Selective laser stimulation of corneal stem cells

Abstract

To provide methods and apparatus for treatment of an eye, and particularly, treatment of conditions of a cornea.SOLUTION: An apparatus for ophthalmic treatment includes an optical unit 30. The optical unit includes: a camera 54 configured to capture an image of an eye of a patient; a laser 48 configured to emit pulses of laser radiation; and beam conditioning and scanning optics 49, 50 configured to focus and direct the laser radiation to impinge on an anterior surface of the eye. A controller 44 is configured to analyze the image so as to identify a limbus of the eye, and to control the optical unit such that the laser radiation impinges on a set of one or more locations on the anterior surface of the eye that are in the vicinity of the limbus with a pulse duration and an energy that are selected to stimulate stem cells at the one or more locations.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention generally relates to methods and devices for treating the eye, particularly for treating corneal conditions.

[0002] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application 62 / 899,162, filed on September 12, 2019 (Patent Document 1), which is incorporated herein by reference.

Background Art

[0003] The corneal epithelium is composed of several layers of cells on the front surface of the eye. Since these cells are almost continuously exposed, they are constantly replaced. The cornea is the most innervated tissue in the body. As a result, disorders of its epithelial surface cause symptoms such as pain and discomfort, which can be severe. Furthermore, the coating of the corneal epithelium and its tear layer are involved in the proper optical transparency of the eye.

[0004] Dry eye syndrome occurs when the eye does not produce enough tears or when tears evaporate rapidly. It affects 5 - 34% of people up to a certain age and up to 70% of the elderly. Symptoms of dry eye include irritation, redness, discharge, and easily fatigued eyes. In more severe cases, it can lead to blurred vision and corneal scarring.

[0005] The corneal endothelium covers the inner surface of the cornea and is responsible for the transparency of the tissue. Endothelial defects can lead to corneal swelling and visual impairment, whether due to disease or trauma.

[0006] Light acts on various mechanisms within cell tissues to stimulate or inhibit biological activity in a process commonly known as photobiomodulation (PBM) or low-light-level therapy (LLLT). Although the clinical effectiveness of this type of therapy has not been definitively established, it has been proposed for the treatment of various eye conditions. For example, U.S. Patent Application Publication 2016 / 0067087 (Patent Document 2) describes a wearable ophthalmic phototherapy device and associated treatment method for exposing the eye to selected multi-wavelength light to promote the healing of damaged or affected eye tissue. The device comprises: a frame having a front portion and two earpiece portions extending from the front portion; and at least one light source that generates a light beam having a therapeutic wavelength and is positioned within or on the frame.

[0007] As another example, U.S. Patent No. 9,192,780 (Patent Document 3) describes a system and method for treating cell disorders, particularly retinal epithelial cells, using light modulation and / or photorejuvenation. The process of treating retinal cells to mitigate or reverse the effects of visual pathway disorders uses a narrowband source of multicolor light applied to the retinal cells to provide a very low energy fluence. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Provisional Patent Application 62 / 899,162 [Patent Document 2] U.S. Patent Application Publication No. 2016 / 0067087 [Patent Document 3] U.S. Patent No. 9,192,780 [Overview of the project]

[0009] The embodiments of the present invention described below provide improved apparatus and methods for eye treatment.

[0010] According to one embodiment of the present invention, an apparatus for ophthalmic treatment is provided, comprising: an optical unit having: a camera configured to acquire an image of a patient's eye; a laser configured to emit pulses of laser radiation; and a beam-tuning and scanning optical system configured to focus the laser radiation and cause it to collide with the front of the eye. A controller analyzes the image to identify the limbus of the eye and controls the optical unit to cause the laser radiation to collide with a set of one or more locations on the front of the eye near the limbus, with a pulse duration of less than 1 μs and an energy of less than 5 mJ per pulse, thereby stimulating stem cells at one or more locations.

[0011] In one disclosed embodiment, the laser radiation is focused to collide with one or more locations with a beam diameter of 1 mm or less. Additionally or alternatively, the pulse duration is less than 100 ns, and may be less than 10 ns, or even less than 5 ns. Further additionally or alternatively, the energy per pulse is less than 3 mJ. Generally, the laser radiation is focused to collide with one or more locations with a fluence of less than 0.4 J / cm².

[0012] In some embodiments, the controller is configured to activate the laser to apply a plurality of pulses to each of one or more locations. In one disclosed embodiment, the plurality of pulses include 200 or fewer pulses at each location, and possibly 100 or fewer pulses. Additionally or alternatively, the plurality of pulses deliver laser radiation with a cumulative energy of 100 mJ or less, and possibly 70 mJ or less, and possibly 40 mJ or less at each location.

[0013] In one disclosed embodiment, one or more positions on the anterior surface of the eye are displaced at least 1 mm, and possibly at least 2 mm, from the limbus of the cornea.

[0014] Additionally or alternatively, beam aligning and scanning optics are configured to direct the laser radiation to strike the front of the eye at an oblique angle with respect to the direction of the optical axis. In one embodiment, the beam aligning and scanning optics include a ring mirror positioned around the optical axis of the eye to reflect the beam at oblique angles toward a plurality of locations near the limbus of the cornea.

[0015] According to one embodiment of the present invention, an apparatus for ophthalmic treatment is provided, having the optical unit described above. The controller analyzes an image to identify the limbus of the eye and controls the optical unit to cause a laser beam to collide with one or more locations on the anterior surface of the eye near the limbus, with a pulse duration between 1 millisecond and 500 ms and an energy per pulse of less than 100 mJ, thereby stimulating stem cells in one or more locations.

[0016] In some embodiments, the pulse duration may be less than 50 ms, and possibly less than 10 ms or less than 5 ms. Additionally or alternatively, the energy per pulse may be less than 50 mJ, and possibly less than 5 mJ. Generally, the laser emission is focused to collide with one or more locations with a fluence of less than 30 J / cm².

[0017] In some embodiments, the controller is configured to activate the laser so that the laser applies multiple pulses to each of one or more locations. In one disclosed embodiment, the multiple pulses include no more than 2000 pulses at each location, and the number of pulses may be 500 or 200 or less. Additionally or alternatively, the multiple pulses deliver laser radiation with a cumulative energy of 10 J or less at each location, and the cumulative energy may be 1 J or 400 mJ or less.

[0018] An additional method of ophthalmic treatment is provided, characterized by comprising: locating the limbus of the cornea of ​​a patient's eye; and directing pulses of laser radiation, with a pulse duration of less than 1 μs and an energy of less than 5 mJ per pulse, to strike one or more locations on the anterior surface of the eye near the limbus, thereby stimulating stem cells at one or more locations.

[0019] One embodiment of the present invention provides an ophthalmic treatment method characterized by further comprising: locating the limbus of the cornea of ​​a patient's eye; and directing pulses of laser radiation, with a pulse duration of less than 100 ms and an energy per pulse of less than 100 mJ, to strike one or more locations on the anterior surface of the eye near the limbus, thereby stimulating stem cells at one or more locations.

[0020] According to one embodiment of the present invention, an additional apparatus for treating a patient's eye is provided. The apparatus includes an optical unit, the optical unit having: a laser configured to emit laser radiation; one or more mirrors arranged around the optical axis of the eye; and a beam-tuning and scanning optical system configured to focus and direct the laser radiation reflected from one or more mirrors so as to strike the front of the eye at an oblique angle with respect to the optical axis. A controller is configured to control the optical unit so that the laser radiation strikes the eye at an oblique angle and with a fluence selected to stimulate stem cells at one or more locations in a set of one or more locations near the limbus of the cornea.

[0021] In one disclosed embodiment, one or more mirrors have a ring mirror surrounding the optical axis.

[0022] In one embodiment, the controller is configured to control the optical unit such that the laser radiation impinges on and stimulates stem cells in the epithelium of the eye. Alternatively or additionally, the controller is configured to control the optical unit such that the laser radiation impinges on and stimulates stem cells in the corneal stroma of the eye. Further additionally or alternatively, the controller is configured to control the optical unit such that the laser radiation impinges on and stimulates stem cells in the endothelium of the eye.

[0023] According to one embodiment of the present invention, there is provided an ophthalmic treatment method, further comprising the step of contacting a gonioscope with the cornea of a patient's eye. Pulses of laser radiation pass through the gonioscope, reflect from the side mirror surface of the gonioscope, and then pass obliquely through the cornea and impinge on the endothelial tissue near the trabecular meshwork of the eye with an energy and duration of the pulses selected to stimulate the stem cells of the endothelial tissue.

[0024] In some embodiments, the pulses have a pulse duration of less than 1 μs and an energy of less than 0.1 mJ per pulse. In one disclosed embodiment, the step of directing the pulses comprises controlling the laser radiation to impinge on the corneal endothelial tissue with a fluence of 0.1 J / cm2 or less. Additionally or alternatively, the pulses have a pulse duration between 1 - 500 ms and a fluence of 10 J / cm2 or less.

Brief Description of the Drawings

[0025] The present invention will be more fully understood from the following detailed description with reference to the accompanying drawings: [Figure 1] FIG. 1 is a schematic side view of a system for ophthalmic treatment according to one embodiment of the present invention. [Figure 2] FIG. 2 is a block diagram schematically showing details of a laser treatment apparatus in the system of FIG. 1 according to one embodiment of the present invention. [Figure 3] FIG. 3 is a schematic cross-sectional view of the structure of an eye under treatment by laser radiation according to one embodiment of the present invention. [Figure 4] This is a schematic cross-sectional idealization of the limbal region of the eye, illustrating the propagation of a laser beam through that region according to one embodiment of the present invention. [Figure 5A-B] Figures 5A and 5B are schematic cross-sectional idealizations of eye tissue showing the distribution of optical fluence under irradiation by laser beams with different focal characteristics, according to one embodiment of the present invention. [Figure 6-7] Figures 6 and 7 are schematic cross-sectional views of a system for ophthalmic treatment according to an alternative embodiment of the present invention. [Figure 8] This is a schematic cross-sectional view of an apparatus for ophthalmic treatment according to yet another embodiment of the present invention. [Modes for carrying out the invention]

[0026] (overview) Stem cells play a crucial role in maintaining ocular homeostasis and tissue repair. For example, insufficient stem cell activity appears to be one of the causes of dry eye and other corneal pathological conditions. Stimulating stem cell activity may be an effective treatment for such conditions.

[0027] LLLT, which uses visible or infrared laser radiation, has been shown to stimulate stem cell activity in various tissues within the body. This type of therapy typically uses CW (continuous wave) laser radiation at moderate energy levels. However, application of such radiation to the eye can result in serious unintended consequences, including temporary and possibly permanent damage to the retina and other physiological structures. For example, laser irradiation of the area around the limbus of the cornea at sufficient intensity has been shown to lower intraocular pressure, as described in U.S. Patent No. 10,702,416, whose disclosure is incorporated herein by reference. While this effect is useful in treating glaucoma, it can result in dangerously low pressure when applied to patients with initial intraocular pressure within the normal range.

[0028] In response to these needs and constraints, embodiments of the present invention described herein provide apparatuses and methods for treating the cornea using pulsed laser radiation having pulse parameters specifically selected to stimulate corneal stem cells while minimizing undesirable side effects. The disclosed techniques can be adapted to stimulate stem cells in any and all layers of the cornea, including the corneal epithelium, corneal stroma, and corneal endothelium. They are particularly effective in stimulating the activity of epithelial stem cells and thus in treating corneal epithelial conditions such as dry eye. In another embodiment, corneal endothelial stem cells are activated by this type of laser irradiation.

[0029] The embodiments described below use an optical unit equipped with a camera that acquires an image of the patient's eye. A laser within the optical unit emits pulses of laser radiation. These pulses are focused and directed by beam-tuning and scanning optics and strike the front of the eye. A controller analyzes the image to identify the limbus and then controls the optical unit to strike one or more locations on the front of the eye near the limbus, including locations deviated by a predefined radial distance of at least 1 mm, and possibly 2, 3, or 4 mm, from the limbus. These are locations where stem cell stimulation may be effective while avoiding undesirable effects on structures present beneath them. Alternatively, the irradiated locations may be identified by other image analysis and gaze-tracking methods known in the art, such as pupil tracking or pattern recognition.

[0030] There are two regimes of laser pulse parameters that the inventors have found to be effective in stimulating corneal stem cells (particularly epithelial) while minimizing other undesirable effects. In some embodiments, the laser radiation strikes the eye with a pulse duration of less than 1 μs and an energy of less than 5 mJ per pulse. In alternative embodiments, the pulse duration can range up to 100 milliseconds, and the pulse energy is up to 100 mJ per pulse. The fluence of the laser radiation to the eye in each pulse is kept below predefined limits, for example, less than 2 J / cm² in short pulse domains (less than 1 μs) and less than 120 J / cm² in long pulse domains (up to 100 milliseconds). The cumulative energy applied at each location is similarly kept below limits chosen to provide substantial stem cell stimulation while avoiding collateral effects.

[0031] In either case, the laser beam is typically focused into a small spot at each location. For example, the beam diameter is less than 1 mm. The use of this type of small spot size is advantageous, especially for concentrating the beam intensity and therefore for stimulating stem cells in the epithelial layer. The intensity reaching the endothelium, which could affect structures such as the trabecular meshwork, is much lower.

[0032] Some embodiments of the present invention utilize the intrinsic scattering properties of the tissues within the limbus. Simulations show that only about 11% of the laser energy incident on the limbus reaches the underlying trabecular meshwork. Clinical studies conducted by the inventors have shown that irradiation of the trabecular meshwork on the outer surface of the limbal region with a laser pulse having a pulse energy of 0.8 mJ is effective in lowering intraocular pressure. A dose-response relationship has been observed with this type of irradiation, meaning that higher energy leads to a greater decrease in pressure. Therefore, in some embodiments of the present invention, laser pulse energies of less than 0.8 mJ are used so that only corneal epithelial and stromal stem cells are stimulated. Further energy reduction may be useful to ensure that endothelial stem cells are not stimulated in order to avoid an undesirable decrease in intraocular pressure. However, in alternative embodiments, the energy and direction of the incident laser beam are selected so that endothelial stem cells are significantly stimulated.

[0033] There appear to be multiple pathways through which laser radiation can stimulate ocular stem cells. These include, but are not limited to, thermal heating, nonlinear absorption processes, and photoacoustic processes. Nanosecond laser pulses require approximately two orders of magnitude less fluence than millisecond-range pulses to achieve a similar level of stem cell stimulation. At the levels of fluence used in embodiments of the present invention, the attenuation of laser energy propagating through the limbus is independent of pulse duration and energy, resulting in approximately 11% attenuation even for longer laser pulses of higher energy.

[0034] (System description) Herein, we refer to Figures 1 and 2 schematically illustrating a system 20 for ophthalmic treatment using LLLT according to one embodiment of the present invention. Figure 1 is a side view of the system, and Figure 2 is a block diagram detailing the laser treatment apparatus 21 of system 20. In its design, system 20 is similar to the system for direct laser selective trabeculoplasty described in PCT international application publication WO2020 / 008323, whose disclosure is incorporated herein by reference. However, in this embodiment, the laser beam parameters and treatment modality in system 20 are particularly adapted for targeted stimulation of stem cells while minimizing the effect of the laser beam on the trabecular meshwork.

[0035] The laser treatment device 21 includes an optical unit 30 which includes a radiation source 48, such as a laser, that outputs a beam of pulsed radiation toward the eye 25 of the patient 22. The optical unit 30 further includes a beam adjustment optical system 49 for adjusting the focal characteristics of the laser beam. This ensures that the beam is incident on the surface of the eyeball 25 with a desired spot size and energy. A scanner 50 directs the beam to a desired target position for LLLT treatment. The scanner 50 may comprise, for example, one or more galvanometric mirrors, or any other suitable type of optical scanner known in the art. An F-theta lens 51 can be used to maintain uniform beam characteristics across the scanning range. A beam combiner 56 directs the laser beam toward the eye 25 through an aperture 58 located in front of the optical unit 30.

[0036] The optical unit 30 further includes a camera 54 that acquires images of the eye 25 via a beam combiner 56 before and during LLLT procedures. In the illustrated embodiment, to assist in imaging the eye, the optical unit 30 includes an illumination source 60 which includes one or more light-emitting diodes (LEDs), such as a ring of LEDs surrounding an aperture 58. The controller 44 processes the images output by the camera 54 and, based on the images, controls the radiation source 48, as well as the beam adjustment optics 49 and scanner 50. Specifically, for the purpose of LLLT, the controller identifies the limbus of the eye 25 and then aims the laser beam to direct a radiation pulse of the desired fluence to a location near the limbus, which means a location on the limbus or radially offset from the limbus by a suitable distance along the anterior surface of the eye. The limbus can be identified, for example, by finding the circular edge between the iris and sclera in the image using any suitable image processing method known in the art. A method for determining the position of the ring portion is further described in U.S. Patent No. 10,702,416 mentioned above.

[0037] Typically, as a preparatory step before starting treatment, a user of the system 20, such as an ophthalmologist, uses a control mechanism 36, such as a joystick, to position the optical unit 30 at a predetermined distance D from the eye. To facilitate this positioning, the optical unit 30 may be equipped with multiple beam emitters 62 (including, for example, laser diodes) each directing a distance-measuring beam 64 towards the eye. The beams 64 form a composite pattern on the eye, allowing the user to confirm that the optical unit is at a predefined distance.

[0038] The optical unit 30 is mounted on an XYZ stage 32 controlled by a control mechanism 36. Using the control mechanism 36, a user of the system 20 positions the optical unit in the appropriate position before treating a patient's eye. In some embodiments, the XYZ stage 32 includes one or more motors, and the control mechanism 36 is connected to the XYZ stage via an interface circuit 46 and a controller 44. In other embodiments, the XYZ stage 32 is manually controlled by operating the control mechanism.

[0039] During the procedure, the patient 22 places their head on a headrest 24 attached to a horizontal surface 38, such as a tray or table. The headrest 24 includes a forehead rest 26 and a chin rest 28. During the LLLT procedure, the patient 22 presses their forehead against the forehead rest 26 while resting their chin on the chin rest 28. A restraint strap 27 secures the patient's head from behind, thereby keeping the patient's head pressed against the headrest.

[0040] In the illustrated embodiment, the base unit 34 of the laser treatment apparatus 21 is mounted on the surface 38, and the XYZ stage 32 is mounted on the base unit 34. In such an embodiment, the controller 44 and interface circuit 46 may be included within the base unit. In other embodiments, the XYZ stage is mounted directly on the surface 38.

[0041] As shown in Figure 1, while illuminating the patient's eye, the optical unit 30 is oriented obliquely upward toward the eye, while the eye may be advantageously directed obliquely downward toward the optical unit, i.e., the optical path 23 between the eye. The optical unit is oblique, not horizontal. For example, the optical path 23 may be oriented at an angle θ between 5 and 20 degrees to reduce obstruction of the patient's eye by the patient's upper eyelid and associated anatomical structures. If necessary, one or both eyelids can be retracted using a finger, microscope, or another tool to further expose the eye. In the embodiment shown in Figure 1, the oblique orientation of the optical path 23 is achieved by mounting the optical unit 30 on a wedge 40 attached to an XYZ stage 32. Alternatively, the patient's head can be intentionally tilted on the headrest 24.

[0042] System 20 optionally includes a monitor 42 that displays images of the eye 25 acquired by the camera 54, allowing the user to verify the proper alignment and operation of the system. The monitor 42 can be connected directly to the controller 44 via a wired or wireless communication interface, or indirectly via an external processor, such as a processor belonging to a standard computer.

[0043] The configurations of the system 20 and treatment apparatus 21 shown in Figures 4 and 5 are shown and described herein only as examples. The principle of LLLT therapy described herein can be carried out with necessary modifications in other system configurations that can irradiate the patient's eye at the appropriate position with appropriate beam parameters as defined herein. All such alternative implementations are considered to be within the scope of the present invention.

[0044] The controller 44 typically includes a general-purpose microprocessor that is software-programmed to perform the functions described herein and has appropriate interfaces for communicating with other elements of the system 20. The software can be downloaded to the controller in electronic form, for example, over a network. Alternatively or additionally, the software may be provided and / or stored in a non-transient tangible medium such as magnetic, optical, or electronic memory. When such software is provided to the controller, it generates a machine or dedicated computer configured to perform the tasks described herein. Alternatively or additionally, at least some of the functions of the controller 44 may be implemented in dedicated or programmable hardware logic, for example, using one or more application-specific integrated circuits (ASICs) or field-programmable gate arrays (FPGAs).

[0045] (Treatment method) Figure 3 is a schematic cross-sectional view of the structure within the limbal region 70 of the eye under treatment with laser radiation 80 according to one embodiment of the present invention. (The limbus itself is located approximately in the center of this region.) The limbal region 70 includes corneal epithelium 72 containing corneal epithelial stem cells 82. The laser radiation 80 is generated, for example, by the optical unit 30 of the system 20, as described above. The beam parameters of the laser radiation 80, including the number of laser pulses, the energy and duration per pulse, and the focal size of the laser beam on the epithelium 72, are selected to selectively stimulate the epithelial stem cells 82.

[0046] The cornea beneath the corneal epithelium includes the corneal stroma 78, which contains corneal stromal stem cells 83, and the corneal endothelium 74, which comprises the trabecular meshwork and Schlemm's canal 76 (among other structures) and corneal endothelial stem cells (not shown). In this embodiment, the laser beam parameters are selected to minimize the penetration of laser energy into these inner layers and thus avoid stimulating the stem cells in these layers. This selectivity can be enhanced, for example, by directing the laser irradiation 81 to collide obliquely with the region of corneal epithelial stem cells 82. (As used herein and in the claims, the term “oblique” means that the laser beam strikes the eye at an angle of at least 5 degrees with respect to the direction of the optical axis of the eye, i.e., the axis passing through the center of the pupil and reaching the macula. In some embodiments, the laser beam may strike the eye at an angle of 10 degrees or more.)

[0047] However, in alternative embodiments, the laser beam parameters may be modified, for example, by increasing the fluence and / or focal spot size to stimulate stem cells in the corneal stromal 78 and corneal endothelial 74. Increasing the energy dose sufficient to affect the trabecular meshwork, in conjunction with the effect of the laser radiation on corneal endothelial stem cells, can also lower intraocular pressure as described in U.S. Patent No. 10,702,416 above. Additionally or alternatively, the laser radiation 85 may be directed to strike the eye at the edge of the limbal region 70 at an oblique angle selected to stimulate corneal endothelial stem cells while avoiding corneal epithelial and corneal stromal stem cells.

[0048] Figure 4 is a schematic and idealized cross-sectional view of the limbal region 70 of the eye, showing the propagation of non-scattering laser radiation 80 through the limbal region according to one embodiment of the present invention. The laser radiation 80 collides with an entry spot 90 located at a target position on the corneal epithelium 72 on the anterior surface of the eye. As previously mentioned, the entry spot 90 is typically less than 1 mm in diameter and may be smaller. The radiation passes through the cornea 84 of the eye and collides with the endothelium 74 at the exit spot 92.

[0049] The intensity of the laser radiation decreases sharply (usually by more than 90%) between the entry spot 90 and the exit spot 92, mainly due to scattering of radiation within the peripheral tissue. These scattering characteristics can make the stimulation of epithelial stem cells up to 20 times stronger than that of endothelial stem cells (or even stronger depending on the wavelength of light and the anatomical structure of the patient's eye). This disparity effect can be further enhanced by sharply focusing the radiation 80 onto the entry spot 90.

[0050] Figures 5A and 5B are schematic cross-sectional views of tissue in the limbal region 70 of the eye, showing the distribution of optical fluence under emission by laser beams 80a and 80b with different focal characteristics according to embodiments of the present invention. Beam 80a is sharply focused on the anterior surface of the eye, while beam 80b has a much larger spot size. The contour lines in the figure show the relative decrease in fluence as the beam propagates through the tissue. The larger spot size of beam 80b increases the relative fluence reaching the endothelium, and therefore allows for greater stimulation of internal structures such as the stroma and endothelial stem cells.

[0051] In some embodiments, the optical unit 30 (Figure 1) is operated to emit pulses having a pulse duration of less than 1 μs and an energy of less than 5 mJ per pulse. Alternatively, the pulses may be even shorter, for example, less than 100 ns. In some cases, a pulse width of less than 10 ns or less than 5 ns is advantageous. Additionally or alternatively, the pulse energy may be smaller, for example, less than 3 mJ. Typically, the laser radiation is focused to hit each treated location with a fluence of less than 0.4 J / cm². The controller 44 typically operates the laser 48 and controls the scanner 50 to apply a sequence of multiple pulses to each of the treatment locations on the anterior surface of the eye. Typically, 200 pulses at each location provide a sufficient therapeutic effect, and 100 pulses or less may be preferable to accelerate treatment and reduce incidental effects. For the same reason, the cumulative energy supplied by the optical unit 30 to each such location is less than 100 mJ, and may even be less than 70 mJ or 40 mJ.

[0052] In other embodiments, the optical unit 30 can apply pulses with lower peak power but higher total energy to the front of the eye. In such embodiments, the laser 48 emits pulses with a pulse duration of less than 500 milliseconds and an energy of less than 100 mJ per pulse. Alternatively, the pulses may be shorter, for example, less than 100 milliseconds. In some cases, a pulse width of less than 50 milliseconds, and possibly less than 10 milliseconds or less than 5 milliseconds, is advantageous. Additionally or alternatively, the pulse energy may be smaller, for example less than 50 mJ or possibly less than 5 mJ. Typically, the laser emission is focused to collide with each treatment location with a fluence of less than 30 J / cm². The controller 44 typically operates the laser 48 and controls the scanner 50 to apply a sequence of multiple pulses to each treatment location, typically 2000 pulses or less per location. Alternatively, as in the embodiments described above, 500 pulses or less, or even just 200 pulses, may be preferred at each location to accelerate treatment and reduce comorbid effects. The cumulative energy supplied to each such location by the optical unit 30 is less than or equal to 10 J, and may even be less than 1 J or less than 400 mJ.

[0053] (alternative) Figures 6 and 7 are schematic cross-sectional views of systems 100 and 110, respectively, for ophthalmic treatment according to alternative embodiments of the present invention. These systems are similar to systems 20 shown in Figures 1 and 2, but include additional optical components to facilitate directing the laser radiation to strike the front of the eye at an oblique angle with respect to the direction of the optical axis of the eye. The laser radiation can be pulsed as described above or as a continuous wave (CW). As previously described, this type of oblique irradiation helps to selectively stimulate stem cells in specific layers of the cornea, such as epithelial, stromal, or endothelial stem cells.

[0054] In system 100, the ring mirror 102 is positioned around the optical axis of the eye and surrounds the optical axis and the beam combiner 56. In one embodiment, the ring mirror 102 comprises a single ellipsoidal reflector. Alternatively, the ring mirror 102 may include multiple mirror segments, such as flat segments, arranged to emulate the optical properties of an ellipsoid. In either case, when the scanner 50 directs the laser beam towards the ring mirror 102, the beam is reflected towards the eye at an oblique angle to the optical axis.

[0055] In system 110, the ring mirror 112 is mounted externally to the optical unit so as to surround the optical axis of the eye. The ring mirror 112 may be constructed and mounted in the manner in which a frustoconical conduit is attached to the optical unit, for example, in PCT patent application PCT / IB2020 / 052020, filed March 9, 2020, which is incorporated herein by reference. In this case as well, when the scanner 50 directs the laser beam towards the ring mirror 112, the beam is reflected toward the eye at an oblique angle to the optical axis.

[0056] Figure 8 is a schematic cross-sectional view of an apparatus 120 for ophthalmic treatment according to yet another embodiment of the present invention. In this embodiment, a gonioscope 122 is held in contact with the cornea 124 of the eye. A laser beam 126 is reflected from the side mirror surface 128 of the gonioscope 122 and thus directed to pass obliquely through the transparent area of ​​the cornea 124 and strike the endothelial tissue near the trabecular meshwork 74. This type of optical approach is used in several methods of laser trabeculoplasty known in the art.

[0057] However, in this embodiment, the laser pulse energy is much lower than the threshold for effective trabeculoplasty. For example, the laser beam 126 may include pulses with a pulse duration of less than 1 μs and an energy of less than 0.1 mJ per pulse, and a fluence of 0.1 J / cm² or less. Alternatively, the pulse duration may be 1 to 500 milliseconds and the fluence may be 10 J / cm² or less. These laser pulses stimulate endothelial stem cells. Due to the large incidence angle of the laser beam and the high scattering loss of tissue in the limbal region 70, relatively little laser energy penetrates outward from the corneal endothelium to epithelial and stromal stem cells. In this case, endothelial stem cells are selectively stimulated.

[0058] The embodiments described above are cited as examples, and it will be understood that the present invention is not limited to those specifically shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described above, as well as variations and modifications thereof not disclosed in the prior art, which will be recalled by those skilled in the art when reading the foregoing description.

Claims

1. It is an optical unit: A camera configured to acquire images of the patient's eyes; A laser configured to emit pulses of laser radiation; A beam adjustment and scanning optical system configured to focus the laser radiation and cause it to collide with the front of the eye; An optical unit having; and A controller configured to analyze the image to identify the limbus of the eye, and to control the optical unit to cause the laser radiation to collide with one or more locations on the anterior surface of the eye near the limbus, with a pulse duration of less than 500 ms and an energy of less than 100 mJ per pulse, thereby stimulating stem cells in the one or more locations; It has, The laser radiation is focused to collide with each of the one or more locations with a fluence of less than 30 J / cm². The apparatus for ophthalmic treatment is characterized in that the beam adjustment and scanning optical system is configured to direct the laser radiation so as to collide with the front surface of the eye at an oblique angle to the direction of the optical axis of the eye.

2. The apparatus according to claim 1, characterized in that the laser radiation is focused so as to collide with each of the one or more locations with a beam diameter of 1 mm or less.

3. The apparatus according to claim 1, characterized in that the pulse duration is less than 100 ms.

4. The apparatus according to claim 3, characterized in that the pulse duration is less than 50 ms.

5. The apparatus according to claim 4, characterized in that the pulse duration is less than 10 ms.

6. The apparatus according to claim 5, characterized in that the pulse duration is less than 5 ms.

7. The apparatus according to claim 1, characterized in that the energy per pulse is less than 50 mJ.

8. The apparatus according to claim 7, characterized in that the energy per pulse is less than 5 mJ.

9. The apparatus according to any one of claims 1 to 8, characterized in that the controller is configured to activate the laser so as to apply a plurality of pulses to each of the one or more positions.

10. The apparatus according to claim 9, characterized in that the plurality of pulses include 2,000 or fewer pulses at each position.

11. The apparatus according to claim 10, characterized in that the plurality of pulses include 500 or fewer pulses at each position.

12. The apparatus according to claim 11, characterized in that the plurality of pulses include 200 or fewer pulses at each position.

13. The apparatus according to claim 9, characterized in that the plurality of pulses deliver laser radiation with a cumulative energy of 10 J or less at each position.

14. The apparatus according to claim 13, characterized in that the cumulative energy is 1 J or less.

15. The apparatus according to claim 14, characterized in that the cumulative energy is 400 mJ or less.

16. The apparatus according to any one of claims 1 to 8, characterized in that one or more of the positions on the anterior surface of the eye are displaced by at least 1 mm from the limbus of the cornea.

17. The apparatus according to claim 16, characterized in that one or more of the positions on the anterior surface of the eye are displaced by at least 2 mm from the limbus.

18. The apparatus according to claim 1, wherein the beam adjustment and scanning optical system comprises a ring mirror positioned around the optical axis of the eye to reflect the beam at an oblique angle toward a plurality of positions near the limbus of the cornea.

Images