mm / sec, producing more than 99% inter-pulse overlap, according to the method of any one of items 46-89. (Item 91) The laser energy is directed transpupillarily with a pulse repetition period of 2 ms and a pulse duration of 100 μs, according to any one of items 46-90. (Item 92) The method according to any one of items 46-91, wherein the curve pattern is configured to target retinal pigment epithelial (RPE) cells. (Item 93) A patient interface assembly for docking a laser treatment device to an eye to be treated with the laser treatment device, wherein the patient interface system is A lens holder configured to hold a contact lens heat sink in place of the eye, wherein the lens holder includes an internal cooling channel communicating with fluid flow inlet and outlet ports, To maintain the laser output at a distance from the contact lens heat sink, a spacer dockable to the lens holder and A patient interface assembly equipped with the following features. (Item 94) The patient interface according to item 93, further comprising an elastic sealing ring on the lens holder that extends around the contact lens, creates a sealing chamber between the contact lens and the eye, and when an inhalation force is applied to the sealing chamber and the sealing chamber communicates with an inhalation port, the lens holder is secured to the eye. (Item 95) The patient interface according to item 94, comprising a contact lens having a central opening that allows air to pass into the seal chamber while still maintaining negative pressure within the seal chamber. (Item 96) A patient interface according to any one of items 93-95, further comprising a microscope, the microscope comprising jaws for holding opposing eyelid blades in a spaced-out relationship, the blades configured to fit around and secure the lens holder. (Item 97) A patient interface according to any one of items 93-96, further comprising a laser triangulation system for Z-focus camera visualization of the contact lens. (Item 98) The patient interface according to any one of items 93-97, further comprising an XYZ positioner for positioning the patient interface relative to the target eye using the sealing ring of the lens holder, wherein the spacer is docked to the lens holder. (Item 99) A patient interface for docking a laser treatment device to the eye to be treated with the laser treatment device, wherein the patient interface is A spacer such as a frustoconical spacer that tapers from the enlarged first surface to a smaller second surface, and a laser emission source that is transported by the cone and separated from the smaller second surface, A lens holder collar, wherein the lens holder collar tapers from a larger first surface for engaging with a second surface of the spacer to a smaller second surface that is circulated by a resilient patient restraint ring and forms a seal to the eye to be treated, and the collar comprises an internal cooling fluid passage, an inlet port, and an outlet port for circulating a cooling fluid through the collar, A heat sink contact lens that is held within the collar above the fixing ring and forms an inhalation chamber between the contact lens and the eye when the collar is docked to the target eye, and an inhalation port that communicates with the inhalation chamber. A patient interface equipped with this feature. (Item 100) A method for docking a laser treatment device described in item 99 to an eye to be treated with the laser treatment device, the method comprising: inserting the blades of the microscope into the eye, separating the eyelids and exposing the sclera; holding the lens holder between the blades of the microscope and optionally drawing air from the seal chamber; activating the XYZ positioner and docking 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 through the fluid outlet port. (Item 101) The method according to item 100, further comprising visualizing the contact lens and the eye using optical viewing software. (Item 102) The method according to item 100, further comprising visualizing the retina of the eye using optical viewing software. (Item 103) The method according to item 101 or 102, further comprising performing laser treatment of the sclera and / or retina through the patient interface using a laser held in a separated relationship with respect to the sclera. [Brief explanation of the drawing]

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

[0038] [Figure 2A] Figures 2A and 2B schematically illustrate an embodiment of a transscleral laser trabeculoplasty method in which laser energy is directed to the surface of the eye without contact with the surface. The laser beam is directed extraocularly to the corneal margin area through the cornoscleral junction across the outflow pathway structure. [Figure 2B] Figures 2A and 2B schematically illustrate an embodiment of a transscleral laser trabeculoplasty method in which laser energy is directed to the surface of the eye without contact with the surface. The laser beam is directed extraocularly to the corneal margin area through the cornoscleral junction across the outflow pathway structure.

[0039] [Figure 3] Figure 3 schematically illustrates the anatomical structure of the cornoscleral junction, which is bordered anteriorly by the corneal marginal junction and posteriorly by the scleral marginal junction.

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

[0041] [Figure 4C]Figure 4C is a frontal view of the eye, schematically illustrating a laser irradiation treatment pattern directed towards the cornoscleral junction region to reduce IOP. The arcuate pattern is interrupted nasally and temporally. The illustrated superior and inferior arcs are continuous in that they do not have internal interruptions in either arc.

[0042] [Figure 4D] Figure 4D is similar to Figure 4C, but illustrates a laser irradiation treatment pattern that is continuously directed to the peri-corneal region without nasal or temporal interruptions.

[0043] [Figure 4E] Figure 4E is a frontal view of the eye similar to Figure 4C, but directed towards the cornoscleral junction region at locations R1, R2, and R3, showing multiple ring-shaped patterns with laser energy that reduces IOP. The arcs have the optical axis as a common center of curvature, but are spaced posterior to the outer corneal limbus and therefore at different distances from the center of the optical axis.

[0044] [Figure 4F] Figure 4F illustrates a method for applying transscleral laser energy to the eye without contact with the surface of the eye.

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

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

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

[0048] [Figure 4M] Figure 4M schematically illustrates the sustained movement of the laser beam as it moves through the contact lens along an annular treatment pattern, inducing a heat wave within the sclera.

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

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

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

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

[0054] [Figure 7A] Figure 7A illustrates a microscope that will be placed inside the eye of a subject for a transscleral procedure, exposing the sclera. Figure 7B schematically illustrates the assembled patient interface inside the eye. Typically, the interface will be inserted into the eye of a person in a supine position, but a perspective view is shown for illustrative purposes. [Figure 7B] Figure 7A illustrates a microscope that will be placed inside the eye of a subject for a transscleral procedure, exposing the sclera. Figure 7B schematically illustrates the assembled patient interface inside the eye. Typically, the interface will be inserted into the eye of a person in a supine position, but a perspective view is shown for illustrative purposes.

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

[0056] [Figure 9A] Figure 9A is a side view of the control box for the patient interface and the coolant source. The patient interface includes a laser cone projected from the bottom surface of the control box and connected to the lens holder and microscope. Tubing connects the coolant source to the interface and cools the lens. Figure 9B is a perspective view of the control box in Figure 9A, illustrating tubing clamps that reduce tip / incline stress on the contact lens holder, and more clearly, the inlet and outlet tubing for the coolant and the suction power control tubing that communicates with the suction chamber. Figure 9C is a perspective view of the control arm for positioning the patient interface and docking it with the target eye. [Figure 9B] Figure 9A is a side view of the control box for the patient interface and the coolant source. The patient interface includes a laser cone projected from the bottom surface of the control box and connected to the lens holder and microscope. Tubing connects the coolant source to the interface and cools the lens. Figure 9B is a perspective view of the control box in Figure 9A, illustrating tubing clamps that reduce tip / incline stress on the contact lens holder, and more clearly, the inlet and outlet tubing for the coolant and the suction power control tubing that communicates with the suction chamber. Figure 9C is a perspective view of the control arm for positioning the patient interface and docking it with the target eye. [Figure 9C]Figure 9A is a side view of the control box for the patient interface and the coolant source. The patient interface includes a laser cone projected from the bottom surface of the control box and connected to the lens holder and microscope. Tubing connects the coolant source to the interface and cools the lens. Figure 9B is a perspective view of the control box in Figure 9A, illustrating tubing clamps that reduce tip / incline stress on the contact lens holder, and more clearly, the inlet and outlet tubing for the coolant and the suction power control tubing that communicates with the suction chamber. Figure 9C is a perspective view of the control arm for positioning the patient interface and docking it with the target eye.

[0057] [Figure 10A] Figures 10A and 10B are schematic diagrams of an automated computer-controlled system for a treatment method. [Figure 10B] Figures 10A and 10B are schematic diagrams of an automated computer-controlled system for a treatment method.

[0058] [Figure 11] Figure 11 shows an image of the corneal limbus illustrated above the eye, along with an image of the eye taken by a camera after the patient interface and system have been docked to the eye according to the embodiment. The location of the corneal limbus helps to identify the cornosclera or corneal marginal junction. The anterior boundary of the corneal limbus is the corneal marginal junction.

[0059] [Figure 12A] Figure 12A shows an imaging scheme that may be used to estimate the shape of the limbus and cornosclera or corneal margin junction.

[0060] [Figure 12B] Figure 12B is a flowchart illustrating an exemplary method for imaging and determining the treatment site.

[0061] [Figure 13]Figures 13A–13D illustrate an exemplary process for generating a treatment pattern based on one or more locations in the limbus and cornoscleral junction.

[0062] [Figure 14] Figure 14 is a flowchart of a method for determining the target therapeutic site according to an embodiment.

[0063] [Figure 15] Figure 15 shows a schematic cross-section of a human eye with strabismus.

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

[0065] [Figure 17A] Figure 17A is a retinal image similar to the image in Figure 16, but showing the target area for panmacular non-damaging laser light stimulation as visible through the pupil. A cross-section of the macula is shown below Figure 4A, illustrating the variable thickness of the macula from the center to the periphery.

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

[0067] [Figure 18A] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy. [Figure 18B] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy. [Figure 18C] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy. [Figure 18D] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy. [Figure 18E] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy. [Figure 18F] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy. [Figure 18G] Figures 18A–18G are a series of retinal images similar to Figure 17B, illustrating the pattern of retinal irradiation during subsequent panmacular laser photostimulation therapy.

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

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

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

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

[0072] [Figure 23] Figure 23 is a flowchart illustrating an exemplary treatment method.

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

[0074] [Figure 25] Figure 25 shows a schematic diagram of an exemplary laser treatment device. [Modes for carrying out the invention]

[0075] (Detailed explanation) term As used in this application and claims, the singular forms “a,” “an,” and “the” include the plural form unless otherwise clearly determined by the context. In addition, the term “includes” means “comprises.” Furthermore, the term “coupled” does not exclude the presence of intermediate elements between the coupled items.

[0076] The systems, apparatus, and methods described herein should not be construed as limiting in any way. Rather, this disclosure covers all novel and opaque features and aspects of the various disclosed embodiments, individually and in various combinations and secondary combinations. The disclosed systems, methods, and apparatus are not limited to any specific aspect or feature or combination thereof, and the disclosed systems, methods, and apparatus do not require that any one or more specific advantages exist or problems are solved. Any theories of operation are for illustrative purposes only, and the disclosed systems, methods, and apparatus are not limited to such theories of operation.

[0077] Some of the operations of the disclosed methods are described in a specific sequence for convenience; however, please understand that this style of description includes reordering unless a specific ordering is required by the specific terms set forth below. For example, operations described sequentially may, in some cases, be rearranged or performed in parallel. Furthermore, for the sake of simplification, the accompanying diagrams may not show the various ways in which the disclosed systems, methods, and apparatus may be used in conjunction with other systems, methods, and apparatus.

[0078] Referring to the anatomical structure of the eye, "anterior" refers to the front of the eye, towards the anterior pole. "Posterior" refers to the back of the eye, towards the posterior pole.

[0079] A treatment pattern "contoured along the limbus" refers to a treatment site on the surface of the eye that mimics the contour of the limbus of that eye. The treatment pattern may be located within the limbus itself or spaced posterior to the corneal marginal junction, but may retain the limbal contour of the specific patient being treated.

[0080] A "non-contact laser source" refers to a laser source (including, for example, 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 directed towards an intended target and does not have any components that come into contact with the target surface irradiated by the laser source. For example, in a non-contact laser source, the laser beam is not emitted from a probe that comes into contact with the irradiated surface.

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

[0082] "Therapeutic biostimulation" refers to the stimulation of biological mechanisms that achieve therapeutic effects (such as reducing IOP or improving nutrient function within the retina).

[0083] "Thermal pre-conditioning" refers to the preliminary, mild, stepwise heating of tissue to protect it from thermal damage and make it more resistant to higher temperatures. While not constrained by theory, initial mild heating ("hypertherapy") is thought to induce heat shock proteins that minimize the folding of still-viable cells, such as cells that are stressed but non-lethally damaged by laser irradiation, or promote their productive refolding.

[0084] Treatment patterns may have various shapes. A circumferential pattern surrounds a curved structure, such as the limbus, in a curved or polygonal shape, for example. An annular pattern surrounds a reference structure (such as the limbus or foveal avascular area) and is generally ring / oval in shape.

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

[0086] Introduction An extraocular transscleral automated photothermal laser delivery system reduces intraocular pressure by irradiating the eye in a target area from a non-contact laser energy source configured to direct laser energy from a location spaced apart from the eye. In the disclosed embodiments, the laser energy has a near-infrared wavelength of 0.8 to 2.2 μm or 1 to 2.2 μm, such as 1.0 to 1.7 μm, for example, a wavelength of about 0.80 to 0.85 μm or about 1.4 to 1.6 μm. In some disclosed embodiments, the wavelength is 1.47 μm. A processor may be configured with instructions for directing 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 are, for example, 0 to 5 mm (1 to 5 mm, etc.) anterior or 0 to 4 mm (1 to 4 mm, etc.) posterior to the corneal marginal junction, and the laser energy is repeatedly directed to the same irradiated treatment locations on the eye. The treatment site is one or more structures of the eye, namely the trabecular meshwork and / or ciliary body, which are irradiated at time intervals to induce protective thermal pre-conditioning and therapeutic biostimulation, thereby reducing IOP.

[0087] The energy delivery system, coupled to the energy source and processor, is configured to repeatedly deliver energy to multiple predetermined irradiation sites on a given treatment pattern at time intervals, specifically to induce protective thermal pre-conditioning, propagation of heat waves to deeper targeted structures within the eye, and hyperthermia and biostimulation of the targeted structures. While not constrained by theory, these photothermal effects are thought to activate cell biological chains that ultimately induce biomechanical and biochemical responses, such as modification of the extracellular matrix, and reduce intraocular pressure, without the need for tissue photocoagulation and destruction.

[0088] In some embodiments, the processor is configured with instructions for iteratively delivering energy to multiple irradiation treatment sites at time intervals, specifically targeting an increase in the temperature of the outer 200–550 μm scleral layer up to a temperature of approximately 43–57°C. For example, the irradiance of the laser energy and the scanning speed at which the laser energy moves along the treatment pattern increase the temperature of the outer 200–550 μm scleral layer to a temperature of approximately 43–57°C or below 45°C or approximately 43–45°C. The increase in tissue temperature is, for example, 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 also be configured with instructions for receiving an input corresponding to the location of the corneal marginal junction or limbal cornea of ​​interest and, in response to the input, determining multiple treatment sites. The treatment sites are radially offset outward from the input locations corresponding to the corneal marginal junction or limbal cornea, contouring the treatment pattern to the anatomical structure of the eye of interest and achieving customized delivery of heat waves to targeted deeper structures.

[0089] In some embodiments, the treatment sites are within a 360° pattern posterior to the corneal marginal junction. The treatment sites may be contiguous 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). During the first treatment cycle, the processor directs laser energy to a set of pre-identified treatment sites on the surface of the eye, and during one or more subsequent treatment cycles (repeated cycles), directs laser energy to the same or identical subsets of pre-identified treatment sites. The precise circulating heat rise of the scleral tissue beneath the pre-identified treatment sites at a given time interval induces a heat rise / relaxation cycle in the irradiated tissue, causing the propagation of heat waves to deeper target structures within the eye between treatment cycles.

[0090] In some embodiments, the processor sets the speed of each treatment cycle and achieves thermal relaxation by spacing out irradiations of the treatment site at time intervals, producing a targeted time-temperature history. For example, the time interval between irradiations of the same treatment site produces a load time ratio (ratio of active exposure on time / [active exposure + relaxation off time]) in the range of 2-50%. In some embodiments, the time interval between irradiations of the same treatment site is approximately 10-300 ms, for example, 100-200 ms. However, the time interval between irradiations of a specific treatment site may vary depending on other parameters.

[0091] In some embodiments, a predetermined treatment pattern extends through a 360° limbal guided circumferential pattern or annular shape, located approximately 1–1.5 mm posterior to the corneal marginal junction. Generally, annular treatment patterns are referred to, but the energy pattern can be delivered in many configurations, such as a portion of an annular shape, polygon, or intermittent treatment along a substantially circumferential pattern. In one embodiment, the treatment pattern extends through a 120° arc. Other predetermined treatment patterns may extend through a substantially annular shape approximately 2–3 mm and / or 3–4 mm posterior to the corneal marginal junction. Since the corneal limbus and corneal marginal junction may not be circular, a pattern spaced at a fixed distance from the corneal marginal junction throughout 360° would mimic the shape of the corneal limbus and corneal marginal junction. The limbal guide pattern may be, for example, oval, elliptical, roughly arcuate with non-arctic sections, or irregular in shape, but may otherwise surround the limbus. The treatment pattern provides a template on which treatment sites may be located, and the treatment sites on the treatment pattern may be continuous (located in a continuous pattern) or discontinuous (spaced treatment sites such as spots or arcs located at intervals around the treatment pattern).

[0092] The prescribed 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 embodiments, the annular pattern is spaced approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the corneal marginal junction, targeting the outflow pathway at 1.5 mm, the ciliary process at 2.5 mm, and the ciliary slab at 3.5 mm. The 360° pattern may be interrupted to avoid intraocular anatomical structures that may be harmed by irradiation. For example, the pattern may be interrupted nasally and temporally, such as 10-30° nasally and / or 10-30° temporally. In some embodiments, a heat sink, such as a curved contact lens, is placed in contact with the eye across the treatment site to transfer heat away from the treated surface of the eye. The lens may be a cooled lens that substantially conforms to the surface of the eye, which is either pre-cooled or cooled in situ while spread horizontally over the surface of the eye.

[0093] Protective thermal pre-conditioning and therapeutic biostimulation may be controlled by one or more of the following: laser power, irradiance, scanning speed, cycle repeat rate, number of cycle repeats, spot size, and duty cycle. For example, the processor is configured to direct laser energy to the treatment site 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 limbus and / or corneal junction of the target. The processor may be configured to identify a given treatment site as determined by the shape and size of the limbus and / or corneal junction of the target eye. The 360° site identified by the processor may be circular, oval, elliptic, egg-shaped, non-circular, non-elliptic, asymmetric, or other shapes, as determined by the anatomical structure of the individual limbus. The ring shape, contoured by the shape of the limbus or corneal junction, is effectively a larger (larger diameter, etc.) version of the limbus or corneal junction of the specific target being treated.

[0094] Embodiments disclosed in this method deliver laser energy, for example, near-infrared laser energy with low scattering (e.g., from a 1.475 μm IR laser), 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 directly below the surface of the sclera), rather than 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, affecting cellular transduction chains in deeper ocular structures. The laser energy may be applied repeatedly and specifically to the same treatment site at time intervals spaced apart by the treatment cycle, generating a heat wave that propagates three-dimensionally or 360° spherically into deeper scleral layers and the aqueous humor outflow pathway and / or ciliary body structure at each treatment site. Energy delivery achieves the phototherapy threshold through a slow photothermal rise, avoiding complications such as ALT burns or those associated with SLT cavitation interactions. This method avoids the need for gonioscopy targeting of the laser to the trabecular meshwork in the iris-corneal angle (Figure 1) and avoids the iatrogenic disadvantage of moving the contact probe across the surface of the eye. This procedure may also be performed under local anesthesia and without retrobulbar block.

[0095] In one disclosed embodiment, a laser is continuously irradiated over a 360° treatment pattern or a portion of a pattern, moving in one direction throughout the 360°, starting at 0° in a clockwise direction, and starting the cycle again before repeating. Alternatively, such a cycle may proceed counterclockwise 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 continuously irradiate the target pattern throughout the entire 360° pattern in a ping-pong fashion, such as 0°, 180°, 10°, 190°, 20°, 200°, 30°, 210°, 40°, 220°, etc., forming either a continuous or intermittent pattern. In some disclosed embodiments, each cycle may irradiate a selected treatment area, and all treatment areas may be irradiated before proceeding to the next cycle. Multiple treatment locations on the pattern may correspond to angles within a range of approximately 30° to 360° around the sclera of the eye, for example, within a range of approximately 90° to 360°, within a range of approximately 90° to 150°, 160°, 170°, or 180°, or within a range of approximately 180° to 360°. Multiple treatment locations may correspond to angles of approximately 30°, 45°, 60°, 75°, 90°, 150°, 180°, 270°, or 360°.

[0096] The treatment pattern may be a continuous treatment pattern, such as an annular shape, forming an uninterrupted curve, or an intermittent treatment pattern, having spaces between treatment "dashes" or "spots" along the treatment pattern. The treatment pattern may consist of multiple treatment patterns, which may overlap or not overlap. For example, multiple annular shapes may overlap, generating a treatment annular shape with a width exceeding the spot size of the laser energy beam. Non-overlapping annular shapes may have a predetermined radial direction at the distance between each of the multiple treatment patterns. For example, each non-overlapping treatment pattern may be at a different fixed distance from the corneal margin junction, such that each pattern is a limbal contour guidance pattern with a different circumference.

[0097] In some embodiments, the scanning speed of the circumferential movement of the laser around the treatment pattern to treat all treatment sites determines the time interval between irradiations of each treatment site on the ring. The movement of the laser during the time intervals between repeated irradiations of specific treatment sites fractionates the energy delivery to each treatment site and allows for thermal relaxation between irradiations of each treatment site. The total energy delivered to each treatment site may be partially determined by the number of cycles, where the total energy is the product of the number of cycles × the energy applied per cycle.

[0098] Detailed description of the illustrated embodiment (Figure 2-4) Detailed embodiments of this method and system will be described with reference to the drawings. Figure 2A schematically illustrates a method for reducing IOP. Laser energy is emitted from a non-ocular contact laser energy source 18 spaced away from the surface of the eye and directed toward the cornoscleral junction 20, which is the transition region between the cornea and the sclera. Figure 2B is a magnified view of the box in Figure 2A, illustrating in more detail the cornoscleral junction where the laser energy is directed to propagate a heat wave to the underlying trabecular meshwork and other structures of the aqueous humor outflow pathway. Figure 3 is a further magnified view of the cornoscleral junction 20 where the cornea 22 abuts the sclera 24. The limbus 26, which forms the cornoscleral junction, is internally (intraocularly) bounded by the Schwalbe line (SL) 28 and the scleral promontory (SS) 30. The limbus 26 is externally (on the surface of the eye) bounded by the corneal marginal junction (CLJ) 32 and the scleral marginal junction (SLJ) 34. The CLJ32 is also known as the apparent or anterior limbus, and the SLJ34 is also known as the surgical or posterior limbus. The conjunctiva and Tenon's capsule (not shown) fuse before inserting about 0.5 mm posterior to the CLJ. The inferior ciliary body36, which produces aqueous humor, is divided into the ciliary process38 and the ciliary slab40. The trabecular meshwork™42 is located around the base of the cornea22 near the ciliary body36 and is part of the apparatus for draining aqueous humor from the eye. Schlemm's canal44 is a rounded lymphoid vessel around the base of the cornea22 adjacent to the trabecular meshwork™42, which is also part of the aqueous humor outflow pathway. The distance from the corneal marginal junction32 to the scleral marginal junction34 is about 2 mm in a typical eye.

[0099] Irradiation of the limbus and / or peri-marginal region of the cornea propagates a heat wave that proceeds through the sclera, photostimulating most of the structures of the primary aqueous humor outflow pathway, including the collecting ducts and / or their pores, Schlemm's canal, para-Schlemm's canal™, cornosclera™, and uvea™. All of these structures are located in the space directly beneath the limbus. In some cases, only a single treatment pattern at a distance R1 posterior to the corneal marginal junction is used. In other cases, two treatment patterns at R1 and R2 posterior to the corneal marginal junction are used to achieve greater diffusion of the heat wave to more of the aqueous humor outflow pathway structures and / or aqueous humor production structures (within the ciliary body). In yet another case, three treatment patterns R1, R2, and R3 posterior to the corneal marginal junction are treated to achieve broad diffusion of the heat wave to targeted structures of aqueous humor production and outflow. In other embodiments, more than three treatment patterns may be used, for example, four, five, or six treatment patterns at fixed distances from the cornoscleral junction.

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

[0101] Figures 3, 4A, and 4B show examples of locations where the pericorneal margin region may be illuminated at distances R1, R2, and / or R3 posterior to the corneal margin junction 32. For example, R1, R2, and R3 may be approximately 0, 1.5, and 2.5 mm posterior to the corneal margin junction 32, or approximately 1.5 mm, 2.5 mm, and 3.5 mm posterior to the corneal margin junction 32, respectively. In some embodiments, R1 may be 0–2 mm posterior to the corneal margin junction, R2 may be 2–3 mm posterior to the corneal margin junction 32, and R3 may be 3–4 mm posterior to the corneal margin junction 32. In other iterations, R1, R2, and R3 may be any combination of the following: R1 = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, or 1.7 mm or more posterior to the corneal marginal junction; R2 = 2.25, 2.5, 2.75, 3.0, or 3.25 mm or more posterior to the corneal marginal junction; and R3 = 3.5, 3.75, 4.0, 4.25, 4.5, 4.75 mm or more posterior to the corneal marginal junction. In some embodiments, R1 is about 1–2 mm from the corneal marginal junction, R2 is about 2–3 mm posterior to the corneal marginal junction, and R3 is about 3–4 mm posterior to the corneal marginal junction, with R1, R2, and R3 being at different distances.

[0102] In some embodiments, the anatomical structure of the eye may be imaged, for example, using a surgical microscope, and then the shape of the limbus may be identified for overlaying onto a treatment pattern that can be applied to the eye by automated irradiation of the treatment site at a designated treatment site. In other embodiments, an image analysis software program will recognize the limbus and its anterior edge (corneal marginal junction). The automated system may be programmed to identify the treatment pattern based on a “custom limbus” pattern that is offset posteriorly from the corneal marginal junction by a selected fixed distance from the corneal marginal junction so that the treatment ring shape mimics the actual shape of the patient’s limbus. The shape of the limbus often varies from patient to patient, and therefore, 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 occur due to unintentional irradiation of ocular structures in patients with unusual ocular biostructures.

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

[0104] Optical coherence tomography (OCT) or high-intensity focused ultrasound (HIFU) are examples of imaging modalities used to identify one or more of a targeted structure. For example, 360° locations of the medial and lateral margins of the limbus may be imaged by OCT, as disclosed in U.S. Patent No. 9,618,322. Once the anterior margin of the limbus is identified and mapped, the treatment location may be selected on an annular shape offset by desired distances R1, R2, and / or R3 from that anterior margin. An automated system can then precisely illuminate the treatment annular shape or multiple annular shapes at the reproducible location.

[0105] Locations R1, R2, and R3 irradiate the sclera covering different structures of IOP homeostasis, such as the aqueous humor outflow pathway and production structures. In the illustrated embodiment, R1 is positioned to irradiate the primary aqueous humor outflow pathway, R2 is positioned to irradiate the ciliary process and ciliary body that produce aqueous humor, and R3 is positioned to irradiate the ciliary squamata and unconventional uveoscleral outflow pathway. Adjusting 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 the laser energy to targeted locations that will restore IOP homeostasis. In one embodiment, if the increased IOP is likely due to excessive aqueous humor production, the laser energy and thermotherapy stimulation may be directed at least or exclusively to the ciliary body (e.g., the ciliary process at R2 and / or the ciliary squamata at R3). If the increased IOP is considered to be due to conventional or uveoscleral outflow pathway resistance, the laser energy and cryo-stimulation may be directed at R1, or at least exclusively. If the increased IOP is likely due to both overproduction and impaired outflow of aqueous humor, both the production and outflow pathways may be targeted, for example, at R1, R2, and R3.

[0106] In the embodiment shown in Figure 4C, an annular treatment pattern is applied at a distance of approximately 1.5 mm posterior to the corneal marginal junction, and the treatment area is interrupted to form multiple arcs, such as an upper arc 50 and a lower arc 52. Each of these illustrated arcs is uninterrupted in that the treatment area is 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 area is treated by moving a sustained-wave laser beam along the arc with the laser turned on. Interruptions may be formed by turning the laser off and on in pulses to form discontinuous treatment areas. In some embodiments, the laser beam is moved circumferentially over the upper and / or lower arcs 50, 52 at a steady and repeatable speed by a computer-driven electro-optic scanner, ensuring consistent and always reproducible treatment with a reliable amount of laser energy deposition. In Figures 4C and 4E, the laser energy is delivered in an arc pattern, producing two 150° arcs. The illustrated arc is sustained, except for interruptions at approximately 8:30–9:30 (255°–285°) and 2:30–3:30 (75°–105°) positions to avoid the long ciliary nerve, minimize pain, and avoid the risk of anterior segment ischemia.

[0107] In Figure 4D, an annular treatment pattern 54 is applied in a non-discontinuous pattern, located approximately 3.5 mm posterior to the corneal marginal junction, but not divided into upper and lower arcs. In Figure 4E, multiple annular treatment patterns are applied at R1, R2, and R3 within the upper and lower arcs. Figure 4F illustrates a treatment pattern including an upper primary arc 56 and a lower primary arc 58, where each of the upper and lower arcs itself is a series of auxiliary discontinuous arcs irradiated by a laser beam of its path or shape, which pulses (turns on / off) as it moves through arcs 56 and 58, respectively. In this example, the laser beam 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 site does not always need to be progressive in a circular direction around the eye. For example, after one of the auxiliary arcs in the primary arc 56 is irradiated, the irradiation of an auxiliary arc in the lower arc 58 may follow, and the irradiation pattern may move back and forth between arcs 56 and 58. However, the sequence in which the auxiliary arcs are irradiated is generally the same in each treatment cycle, setting a pre-selected period during which the desired thermal relaxation may occur at each treatment site before the next irradiation cycle begins.

[0108] The speed of the laser beam's movement along the arc and / or the use of a pulsed laser can both affect the duty cycle, and the selection of a uniform period per cycle establishes a fixed interval between irradiations of each treatment site. 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 pre-conditioning 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 site is also set by the period of each cycle. For example, Figure 4G illustrates a single cycle in which irradiation of the eye begins at the 90° location and continues clockwise around the eye through the 180°, 270°, and 360° locations before returning to the 90° location. The next cycle then repeats the process. This pattern can be repeated by moving the laser beam of a continuous wave (CW) laser across the surface of the eye, for example, at a speed such as a pre-selected constant speed, to set the period of thermal relaxation for each treatment site. For example, the treatment site at 90° may be the first site irradiated in the first cycle and the first site irradiated in the second cycle and subsequent cycles. In this embodiment, the time interval between irradiations of the 90° treatment site is equal to the period of the cycle.

[0110] In the embodiments of Figures 4H and 4K, the cycle begins with the laser irradiating the surface of the eye at 285° and moving along the treatment ring to the 75° position. The laser is then turned off as it moves from the 75° to the 105° position, but the laser is then turned on again at the 105° to 255° position. In this embodiment, the formation of the upper and lower arcs occurs in one cycle. In some embodiments, only one of the upper or lower arcs is irradiated, and in such embodiments, the laser may start at 285° and move to 75° for the completion of one cycle, for example. 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 directly redirecting the laser beam from the 75° position to the 285° position. Each movement of the laser through a 360° ring pattern (or treatment of all locations within the pattern being used) will constitute a single treatment cycle, which can be repeated a desired number of times. The period for thermal relaxation (the cycle period) is generally fixed throughout multiple irradiation cycles by moving the laser beam at a constant speed throughout the entire cycle; however, variable intervals may also be used, as desired, to achieve the therapeutic effect.

[0111] Figure 4I illustrates yet another embodiment of a treatment pattern, in which multiple arcs of intermediate length are applied in a clockwise direction around a treatment ring. Figure 4J illustrates yet another treatment pattern, in which the treatment ring is formed from multiple laser spots or arcs, applied sequentially. The first cycle may constitute the completion of the arc sequence in Figure 4I or the laser spot sequence shown in Figure 4J, and subsequent cycles would constitute subsequent scleral irradiation at 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 also be applied in other patterns, such as counterclockwise, or not uniformly moving in one or the other direction around the eye. The cyclical nature of repeated irradiation of the same location is illustrated with respect to Figure 4K, which divides the right and left eyes into 36 equally spaced 10° sections. Treatment locations may be identified, for example, in 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] Figure 4L schematically 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 positioned outward from the eye 70 and directs a laser beam 76 toward the surface of the eye at an angle θ with respect to OA, irradiating the surface of the eye and generating a heat wave that penetrates the aqueous humor outflow tract structure and / or the ciliary body. The laser beam does not continue through the center of the sphere, but the path of the laser is traced by a dashed line to the center of the eye to illustrate the angle between the laser beam and OA. In this embodiment, the angle θ is 30 to 50°, for example, 35 to 40°, but the angle at which the beam 76 strikes the eye may vary, as the therapeutic effect of the disclosed method is achieved by the generation of a wave that can propagate nonspecifically through the sclera and heat the aqueous humor outflow tract structure and / or the ciliary body. Therefore, the laser beam does not need to be directly aimed at the structure in order to utilize the propagated heat wave.

[0114] Figure 4M illustrates a laser beam 76 directed towards 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, with a selected velocity, moves in the direction of movement 84, generating a heat wave 86 that diffuses three-dimensionally in the x, y, and z directions through the superficial sclera toward the underlying target in order to modulate IOP homeostasis. As the beam 76 moves in the y direction along the sclera 78, the heat wave propagates three-dimensionally into the underlying tissue along the laser path. For example, the laser is moved along a pattern shown in any one of Figures 4C-4J. The angle of impact with the sclera may be selected to minimize reflection and scattering of laser energy and facilitate effective tissue penetration. In some embodiments, the laser impacts the sclera at an angle of 90 ± 45° with respect to the tangent to the eyeball at the point of impact. As discussed below, the contact lens 80 or the sclera 78 itself can contribute to or produce the general direction of propagation of the beam 76 into the sclera 78.

[0115] The contact lens 80 (Figure 4M) acts as a heat sink, transferring heat away from the surface of the eye. The heat sink is fully disclosed in US2018 / 0177632, which is incorporated by reference, to the extent that it is not inconsistent with this disclosure. In summary, the lens has suitable optical properties for enabling visualization of the eye through the lens and for providing, or assisting in providing, a selected angle of incidence on the sclera. In a typical embodiment, light is directed parallel to the optical axis of the objective lens relative to the eye through an objective lens (such as an Fθ lens) using a laser scanner (such as a two-mirror galvanometer scanner), and typically the OA of the eye is aligned collinearly with the optical axis of the objective lens. The sclera and eye have refractive indices higher than those of air (approximately 1.0), (e.g., 1.3–1.5), and the radial position of impact in the sclera is associated with a tangent that is not perpendicular to the ocular ophthalmoplegia (OA) of the eye. Therefore, even without the presence of the contact lens 80, the incident laser beam is refracted toward the ophthalmoplegia at an angle, not parallel to it. The contact lens 80 can also assist this refraction with a pre-configured refractive index or curvature that produces a desired angle of incidence toward the sclera for the beam received by the contact lens 80, which propagates parallel to the ophthalmoplegia.

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

[0117] Time-dependent three-dimensional propagation of heat waves The temporal propagation of heat waves through the scleral wall divisions is further illustrated in Figures 4N-P. These figures illustrate sequential events resulting from a ring-shaped laser irradiation, described by the sliding of a series of interrupted spots from a laser beam moving across the scleral surface at a speed of 50 mm / second. In Figure 4N, the laser energy is generally applied perpendicular to the scleral surface, and as each laser spot is irradiated, heat propagates within the heat wave toward deeper structures below the scleral surface. Figure 4O shows the heat wave propagating deeper into the sclera until it reaches targeted subscleral structures (insert diagram) such as the trabecular meshwork and ciliary body. In Figure 4P, the wave decays toward the scleral surface again as thermal relaxation occurs. This sequence is illustrated with respect to one such spot in Figures 4N-P, but the same process occurs at each laser spot as the laser moves across the scleral surface.

[0118] Figures 4Q-4X similarly illustrate the propagation and attenuation of heat waves toward and away from the trabecular meshwork (TM level). In Figure 4Q, the heat wave propagates to the scleral surface by laser irradiation. In Figures 4R, S, T, and U, the wave gradually advances over the next 1.64 seconds, penetrating the TM and passing through it. Figures 4V, W, and X show the thermal relaxation period, during which the heat wave moves away from the TM level and then back toward the scleral surface.

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

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

[0121] Beam size The diameter of the laser beam on the surface of the eye is large enough to direct the heat wave towards targeted aqueous humor production and / or outflow structures. Beam placement refers to the location of the beam's center relative to a reference point. For example, the beam diameter may be 500 to 1,000 μm, such as 600 μm. A 600 μm diameter laser beam can be centered on an annular therapeutic pattern 1.5 mm posterior to the corneal marginal junction, allowing for therapeutic stimulation of a large portion of the primary aqueous humor outflow tract structure with the generated heat and diffusing heat wave. A 600 μm diameter laser beam may also be projected in an annular pattern with a beam centered 3.5 mm posterior to the corneal marginal junction, targeting the unconventional uveoscleral outflow tract of the ciliary body. In some embodiments, a 600 μm diameter laser beam may also be projected in an annular pattern with a beam centered 2.5 mm posterior to the corneal marginal junction, targeting the ciliary process.

[0122] Transscleral laser circulation using a beam of this size induces localized photothermal elevation, producing a biomechanical response involving movement and reorganization of the aqueous humor outflow pathway, resulting in improved conventional (trabecular meshwork) and unconventional (uveoscleral) outflow, along with subtle morphological changes in the microstructures of the pericorneal margin, ciliary process, and ciliary squamous region, leading to early IOP reduction. Concurrent photothermal therapy (e.g., up to 43-45°C) leads to thermal diffusion and attenuation within the surrounding tissue without scleral photocoagulation, reequilibrium at the treatment site, moving towards or returning to baseline body temperature. While not wishing to be constrained by theory, repeated irradiation and thermal attenuation are thought to induce a biochemical response, accompanied by a biological chain of cytokine expression and subsequent endogenous molecular transcriptional activity, contributing to the long-term IOP reduction effect.

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

[0124] Irradiance, scanning speed, exposure time, cycle repeat rate The combined therapeutic effect and protective thermal pre-adjustment are controlled by various factors that govern the temperature generation-re-equilibrium photothermal process. These parameters include laser power (W) and irradiance (W / cm²). 2 The parameters include the exposure time (scanning speed in mm / second), and the cycle repetition rate (period T between two consecutive exposures on the same cell spot), which determines the loading time ratio, i.e., on time / period T (%) and the number of cycle repetitions (total treatment duration). The laser beam may be projected through a limbal guided scanning computer-controlled electro-optic delivery system to irradiate the sclera at different arc patterns, at different distances posterior to the limbus, at programmed scanning speeds (exposure time), and other selected variables, generating a unique time-temperature history accompanied by photothermal rise, which incidentally produces an IOP-reducing biomechanical and biochemical response.

[0125] Laser irradiance (W / cm²) 2 The power per unit area and scanning circular speed (mm / sec) may be selected to produce a temperature rise of 8-20°C above the 37°C body temperature within the sclera when irradiated by a scanning laser beam, for example, a 0.6 mm diameter laser beam. -1 Assuming an absorption coefficient of 1.475 μm IR wavelength within the given range, the temperature of the first 200 μm deep scleral layer (through the scleral depth from the conjunctiva of 160-200 μm) is given by the laser irradiance (W / cm²). 2By controlling the laser power and exposure duration (determined by the scanning speed in mm / second and the number of repetitions), the temperature can be raised to approximately 45° to 57° (37° + 8° or 20°). To reduce the risk of cumulative thermal damage to the first absorption layer on the surface of the conjunctiva and sclera, the laser power for the first treatment cycle may be set to start from a certain threshold power fraction (e.g., less than 50%, 40%, 30%, or 20%) that will cause an immediate coagulation reaction. At the completion of the first cycle, the laser power is automatically increased stepwise in each subsequent 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%, and 95% in each subsequent cycle) to 100% in the 17th cycle without causing any visible coagulation effect, due to a thermal conditioning process that increases heat resistance or resistance to thermal cell death. In alternative embodiments, the targeted peak temperature may be reached rapidly and then decreased to maintain a dwell period in the peak temperature rise.

[0126] When the electro-optic scanner moves the beam at a constant circular speed of 50 mm / second around the treatment ring, each portion of the scleral ring irradiated by the 0.6 mm diameter beam receives an exposure duration of 12 ms (0.6 mm ÷ 50 mm / second = 0.012 s) that increases the local temperature. As the laser beam moves away, exposure and heat production cease, but the generated heat diffuses and attenuates towards the adjacent, cooler surrounding tissue in a thermal relaxation process, eventually re-equilibrium with the body baseline temperature (37°C). This thermal relaxation process is interrupted when the laser beam returns to the same spot after completing a 360° cycle and initiating the next cycle, converting the thermal relaxation into a new temperature increase. In one embodiment, using treatment in a circular pattern having a diameter of 13 mm and a circumference of 40 mm, each cycle would take approximately 800 ms (40 mm ÷ 50 mm / sec = 0.8 s) to irradiate with a load time rate of 1.5% (12 ÷ 800 = 0.015 or 1.5%).

[0127] In some embodiments, the exposure duration for each portion of the scleral ring is approximately 2–120 ms, e.g., 2–20, 10–20, 10–15, 12, 24, 60, or 120 ms. In some embodiments with a constant beam diameter spot size of 0.6 mm (600 μm), the irradiation duration at each point within the center of the ring width may depend on the beam circular scanning speed. Specifically, at 1.0 mm / second, the irradiation time in each cycle is 0.6 s or 600 ms; at 5.0 mm / second, the irradiation time in each cycle is 0.12 s or 120 ms; at 10.0 mm / second, it is 60 ms; at 15.0 mm / second, it is 40 ms; at 20.0 mm / second, it is 30 ms; at 25.0 mm / second, it is 24 ms; at 30.0 mm / second, it is 20 ms; at 50.0 mm / second, it is 12 ms; at 100.0 mm / second, it is 6 ms; and at 300.0 mm / second, it is 2 ms.

[0128] The process is continued over N cycles to withstand the thermal rise for a programmed time-temperature history. In addition to thermal pre-conditioning to improve the thermal resistance of the first energy absorption layer of the sclera, heat may also be continuously reduced from the conjunctival / scleral superficial layers by a heat sink such as a deeply cooled contact lens, which cools, protects, and preserves their superficial layers from cumulative thermal damage. The heat sink allows the duration of the temperature rise to be extended for the time required to allow its 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 induce therapeutic photothermal effects without the use of a contact probe having a projection optical fiber tip that is pulled along the eye and potentially causes discomfort and scratches the sclera. The non-contact laser source may also move at a faster speed through the treatment pattern than can generally be achieved by moving a contact probe relative to the eye. The automated or computer-implemented features of the system also help to achieve more consistent treatment, avoiding subjective fluctuations in precisely positioning and controlling the rate of laser energy delivery. Transscleral circulating 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. Circulating laser therapy also produces beneficial photothermal stimulation / hypertherapy 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 load time rate) and the number of repeated cycles (duration of sustained hyperthermia therapy).

[0130] Patient Interface In some embodiments, the system includes a patient interface for docking a non-contact laser energy source away from the eye. The patient interface may include a spacer that maintains the eye in a substantially fixed position and / or focal length 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 away from (without contact with) the surface of the eye. The patient interface may further include a microscope for placement between the eyelids of the target to keep the eye open and allow the eye (particularly the sclera) to be better exposed to the laser energy. In some embodiments, the patient interface includes a lens holder that stably positions a contact lens across the surface of the eye and acts as a heat sink, transferring heat outward away from the eye. For example, the lens may be a scleral contact lens that contacts the sclera at the treatment site. In the disclosed embodiments, the contact lens holder may also include a retaining 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 retaining ring between the eye and the contact lens, to fix the patient interface to the surface of the eye, and to substantially immobilize the eye in question during the procedure.

[0131] In some embodiments, a positioning arm positions the patient interface in a therapeutic orientation relative to the surface of the target eye in a selected therapeutic 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 retaining ring may be cooled to protect the superficial layer of the sclera from thermal damage during laser irradiation of the eye. For example, an internal fluid channel may be present within the spacer and / or lens holder, and the system may be configured to introduce a cooled fluid (such as water or saline solution) through the fluid flow channel to cool the spacer and / or retaining ring and / or contact lens.

[0133] The spacer can be docked to the lens holder to maintain the laser output at a distance away from the contact lens heat sink. An elastic sealing ring on the lens holder, extending around the contact lens and creating a sealing chamber between the contact lens and the eye, secures the lens holder to the eye and, when suction force is applied to the sealing chamber, substantially immobilizes the eye or at least neutralizes differential movement of the eye relative to the laser. The sealing chamber beneath the lens communicates with a suction input port through which negative pressure is selectively and / or accommodatively applied to the sealing chamber, optionally fixing the lens holder to the eye and controlling eye movement during the procedure. A laser triangulation system provides Z-focus camera visualization of the contact lens, and an XYZ positioner positions the patient interface with the lens holder's sealing ring relative to the target eye with the spacer docked to the lens holder.

[0134] In some embodiments, the patient interface assembly includes a spacer cone, such as a frustoconical spacer, which tapers from an enlarged first surface to a smaller second surface. The laser emission source (such as an objective lens) is supported by the cone and spaced apart from the smaller second surface. The lens holder is a collar which tapers from a larger first surface, similar in shape and size to the second surface of the spacer, to a smaller second surface of a lens holder collar, which is circumsed by a resilient patient retention ring and forms a seal to the eye to be treated. The lens holder collar includes an internal cooling fluid passage, an inlet port, and an outlet port for circulating a cooling fluid through the collar. The heat sink contact lens is held within the retention ring, and when the collar docks to the target eye, the air in the inhalation chamber is removed from the chamber, forming an inhalation chamber between the contact lens and the eye. The inhalation force applied by the inhalation chamber may vary depending on the clinical situation. For example, to avoid an increase in intraocular pressure (IOP) in any potentially damaged patient, vacuum may be used at a very low level or not at all.

[0135] In the patient interface method, the microscopy blade is inserted into the eye, the eyelid is separated, and the sclera is exposed. The lens holder is held between the microscopy blades, and air is optionally drawn in through a seal chamber. An XYZ positioner is adjusted to dock the spacer to the lens holder, and a coolant is introduced through fluid inlet and outlet ports via an internal cooling channel in the lens holder. The contact lens and eye are visualized using optical visualization software, and laser treatment of the eye may be performed through the patient interface with the laser held in a spaced-out relationship with the sclera.

[0136] The spacer allows therapeutic laser energy to be applied to the eye from a laser energy source spaced apart from the surface of the eye. Specific embodiments of such a device are shown in Figures 5A, 5B, and 5C, where a patient interface 100 docks the laser therapy 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 surface of the eye 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 having a corneal apex curvature space (e.g., 1 mm apex curvature space), and the peripheral edge of the lens sits against the sclera. The lens is arched across the eye and forms an inhalation chamber.

[0137] As shown in Figure 5B, the elastic 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 to which it is placed, so that the lens 106 arches across the eye, forming an inhalation 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, having a diameter of, for example, 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 Figure 5B, the inhalation passage 124 extends through the wall of the lens holder 104 and communicates with the external inhalation port 126. The hole 122 in the lens 106 still allows air to pass into the seal chamber while maintaining negative pressure within the seal chamber. The video camera displays the docking contact proximity by triangulating over hole 122 as two low-power laser spots are focused onto the patient's eye, indicating the proximity sensing displayed by the cone contact lens. The triangulation laser spots generated by laser emitter 128 coincide at the center of the contact lens within the treatment eye's 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 dissipation properties of the lens, as disclosed in detail in US2018 / 0177632. Within the lens holder 104, there is an internal cooling channel 108 (Figure 5B) that communicates with a fluid flow inlet port 110 and an outlet port 112, and circulates a cooling fluid (such as chilled water) from the inlet line 114 through the channel 108 into the outlet line 116. A spacer 102 is fixed to a control box 118 containing a laser source, which can control a laser beam 82 (Figure 4M) to be targeted toward the contact lens 106 through a chamber within the spacer 102. The laser beam 84 may be controlled to move through an arc-shaped path 84 (Figures 4M and 8A), for example, directing the laser energy toward the eye and irradiating the eye in an annular treatment pattern. The laser beam 84 passes through the contact lens 106 and, within the sclera and / or retina of the eye being treated, propagates a heat wave to adjacent tissues within the eye, inducing targeted hyperthermia with a selected time-temperature history response. The angle of incidence may depend on the selected treatment site. For example, the impact of the treatment beam on the sclera may be normal to the tangent to the sclera (or otherwise at some angle not parallel to the optical axis of the eye) and pass transpupillarily through the pupil; the impact of the treatment beam will generally propagate parallel to (or nearly parallel to) the optical axis and treat a panmacular ring concentric to a foveal avascular area or other fundus features. 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 site. In further embodiments, a mirror surface similar to that of a gonioscopy lens delivery configuration may be used to deliver an extraocular lens to the sclera, for example, by having a conical reflective inner surface of the patient interface 100 (using a conical spacer 154, etc., as discussed below).

[0139] Interface 100 may also include an ophthalmoscope 132 (Figures 6A and 6B), which includes a pair of opposing plastic arms 134, 136 joined at a flexible pivot point 142 that biases the arms 134, 136 to the open position shown in Figures 6A and 6B. The unjointed open ends of the arms 134, 136 each carry curved ophthalmoscope blades 138, 140, configured to fit into the palpebral fissure of the eye. The ophthalmoscope 132 is sufficiently flexible about the pivot point 142 so that the ophthalmoscope arms 134, 136 can move toward each other, narrowing the distance between the blades 138, 140, facilitating insertion of the ophthalmoscope into the eye and allowing for better exposure of the sclera to be irradiated. Outward biasing of the arms 134, 136 will return the arms to the open position shown in Figures 6A and 6B, maintaining exposure of the targeted ocular tissue to be treated. Microscopes of different sizes may be used to open the eyelids to a pre-selected distance, for example, 20 mm, 22 mm, or 24 mm, at the point of maximum separation between the eyelids.

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

[0141] The embodiment of spacer 102 in Figure 6D has a shape that tapers from an open upper surface circumscribed by a circular edge 150 to a narrower bottom surface circumscribed by a circular edge 152 that engages with the upper portion 144 of collar 104. Spacer 102 includes an upper substantially cylindrical collar 152 that tapers to a docking section 156, from which a snap fitting member 158 hangs down and engages with the inner surface of portion 144 of collar 104, selectively engaging and securing spacer 102 with collar 104, and is joined to a frustoconical central section 154. The snap fitting member 158 is coupled to a complementary member inside collar 104 for releasably interconnecting spacer 102 and collar 104 using a compression joint that conveniently connects to and disconnects from 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] Figure 6E is a magnified view of the collar 104, with the central hole 122 centered within the collar 104 and the peripheral edge of the contact lens 106 seated within the inner edge of the collar 104. An inhalation chamber 123 is formed below the contact lens 106, and the chamber 123 communicates with the inhalation line 124 through an opening in the collar 104 below the peripheral edge of the contact lens 106. The external inhalation port 126 draws inhalation force through the line 124, establishing inhalation force between the contact lens 106 and the surface of the eye, and keeping the collar 104 and patient interface 100 relatively immobile relative to the eye.

[0143] Figure 7A illustrates a microscope 132 positioned within the palpebral fissure 158 of the subject to expose the sclera 24 for treatment. Figure 7B shows an assembled interface 100 in which the spacer 102 is docked to the collar 104, with the contact lens 106 positioned against the surface of the eye (e.g., the cornea and / or sclera), and the collar 104 itself is held in place between the blades 138, 140 of the microscope 132. The interface 100 substantially immobilizes the eye of the subject being treated, preventing differential movement of the eye to a laser beam directed toward the eye from a laser energy source 74 spaced outward from the surface of the eye. Control of eye movement is effectively achieved, in particular, by drawing air from an inhalation chamber in a sealing ring 120 beneath the contact lens 106. The inhalation force may be induced by the clinical situation. For example, the procedure may be performed with or without inhalation force. When an inhalation force is applied, the negative pressure in the inhalation chamber is controlled to, for example, below 35 mmHg. A slow level of inhalation force that does not exceed 5 mmHg and does not increase IOP is preferred. The central hole 122 of the contact lens 106 allows air to flow into the inhalation chamber and, 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 uses an optical imaging system to improve the detection of the limbus and / or corneal marginal junction. Differential eye movement relative to the laser beam can also be minimized by controlling the relative eye movement using the patient interface 100 (Figure 8A) to avoid interference with the targeted delivery of laser energy. The elastic sealing surface of the seal ring 120 is seated against the eye, and the 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 optical system 74 at a predetermined distance from the surface of the eye 70, preventing contact.

[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 at i) the circumlimbal outflow structures (collecting ducts, Schlemm's canal, trabecular meshwork), ii) the ciliary processes, and iii) an arcuate or circumferential arc pattern at selectable scleral meridian positions posterior to the apparent limbus over the pars plana vitreoscleral region, infrared (I.R.) electromagnetic energy (e.g., 1.475 μm laser energy) for circumlimbal induction non-contact transscleral circulating deposition, using a computer-driven electro-optical scanning beam delivery system 200 (FIG. 8B). The scanning speed is adjustable and, for example, within the range of 0.1 to 50 mm / second.

[0146] The amount of infrared laser energy delivered is dose-set using laser irradiance (W / cm 2 ) and exposure duration (by controlling the circulating scan rotation speed in mm / second) and can produce a localized photothermal rise, which is non-coagulative but results in a reorganization of the aqueous humor (AH) outflow pathway, improving both conventional (trabecular meshwork) and non-conventional (vitreoscleral) outflow pathways, with fine morphological changes in the microstructures of the circumlimbal, ciliary process, and pars plana regions, and can induce a biomechanical response. The method also induces a biochemical response induced by adjunctive photostimulation hyperthermia (43 - 45°C) as heat diffuses and attenuates within the surrounding tissue, re-equilibrates, and returns 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] The laser treatment optical system of FIG. 8B Figure 8B shows a typical optical system 200 configured to direct a laser beam onto a targeted surface of the eye 70 and rapidly move the beam in rotation or other cycles around the optical axis OA of the eye (as in Figure 4M or 8A). For example, the optical system may be a digital galvanometer scanner system, such as a Canon system, 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, clockwise or counterclockwise within the interface 100.

[0148] The optical system 200 in Figure 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 semiconductor diode lasers, fiber lasers, solid-state lasers, and frequency-varying nonlinear optical materials (e.g., frequency doubling). In a typical 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 with wavelengths of approximately 800 to 2,200 nm or 1,000 to 2,100 nm, e.g., 1,000 to 2,100 nm. Generally, the predetermined wavelength of the optical beam 202 is selected to produce transscleral hyperthermia therapy as already described. For example, a predetermined wavelength may be selected to be long enough so that the optical beam 202 is absorbed by the water in the scleral cells of the eye 104, over a wider range than what would occur at shorter wavelengths such as 808 nm, 650 nm, 532 nm, and 355 nm. In one embodiment, the optical beam 202 has a wavelength of 1,475 nm and is generated in an optical beam source 206 with a 14.75 nm diode laser. The increased absorption at longer predetermined wavelengths can allow the optical beam 202 to be directed towards 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, e.g., 45–55 mm. In the disclosed embodiment, the offset is 35–45 mm, e.g., 40 mm.

[0149] In a typical embodiment, the optical beam 202 is emitted from the optical beam source 206 as the collimated beam propagates along the optical axis 210. A lens group 212 is configured to adjust beam characteristics such as beam area, divergence, and convergence. For example, the beam width, generally shown in relation to the side rays 213a and 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 and can move the beam in a rotational motion within the interface 100, for example. For illustrative purposes, the optical scanner 214 is shown to deflect the optical beam 202 along three optical beam paths 216a, 216b, and 216c. A reflective element 218 is installed to redirect the optical beam 202 along the beam paths 216a-216c. The beam splitting element 219 receives the optical beam 202 and is positioned to pass the optical beam 202 through a focusing lens 220, which may include one or more lens elements. The camera 222 is also coupled to the optical system 200 by the beam splitting element 219. The 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 reflecting element 226 that 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 against the eye target 70, including an XY galvanometer scanner, a 3D scanner, an electro-optical scanner, or an acoustic-optical scanner. The 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 using the optical scanner 214, and the alignment of the optical scanner 214 with respect to 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 scanning 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 RAM, as well as non-volatile memory, or a combination thereof. The memory is accessible by the controller's processor (or multiple processors) and can store software in the form of computer-executable instructions that can be executed by the processor. In some embodiments, the controller 228 can be distributed between different components (e.g., between the optical beam source 206 and the optical scanner 214), and in some embodiments, communication is not required between all components.

[0151] In a typical embodiment, the optical beam 202 is a sustained-wave beam that is focused or defocused to a selected spot size at a predetermined location radially outward from the corneal margin or cornoscleral junction of the eye 70. For example, the optical beam 202 is directed along optical beam paths 216a, 216c to a location in the eye target 70 radially outward from the corneal margin or cornoscleral junction, and the optical beam path 216b in the eye target 70 can also be understood as radially outward from the corneal margin junction if the location is sufficiently below or above the plane of the figure. In a typical embodiment, the controller 228 controls the optical scanner 214 to scan the optical beam 202 in a circulating annular pattern radially outward from the cornoscleral junction. Scanning the optical beam 202 produces a selected duty cycle of heating at sequential azimuthal positional positions of the annular pattern in the eye target 70, so that thermal relaxation may occur between scanning cycles.

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

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

[0154] As clearly illustrated in Figure 9B, the pump 176 moves the cooled liquid from the control box 118 to the interface 100 through an inlet line 182 communicating with the inlet port 110, and moves the cooled liquid through a channel 108 in the lens holder 104 to cool the lens 106 in situ. The liquid then passes through the outlet port 112 and the outlet line 184. The suction line 186 communicates with the suction port 126 for drawing suction force downwards from the lens 106, improving contact between the resilient seal ring 120 and the surface of the eye 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 for accommodating one or more optical fibers or light source cables. The optical system tray may support one or more optical components that direct one or more lasers, for example, as described with respect to FIG. 8B, to the surface of the eye 70. The one or more optical components may also be contained within the interface 100 and illuminate the eye.

[0156] The control box 118 may be suspended from a positioning arm, such as the X - Y - Z positioning arm 186 (FIG. 9C), which can be computer - controlled for precise installation of the control box 118 and the interface 100. The arm 186 has a positioning knob 190 that can be relaxed and move the flange 188 in a horizontal plane. The flange 188 is fixed to the box 118.

[0157] Patterned Energy Delivery System and Processor For any of the desired treatment patterns, the processor may be configured with instructions to provide an automated or computer - implemented treatment method that couples a laser energy source and a scanner to heat tissue at multiple treatment sites and deliver energy more precisely to pre - selected treatment sites. The multiple treatment sites, for example, the first annular treatment pattern and the second annular treatment pattern, may avoid underlying anatomical structures such as the attachment points of intraocular muscles. In some embodiments, the computer implementation of the automated treatment pattern can achieve controlled heating of specific locations to achieve the desired treatment outcome.

[0158] Figure 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 operably 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 scanned by an XY scanner 616 onto the eye 602 through an optional mask 618 and an optional heat sink 620. A mirror 622 directs the light energy from the eye 602 to a viewing camera 627 coupled to a display 628. For example, an independent non-therapeutic light source for an 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. Prior to passing through the XY scanner 616, the second light source 610 emits a second beam of light 630, which is combined with the first beam of light 614 by the first beam combiner 632. Prior to passing through the first beam combiner 632, the third light source 612 emits a third beam of light 634, which is combined with the second beam of light 630 by the second beam combiner 636.

[0159] The processor may be configured with one or more than one instruction for performing any of the methods and / or any one or more steps and sub-steps of a method or treatment described herein. The processor may comprise a memory having instructions for performing the method, and the processor may comprise a processor system, for example, configured to perform the method. In many embodiments, the processor comprises array logic, such as programmable array logic (「PAL」), configured to perform any one or more steps of any of the methods or treatments described herein. The processor is embodied on a tangible medium such as computer memory or a gate array and may comprise one or more than one instruction of a treatment program for performing 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 for determining one or more than one location of a limbal ring and / or one or more than one location of a limbus junction. Responsive to the determined location of the limbal ring, for example, one or more than one location of the limbus junction may be determined. The processor may be configured with instructions for determining a treatment pattern based on one or more than one location of the limbal ring and / or one or more than one location of the limbus junction. The treatment pattern may comprise, for example, a treatment pattern spaced apart by only one or more than one of 1.5 mm, 2.5 mm, and 3.5 mm from the limbus junction. The processor may be configured to deliver non-coagulating energy to treatment locations on the treatment pattern to induce the thermal effects described herein.

[0161] The optical energy 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 iterative heating cycles. In some embodiments, beams of light 614, 630, and 634 can be scanned over the eye 602 by the XY scanner 616 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 while treating other parts, for example, to protect the masked portion of the eye 602, as described herein. An optional heat sink 620 can be placed over the eye 602 during treatment to avoid heating of a 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 preferred therapeutic 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 different wavelengths of light. The processor can be coupled to each of the light sources and selectively irradiate the eye with light having wavelengths within a desired range of wavelengths. The software may 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 a commercially available OCT system, such as those sold by Tomey, Heidelberg, Visante, or Optovue. The OCT system can be coupled to a laser delivery system with a viewing optical system and a beam splitter 626. The viewing optical system 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 optical systems. The OCT system can be used to measure the eye in situ during treatment. For example, the OCT system can be used to generate tomography of the eye and OCT images, as described herein, to determine the location, movement, and extension of target tissue. 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 eye imaging device can be used to generate images of the outside and / or inside of the eye and may include an imaging detector such as a CCD or CMOS detector.

[0164] The processor may be configured, as described herein, with instructions for scanning the laser beam over the eye according to the treatment pattern and parameters.

[0165] Figure 10B shows another embodiment of a treatment system that may be used for any of the treatment methods described herein. The system may include a laser scanner (such as the one shown in Figure 8B) which directs and scans laser energy from a sustained-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 binding structure as described herein. The scanner may further be coupled to an imaging system such as a camera, OCT, UBM, or ophthalmoscope, as described herein. The imaging system may be used to capture images of one or more of the eye before, during, or after treatment, as described herein.

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

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

[0168] In some embodiments, the therapeutic systems described herein may comprise two or more lasers. The processor may be configured with instructions for treating the eye using light of a first wavelength at a first location (or more locations) and using light of a second wavelength at a second location (or more locations). The therapeutic systems described herein may comprise 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] Figure 11 shows an image of an in vitro pig eye taken with a camera after the patient interface and system were docked to the eye. The limbus was clearly visible for use in patterning glaucoma treatment to the location of the limbus or corneal margin junction. The patterning may be manually selected by the 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 points of focus. 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, as described herein, for example. The location of the limbus may comprise the complete annular contour of the limbus, or may comprise multiple locations along the limbus (i.e., an incomplete contour of the limbus) that can be used as reference points for determining the shape of the limbus and / or where treatment should occur.

[0170] Identification of one or more locations in the limbus, as described herein, may be used to estimate one or more treatment locations. The anterior boundary of the limbus may be used as a substitute for the corneal marginal junction 32. Alternatively, or in combination, one or more locations in the corneal marginal 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 in the corneal marginal junction (one on each side of the eye), and the treatment location / pattern may be determined in response to the two identified corneal marginal junction locations. In some cases, multiple OCT images may be taken at different angles relative to the center of the eye, and multiple corneal marginal junction locations may be identified and used to estimate the shape of the corneal marginal junction. Figure 12A shows one such imaging scheme, which may be used to estimate the shape of the corneal marginal junction. Multiple OCT images may be acquired across the center of the eye at a variable angle, and a location at or above the corneal marginal junction may be estimated from each image. The location (optionally, as shown in the image) may then be used to estimate the shape of the corneal marginal junction using partial 3-D reconstruction.

[0171] In some cases, the location and / or shape of the corneal marginal junction may be estimated in response to multiple limbal locations of the eye. For example, an image including the limbus (e.g., an anterior image of the eye) may be obtained (e.g., as shown in Figure 11). The location of one or more limbal locations may be determined based on the image of the eye. For example, the locations of multiple limbal locations may be determined by detecting changes in intensity within the anterior image (e.g., across images across a series of images). In some cases, one or more processors may be used to analyze the image and determine the limbal locations. Based on the multiple limbal locations, multiple corneal marginal junction locations may be estimated so as to substantially explain them throughout. Preferred techniques for automated image analysis include automated digital image processing techniques, including machine learning, object recognition algorithms, pattern recognition algorithms, video tracking algorithms, convolutional neural networks, etc. Figure 12B shows an example of an automated process 1200 for determining treatment locations. In 1202, an image of the eye is acquired using a suitable imaging device, and in 1204, image features in the image are analyzed using digital image processing techniques, such as through one of the digital image processing techniques described herein. In 1206, a suitable treatment site is determined for features in the image. If anatomical features are found, such as the corneal margin junction in transscleral treatment or fundus features such as the macula or optic disc in transpupilation, a suitable treatment site can be determined for and based on the found features. In 1208, the treatment site can be converted into a scanner command table that maps the map scanner command values ​​to one or more scanning planes, surfaces, or volumes, and to a suitable laser scanner command for a matched and calibrated laser scanner.

[0172] Figures 13A-13D illustrate an example of a process for generating a treatment pattern based on one or more locations within the limbus. Figure 13A shows an anterior image of the eye taken using the frontal camera of the CASIA2 OCT system. The anterior image of the eye may be transferred to a processor for detection of the limbal rim. Figure 13B shows a processed image for determining the boundary (rim) of the limbus. The portion of the eye within the limbus is colored white, while the portion of the eye outside the limbus is colored black. These black and white images may then be used to generate the XY coordinates of the limbal rim. The processor may then use the XY coordinates to generate the limbal contour, which may be overlaid on a real-time image of the eye shown on a display, as shown in Figure 13C. The XY coordinates may be aligned with the real-time image of the eye so that the limbus shown on the display and the XY coordinate-generated limbal contour are co-aligned. The 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 upward / downward or with a selected azimuth angle. In some embodiments, a posterior transpupillary image is taken using a CASIA2 OCT system or another camera, and the anatomical feature boundary can be determined so that the laser scanning coordinates can be generated relative to the anatomical feature boundary.

[0173] The image may also display a reference point to the center of the eye to assist in centering the treatment, for example, circles displayed radially outward at 5 mm intervals 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, for example, a series of limbal guided treatment locations. During use, the limbal contour and / or treatment pattern may be aligned with each other (i.e., co-aligned) such that the limbal contour and real-time locations overlap or are offset by a pre-selected amount, and the limbal guided treatment pattern is separated from the corneal marginal junction by a desired distance.

[0174] Figure 14 illustrates a method for determining a target treatment site. This method may use one or more of the systems described herein. In the 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 captured. In the second step, the image of the eye may be displayed to the user as described herein, although in some embodiments, image display for the user or user intervention based on the acquired image is not required. In the third step, an image of one or more of the eye, such as a video or OCT image, may be optionally acquired. In the fourth step, multiple locations of the corneal margin junction (or limbus or other criteria described herein) may be determined from an anterior image of the eye, an OCT image of one or more of the eye, or any combination thereof. In some embodiments, multiple locations of macular features, such as the foveal avascular area and optic nerve, may be determined from a posterior image, an OCT image, or a combination thereof. Multiple locations of the corneal margin junction or macula may be estimated manually by the user or automatically by a processor. Multiple corneal marginal junction locations may optionally be aligned with corresponding multiple anterior or posterior image locations. In the fifth step, multiple treatment locations for an eye may be determined in response to multiple locations of corneal marginal junction or macular features. Multiple treatment locations may be determined manually by the user or automatically by a processor. In the sixth step, the treatment locations may be overlaid on an anterior image shown on a display, although such a display may be omitted in automated or efficient processing. The treatment locations may optionally be adjusted or authenticated by the user. In the seventh step, treatment energy may be directed by a laser source and scanner to the treatment locations shown on the image, as described herein. Typically, the laser source includes multiple lasers suitable for operating at different wavelengths or in selected modes (pulsed, sustained, or selected pulsed characteristics such as repetition rate, pulse duration, power, pulse energy, etc.).In the eighth step, the treatment may be adjusted or stopped if eye movement occurs, as the treatment is visually and / or automatically monitored in real time at the treatment site.

[0175] A processor may be provided, comprising instructions for performing a series of steps illustrated in Figure 14. In some cases, the processor may provide instructions for acquiring anterior and / or posterior images of the eye. For example, the eye image may be acquired using a camera with the assistance of the processor. In some cases, the processor may be configured with instructions for receiving the eye image.

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

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

[0178] In some cases, the processor may provide instructions for overlaying treatment locations onto anterior and / or posterior images of the eye. The processor may be configured with instructions for overlaying multiple treatment locations and multiple corneal margin-junction locations onto anterior images of the eye. Optionally, the processor may further be configured to align multiple anterior image locations with multiple corneal margin-junction locations. Optionally, the processor may further be configured with instructions for overlaying multiple treatment locations and multiple retinal locations onto posterior images of the eye, and the processor may further be configured to align multiple posterior image locations with multiple retinal locations.

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

[0180] The steps described above involve obtaining an image of the eye and treating tissue in a treatment area selected by the user; however, those skilled 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 removed. Some of the steps may include substeps. Many of the steps may be repeated as many times as necessary to treat the tissue, as desired. The steps can be applied using any suitable apparatus described herein and are not limited to transscleral treatment examples.

[0181] Examples herein include devices and methods for performing selected trans-pupillary retinal therapy and combined trans-scleral - trans-pupillary therapy.

[0182] FIG. 15 schematically shows 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 towards 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 representative examples herein, the sclera of the eye (adjacent to the cornea) is targeted for irradiation with a 1,475 nm trans-scleral laser beam with a selected set of trans-scleral lasers and scanning parameters for IOP reduction therapy, and / or the retina of the eye, e.g., the macula, is targeted for irradiation with a separate set of 810 nm trans-pupillary lasers and scanning parameters for pan-macular neuroprotection therapy, thereby inducing sub-lethal and therapeutically advantageous biomodulation or bio-stimulation of the eye tissue at one or both locations, e.g., between complete treatment windows or cases. Therapeutic advantages can include comprehensive management of glaucoma such as reduced intraocular pressure (IOP), neuroprotection, and open-angle glaucoma.

[0183] Biological mechanism According to representative embodiments of this specification, the central retina of the eye can receive sublethal laser light stimulation for the treatment of chronic progressive neurodegenerative vascular retinopathy and other disorders such as POAG, which share similar common characteristics. Sublethal non-damaging laser light stimulation of the central retina targets retinal pigment epithelial (RPE) cells using subthreshold laser energy to induce a stress response. By using carefully selected laser parameters and / or scanning patterns, the stress response can be configured to activate a chain of molecular cellular biochemical activities that can reequilibrium pathological retinal vascular neurotrophic deficiencies and reverse progressive apoptotic processes (i.e., loss of retinal ganglion cells in POAG) as preventive and potentially. Thus, in representative embodiments, the laser parameters are selected to be delivered in a pattern configured such that the energy is above the activation threshold but below the lethal threshold (e.g., 44°C–50°C) within the photothermal stimulation therapy window for producing biological effects. Generally, various parameters (laser pulse energy, duration, fluence, irradiance, pattern, etc.) are selected to mobilize and activate RPE cells in a pathologically selective manner, preferably as the highest possible number of RPE cells for the physical photostimulation process. Such photothermal stimulation can be configured to activate endogenous repair and / or regeneration processes, which 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 protein (HSP) and cytokine expression, which induces a chain of events leading to RPE cell repair, replacement, and regeneration. These events may result in improved transport function, normalized retinal autoacquisition, reduced biomarkers of chronic inflammation, repair of acute inflammation, and immunomodulation. Such effects provide neuroprotection and improved neuronutrition, along with the recovery and / or regeneration of affected, dysfunctional cells, thereby reducing, delaying, or preventing blindness and restoring visual function in various chronic progressive degenerative retinal disorders and POAG (which may share similarities).

[0184] The effects of subthreshold laser central retinal sublethal photostimulation (SPE) in cases of unidentifiable retinal damage are entirely "homeotropic," normalizing retinal function and reducing the risk of disease progression and visual loss. Normalization of retinal cytokine expression can be neuroprotective in POAG, in the same way as retinal protection in diverse chronic progressive retinopathy, which are pathogenically heterogeneous and exhibit very different drug response profiles (e.g., diabetic macular edema (DME) and central serous retinopathy (CSR)), responding in ways specific to the particular disease process and its characteristics. Sublethal RPE laser stimulation can be a nonspecific inducer of disease-specific RPE HSP activation and cell repair. Furthermore, sublethal RPE laser stimulation can normalize only the function of dysfunctional cells and is pathologically selective, affecting abnormal cells while having negligible effects on healthy cells, as clinically significant improvements have been observed in eyes with the worst pretreatment conditions.

[0185] Disease-specific responses can be further demonstrated by characteristically different patterned electroretinogram (PERG) responses in dry AMD compared to PERG responses in hereditary retinopathy after subthreshold laser central retinal sublethal photostimulation therapy. In both cases, retinal abnormalities are present. Therefore, a nonspecific therapeutic response to sublethal laser photostimulation is observed. In both cases, the retinal abnormalities are different. Therefore, the therapeutic response is always homeotropic but different, reflecting the nature of the underlying retinal abnormalities (disease-specific repair responses). POAG may, at least partially, represent the 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 indicators of ganglion cell and optic nerve function. Therefore, by treating the retina, a unique disease-specific therapeutic response in glaucomatous optic nerves can be induced. Therefore, there may be an unidentified retinal abnormality underlying at least some cases of POAG, which could help explain progressive optic nerve atrophy observed in "normal" or "low" intraocular pressure glaucoma despite IOP reduction. Furthermore, neurotrophic retinal dendritic loss may be a distinct and unique retinal disease entity underlying some or all cases of OAG, but further research is needed.

[0186] Subliminal panmacular micropulse laser photostimulation therapy is 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 panmacular micropulse lasers can restore RPE cell transport and gene expression function, improve retinal trophotrophic deficiencies, and result in increased ganglion cell electrophysiological function on pattern electroretinography (PERG) and improved visual function on automated visual field testing. These improvements suggest that, potentially, through the upmodulation of intrinsic neuronostrengthening and neuroprotective neurotrophic factors, sublethal laser photostimulation may rescue dysfunctional but still viable retinal elements, promote long-term survival, and improve the functionality of ganglion cells and other neurons. POAG shares most of the common characteristics found in all chronic progressive degenerative retinopathy (AMD, DR, CSC, RP, etc.), and POAG can similarly benefit from the same sublethal laser light stimulation as RPE.

[0187] Theoretically, the primary mechanism of action of sublethal photostimulation of RPE is a reparative acute inflammatory response that promotes the activation of heat shock proteins (HSPs), which induces a chain reaction resulting in a restorative immunomodulatory response that includes cytokine expression, upregulation of pigment epithelial-derived factor (PEDF), intracellular repair, replacement, regeneration, improved RPE cell function, normalized retinal homeotropic automodulation, suppression of apoptosis, reduction of chronic inflammatory biomarkers, and recruitment of bone marrow-derived hematopoietic stem cells differentiated into epithelial and / or endothelial cells to the retina. In vivo studies have shown that improvements in retinal electrophysiological indicators on PERG and twilight visual function on automated visual field testing can be demonstrated within 24 hours of sublethal treatment. The absence of discernible iatrogenic injury makes neuroprotective homeotropic sublethal laser photostimulation therapy a natural, regenerative physiological process, along with its potential for early POAG treatment, preventive therapy, and periodic retreatment, thus maintaining homeotropic effects, slowing disease progression, and reducing the risk of visual loss.

[0188] The use of laser transpupillary thermotherapy (TTT) to induce a retinal biochemical response accompanied by the expression of endogenous neuroprotective heat shock proteins (HSPs) is also mentioned in 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)). Also proposed by 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 viability even under more severe stress conditions. Some HSPs are constitutively expressed, while others are induced in response to various types of stress. In the nervous system, the HSP70 system, consisting of Hsc70 or a structural form and HSP72 or an induced form, can have a protective effect against ischemia, seizures, and axonal transection. Furthermore, retinal ganglion cells (RGCs) can be protected against increased intraocular pressure or axonal transection by induction of HSP72 through 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, while several methods have been shown to increase HSP expression with neuroprotective effects, non-invasive and safe methods for inducing HSPs without any systemic effects deserve further investigation.

[0189] TTT is a therapeutic modality in which hyperthermia is generated when infrared irradiation energy is delivered directly to the posterior compartment of the eye, for example, by an 810 nm diode laser. TTT can be performed using broad beams and long exposure times. 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 within 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. Because TTT increases the temperature within the treated tissue, TTT may 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 parameter for TTT for maximal HSP72 expression in the optic nerve head, without damage to ocular tissue, was determined 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) to be 100 mW over 60 s. In this setting, tissue damage was not detected using confocal scanning laser ophthalmoscopic, light microscopy, scanning electron microscopy, and fundus examination. In the next step, TTT was applied to a rat optic nerve crushing injury model to investigate its neuroprotective effects, and it was found that the use of TTT increased the survival rate of RGCs in the retinal area near the optic nerve head within the rat optic nerve crushing injury model.

[0190] In representative embodiments of this specification, many patients may require or benefit from IOP-reducing treatment complemented by neuroprotective therapy. In these cases, a transpupillary sublethal photothermal stimulation method is optionally performed in conjunction with a system configured for transscleral laser treatment for IOP reduction. Thus, the system embodiment is operable to perform central retinal neuroprotective transpupillary sublethal photothermal stimulation that can induce a biochemical response that may result in neuroprotection, neurenhancement, and possibly regeneration of retinal ganglion cells (RGCs), including, for example, “deficient, affected, but not yet dead” RGCs, with the goal of delaying, preventing, or further restoring intraocular visual function loss and other retinal vascular neuropathy associated with POAG. According to the embodiments herein, sublethal retinal photostimulation is achieved using annular (e.g., circular) treatment that produces a favorable temperature distribution profile with flat upper histogram characteristics over the panmacular area (including the fovea, if required), not exceeding 45–47°C, thereby avoiding central cumulative heat peak rise with a Gaussian heat peak profile. In some embodiments, a diode laser operating in a repetitive micropulse emission mode (for fine control of laser-induced heat rise at the RPE level) at a selected wavelength, e.g., 810 nm, is directed in a circular pattern that irradiates an annular shape, avoiding irradiation of the 1.0–2.0 mm central hole centered across the fovea, and extending the outer edge to a predetermined distance such as up to approximately 3 disc diameters (4.5–5.0 mm). Thus, the panmacular area of ​​the eye, including the foveal central region (which will be heated indirectly by conductive heating rather than directly by laser-induced heating), can receive a safe heating stimulus.

[0191] Exemplary systems and methods for transpupillary and / or transscleral treatment An exemplary interface device 100 shown in Figure 8A can be used to couple a non-contact laser system 74 (the scanning optical system portion of the laser system is shown for convenience) to an eye 70 receiving biostimulation therapy according to the method embodiments of this specification. In the transpupil 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] An exemplary optical scanning system 200, shown in Figure 8B, can be configured to direct the beam transscleral and transpupillary. An optical beam source 206 emits an optical beam 202 into the eye 70, which is directed through an optical system using a laser scanner 214 (e.g., a two-axis or three-axis galvanometer scanner) and a focusing optical system 220. In typical embodiments, for transscleral treatment, the optical beam 202 may have a wavelength of approximately 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 may have a wavelength of approximately 810 nm, based on emission from an 810 nm diode laser of the optical beam source 206. It should be understood that other wavelengths may also be used. Generally, the wavelength can be selected based on the location and absorbance (e.g., absorbing chromophores) of the targeted ocular tissue. In some embodiments, the optical scanning system 200 is configured to direct the optical beam 202 transscleral (e.g., 1,475 nm) or transpupillary (e.g., 810 nm) or both, at least one of the above.

[0193] In Figure 17A, the macula of the retina is divided into multiple concentric circular (or oval) regions centered on the cone, in order of increasing diameter and radial distance from the center of the cone, including the fovea, foveal avascular zone (FAZ), fovea, parafovea, and perifovea. Typical dimensions of the illustrated regions are shown. Figure 17B shows multiple concentric pathways for directing a laser beam to the macula for biostimulation therapy. Using a spot size of approximately 0.5 mm, five adjacent concentric pathways 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 to 2.75 mm from the center of the cone). In some embodiments, predetermined values ​​for spot size and scanning pattern radius may be based on the average or typical dimensions of the macula, and in further embodiments, the radius and / or spot size may be adjusted or selected after imaging and examining the patient's macula (e.g., by a specialist or using machine learning image recognition software tools, through anatomical estimation of dimensional differences such as color relative to a typical macula).

[0194] Figures 18A–18G depict exemplary transpupilation treatment methods at different times during the treatment process. In Figure 18A, at initial time 500a, a spot 502 of a pulsed laser beam is directed through the pupil of a human eye and strikes a location outside the macula 504 of the eye (e.g., within or adjacent to the fovea). The macula 504 is shown axially through the pupil, and a cross-sectional depiction is projected below the axial view. Figure 18B shows time 500b immediately following initial time 500a, as the spot 502 is scanned clockwise along the untreated first annulus 506a of the curved scanning path 508, centered on the macula 504. Untreated second, third, fourth, and fifth annulus 506b–506e are also shown adjacent to each other at their neighboring beam boundaries, forming a continuous area for treatment that excludes the FAZ, fovea, and cone. In a typical embodiment, the beam boundary is defined by the pulse intensity of the pulsed laser beam, with full width at half maximum (FWHM), 1 / e, and 1 / e 2It is defined as the radial location of spot 502, which drops to a predetermined value, such as zero. The beam intensity is preferably uniform across the spot to avoid non-uniform heating or temperature spikes directed toward the spot center. Uniform intensity can be achieved through various methods, such as homogenizing optical pipes, lens arrays, diffusers, etc. The spot size is fixed in some embodiments or can be adjusted using, for example, a beam expander or other optical system. Figure 18C depicts time 500c after spot 502 has completed the treatment of the untreated first annulus 506a and formed the treated first annulus 510a. Spot 502 moves along the curved scanning path 508, where it scans clockwise along the untreated second annulus 506b. Figure 18D shows time 500d during laser treatment after pulses of the pulsed laser beam have been scanned and completed the treated second annulus 510b. Spot 502 is then directed to begin scanning along the curved scanning path 508 around the untreated third annulus 506c. At time 500e, shown in Figure 18E, the treatment process has formed the treated third annulus 510c, and the laser spot 502 is directed along the curved scanning path 508, using pulses of the pulsed laser beam to begin treatment of the untreated fourth annulus 506d. Figure 18F shows time 500f during the laser treatment, after which the treated annulus 506a-506d are completed and scanning of the untreated annulus 506e begins. Figure 18G shows time 500g after spot 502 has been directed and continuously directed through each of the untreated annulus 506a-506e to form the treated annulus 510a-510e. In selected embodiments, more or fewer than five ring shapes can typically be used with different or variable beam spot diameters.

[0195] Figure 19 shows the dimensional representation 1900 of the positions of beam spots 1902a-1902e at different distances from the central conical projection position 1904, and the positions of beam spots 1906a-1906e arranged at opposing positions, corresponding to a distance that is the diameter length of individual concentrically arranged treatment rings such as rings 506a-506e shown in Figures 18A-18F. In a typical embodiment, the FAZ is about 0.5 mm wide, and therefore the radially internal positions of the beam boundaries of beam spots 1902e, 1906e define a distance 1908, corresponding to the circular area between the ring treatments where laser beam treatment does not occur through direct irradiation. In embodiments where the size of beam spots 1902a-1902e extending radially outward from the central conical projection position 1908 is the same for each annular shape, and the boundaries of adjacent beam spots 1902a-1902e are adjacent to each other, the cumulative radial lengths 1912a, 1912b can be defined to 2.5 mm, etc., for a common spot size of 0.5 mm. Thus, the overall length 1914 can be defined for the outer treatment diameter, and the outer annular diameter 1916 (aligned with the beam spot center) can be smaller by the size of one radially extending spot.

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

[0197] In certain embodiments, 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 rings, thereby providing a 300 ms exposure time to each RPE cell irradiated by the beam spot diameter within the scanning ring. It should be understood that other speeds can also be selected in additional embodiments to produce exposure time ranges such as 10 ms, 50 ms, 100 ms, 200 ms, 500 ms, etc. A series of processing pulses are generated and directed to the macula according to the ring pattern of the five rings at a constant scanning speed. For the pulsed laser beam, the processing pulse 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 of 100 μs (FWHM or other preferred measurement). With a scanning speed of 1.66 m / sec and a beam spot diameter of 0.5 mm, an inter-pulse area overlap of over 99% in the macula is achieved, accompanied by an irradiation area density of over 99% in the macula. When the peak power of a micropulse is set to 100mW (e.g., with a 5% duty cycle—0.1ms "on" and 2ms period), this can correspond to an average power of 5mW for a continuous wave (CW) equivalent setting. The power density (irradiance) for a laser micropulse in the macula is approximately 50W / cm². 2 (Without considering absorption / scattering losses within the intermediate transparent body). In another embodiment, the peak power of the micropulse was set to 1,000 mW with the same 5% duty cycle, producing an average power of 50 mW for a sustained wave equivalent setting, resulting in 510 W / cm². 2 This results in a power density in the macula. According to different embodiments, the laser and scanning treatment parameters can be varied by a selected amount, such as 1%, 2%, 5%, 10%, 50%, 100%, etc., to achieve similar therapeutic effects.

[0198] By using the aforementioned spot size and five ring radii, a continuous scanning area is defined through the inner radial beam boundary of each adjacent ring to the outer radial beam boundary of an adjacent, smaller ring, resulting in approximately 23.5 mm. 2The total area is 600 mJ / cm² using a 100 mW micropulse peak power. 2 The treatment is performed using a processing pulse that results in the delivery of a total energy of 141 mJ at the fluence. This delivery is delivered directly to RPE cells with 150 micropulses of 1 mJ each, over a duration of 300 ms, totaling approximately 760 mJ / cm². 2 This can be similar to the fluence. For peak powers in the range of 1.0–2.0 W for micropulses, each 0.5 mm diameter area accepts a total energy of 15–30 mJ. In general, repetitive pulse application at low duty cycles can reduce the significance of the total process fluence depending on the therapeutic efficacy, as this is responsible for the increased significance of time-based characteristics. Scanning interruptions or pauses may occur between rings or during the processing of rings, 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 pulse, and the processing pulses are generated by modulating or interrupting the CW pulse. 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 continuously through the ring, the temperature within the FAV, pits, and conical projections is, for example, not exceeded by a certain range. LOWER ~T UPPER The treatment area can be increased to remain within a therapeutically advantageous range (for example, by avoiding temperature profiles such as those depicted using the “overtreatment” line). Thus, temperature uniformity across the macular treatment area can be improved, and Gaussian heat spikes associated with the central macular area can be avoided or reduced.

[0199] Figure 21 shows an embodiment of the apparatus 2100 that may be used to treat the retina 2102 and / or sclera 2104 of the eye 2106 of a patient (typically a human) and other target tissues of the eye 2106. The apparatus 2100 includes a patient interface device 2108 that connects the apparatus 2100 to the eye 2106. The apparatus 2100 includes a light source that includes multiple laser sources, such as a transpupil laser source 2110 that can 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 can generate a sustained-wave laser beam at 1,475 nm. In different embodiments, other additional laser sources may also be used, and other laser source characteristics, including sustained-wave or pulsed, wavelength, power, etc., may be selected based on the ocular tissue to be targeted and the type of laser treatment process used for the targeted ocular tissue.

[0200] 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 laser beams from the multiple laser sources and directs the beams toward a predetermined location in the eye 2106 according to a predetermined scanning pattern, depending on the selected treatment process. In a typical embodiment, a detector 2118 of a camera, photodiode, CCD, CMOS, imaging system (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, but other locations, including between the beam splitter 2114 and the optical beam scanner 2116, are also possible. The detector 2118 can be used to monitor the location of ocular tissue that will be processed or is being processed, so that, for example, an optical beam scanner 2116 can direct laser beams or multiple beams from multiple laser sources to a targeted location in the eye 2106. In some embodiments, the working distance of the laser beam or multiple beams is substantially greater than the difference in propagation distance between the scleral and retinal tissues so that the commanded focal plane does not change while processing different parts of the eye 2106. In further embodiments, the commanded focal point may vary, for example, between a location in the sclera and a location in the retina, or at different locations in the sclera or retina.

[0201] Multiple laser sources, such as laser sources 2110 and 2112, an optical beam scanner 2116, and a detector 2118 can be coupled to a computing unit 2122. The computing unit 2122 includes a processor 2124 and a memory 2126 that stores instructions executable by the processor 2124 to control laser treatment, such as laser beam characteristics, laser wavelength selection, pulse repetition rate, duty cycle, beam start, scanning pattern commands, and eye alignment and / or scanning calibration. The memory 2126 may be configured with one or more pattern command files that define scanning 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 a predetermined position. In some embodiments, 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 an image of the eye 2106. In some embodiments, the detector 2118 can provide location information about the eye 2106 so that the pattern command file can be updated so that scanning can be performed in relation to the detected location information. Preferred location information may include anatomical reference features, color variations, reflectance variations, etc. In some embodiments, the detector 2118 can be configured to detect the temperature of the target eye tissue, for example, using a pyrometer, and the detected temperature can be used to adjust laser beam characteristics such as pulse duration, peak power, and repetition rate, including the situation during treatment. In some embodiments, the memory 2126 controls the delivery to the macular annulus by the processor 2124, and 20 mm 2 ~30mm 2 (For example, 23.5mm) 2Within an annular treatment area surrounding the foveal avascular region, the laser is directed with a peak pulse power in the range of 1W to 2W, delivering a total laser energy in the range of 1J to 3J to an annular shape on the sclera at a constant scanning speed in the range of 5mm / sec to 200mm / sec, along the circumferential arc length at the scleral radius, with a temperature rise in the range of 8°C to 20°C and a proportionally reduced exposure time, corresponding to a cycle load time rate for an annular shape in the range of 0.5% to 50%, which does not produce a photocoagulation effect. Preferred values ​​can be determined from clinical practice with respect to specific patient cohorts. For example, to provide subliminal non-damaging panmacular laser photothermal stimulation for diverse patients, the treatment parameters may vary with respect to different ethnicities, pigmentation, morphological structure, ocular characteristics, and glaucoma conditions. In particular, the non-uniformity or significant variability of the distribution of melanin (the major absorbing chromophore) in human retinal pigment epithelial cells (RPE) tends to alter the photothermal effect more than the laser pulse fluence parameters. The energy value, which may be determined by or based on the selected wavelength, including interpatient pigmentation variations, may affect and determine the favorable thermal rise. Such delivery to the macular ring was 150 micropulses over each consecutive 300 ms period, with a laser spot diameter of 500 μm and a pulse length of 0.00196 cm². 2 Laser spot area: 510-1,020 W / cm² 2 With an irradiance range of 15-30 mJ, a single micropulse duration of 0.1 ms within an energy range of 0.1-0.2 mJ, and an exposure energy range of 51-102 mJ / cm², this device produces a 150 pulse exposure energy range of 15-30 mJ and a 50 pulse exposure energy range of 51-102 mJ / cm². 2 It can accommodate the delivery of repetitive pulse trains of a single micropulse fluence.

[0202] For example, in clinical validation and demonstration studies, laser parameters using other retinal laser devices have demonstrated successful and effective non-damaging panmacular photostimulation retinal treatment, and the exemplary device described herein can be controlled to deliver laser exposure similar to such clinically validated procedures. Laser parameters include a 5% duty cycle with a 2.0 ms period (0.1 ms on + 1.9 ms off) and a repetition rate of 500 pps, an exposure duration of 300 ms (delivering 150 micropulse trains), a laser spot diameter of 500 μm, and a pulse width of 0.00196 cm². 2 Laser spot area, 1.7W laser power, 867W / cm² 2 Irradiance of 0.17 mJ for a single micropulse (0.1 s) energy, 25.5 mJ for a total exposure energy of 150 pulses, and 86.7 mJ / cm². 2 In a single micropulse fluence, an 810 nm diode laser operating in micropulse emission mode was included. The 0.00196 cm² spot had a diameter of 500 μm. 2 Targeted by area: 10–14 μm diameter and approximately 4,220 ± 727 cells / mm² 2Each single RPE cell, with a macular area density (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 parameters described above. In the exemplary annular macular treatment pattern described herein, without overlap, RPE cells at the edge of the selected annulus may be exposed to laser energy for a shorter duration than the central portion due to the selected annulus (due to the circular shape of the spot) and will receive less energy (e.g., fewer than 150 pulses). However, this reduction can be compensated for by the proximity to the photothermal stimulation effect from adjacent treatment annuluses. In some embodiments, radial overlap of adjacent annuluses is provided to reduce radial fluence fluctuations.

[0203] In typical treatment implementations combining scleral and retinal treatments, one or more pattern command files may include a first set of pattern commands for transscleral treatment, a second set of pattern commands for transpupillary treatment adjacent to the macula, and a third set of pattern commands for transpupillary treatment adjacent to the optic nerve disc. In particular, some treatments can be applied prophylactically, such as before the onset of glaucoma or without any indicators of glaucoma, to reduce the probability of developing glaucoma or to delay its onset. For example, this can be determined from the patient's family history, genetics, or population, whether they are more likely to be predisposed to a certain eye disease, and whether the treatment can be applied based on a positive decision. Alternatively, other treatments can also be applied to any indicator or with few indicators of predisposition, providing neuroprotective therapies that can slow, halt, and / or reverse the progression of neurodegeneration. The eye diagram shown in Figure 22 illustrates examples of transscleral and transpupillary annular scanning pathways overlaid on the eye. The transscleral pattern command can be configured to control beam characteristics and direct the beam to multiple treatment locations 0–4 mm posterior to the corneal marginal junction on the outer surface of the sclera 2104. At least one (and typically all) of the treatment locations may include a curved or arc-shaped scanning path section of a predetermined length (e.g., a perfect circle or its arc portion), and the laser beam is operated in sustained wave mode (however, in some embodiments, a sustained series of pulses may be used) and iteratively directed to scan along the same scanning path section at a predetermined scanning speed. The length and scanning speed can define a loading time rate for iterations that is sufficient to provide protective thermal pre-conditioning and therapeutic biostimulation to one or more of the trabecular meshwork and / or ciliary body of the eye.In some embodiments, multiple transscleral treatment sites are defined by three concentric circular scanning paths of 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 corneal marginal junction on the outer surface of the eye, and each circular scanning path includes multiple arc-shaped sections, including a single scanning path arc section that forms a perfect circle or a near-perfect circle, or including continuous, spaced-out, and / or overlapping sections. In certain embodiments, each circular scanning path includes an upward 150° arc from 9:30 to 2:30 and a downward 150° arc from 3:30 to 8:30, while avoiding nasal and temporal 30° arcs.

[0204] A second set of transpupilation treatment commands can be configured to control beam characteristics and direct the beam to multiple treatment locations in the macular region of the retina 2102, excluding the FAZ, fovea, and cone. In a typical embodiment, the multiple treatment locations include five concentric ring-shaped scanning paths centered on the FAZ, scanned in a sequence from the outermost, larger diameter ring to the innermost, smallest diameter ring. The innermost ring has an inner beam boundary adjacent to or adjacent to the FAZ to avoid direct irradiation of the FAZ, and starting from the innermost ring, each outer beam boundary is adjacent to or adjacent (or, in some embodiments, overlapping) the next larger diameter ring to form a continuous treatment area. By using a beam dimension of 0.5 mm radially outward from the FAZ and using adjacent rings with adjacent boundaries of the outermost rings of the five rings, the outer beam boundary can be set to a radius of 2.75 mm for the macula of a typical human eye. In other embodiments, fewer or more than five annular shapes may be scanned, and different beam spot dimensions in the radial direction may be used. In typical embodiments, the beam spot is circular, resulting in a common value for the beam spot dimension along the scanning direction and the beam spot dimension radially from the conical projection; in further embodiments, oval, square, rectangular, or other non-circular beam spot shapes may also be used. The therapeutic annular shapes may be scanned in a sequence from the maximum diameter to the minimum, and the sequence may be associated with a preferred temperature increase of the FAZ, fovea, and conical projection up to a therapeutic temperature range such as 37–47°C. In some embodiments, the thickness of the different annular shapes may vary.

[0205] The beam characteristics for a laser beam targeting the macular region can include pulsed operation with selectable pulse characteristics. For example, the pulse repetition rate and curve scanning speed can be selected so that each individual retinal pigment epithelial (RPE) cell within the laser treatment area receives approximately 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) are used, thereby allowing approximately 150 pulses to be delivered over 300 ms. By using selected suitable pulse durations and peak powers (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 rate of temperature change that induces a biological stress response but does not kill the RPE cell. When generating a non-lethal 7°C gradient with a 0.1 ms upward trajectory, each spike can be estimated to inflict a heat shock on the cell at a rate of approximately 70,000°C / second.

[0206] A third set of transpupilation treatment commands can control beam characteristics and be configured to direct the beam to multiple treatment locations that are close to the optic nerve disc region of the retina 2102 but excluding the optic nerve disc and the underlying optic nerve (for example, by causing the irradiated laser light to avoid substantial collision with the area bounded by the dura mater of the optic nerve). The multiple treatment locations are similar to the second set of transpupilation treatment commands, but instead may include scanning patterns that navigate around the optic nerve disc. For example, the multiple treatment locations may include five concentric ring-shaped scanning paths as the center of the optic nerve disc, scanned in sequence from the outermost larger diameter ring to the innermost smallest diameter ring. The innermost ring has an inner beam boundary adjacent to or adjacent to the optic nerve disc to avoid direct irradiation of the optic nerve, and starting from the innermost ring, each outer beam boundary is adjacent to or adjacent to (or overlapping in some embodiments) the next larger diameter ring to form a continuous treatment area. By using a beam dimension of 0.5 mm radially outward from the large diameter (approximately 1.92 mm) of the optic disc, and by using adjacent rings with adjacent boundaries, the outermost ring of the five rings 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 rings can be oval-shaped, and for example, the outer beam boundary can be at a radius of 3.38 mm for the optic disc of a typical human eye, along the small diameter (approximately 1.76 mm) direction. In other embodiments, fewer or more rings may be scanned, and different beam spot dimensions in the radial direction may be used. In typical embodiments, the beam spot is circular, resulting in a common value for the beam spot dimension along the scanning direction and the beam spot dimension radially from the center of the optic disc; in further embodiments, oval, square, rectangular, or other non-circular beam spot shapes may also be used. The therapeutic ring shape can be scanned in a sequence from the maximum diameter to the minimum diameter, and the sequence can be associated with a suitable temperature-increasing retina area having retinal cells surrounding the optic nerve disc up to a therapeutic temperature range such as 37-47°C.In some embodiments, the thickness of the ring shape may vary.

[0207] Due to the proximity between the macula and optic disc in the fundus of a typical human eye, annular embodiments formed using a second and third set of transpupilational treatment commands can overlap in the fundus, resulting in double stimulation treatment of a selected area. Embodiments herein can also include avoiding double treatment by altering the scanning pattern associated with the second and / or third set of transpupilational treatment commands such that beam spots delivered along one beam scanning path (e.g., a path surrounding the macula) substantially overlap with beam spots delivered along an adjacent beam scanning path (e.g., another path surrounding the optic disc). Additional treatment pattern options are shown in Figures 24A–24C. In Figure 24A, the transpupilational treatment commands produce an exemplary laser scanning path that generally follows the oval contour of the optic disc and is close to the optic disc. If a transpupil macular treatment command is provided, the scanning path can be adjusted to terminate to prevent overlap, using the indicated interrupted scanning oval, etc., to avoid over-treatment of the area to be treated adjacent to the macula (or within the foveal avascular area). Figure 24B shows a transpupil treatment area surrounding and avoiding the optic disc and foveal avascular area. In some embodiments, the scanning path or multiple paths defining the transpupil treatment area may include contoured ovals and ovals (similar to those shown in Figure 24A), but other scanning paths can also be selected to "fill in" the selected treatment area adjacent to the optic disc and macula. In a typical embodiment, the scanning path of the laser beam treats the area in a single pass without overlapping scanning path sections, but additional exemplary paths can be retraced. As discussed herein, therapeutic parameters are selected to produce subliminal sublethal laser light stimulation of the retina that induces a stress response by targeting retinal pigment epithelial (RPE) cells through continuous scanning of a laser beam, according to a predetermined scanning pattern and using selected CW or pulsed laser parameters and laser scanning parameters.Figure 24C shows 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 pacifimacular nerve bundle is avoided. As shown, the macular area including the perifovea and other macular areas outside the FAZ are avoided, but in some embodiments, a macular area excluding the pacifimacular nerve bundle, or including the pacifimacular 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 localized and their positions determined, and the second and third treatment locations and corresponding sets of treatment commands can be defined in relation to the determined locations. The locations can be found by a trained person performing the treatment, but in a typical embodiment, a coupled control device can be used to compare detected features of the patient's fundus with an image or outline depicting the macula and optic disc. For example, the detected features can be processed through one or more image recognition or pattern recognition algorithms (deep learning, convolutional neural networks, circle-Hough transform, etc.) to determine the centroid position, boundary, orientation, relative position, distance, etc. for the patient's macula and optic disc (or corneal / scleral features in transscleral treatment), and the treatment commands can be updated to ensure that the laser beam is scanned to the correct position in the patient's eye.

[0209] Treatment or multiple treatments can be performed using a calibrated system. For example, in method 2300 shown in Figure 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 location commanded for laser beam delivery using an optical beam scanner and patient interface device can be compared to the actual location of beam delivery on one or more predetermined working planes or surfaces (e.g., aligned with the expected scleral or retinal surface) using a laser test surface and / or a spatial calibration device such as a coordinate measuring machine or probe. In 2304, using the calibrated device, one or more sets of treatment pattern commands, which are for a specific patient and correspond to a pre-planned nomogram or custom-generated nomogram, can be produced using software. In 2306, the patient is prepared for supine position treatment, and an anesthetic may be applied, if appropriate, including pre-instillation of Duo eye drops (Thealose 3% API-Thea Pharma) at a rate of 2 drops / minute onto the selected eye to receive treatment for 10 minutes or longer prior to anesthetic eye drops. Local proparacaine eye drops may be instilled when ready to begin treatment. In 2308, a microscope may be placed in the eye, and a patient interface device may be fitted onto the cornea. Inhalation force may be applied, and the cone of the microscope may be docked to the PID. In 2310, the eye position may be detected through the laser treatment system, and any modifications to the treatment pattern may be applied using software, which may improve accuracy such as XY centering or annular diameter or shape. Transscleral and / or transpupil treatment can then be carried out in 2312, and upon completion in 2314, the suction force can be disengaged and the PID can be removed.

[0210] Figure 25 shows an exemplary laser treatment apparatus 2500 that may be used to deliver laser treatment according to various embodiments described herein. The apparatus 2500 includes a laser head 2502 which is slidably coupled to rails 2504a, 2504b such that the laser head 2502 may be fixed in a predetermined orientation in relation to a headrest 2506 and may slide toward the headrest 2506. The rails 2504a, 2504b are arranged in a fixed relationship with respect 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) having a back and / or footrest that leans backward and can be finely adjusted through electrical control. The patient may also be positioned supine on a wheeled stretcher. In an additional embodiment, the patient may be positioned upright, as shown in the diagram in Figure 25, viewed from below the patient's head. The headrest 2506 may be securely attached to the body support 2508 through one or more pivotable support members 2510a-2510d and adjustable thereto. The headrest 2506 may be configured as a horseshoe-shaped headrest including opposing adjustable pads 2512a, 2512b coupled to support members 2410a, 2510b. In a typical embodiment, the headrest 2506 may be adjustable to accommodate different head sizes.

[0211] The laser head 2502 can be coupled to the ends of articulated support arms and stands 2514, including pivotal support members 2516a-2516c, which are configured to allow movement and rotation of the laser head 2502 and allow the laser head 2502 to be brought close to the body support 2508 and headrest 2506. In a typical embodiment, the laser head 2502 can be detachably coupled to rails 2504a, 2504b so that the laser head 2502 can be fixed and slidably translated along rails 2504a, 2504b. Once mechanically mounted or "click-fitted" to rails 2504a, 2504b, the laser head 2502 can also be adjusted in various directions using internal movement steps for fine adjustments and to align the optical components of the laser head 2502 with the patient's eye. In some embodiments, when the laser head 2502 is mounted on rails 2504a, 2504b, a physician can be seated adjacent to the patient's head and control the coupling of the laser head 2502 to one or both of the patient's eyes through a patient interface device (PID) 2518 (for example, patient interface device 100 shown in Figures 5A-5C). The PID 2518 can be attached to the laser head 2502 and can be in contact with the patient's face and eyes. The PID 2518 may include a coolant inhalation ring configured to supply a coolant solution (such as 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 headrest 2506. Foot pedals 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, three, four, or more laser sources, and a laser scanner, such as a two-mirror galvanometer scanner or two double-wedge prisms. In some embodiments, 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 for reducing intraocular pressure or providing prophylactic treatment. In some embodiments, 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 810 nm laser source (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 ciliary body photocoagulation (LCP). In some embodiments, the laser head 2502 further includes a laser source configured to generate a laser beam at approximately 635 nm, which may be used to aim and center other laser beams generated and scanned using the laser head 2502. The laser scanner of the laser head 2502 may be used to guide one or more laser beams through a PID 2518 and / or contact lens coupled to the patient's eye. In a typical embodiment, a fixed objective lens (such as an Fθ lens or other scanning optical system) is positioned to receive the beam scanned to a selected position using a scanning mirror and to focus (or otherwise direct) the received beam to a targeted treatment location. In some embodiments, a rotatable lens holder may be provided so that an alternative objective lens (or no objective lens) can be coupled between the laser scanner and the PID 2518.In typical embodiments, the laser beams emitted from the laser source may each have a fixed spot size, but some embodiments may include a variable spot size, for example, using an in-line beam expander or zoom lens. The laser beam typically has a uniform "top hat" intensity profile, provided by a suitable homogenization optical system such as a homogenization waveguide and / or lens array.

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

[0214] While 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 sequence 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. Furthermore, technology from any embodiment can be combined with technology described in any one or more of the other embodiments. It should be understood that techniques 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 may be provided. The particular sequences described above are provided for illustrative purposes only, and other sequences may 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 representative examples only and should not be considered as limitations of the scope of this disclosure. The alternatives specifically described in these sections are merely illustrative and do not constitute all possible alternatives to the embodiments described herein. For example, the various components of the system described herein may be combined in function and use. Accordingly, all that fall within the scope of the appended claims are claimed.

Claims

1. An extraocular automated laser treatment system for treating the eye in a subject, wherein the extraocular automated laser treatment system is A non-contact laser source configured to treat an eye by generating a laser beam having at least one wavelength and directing the laser beam from a location spaced away from the eye, wherein the at least one wavelength is in the range of about 0.5 μm to about 2.2 μm, and the at least one wavelength includes a transpupil laser beam wavelength. A laser scanner that receives the laser beam from the non-contact laser source and is optically coupled to the non-contact laser source to scan the laser beam toward the eye, A processor and memory comprising, 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 transpupillary treatment locations and to induce a sublethal fever rise in the target ocular tissue of the eye within a predetermined therapeutic temperature range, wherein the plurality of transpupillary treatment locations include a predetermined curved treatment pattern on the target ocular tissue of the eye, and the predetermined curved treatment pattern includes a plurality of concentric rings on the macula that are around but not on the foveal avascular area. An extraocular automated laser treatment system equipped with the following features.

2. The extraocular automated laser treatment system according to claim 1, wherein the memory includes stored computer-readable commands causing the laser treatment system to direct the laser beam to a plurality of transpupil treatment locations and to induce a sublethal fever rise in the target eye tissue to induce therapeutic biomodulation within a predetermined therapeutic temperature range, the plurality of transpupil treatment locations including (i) an area surrounding the macula but not on the foveal avascular area, and (ii) an area surrounding the optic nerve disc but not on the optic nerve disc or an adjacent perioptic crescent.

3. The extraocular automated laser treatment system according to claim 1, wherein the memory includes stored computer-readable instructions causing the laser treatment system to direct the laser beam to a plurality of transpupil treatment locations and to induce a sublethal fever rise in the target eye tissue to induce therapeutic biomodulation within a predetermined therapeutic temperature range, the plurality of transpupil treatment locations further include areas surrounding the optic nerve disc but not on the optic nerve disc or adjacent peripapillary crescent.

4. The extraocular automated laser treatment system according to claim 1, wherein the memory includes stored computer-readable commands causing the laser treatment system to direct the laser beam to a plurality of transpupil treatment locations and to induce a sublethal fever rise in the target eye tissue to induce therapeutic biomodulation within a predetermined therapeutic temperature range, the plurality of transpupil treatment locations further include areas adjacent to the foveal avascular area but not on the area of ​​the pacifopalacular bundle.

5. An extraocular automated laser treatment system according to claim 1, wherein each ring shape on the macula of the predetermined curved treatment pattern includes a plurality of laser pulse spots, the plurality of laser pulse spots are delivered in succession at uniformly spaced centers along a perfect circle having overlapping beam areas so as to generate an irradiated ring-shaped treatment area within each ring shape, and the plurality of laser pulse spots are delivered to all macular ring shapes at a common scanning speed.

6. The extraocular automated laser treatment system according to claim 5, wherein the plurality of concentric ring shapes include radially continuous irradiation ring-shaped treatment areas on the macula.

7. The extraocular automated laser treatment system according to claim 1, wherein each concentric ring has a width of 400 μm to 600 μm.

8. The extraocular automated laser treatment system according to claim 1, wherein the plurality of concentric rings include three to five consecutive concentric rings on the macula, and each ring has substantially equal width.

9. The extraocular automated laser treatment system according to claim 1, wherein the plurality of concentric rings include five consecutive rings on the macula, and each ring has a width of about 500 microns.

10. The extraocular automated laser treatment system according to claim 1, wherein the sublethal fever rise corresponds to a rise in the temperature of the target tissue within the plurality of concentric rings on the macula to a temperature of 47°C or lower.

11. The extraocular automated laser treatment system according to claim 1, wherein the laser source includes a first diode laser source, the first diode laser source is operable to generate a pulsed laser beam at 810 nm for directing to the plurality of transpupil treatment locations.

12. The extraocular automated laser treatment system according to claim 1, wherein the stored computer-readable command causes the laser treatment system to direct the laser beam to the plurality of transpupil treatment locations, the subjects having clinically normal intraocular pressure and / or not having glaucoma symptoms or a diagnosis.

13. The extraocular automated laser treatment system according to claim 1, further comprising a heat sink, wherein the heat sink is positioned in contact with the eye in such a manner that it transfers heat away from the surface of the eye.

14. The extraocular automated laser treatment system according to claim 13, wherein the heat sink includes a curved contact lens placed on the surface of the eye.

15. The extraocular automated laser treatment system according to claim 14, wherein the contact lens includes a cooled contact lens that substantially conforms to the surface of the eye.

16. The extraocular automated laser therapy system according to claim 1, further comprising a patient interface for docking the non-contact laser source, which is separated from the eye, the patient interface comprising a spacer for maintaining the eye in a substantially fixed position for imaging and treatment, the spacer for maintaining the non-contact laser source, which is separated from and without contact with the external surface of the eye.

17. The patient interface further comprises a microscope for placement between the eyelids of the target to expose the eye to the laser beam, and / or the patient interface further comprises a retaining ring for a contact lens, the retaining ring comprising an elastic sealing surface, and the extraocular automated laser treatment system is configured to fix the patient interface to the outer surface of the eye and substantially immobilize the target eye by maintaining negative pressure between the contact lens and the retaining ring, and / or the negative pressure is adjustable, and / or the extraocular automated laser treatment system comprises the spacer and An extraocular automated laser treatment system according to claim 16, wherein the system is configured to cool the spacer and / or the fixing ring and / or the contact lens, and / or the spacer and / or the fixing ring has an internal fluid flow channel, and the extraocular automated laser treatment system is configured to cool the spacer and / or the fixing ring and / or the contact lens by introducing a cooled fluid through the internal fluid flow channel, and / or the extraocular automated laser treatment system further comprises a positioning arm for positioning the patient interface in place relative to the external surface of the eye of the subject.

18. The extraocular automated laser treatment system according to claim 1, further comprising a detector optically coupled to the target eye tissue, wherein a stored computer-readable command causes the laser scanner to selectively direct the laser beam to the target eye tissue based on a change in the position of the target eye tissue detected using the detector.

19. The extraocular automated laser treatment system according to claim 1, wherein the laser source is configured to generate a laser beam having pulses with a pulse repetition period in the range of 1 ms to 3 ms, a pulse repetition rate of 1000 pulses / second to 333 pulses / second, and a pulse duration in the range of 20 μs to 500 μs, and / or the laser source is configured to generate a laser beam having pulses with a pulse repetition period in the range of 1.5 ms to 2.5 ms, a pulse repetition rate of 666 pulses / second to 400 pulses / second, and a pulse duration in the range of 50 μs to 150 μs, and / or the laser source is configured to generate a laser beam having pulses with a pulse repetition period in the range of 1.8 ms to 2.2 ms, a pulse repetition rate of 556 pulses / second to 455 pulses / second, and a pulse duration in the range of 80 μs to 120 μs.

20. The non-contact laser source is further configured to generate a perimarginal scleral laser beam having a wavelength different from the transpupil laser beam wavelength, and the memory includes stored computer-readable commands causing the laser treatment system to direct the perimarginal scleral laser beam to a plurality of perimarginal scleral treatment locations posterior to the corneal margin junction so as to irradiate the outer surface of the eye in a predetermined treatment pattern, the plurality of perimarginal scleral treatment locations being 0 mm to 4 mm posterior to the corneal margin junction, and as a result, the laser energy The energy is absorbed by water-containing cells in the superficial sclera, generating a thermal rise so that cellular transduction chains in deeper ocular structures are affected, and directing the perimarginal sclera laser beam involves repeatedly directing the perimarginal sclera laser beam to multiple irradiated perimarginal sclera treatment sites on the outer surface of the eye at periodic repetition time intervals sufficient to induce protective thermal pre-conditioning and therapeutic biostimulation of one or more of the trabecular meshwork, uveoscleral meshwork, and / or the ciliary body, without photocoagulation of the eye tissue. An extraocular automated laser treatment system according to claim 1, wherein the laser parameters are configured to provide the irradiance of the perimarginal scleral laser beam, the scanning parameters are configured to move the perimarginal scleral laser beam according to a predetermined treatment pattern, and the laser parameters and the scanning parameters are adapted to increase the 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.

Images